Reviews

Advances in radiotherapy over the past 50 years have dramatically improved outcomes in patients with malignancy. Five-year overall survival rates for Hodgkin lymphoma and non-Hodgkin lymphoma now stand at 80%, and breast cancer survival is 90%.¹

Increased longevity, however, has come at the cost of late side effects such as radiation-induced heart disease (RIHD). Cardiac dysfunction due to radiation involves a spectrum of disease processes in patients who have undergone mediastinal, thoracic, or breast radiotherapy and may involve any cardiac structure, including the pericardium, myocardium, valves, conduction system, and coronary arteries.

Overall, compared with nonirradiated patients, patients who have undergone chest radiotherapy have a 2% higher absolute risk of cardiac morbidity and death at 5 years and a 23% increased absolute risk after 20 years.²

This article will review the pathophysiology and epidemiology of RIHD and will offer a practical approach to its diagnosis and management.

MOST DAMAGE IS ENDOTHELIAL 

Cardiac myocytes are relatively resistant to radiation damage because of their postmitotic state. But endothelial cells remain sensitive to radiation, and the pathophysiology of most forms of RIHD appears to be associated with damage to endothelial cells. Conventional cardiac risk factors such as hyperlipidemia and smoking have been shown to compound and accelerate radiation-induced endothelial damage in animal models.³

Radiation is believed to result in transient increases in oxidative stress, resulting in formation of reactive oxygen species and a subsequent inflammatory response that includes activation of nuclear factor-kappa B. Upregulation of proinflammatory pathways results in increased expression of matrix metalloproteinases, adhesion molecules, and proinflammatory cytokines and downregulation of vasculoprotective nitric oxide.⁴ Indirect evidence for radiation-induced vascular inflammation comes from numerous studies that demonstrated increased levels of the proinflammatory cytokines interleukin 6, tumor necrosis factor alpha, and interferon gamma in Japanese atomic bomb survivors.⁵

RISK FACTORS

Risk factors for RIHD are summarized in Table 1.

The volume of heart irradiated is a major determinant of the development of RIHD.⁶ A retrospective study of 960 breast cancer patients in Stockholm between 1971 and 1976 found that those who had received the highest doses and volumes of cardiac radiation had a threefold higher risk of cardiac death. By comparison, those with lesser volumes of the heart exposed to radiation had no increase in risk of cardiac death compared with the general population.⁷

Younger age at the time of radiotherapy is associated with an increased risk of RIHD in breast cancer and lymphoma patients. A retrospective analysis of 635 patients under age 21 with Hodgkin lymphoma treated with radiotherapy showed a relative risk of fatal myocardial infarction of 41.5 compared with a general population matched for age, sex, and race.⁸

Conventional cardiac risk factors such as smoking, hypertension, diabetes, and hyperlipidemia further increase the risk of RIHD, and radiation increases the cardiotoxicity of chemotherapeutic agents such as anthracyclines.⁹

In general, high-risk patients are defined as those with at least one risk factor for RIHD who underwent anterior or left-sided chest irradiation  (Table 1).¹⁰

CORONARY ARTERY DISEASE

Ischemic heart disease is the most common cause of cardiac death in patients who have undergone radiation therapy. Atherosclerotic lesions in RIHD are morphologically identical to those in nonirradiated vessels and are characterized by intimal proliferation, accumulation of lipid-rich macrophages, and plaque formation.¹¹

A retrospective single-institution study of 415 patients with Hodgkin lymphoma who had undergone radiation therapy found the incidence of coronary artery disease 20 years later to be 10%. The mean time to development of coronary artery disease was 9 years, and all patients who developed it had at least one conventional cardiac risk factor.¹²

A meta-analysis of more than 20,000 breast cancer patients who received radiotherapy in 40 randomized controlled trials found an increase in the rate of non-breast-cancer deaths, primarily from vascular causes (annual event ratio 1.27, P <  .0001).¹³

A randomized controlled trial comparing breast cancer patients who underwent preoperative or postoperative radiotherapy vs those who had surgery alone revealed a significantly higher death rate from coronary artery disease in the postradiotherapy group.⁷

The risk of radiation-induced coronary artery disease is proportional to both the dose and the duration of radiation therapy. A retrospective study of more than 2,000 women undergoing radiotherapy for breast cancer found that the relative risk of coronary artery disease increased linearly by about 7.4% per Gy of radiation to the heart, with no apparent ceiling.¹⁴

The distribution of atherosclerotic coronary arteries correlates well with the areas exposed to the highest doses of radiation. For instance, in left-sided breast cancer, the apex and anterior wall of the heart typically receive the highest doses of radiation; consequently, the left anterior descending and distal diagonal branches are most prominently involved.¹⁵ In patients with lymphoma who undergo radiotherapy to mediastinal nodes and in breast cancer patients receiving radiotherapy to the internal mammary chain, basal structures may be exposed as well. Ostial lesions can also be seen in these patients.¹⁶

The clinical presentation of coronary artery disease in radiotherapy recipients does not differ significantly from that in the general population. Ischemia may be silent, may lead to classic anginal symptoms, or may cause sudden cardiac death. The incidence of silent myocardial infarction has been reported to be higher after mediastinal radiotherapy than it is in the general population, possibly from damage to nerve endings within the radiation field.¹⁷

Management of radiation-associated coronary artery disease

Managing patients with radiation-associated coronary artery disease is challenging, but the therapeutic options remain the same as those in nonirradiated patients and include medical therapy, percutaneous coronary intervention, and coronary artery bypass grafting, depending on the site and extent of disease.¹⁸ Although results are conflicting, there does not seem to be a significant difference in the rates of stent restenosis between patients with a history of radiation therapy and the general population.

Percutaneous coronary intervention is generally preferred to coronary artery bypass grafting in these patients for several reasons. Radiation-induced fibrosis of surrounding structures generally makes surgical procedures more difficult,¹⁹ and inclusion of the internal mammary artery or internal thoracic artery in the radiation field may result in stenosis of these vessels, rendering them unsuitable for harvesting.²⁰ Moreover, many patients with RIHD have concurrent radiation-induced lung damage, which increases the risk of perioperative pulmonary complications.²¹

If the coronary lesions are not amenable to percutaneous intervention, a careful valvular evaluation should be performed preoperatively in view of the frequency of radiation-associated valvular disease. In a study of 72 patients with RIHD undergoing coronary artery bypass grafting, 40% required valvular surgery at the time of surgery or shortly thereafter.²²

Results of studies of coronary artery bypass graft outcomes in patients with a history of thoracic radiation therapy have been conflicting, but success seems to depend on the status of the internal mammary and internal thoracic arteries.²³ Therefore, the patency of these vessels should be elucidated preoperatively by angiography and intraoperatively by visual inspection of the vessels for fibrosis.

A large single-institution study by Wu et al²⁴ revealed higher short-term and long-term mortality rates in patients with RIHD undergoing cardiac surgery than in control patients without RIHD undergoing similar procedures.

VALVULAR DISEASE

Radiation therapy may directly affect heart valves, and both stenotic (Figure 1) and regurgitant lesions have been described. Pathologic findings include leaflet retraction, fibrotic thickening, and late calcification.²⁵

The precise mechanism of radiation-induced valvular disease is unknown but is thought to be a change in the phenotype of valvular interstitial cells from a myofibroblast to an osteoblast-like cell. Radiation results in significant expression of osteogenic factors such as bone morphogenic protein 2, osteopontin, alkaline phosphatase, and runt-related transcription factor 2 by valvular interstitial cells.26

Valvular heart disease is evident in as many as 81% of patients with RIHD, with the aortic and mitral valves affected more commonly than the tricuspid and pulmonic valves.²⁷ Why there are more left-sided valve lesions than pulmonic valve lesions, despite the pulmonic valve’s anterior position in the heart, is unknown but may be due to higher pressures across the left-sided heart valves.

Although valvular disease is common in patients with RIHD, clinically significant disease is not; more than 70% of patients with radiation-induced valvular disease have no symptoms. A study of 38 cases of radiation-induced valvular disease reported a mean time to development of asymptomatic valvular lesions of 11.5 years and an average time to symptomatic valvular dysfunction of 16.5 years, indicating that 5 years seems to be the interval required for progression from asymptomatic to symptomatic valvular RIHD.²⁸

The thickness of the aortomitral curtain (the junction between the base of the anterior mitral leaflet and the aortic root) is an independent predictor of the long-term risk of death in patients with valvular RIHD.²⁹

Management of radiation-induced valvular disease

Management of patients with valvular RIHD poses a major clinical conundrum because of  the high rates of perioperative morbidity and death in patients with a history of chest radiotherapy. In one study,²³ the long-term mortality rate was 45% in postradiotherapy patients undergoing single-valve surgery and 61% in those undergoing surgery on two or more valves, compared with 13% and 17% in patients with no history of chest radiotherapy.²³

Furthermore, valve repair is an unattractive option in these patients because of high failure rates of mitral valve and tricuspid valve repair attributed to ongoing radiotherapy-induced valvular changes after repair.³⁰

As a result, valve replacement is generally preferred in this group. Patients should be advised of the higher risk of perioperative and long-term morbidity and death associated with open heart surgery than in the general population, and that the risks are even higher with repeat open heart surgery.

This risk has implications for the choice of replacement valves in younger patients. Bioprosthetic valves, which deteriorate over time, may not be advisable. Transcatheter aortic valve replacement has been successful in radiation-induced valvular disease and may become the preferred method of aortic valve replacement.³¹

PERICARDIAL DISEASE

Pericardial disease is a frequent manifestation of RIHD and covers a spectrum of manifestations from acute pericarditis, pericardial effusion, and tamponade to constrictive pericarditis. In a necropsy study, 70% of patients with RIHD were found to have pericardial involvement.³²

The mechanism is believed to be radiation-induced microvascular injury resulting in increased capillary permeability and the sometimes rapid development of a protein-rich exudate. Associated inflammation may cause acute pericarditis, which may eventually be complicated by chronic pericarditis. The parietal surface tends to be affected more severely than the epicardium.³³

Perhaps as a result of recent advances such as lower radiation doses, equal weighting of the anterior and posterior fields, and subcarinal blocking, incidence rates of pericarditis as low as 2.5% have been reported.³⁴

Pericardial RIHD may be divided into early acute pericarditis, delayed chronic pericardial effusion, and constrictive pericarditis.

Early acute pericarditis is rare and is thought to represent a reaction to tumor necrosis. It is defined as occurring during radiotherapy and occurs almost exclusively with high-dose radiotherapy for lymphoma. Due to the relatively benign course of acute pericarditis and fear of tumor recurrence, it is not an indication to withhold radiotherapy.³⁵

Delayed chronic pericardial effusion occurs months to years after radiotherapy, is typically asymptomatic, and presents as an enlarged cardiac silhouette on chest imaging.³⁵ Delayed pericardial effusion is followed with imaging. While in many cases it resolves within 2 years, it may also be long-standing. Pericardiocentesis or a pericardial window may be performed to treat symptomatic effusion or delayed effusion causing hemodynamic compromise.^35–37 Hypothyroidism should be ruled out, as it can complicate mantle irradiation and result in chronic pericardial effusion.³⁸

Constrictive pericarditis may occur as a late complication of radiotherapy and typically causes symptoms of congestive heart failure. Pericardial stripping in these patients is complicated by the possibility of coexisting RIHD of the valves, myocardium, or coronary arteries, as well as mediastinal fibrosis. A study of 163 patients who underwent pericardial stripping for chronic pericarditis found a 7-year overall survival rate of only 27%, far lower than the rate for those who had no history of radiation exposure.³⁹ Therefore, these patients are often treated for symptom control with diuretics and a low-salt diet rather than with surgery.

MYOCARDIAL DISEASE

Microvascular injury in the myocardium results in chronic ischemia, which may lead to myocardial fibrosis, typically manifesting as diastolic dysfunction. Chest radiotherapy may result in both systolic and diastolic dysfunction, and dilated and restrictive cardiomyopathy are well-recognized complications.⁴⁰

Historically, high radiation doses resulted in systolic dysfunction in more than half of patients who underwent thoracic radiotherapy.⁴¹ Now, however, fewer than 5% of patients develop reductions in left ventricular ejection fraction, and most cases of radiotherapy-induced cardiomyopathy have a restrictive pattern.⁴²

In a single-institution study, diastolic dysfunction was reported in as many as 14% of patients who underwent thoracic radiotherapy for Hodgkin lymphoma.⁴⁰ Systolic dysfunction is now seen almost exclusively in patients  treated concurrently with cardiotoxic chemotherapeutic agents such as anthracyclines in addition to radiotherapy.⁴³

In a childhood cancer survival series, the hazard ratio of congestive heart failure in patients who had undergone radiotherapy for Wilms tumor was 6.6—almost identical to the occurrence in sibling controls. By contrast, the hazard ratio increased to 18.3 in those who received doxorubicin in addition to radiotherapy.⁴⁴

Treatment of radiation-induced cardiomyopathy

Treatment of radiation-induced cardiomyopathy is similar to that for other forms of cardiomyopathy, with an emphasis on symptom management.

Heart transplant may be an option for highly selected patients with end-stage heart failure secondary to RIHD. In one report, a series of four RIHD patients received a heart transplant, and all four survived past 48 months.⁴⁵ However, data from the United Network of Organ Sharing revealed an increase in the all-cause mortality rate in patients undergoing heart transplant for RIHD compared with those undergoing transplant for cardiomyopathy due to other causes.⁴⁶ This trend may be confounded by a higher prevalence of prior cardiac surgery in the RIHD group—itself an established risk factor for poor posttransplant outcomes.

CONDUCTION SYSTEM DISEASE

Life-threatening arrhythmias have been reported that are distinct from the common, asymptomatic repolarization abnormalities that occur during radiotherapy. Atrioventricular nodal bradycardia, all degrees of heart block, and sick sinus syndrome have all been reported after chest radiotherapy. As conduction abnormalities do not typically manifest until years after radiotherapy, it is difficult to establish causation and, consequently, to define incidence.

Right bundle branch block is the most common conduction abnormality because of the proximity of the right bundle to the endocardium on the right side.⁴⁷

Chest radiotherapy is also associated with prolongation of the corrected QT interval (QTc). A study in patients with a history of thoracic radiotherapy found that the QTc characteristically increased with exercise, a poor prognostic indicator.⁴⁸ In a study of 134 survivors of childhood cancer, 12.5% of those who had undergone radiotherapy had a resting QTc of 0.44 msec or more.⁴⁹

Furthermore, a study of 69 breast cancer survivors found a higher incidence of conduction abnormalities at 6 months and 10 years after radiotherapy compared with baseline. The characteristic electrocardiographic changes at 6 months were T-wave changes. At 10 years, the T-wave abnormalities had resolved and were replaced by ST depression.⁵⁰

As mentioned above, establishing radiotherapy as a cause for these conduction abnormalities is challenging, given the lag between radiation therapy and electrocardiographic changes. The following criteria have been proposed for establishing a link between atrioventricular blockade and prior radiation⁵¹:

• Total radiation dose to the heart > 40 Gy
• Delay of 10 years or more since therapy
• Abnormal interval electrocardiographic changes such as bundle branch block
• Prior pericardial involvement
• Associated cardiac or mediastinal lesions.

SCREENING GUIDELINES

Consensus guidelines for identifying and monitoring RIHD have been published by the European Association of Cardiovascular Imaging and the American Society of Echocardiography (Table 2).¹⁰ The European Society of Medical Oncology has also issued guidelines for the prevention, diagnosis, and management of cardiovascular disease associated with cancer therapy.

Briefly, the guidelines call for aggressive cardiac risk-factor modification through weight loss, exercise, blood pressure control, and smoking cessation, in addition to early detection of RIHD. Cardiovascular screening for risk factors and a careful clinical examination should be performed in all patients. Baseline comprehensive transthoracic echocardiography is advocated in all patients before starting radiotherapy to detect cardiac anomalies. Beyond this, an annual history and physical examination, paying close attention to the signs and symptoms of cardiopulmonary disease, is essential. The development of new cardiopulmonary symptoms or a new physical finding such as a murmur should prompt evaluation with transthoracic echocardiography.

In patients without symptoms, screening transthoracic echocardiography at 10 years after the start of radiotherapy is recommended in light of the high probability of diagnosing cardiac disease at this juncture. In patients with no preexisting cardiac disease, surveillance transthoracic echocardiography should be at 5-year intervals thereafter.

In high-risk patients without symptoms (those who have undergone anterior or left-sided radiotherapy and have at least one risk factor for RIHD), initial screening transthoracic echocardiography is recommended 5 years after radiotherapy. These patients have a heightened risk of coronary events as described above and, consequently, are recommended to undergo noninvasive imaging 5 to 10 years after radiation exposure. If this initial examination is negative, stress testing should be repeated at 5-year intervals. Stress echocardiography and stress cardiac magnetic resonance imaging have higher specificity than stress electrocardiography and therefore are generally preferred. Stress scintigraphy should be used with caution, as it adds to the cumulative radiation exposure.

The role of magnetic resonance imaging and computed tomography depends on the results of initial transthoracic echocardiography and the clinical indication, in addition to the center’s expertise and facilities. However, there are currently no data advocating their use as screening tools, except for early detection of porcelain aorta in high-risk patients.¹⁰

MODERN RADIOTHERAPY TECHNIQUES

In recent years, there has been emphasis on exposing the patient to as little radiation as possible without compromising cure.⁵² The three major strategies employed to decrease cardiac exposure include reducing the radiation dose, reducing the radiation field and volume, and using newer planning and delivery techniques.

Reducing the radiation dose. It is well recognized that the mean dose of radiation to the heart is a significant predictor of cardiovascular disease, with one study demonstrating a linear increase in the risk of coronary artery disease with increasing mean heart radiation dose (excess relative risk per Gy 7.4%, 95% confidence interval 3.3%–14.8%).⁵³

Reducing the radiation field and volume. Modern strategies and computed tomography-based radiotherapy planning have enabled a transition from older techniques such as extended-field radiation therapy, mantle-field radiation therapy, and involved-field radiation therapy to new techniques such as involved-node and involved-site radiation therapy.⁵⁴ These have shown promise. For instance, a study in patients with early Hodgkin lymphoma found a mean heart dose of 27.5 Gy with mantle-field therapy compared with 7.7 Gy with involved-node therapy. This decrease in mean heart dose was associated with a reduction in the 25-year absolute excess cardiac risk from 9.1% to 1.4% and a reduction in cardiac mortality from 2.1% to 1%.⁵⁵

Employing newer planning and delivery systems has also demonstrated some promise in reducing rates of cardiac morbidity and mortality. Extended-field radiation therapy, mantle-field radiotherapy, and involved-field radiation therapy were traditionally based on two-dimensional planning and often resulted in large volumes of myocardium being unnecessarily exposed to large doses of radiation because of the uncertainty in targeting. Involved-site and involved-node radiotherapy are based on computed tomography, resulting in more accurate targeting and sparing of normal tissue.

In addition, newer techniques such as intensity-modulated radiotherapy and proton beam therapy have resulted in further improvements in conformality compared with three-dimensional conformal radiotherapy.^56,57 Respiratory motion management, including deep inspiration breath-holding and end-inspiration breath-holding, have decreased the radiation dose to the heart in patients undergoing mediastinal radiotherapy.^58,59

TOWARD THE GOALS OF PREVENTION AND EARLIER DETECTION

As survival from breast cancer and lymphoma has increased, we continue to see legacy or latent effects of therapy, such as RIHD. Radiation therapy can affect any cardiac structure and is a major cause of morbidity and death in cancer survivors.

Modern radiation techniques use a variety of mechanisms to decrease the radiation dose to the heart. A large body of evidence emanating from an era of higher radiation doses and a lack of knowledge of the cardiac effects of radiation highlight the perilous cardiac consequences of chest radiation. With advances in radiotherapy and the development and widespread implementation of consensus guidelines, we envision earlier detection and less frequent occurrence of RIHD, although the latter trend could be blunted by increased cardiovascular risk factors within the population. Given the lag between irradiation and the cardiac consequences, it may be a number of years before any comparisons can be drawn.

Advances in radiotherapy over the past 50 years have dramatically improved outcomes in patients with malignancy. Five-year overall survival rates for Hodgkin lymphoma and non-Hodgkin lymphoma now stand at 80%, and breast cancer survival is 90%.¹

Increased longevity, however, has come at the cost of late side effects such as radiation-induced heart disease (RIHD). Cardiac dysfunction due to radiation involves a spectrum of disease processes in patients who have undergone mediastinal, thoracic, or breast radiotherapy and may involve any cardiac structure, including the pericardium, myocardium, valves, conduction system, and coronary arteries.

Overall, compared with nonirradiated patients, patients who have undergone chest radiotherapy have a 2% higher absolute risk of cardiac morbidity and death at 5 years and a 23% increased absolute risk after 20 years.²

This article will review the pathophysiology and epidemiology of RIHD and will offer a practical approach to its diagnosis and management.

MOST DAMAGE IS ENDOTHELIAL 

Cardiac myocytes are relatively resistant to radiation damage because of their postmitotic state. But endothelial cells remain sensitive to radiation, and the pathophysiology of most forms of RIHD appears to be associated with damage to endothelial cells. Conventional cardiac risk factors such as hyperlipidemia and smoking have been shown to compound and accelerate radiation-induced endothelial damage in animal models.³

Radiation is believed to result in transient increases in oxidative stress, resulting in formation of reactive oxygen species and a subsequent inflammatory response that includes activation of nuclear factor-kappa B. Upregulation of proinflammatory pathways results in increased expression of matrix metalloproteinases, adhesion molecules, and proinflammatory cytokines and downregulation of vasculoprotective nitric oxide.⁴ Indirect evidence for radiation-induced vascular inflammation comes from numerous studies that demonstrated increased levels of the proinflammatory cytokines interleukin 6, tumor necrosis factor alpha, and interferon gamma in Japanese atomic bomb survivors.⁵

RISK FACTORS

Risk factors for RIHD are summarized in Table 1.

The volume of heart irradiated is a major determinant of the development of RIHD.⁶ A retrospective study of 960 breast cancer patients in Stockholm between 1971 and 1976 found that those who had received the highest doses and volumes of cardiac radiation had a threefold higher risk of cardiac death. By comparison, those with lesser volumes of the heart exposed to radiation had no increase in risk of cardiac death compared with the general population.⁷

Younger age at the time of radiotherapy is associated with an increased risk of RIHD in breast cancer and lymphoma patients. A retrospective analysis of 635 patients under age 21 with Hodgkin lymphoma treated with radiotherapy showed a relative risk of fatal myocardial infarction of 41.5 compared with a general population matched for age, sex, and race.⁸

Conventional cardiac risk factors such as smoking, hypertension, diabetes, and hyperlipidemia further increase the risk of RIHD, and radiation increases the cardiotoxicity of chemotherapeutic agents such as anthracyclines.⁹

In general, high-risk patients are defined as those with at least one risk factor for RIHD who underwent anterior or left-sided chest irradiation  (Table 1).¹⁰

CORONARY ARTERY DISEASE

Ischemic heart disease is the most common cause of cardiac death in patients who have undergone radiation therapy. Atherosclerotic lesions in RIHD are morphologically identical to those in nonirradiated vessels and are characterized by intimal proliferation, accumulation of lipid-rich macrophages, and plaque formation.¹¹

A retrospective single-institution study of 415 patients with Hodgkin lymphoma who had undergone radiation therapy found the incidence of coronary artery disease 20 years later to be 10%. The mean time to development of coronary artery disease was 9 years, and all patients who developed it had at least one conventional cardiac risk factor.¹²

A meta-analysis of more than 20,000 breast cancer patients who received radiotherapy in 40 randomized controlled trials found an increase in the rate of non-breast-cancer deaths, primarily from vascular causes (annual event ratio 1.27, P <  .0001).¹³

A randomized controlled trial comparing breast cancer patients who underwent preoperative or postoperative radiotherapy vs those who had surgery alone revealed a significantly higher death rate from coronary artery disease in the postradiotherapy group.⁷

The risk of radiation-induced coronary artery disease is proportional to both the dose and the duration of radiation therapy. A retrospective study of more than 2,000 women undergoing radiotherapy for breast cancer found that the relative risk of coronary artery disease increased linearly by about 7.4% per Gy of radiation to the heart, with no apparent ceiling.¹⁴

The distribution of atherosclerotic coronary arteries correlates well with the areas exposed to the highest doses of radiation. For instance, in left-sided breast cancer, the apex and anterior wall of the heart typically receive the highest doses of radiation; consequently, the left anterior descending and distal diagonal branches are most prominently involved.¹⁵ In patients with lymphoma who undergo radiotherapy to mediastinal nodes and in breast cancer patients receiving radiotherapy to the internal mammary chain, basal structures may be exposed as well. Ostial lesions can also be seen in these patients.¹⁶

The clinical presentation of coronary artery disease in radiotherapy recipients does not differ significantly from that in the general population. Ischemia may be silent, may lead to classic anginal symptoms, or may cause sudden cardiac death. The incidence of silent myocardial infarction has been reported to be higher after mediastinal radiotherapy than it is in the general population, possibly from damage to nerve endings within the radiation field.¹⁷

Management of radiation-associated coronary artery disease

Managing patients with radiation-associated coronary artery disease is challenging, but the therapeutic options remain the same as those in nonirradiated patients and include medical therapy, percutaneous coronary intervention, and coronary artery bypass grafting, depending on the site and extent of disease.¹⁸ Although results are conflicting, there does not seem to be a significant difference in the rates of stent restenosis between patients with a history of radiation therapy and the general population.

Percutaneous coronary intervention is generally preferred to coronary artery bypass grafting in these patients for several reasons. Radiation-induced fibrosis of surrounding structures generally makes surgical procedures more difficult,¹⁹ and inclusion of the internal mammary artery or internal thoracic artery in the radiation field may result in stenosis of these vessels, rendering them unsuitable for harvesting.²⁰ Moreover, many patients with RIHD have concurrent radiation-induced lung damage, which increases the risk of perioperative pulmonary complications.²¹

If the coronary lesions are not amenable to percutaneous intervention, a careful valvular evaluation should be performed preoperatively in view of the frequency of radiation-associated valvular disease. In a study of 72 patients with RIHD undergoing coronary artery bypass grafting, 40% required valvular surgery at the time of surgery or shortly thereafter.²²

Results of studies of coronary artery bypass graft outcomes in patients with a history of thoracic radiation therapy have been conflicting, but success seems to depend on the status of the internal mammary and internal thoracic arteries.²³ Therefore, the patency of these vessels should be elucidated preoperatively by angiography and intraoperatively by visual inspection of the vessels for fibrosis.

A large single-institution study by Wu et al²⁴ revealed higher short-term and long-term mortality rates in patients with RIHD undergoing cardiac surgery than in control patients without RIHD undergoing similar procedures.

VALVULAR DISEASE

Radiation therapy may directly affect heart valves, and both stenotic (Figure 1) and regurgitant lesions have been described. Pathologic findings include leaflet retraction, fibrotic thickening, and late calcification.²⁵

The precise mechanism of radiation-induced valvular disease is unknown but is thought to be a change in the phenotype of valvular interstitial cells from a myofibroblast to an osteoblast-like cell. Radiation results in significant expression of osteogenic factors such as bone morphogenic protein 2, osteopontin, alkaline phosphatase, and runt-related transcription factor 2 by valvular interstitial cells.26

Valvular heart disease is evident in as many as 81% of patients with RIHD, with the aortic and mitral valves affected more commonly than the tricuspid and pulmonic valves.²⁷ Why there are more left-sided valve lesions than pulmonic valve lesions, despite the pulmonic valve’s anterior position in the heart, is unknown but may be due to higher pressures across the left-sided heart valves.

Although valvular disease is common in patients with RIHD, clinically significant disease is not; more than 70% of patients with radiation-induced valvular disease have no symptoms. A study of 38 cases of radiation-induced valvular disease reported a mean time to development of asymptomatic valvular lesions of 11.5 years and an average time to symptomatic valvular dysfunction of 16.5 years, indicating that 5 years seems to be the interval required for progression from asymptomatic to symptomatic valvular RIHD.²⁸

The thickness of the aortomitral curtain (the junction between the base of the anterior mitral leaflet and the aortic root) is an independent predictor of the long-term risk of death in patients with valvular RIHD.²⁹

Management of radiation-induced valvular disease

Management of patients with valvular RIHD poses a major clinical conundrum because of  the high rates of perioperative morbidity and death in patients with a history of chest radiotherapy. In one study,²³ the long-term mortality rate was 45% in postradiotherapy patients undergoing single-valve surgery and 61% in those undergoing surgery on two or more valves, compared with 13% and 17% in patients with no history of chest radiotherapy.²³

Furthermore, valve repair is an unattractive option in these patients because of high failure rates of mitral valve and tricuspid valve repair attributed to ongoing radiotherapy-induced valvular changes after repair.³⁰

As a result, valve replacement is generally preferred in this group. Patients should be advised of the higher risk of perioperative and long-term morbidity and death associated with open heart surgery than in the general population, and that the risks are even higher with repeat open heart surgery.

This risk has implications for the choice of replacement valves in younger patients. Bioprosthetic valves, which deteriorate over time, may not be advisable. Transcatheter aortic valve replacement has been successful in radiation-induced valvular disease and may become the preferred method of aortic valve replacement.³¹

PERICARDIAL DISEASE

Pericardial disease is a frequent manifestation of RIHD and covers a spectrum of manifestations from acute pericarditis, pericardial effusion, and tamponade to constrictive pericarditis. In a necropsy study, 70% of patients with RIHD were found to have pericardial involvement.³²

The mechanism is believed to be radiation-induced microvascular injury resulting in increased capillary permeability and the sometimes rapid development of a protein-rich exudate. Associated inflammation may cause acute pericarditis, which may eventually be complicated by chronic pericarditis. The parietal surface tends to be affected more severely than the epicardium.³³

Perhaps as a result of recent advances such as lower radiation doses, equal weighting of the anterior and posterior fields, and subcarinal blocking, incidence rates of pericarditis as low as 2.5% have been reported.³⁴

Pericardial RIHD may be divided into early acute pericarditis, delayed chronic pericardial effusion, and constrictive pericarditis.

Early acute pericarditis is rare and is thought to represent a reaction to tumor necrosis. It is defined as occurring during radiotherapy and occurs almost exclusively with high-dose radiotherapy for lymphoma. Due to the relatively benign course of acute pericarditis and fear of tumor recurrence, it is not an indication to withhold radiotherapy.³⁵

Delayed chronic pericardial effusion occurs months to years after radiotherapy, is typically asymptomatic, and presents as an enlarged cardiac silhouette on chest imaging.³⁵ Delayed pericardial effusion is followed with imaging. While in many cases it resolves within 2 years, it may also be long-standing. Pericardiocentesis or a pericardial window may be performed to treat symptomatic effusion or delayed effusion causing hemodynamic compromise.^35–37 Hypothyroidism should be ruled out, as it can complicate mantle irradiation and result in chronic pericardial effusion.³⁸

Constrictive pericarditis may occur as a late complication of radiotherapy and typically causes symptoms of congestive heart failure. Pericardial stripping in these patients is complicated by the possibility of coexisting RIHD of the valves, myocardium, or coronary arteries, as well as mediastinal fibrosis. A study of 163 patients who underwent pericardial stripping for chronic pericarditis found a 7-year overall survival rate of only 27%, far lower than the rate for those who had no history of radiation exposure.³⁹ Therefore, these patients are often treated for symptom control with diuretics and a low-salt diet rather than with surgery.

MYOCARDIAL DISEASE

Microvascular injury in the myocardium results in chronic ischemia, which may lead to myocardial fibrosis, typically manifesting as diastolic dysfunction. Chest radiotherapy may result in both systolic and diastolic dysfunction, and dilated and restrictive cardiomyopathy are well-recognized complications.⁴⁰

Historically, high radiation doses resulted in systolic dysfunction in more than half of patients who underwent thoracic radiotherapy.⁴¹ Now, however, fewer than 5% of patients develop reductions in left ventricular ejection fraction, and most cases of radiotherapy-induced cardiomyopathy have a restrictive pattern.⁴²

In a single-institution study, diastolic dysfunction was reported in as many as 14% of patients who underwent thoracic radiotherapy for Hodgkin lymphoma.⁴⁰ Systolic dysfunction is now seen almost exclusively in patients  treated concurrently with cardiotoxic chemotherapeutic agents such as anthracyclines in addition to radiotherapy.⁴³

In a childhood cancer survival series, the hazard ratio of congestive heart failure in patients who had undergone radiotherapy for Wilms tumor was 6.6—almost identical to the occurrence in sibling controls. By contrast, the hazard ratio increased to 18.3 in those who received doxorubicin in addition to radiotherapy.⁴⁴

Treatment of radiation-induced cardiomyopathy

Treatment of radiation-induced cardiomyopathy is similar to that for other forms of cardiomyopathy, with an emphasis on symptom management.

Heart transplant may be an option for highly selected patients with end-stage heart failure secondary to RIHD. In one report, a series of four RIHD patients received a heart transplant, and all four survived past 48 months.⁴⁵ However, data from the United Network of Organ Sharing revealed an increase in the all-cause mortality rate in patients undergoing heart transplant for RIHD compared with those undergoing transplant for cardiomyopathy due to other causes.⁴⁶ This trend may be confounded by a higher prevalence of prior cardiac surgery in the RIHD group—itself an established risk factor for poor posttransplant outcomes.

CONDUCTION SYSTEM DISEASE

Life-threatening arrhythmias have been reported that are distinct from the common, asymptomatic repolarization abnormalities that occur during radiotherapy. Atrioventricular nodal bradycardia, all degrees of heart block, and sick sinus syndrome have all been reported after chest radiotherapy. As conduction abnormalities do not typically manifest until years after radiotherapy, it is difficult to establish causation and, consequently, to define incidence.

Right bundle branch block is the most common conduction abnormality because of the proximity of the right bundle to the endocardium on the right side.⁴⁷

Chest radiotherapy is also associated with prolongation of the corrected QT interval (QTc). A study in patients with a history of thoracic radiotherapy found that the QTc characteristically increased with exercise, a poor prognostic indicator.⁴⁸ In a study of 134 survivors of childhood cancer, 12.5% of those who had undergone radiotherapy had a resting QTc of 0.44 msec or more.⁴⁹

Furthermore, a study of 69 breast cancer survivors found a higher incidence of conduction abnormalities at 6 months and 10 years after radiotherapy compared with baseline. The characteristic electrocardiographic changes at 6 months were T-wave changes. At 10 years, the T-wave abnormalities had resolved and were replaced by ST depression.⁵⁰

As mentioned above, establishing radiotherapy as a cause for these conduction abnormalities is challenging, given the lag between radiation therapy and electrocardiographic changes. The following criteria have been proposed for establishing a link between atrioventricular blockade and prior radiation⁵¹:

• Total radiation dose to the heart > 40 Gy
• Delay of 10 years or more since therapy
• Abnormal interval electrocardiographic changes such as bundle branch block
• Prior pericardial involvement
• Associated cardiac or mediastinal lesions.

SCREENING GUIDELINES

Consensus guidelines for identifying and monitoring RIHD have been published by the European Association of Cardiovascular Imaging and the American Society of Echocardiography (Table 2).¹⁰ The European Society of Medical Oncology has also issued guidelines for the prevention, diagnosis, and management of cardiovascular disease associated with cancer therapy.

Briefly, the guidelines call for aggressive cardiac risk-factor modification through weight loss, exercise, blood pressure control, and smoking cessation, in addition to early detection of RIHD. Cardiovascular screening for risk factors and a careful clinical examination should be performed in all patients. Baseline comprehensive transthoracic echocardiography is advocated in all patients before starting radiotherapy to detect cardiac anomalies. Beyond this, an annual history and physical examination, paying close attention to the signs and symptoms of cardiopulmonary disease, is essential. The development of new cardiopulmonary symptoms or a new physical finding such as a murmur should prompt evaluation with transthoracic echocardiography.

In patients without symptoms, screening transthoracic echocardiography at 10 years after the start of radiotherapy is recommended in light of the high probability of diagnosing cardiac disease at this juncture. In patients with no preexisting cardiac disease, surveillance transthoracic echocardiography should be at 5-year intervals thereafter.

In high-risk patients without symptoms (those who have undergone anterior or left-sided radiotherapy and have at least one risk factor for RIHD), initial screening transthoracic echocardiography is recommended 5 years after radiotherapy. These patients have a heightened risk of coronary events as described above and, consequently, are recommended to undergo noninvasive imaging 5 to 10 years after radiation exposure. If this initial examination is negative, stress testing should be repeated at 5-year intervals. Stress echocardiography and stress cardiac magnetic resonance imaging have higher specificity than stress electrocardiography and therefore are generally preferred. Stress scintigraphy should be used with caution, as it adds to the cumulative radiation exposure.

The role of magnetic resonance imaging and computed tomography depends on the results of initial transthoracic echocardiography and the clinical indication, in addition to the center’s expertise and facilities. However, there are currently no data advocating their use as screening tools, except for early detection of porcelain aorta in high-risk patients.¹⁰

MODERN RADIOTHERAPY TECHNIQUES

In recent years, there has been emphasis on exposing the patient to as little radiation as possible without compromising cure.⁵² The three major strategies employed to decrease cardiac exposure include reducing the radiation dose, reducing the radiation field and volume, and using newer planning and delivery techniques.

Reducing the radiation dose. It is well recognized that the mean dose of radiation to the heart is a significant predictor of cardiovascular disease, with one study demonstrating a linear increase in the risk of coronary artery disease with increasing mean heart radiation dose (excess relative risk per Gy 7.4%, 95% confidence interval 3.3%–14.8%).⁵³

Reducing the radiation field and volume. Modern strategies and computed tomography-based radiotherapy planning have enabled a transition from older techniques such as extended-field radiation therapy, mantle-field radiation therapy, and involved-field radiation therapy to new techniques such as involved-node and involved-site radiation therapy.⁵⁴ These have shown promise. For instance, a study in patients with early Hodgkin lymphoma found a mean heart dose of 27.5 Gy with mantle-field therapy compared with 7.7 Gy with involved-node therapy. This decrease in mean heart dose was associated with a reduction in the 25-year absolute excess cardiac risk from 9.1% to 1.4% and a reduction in cardiac mortality from 2.1% to 1%.⁵⁵

Employing newer planning and delivery systems has also demonstrated some promise in reducing rates of cardiac morbidity and mortality. Extended-field radiation therapy, mantle-field radiotherapy, and involved-field radiation therapy were traditionally based on two-dimensional planning and often resulted in large volumes of myocardium being unnecessarily exposed to large doses of radiation because of the uncertainty in targeting. Involved-site and involved-node radiotherapy are based on computed tomography, resulting in more accurate targeting and sparing of normal tissue.

In addition, newer techniques such as intensity-modulated radiotherapy and proton beam therapy have resulted in further improvements in conformality compared with three-dimensional conformal radiotherapy.^56,57 Respiratory motion management, including deep inspiration breath-holding and end-inspiration breath-holding, have decreased the radiation dose to the heart in patients undergoing mediastinal radiotherapy.^58,59

TOWARD THE GOALS OF PREVENTION AND EARLIER DETECTION

As survival from breast cancer and lymphoma has increased, we continue to see legacy or latent effects of therapy, such as RIHD. Radiation therapy can affect any cardiac structure and is a major cause of morbidity and death in cancer survivors.

Modern radiation techniques use a variety of mechanisms to decrease the radiation dose to the heart. A large body of evidence emanating from an era of higher radiation doses and a lack of knowledge of the cardiac effects of radiation highlight the perilous cardiac consequences of chest radiation. With advances in radiotherapy and the development and widespread implementation of consensus guidelines, we envision earlier detection and less frequent occurrence of RIHD, although the latter trend could be blunted by increased cardiovascular risk factors within the population. Given the lag between irradiation and the cardiac consequences, it may be a number of years before any comparisons can be drawn.

Advances in radiotherapy over the past 50 years have dramatically improved outcomes in patients with malignancy. Five-year overall survival rates for Hodgkin lymphoma and non-Hodgkin lymphoma now stand at 80%, and breast cancer survival is 90%.¹

Increased longevity, however, has come at the cost of late side effects such as radiation-induced heart disease (RIHD). Cardiac dysfunction due to radiation involves a spectrum of disease processes in patients who have undergone mediastinal, thoracic, or breast radiotherapy and may involve any cardiac structure, including the pericardium, myocardium, valves, conduction system, and coronary arteries.

Overall, compared with nonirradiated patients, patients who have undergone chest radiotherapy have a 2% higher absolute risk of cardiac morbidity and death at 5 years and a 23% increased absolute risk after 20 years.²

This article will review the pathophysiology and epidemiology of RIHD and will offer a practical approach to its diagnosis and management.

MOST DAMAGE IS ENDOTHELIAL 

Cardiac myocytes are relatively resistant to radiation damage because of their postmitotic state. But endothelial cells remain sensitive to radiation, and the pathophysiology of most forms of RIHD appears to be associated with damage to endothelial cells. Conventional cardiac risk factors such as hyperlipidemia and smoking have been shown to compound and accelerate radiation-induced endothelial damage in animal models.³

Radiation is believed to result in transient increases in oxidative stress, resulting in formation of reactive oxygen species and a subsequent inflammatory response that includes activation of nuclear factor-kappa B. Upregulation of proinflammatory pathways results in increased expression of matrix metalloproteinases, adhesion molecules, and proinflammatory cytokines and downregulation of vasculoprotective nitric oxide.⁴ Indirect evidence for radiation-induced vascular inflammation comes from numerous studies that demonstrated increased levels of the proinflammatory cytokines interleukin 6, tumor necrosis factor alpha, and interferon gamma in Japanese atomic bomb survivors.⁵

RISK FACTORS

Risk factors for RIHD are summarized in Table 1.

The volume of heart irradiated is a major determinant of the development of RIHD.⁶ A retrospective study of 960 breast cancer patients in Stockholm between 1971 and 1976 found that those who had received the highest doses and volumes of cardiac radiation had a threefold higher risk of cardiac death. By comparison, those with lesser volumes of the heart exposed to radiation had no increase in risk of cardiac death compared with the general population.⁷

Younger age at the time of radiotherapy is associated with an increased risk of RIHD in breast cancer and lymphoma patients. A retrospective analysis of 635 patients under age 21 with Hodgkin lymphoma treated with radiotherapy showed a relative risk of fatal myocardial infarction of 41.5 compared with a general population matched for age, sex, and race.⁸

Conventional cardiac risk factors such as smoking, hypertension, diabetes, and hyperlipidemia further increase the risk of RIHD, and radiation increases the cardiotoxicity of chemotherapeutic agents such as anthracyclines.⁹

In general, high-risk patients are defined as those with at least one risk factor for RIHD who underwent anterior or left-sided chest irradiation  (Table 1).¹⁰

CORONARY ARTERY DISEASE

Ischemic heart disease is the most common cause of cardiac death in patients who have undergone radiation therapy. Atherosclerotic lesions in RIHD are morphologically identical to those in nonirradiated vessels and are characterized by intimal proliferation, accumulation of lipid-rich macrophages, and plaque formation.¹¹

A retrospective single-institution study of 415 patients with Hodgkin lymphoma who had undergone radiation therapy found the incidence of coronary artery disease 20 years later to be 10%. The mean time to development of coronary artery disease was 9 years, and all patients who developed it had at least one conventional cardiac risk factor.¹²

A meta-analysis of more than 20,000 breast cancer patients who received radiotherapy in 40 randomized controlled trials found an increase in the rate of non-breast-cancer deaths, primarily from vascular causes (annual event ratio 1.27, P <  .0001).¹³

A randomized controlled trial comparing breast cancer patients who underwent preoperative or postoperative radiotherapy vs those who had surgery alone revealed a significantly higher death rate from coronary artery disease in the postradiotherapy group.⁷

The risk of radiation-induced coronary artery disease is proportional to both the dose and the duration of radiation therapy. A retrospective study of more than 2,000 women undergoing radiotherapy for breast cancer found that the relative risk of coronary artery disease increased linearly by about 7.4% per Gy of radiation to the heart, with no apparent ceiling.¹⁴

The distribution of atherosclerotic coronary arteries correlates well with the areas exposed to the highest doses of radiation. For instance, in left-sided breast cancer, the apex and anterior wall of the heart typically receive the highest doses of radiation; consequently, the left anterior descending and distal diagonal branches are most prominently involved.¹⁵ In patients with lymphoma who undergo radiotherapy to mediastinal nodes and in breast cancer patients receiving radiotherapy to the internal mammary chain, basal structures may be exposed as well. Ostial lesions can also be seen in these patients.¹⁶

The clinical presentation of coronary artery disease in radiotherapy recipients does not differ significantly from that in the general population. Ischemia may be silent, may lead to classic anginal symptoms, or may cause sudden cardiac death. The incidence of silent myocardial infarction has been reported to be higher after mediastinal radiotherapy than it is in the general population, possibly from damage to nerve endings within the radiation field.¹⁷

Management of radiation-associated coronary artery disease

Managing patients with radiation-associated coronary artery disease is challenging, but the therapeutic options remain the same as those in nonirradiated patients and include medical therapy, percutaneous coronary intervention, and coronary artery bypass grafting, depending on the site and extent of disease.¹⁸ Although results are conflicting, there does not seem to be a significant difference in the rates of stent restenosis between patients with a history of radiation therapy and the general population.

Percutaneous coronary intervention is generally preferred to coronary artery bypass grafting in these patients for several reasons. Radiation-induced fibrosis of surrounding structures generally makes surgical procedures more difficult,¹⁹ and inclusion of the internal mammary artery or internal thoracic artery in the radiation field may result in stenosis of these vessels, rendering them unsuitable for harvesting.²⁰ Moreover, many patients with RIHD have concurrent radiation-induced lung damage, which increases the risk of perioperative pulmonary complications.²¹

If the coronary lesions are not amenable to percutaneous intervention, a careful valvular evaluation should be performed preoperatively in view of the frequency of radiation-associated valvular disease. In a study of 72 patients with RIHD undergoing coronary artery bypass grafting, 40% required valvular surgery at the time of surgery or shortly thereafter.²²

Results of studies of coronary artery bypass graft outcomes in patients with a history of thoracic radiation therapy have been conflicting, but success seems to depend on the status of the internal mammary and internal thoracic arteries.²³ Therefore, the patency of these vessels should be elucidated preoperatively by angiography and intraoperatively by visual inspection of the vessels for fibrosis.

A large single-institution study by Wu et al²⁴ revealed higher short-term and long-term mortality rates in patients with RIHD undergoing cardiac surgery than in control patients without RIHD undergoing similar procedures.

VALVULAR DISEASE

Radiation therapy may directly affect heart valves, and both stenotic (Figure 1) and regurgitant lesions have been described. Pathologic findings include leaflet retraction, fibrotic thickening, and late calcification.²⁵

The precise mechanism of radiation-induced valvular disease is unknown but is thought to be a change in the phenotype of valvular interstitial cells from a myofibroblast to an osteoblast-like cell. Radiation results in significant expression of osteogenic factors such as bone morphogenic protein 2, osteopontin, alkaline phosphatase, and runt-related transcription factor 2 by valvular interstitial cells.26

Valvular heart disease is evident in as many as 81% of patients with RIHD, with the aortic and mitral valves affected more commonly than the tricuspid and pulmonic valves.²⁷ Why there are more left-sided valve lesions than pulmonic valve lesions, despite the pulmonic valve’s anterior position in the heart, is unknown but may be due to higher pressures across the left-sided heart valves.

Although valvular disease is common in patients with RIHD, clinically significant disease is not; more than 70% of patients with radiation-induced valvular disease have no symptoms. A study of 38 cases of radiation-induced valvular disease reported a mean time to development of asymptomatic valvular lesions of 11.5 years and an average time to symptomatic valvular dysfunction of 16.5 years, indicating that 5 years seems to be the interval required for progression from asymptomatic to symptomatic valvular RIHD.²⁸

The thickness of the aortomitral curtain (the junction between the base of the anterior mitral leaflet and the aortic root) is an independent predictor of the long-term risk of death in patients with valvular RIHD.²⁹

Management of radiation-induced valvular disease

Management of patients with valvular RIHD poses a major clinical conundrum because of  the high rates of perioperative morbidity and death in patients with a history of chest radiotherapy. In one study,²³ the long-term mortality rate was 45% in postradiotherapy patients undergoing single-valve surgery and 61% in those undergoing surgery on two or more valves, compared with 13% and 17% in patients with no history of chest radiotherapy.²³

Furthermore, valve repair is an unattractive option in these patients because of high failure rates of mitral valve and tricuspid valve repair attributed to ongoing radiotherapy-induced valvular changes after repair.³⁰

As a result, valve replacement is generally preferred in this group. Patients should be advised of the higher risk of perioperative and long-term morbidity and death associated with open heart surgery than in the general population, and that the risks are even higher with repeat open heart surgery.

This risk has implications for the choice of replacement valves in younger patients. Bioprosthetic valves, which deteriorate over time, may not be advisable. Transcatheter aortic valve replacement has been successful in radiation-induced valvular disease and may become the preferred method of aortic valve replacement.³¹

PERICARDIAL DISEASE

Pericardial disease is a frequent manifestation of RIHD and covers a spectrum of manifestations from acute pericarditis, pericardial effusion, and tamponade to constrictive pericarditis. In a necropsy study, 70% of patients with RIHD were found to have pericardial involvement.³²

The mechanism is believed to be radiation-induced microvascular injury resulting in increased capillary permeability and the sometimes rapid development of a protein-rich exudate. Associated inflammation may cause acute pericarditis, which may eventually be complicated by chronic pericarditis. The parietal surface tends to be affected more severely than the epicardium.³³

Perhaps as a result of recent advances such as lower radiation doses, equal weighting of the anterior and posterior fields, and subcarinal blocking, incidence rates of pericarditis as low as 2.5% have been reported.³⁴

Pericardial RIHD may be divided into early acute pericarditis, delayed chronic pericardial effusion, and constrictive pericarditis.

Early acute pericarditis is rare and is thought to represent a reaction to tumor necrosis. It is defined as occurring during radiotherapy and occurs almost exclusively with high-dose radiotherapy for lymphoma. Due to the relatively benign course of acute pericarditis and fear of tumor recurrence, it is not an indication to withhold radiotherapy.³⁵

Delayed chronic pericardial effusion occurs months to years after radiotherapy, is typically asymptomatic, and presents as an enlarged cardiac silhouette on chest imaging.³⁵ Delayed pericardial effusion is followed with imaging. While in many cases it resolves within 2 years, it may also be long-standing. Pericardiocentesis or a pericardial window may be performed to treat symptomatic effusion or delayed effusion causing hemodynamic compromise.^35–37 Hypothyroidism should be ruled out, as it can complicate mantle irradiation and result in chronic pericardial effusion.³⁸

Constrictive pericarditis may occur as a late complication of radiotherapy and typically causes symptoms of congestive heart failure. Pericardial stripping in these patients is complicated by the possibility of coexisting RIHD of the valves, myocardium, or coronary arteries, as well as mediastinal fibrosis. A study of 163 patients who underwent pericardial stripping for chronic pericarditis found a 7-year overall survival rate of only 27%, far lower than the rate for those who had no history of radiation exposure.³⁹ Therefore, these patients are often treated for symptom control with diuretics and a low-salt diet rather than with surgery.

MYOCARDIAL DISEASE

Microvascular injury in the myocardium results in chronic ischemia, which may lead to myocardial fibrosis, typically manifesting as diastolic dysfunction. Chest radiotherapy may result in both systolic and diastolic dysfunction, and dilated and restrictive cardiomyopathy are well-recognized complications.⁴⁰

Historically, high radiation doses resulted in systolic dysfunction in more than half of patients who underwent thoracic radiotherapy.⁴¹ Now, however, fewer than 5% of patients develop reductions in left ventricular ejection fraction, and most cases of radiotherapy-induced cardiomyopathy have a restrictive pattern.⁴²

In a single-institution study, diastolic dysfunction was reported in as many as 14% of patients who underwent thoracic radiotherapy for Hodgkin lymphoma.⁴⁰ Systolic dysfunction is now seen almost exclusively in patients  treated concurrently with cardiotoxic chemotherapeutic agents such as anthracyclines in addition to radiotherapy.⁴³

In a childhood cancer survival series, the hazard ratio of congestive heart failure in patients who had undergone radiotherapy for Wilms tumor was 6.6—almost identical to the occurrence in sibling controls. By contrast, the hazard ratio increased to 18.3 in those who received doxorubicin in addition to radiotherapy.⁴⁴

Treatment of radiation-induced cardiomyopathy

Treatment of radiation-induced cardiomyopathy is similar to that for other forms of cardiomyopathy, with an emphasis on symptom management.

Heart transplant may be an option for highly selected patients with end-stage heart failure secondary to RIHD. In one report, a series of four RIHD patients received a heart transplant, and all four survived past 48 months.⁴⁵ However, data from the United Network of Organ Sharing revealed an increase in the all-cause mortality rate in patients undergoing heart transplant for RIHD compared with those undergoing transplant for cardiomyopathy due to other causes.⁴⁶ This trend may be confounded by a higher prevalence of prior cardiac surgery in the RIHD group—itself an established risk factor for poor posttransplant outcomes.

CONDUCTION SYSTEM DISEASE

Life-threatening arrhythmias have been reported that are distinct from the common, asymptomatic repolarization abnormalities that occur during radiotherapy. Atrioventricular nodal bradycardia, all degrees of heart block, and sick sinus syndrome have all been reported after chest radiotherapy. As conduction abnormalities do not typically manifest until years after radiotherapy, it is difficult to establish causation and, consequently, to define incidence.

Right bundle branch block is the most common conduction abnormality because of the proximity of the right bundle to the endocardium on the right side.⁴⁷

Chest radiotherapy is also associated with prolongation of the corrected QT interval (QTc). A study in patients with a history of thoracic radiotherapy found that the QTc characteristically increased with exercise, a poor prognostic indicator.⁴⁸ In a study of 134 survivors of childhood cancer, 12.5% of those who had undergone radiotherapy had a resting QTc of 0.44 msec or more.⁴⁹

Furthermore, a study of 69 breast cancer survivors found a higher incidence of conduction abnormalities at 6 months and 10 years after radiotherapy compared with baseline. The characteristic electrocardiographic changes at 6 months were T-wave changes. At 10 years, the T-wave abnormalities had resolved and were replaced by ST depression.⁵⁰

As mentioned above, establishing radiotherapy as a cause for these conduction abnormalities is challenging, given the lag between radiation therapy and electrocardiographic changes. The following criteria have been proposed for establishing a link between atrioventricular blockade and prior radiation⁵¹:

• Total radiation dose to the heart > 40 Gy
• Delay of 10 years or more since therapy
• Abnormal interval electrocardiographic changes such as bundle branch block
• Prior pericardial involvement
• Associated cardiac or mediastinal lesions.

SCREENING GUIDELINES

Consensus guidelines for identifying and monitoring RIHD have been published by the European Association of Cardiovascular Imaging and the American Society of Echocardiography (Table 2).¹⁰ The European Society of Medical Oncology has also issued guidelines for the prevention, diagnosis, and management of cardiovascular disease associated with cancer therapy.

Briefly, the guidelines call for aggressive cardiac risk-factor modification through weight loss, exercise, blood pressure control, and smoking cessation, in addition to early detection of RIHD. Cardiovascular screening for risk factors and a careful clinical examination should be performed in all patients. Baseline comprehensive transthoracic echocardiography is advocated in all patients before starting radiotherapy to detect cardiac anomalies. Beyond this, an annual history and physical examination, paying close attention to the signs and symptoms of cardiopulmonary disease, is essential. The development of new cardiopulmonary symptoms or a new physical finding such as a murmur should prompt evaluation with transthoracic echocardiography.

In patients without symptoms, screening transthoracic echocardiography at 10 years after the start of radiotherapy is recommended in light of the high probability of diagnosing cardiac disease at this juncture. In patients with no preexisting cardiac disease, surveillance transthoracic echocardiography should be at 5-year intervals thereafter.

In high-risk patients without symptoms (those who have undergone anterior or left-sided radiotherapy and have at least one risk factor for RIHD), initial screening transthoracic echocardiography is recommended 5 years after radiotherapy. These patients have a heightened risk of coronary events as described above and, consequently, are recommended to undergo noninvasive imaging 5 to 10 years after radiation exposure. If this initial examination is negative, stress testing should be repeated at 5-year intervals. Stress echocardiography and stress cardiac magnetic resonance imaging have higher specificity than stress electrocardiography and therefore are generally preferred. Stress scintigraphy should be used with caution, as it adds to the cumulative radiation exposure.

The role of magnetic resonance imaging and computed tomography depends on the results of initial transthoracic echocardiography and the clinical indication, in addition to the center’s expertise and facilities. However, there are currently no data advocating their use as screening tools, except for early detection of porcelain aorta in high-risk patients.¹⁰

MODERN RADIOTHERAPY TECHNIQUES

In recent years, there has been emphasis on exposing the patient to as little radiation as possible without compromising cure.⁵² The three major strategies employed to decrease cardiac exposure include reducing the radiation dose, reducing the radiation field and volume, and using newer planning and delivery techniques.

Reducing the radiation dose. It is well recognized that the mean dose of radiation to the heart is a significant predictor of cardiovascular disease, with one study demonstrating a linear increase in the risk of coronary artery disease with increasing mean heart radiation dose (excess relative risk per Gy 7.4%, 95% confidence interval 3.3%–14.8%).⁵³

Reducing the radiation field and volume. Modern strategies and computed tomography-based radiotherapy planning have enabled a transition from older techniques such as extended-field radiation therapy, mantle-field radiation therapy, and involved-field radiation therapy to new techniques such as involved-node and involved-site radiation therapy.⁵⁴ These have shown promise. For instance, a study in patients with early Hodgkin lymphoma found a mean heart dose of 27.5 Gy with mantle-field therapy compared with 7.7 Gy with involved-node therapy. This decrease in mean heart dose was associated with a reduction in the 25-year absolute excess cardiac risk from 9.1% to 1.4% and a reduction in cardiac mortality from 2.1% to 1%.⁵⁵

Employing newer planning and delivery systems has also demonstrated some promise in reducing rates of cardiac morbidity and mortality. Extended-field radiation therapy, mantle-field radiotherapy, and involved-field radiation therapy were traditionally based on two-dimensional planning and often resulted in large volumes of myocardium being unnecessarily exposed to large doses of radiation because of the uncertainty in targeting. Involved-site and involved-node radiotherapy are based on computed tomography, resulting in more accurate targeting and sparing of normal tissue.

In addition, newer techniques such as intensity-modulated radiotherapy and proton beam therapy have resulted in further improvements in conformality compared with three-dimensional conformal radiotherapy.^56,57 Respiratory motion management, including deep inspiration breath-holding and end-inspiration breath-holding, have decreased the radiation dose to the heart in patients undergoing mediastinal radiotherapy.^58,59

TOWARD THE GOALS OF PREVENTION AND EARLIER DETECTION

As survival from breast cancer and lymphoma has increased, we continue to see legacy or latent effects of therapy, such as RIHD. Radiation therapy can affect any cardiac structure and is a major cause of morbidity and death in cancer survivors.

Modern radiation techniques use a variety of mechanisms to decrease the radiation dose to the heart. A large body of evidence emanating from an era of higher radiation doses and a lack of knowledge of the cardiac effects of radiation highlight the perilous cardiac consequences of chest radiation. With advances in radiotherapy and the development and widespread implementation of consensus guidelines, we envision earlier detection and less frequent occurrence of RIHD, although the latter trend could be blunted by increased cardiovascular risk factors within the population. Given the lag between irradiation and the cardiac consequences, it may be a number of years before any comparisons can be drawn.

Women's health encompasses a variety of topics relevant to the daily practice of internists. Staying up to date with the evidence in this wide field is a challenge.

This article reviews important studies published in 2015 and early 2016 on treatment of urinary tract infections, the optimal duration of bisphosphonate use, ovarian cancer screening, the impact of oral contraceptives and lactation on mortality rates, and the risks and benefits of intrauterine contraception. We critically appraised the studies and judged that their methodology was strong and appropriate for inclusion in this review.

IBUPROFEN FOR URINARY TRACT INFECTIONS

A 36-year-old woman reports 4 days of mild to moderate dysuria, frequency, and urgency. She denies fever, nausea, or back pain. Her last urinary tract infection was 2 years ago. Office urinalysis reveals leukocyte esterase and nitrites. She has read an article about antibiotic resistance and Clostridium difficile infection and asks you if antibiotics are truly necessary. What do you recommend?

Urinary tract infections are often self-limited

Uncomplicated urinary tract infections account for 25% of antibiotic prescriptions in primary care.¹

Several small studies have suggested that many of these infections are self-limited, resolving within 3 to 14 days without antibiotics (Table 1).^2–6 A potential disadvantage of withholding treatment is slower bacterial clearance and resolution of symptoms, but reducing the number of antibiotic prescriptions may help slow antibiotic resistance.^7,8 Surveys and qualitative studies have suggested that women are concerned about the harms of antibiotic treatment and so may be willing to avoid or postpone antibiotic use.^9–11

Ibuprofen vs fosfomycin

Gágyor et al⁶ conducted a double-blind, randomized multicenter trial in 42 general practices in Germany to assess whether treating the symptoms of uncomplicated urinary tract infection with ibuprofen would reduce antibiotic use without worsening outcomes.

Of the 779 eligible women with suspected urinary tract infection, 281 declined to participate in the study, 4 did not participate for reasons not specified, 246 received a single dose of fosfomycin 3 g, and 248 were treated with ibuprofen 400 mg three times a day for 3 days. Participants scored their daily symptoms and activity impairment, and safety data were collected for adverse events and relapses up to day 28 and within 6 and 12 months. In both groups, if symptoms worsened or persisted, antibiotic therapy was initiated at the discretion of the treating physician.

Exclusion criteria included fever, “loin” (back) tenderness, pregnancy, renal disease, a previous urinary tract infection within 2 weeks, urinary catheterization, and a contraindication to nonsteroidal anti-inflammatory medications.

Results. Within 28 days of symptom onset, women in the ibuprofen group had received 81 courses of antibiotics for symptoms of urinary tract infection (plus another 13 courses for other reasons), compared with 277 courses for urinary tract infection in the fosfomycin group (plus 6 courses for other reasons), for a relative rate reduction in antibiotic use of 66.5% (95% confidence interval [CI] 58.8%–74.4%, P < .001). The women who received ibuprofen were more likely to need antibiotics after initial treatment because of refractory symptoms but were still less likely to receive antibiotics overall (Table 1).

The mean duration of symptoms was slightly shorter in the fosfomycin group (4.6 vs 5.6 days, P < .001). However, the percentage of patients who had a recurrent urinary tract infection within 2 to 4 weeks was higher in the fosfomycin-treated patients (11% vs 6% P = .049).

Although the study was not powered to show significant differences in pyelonephritis, five patients in the ibuprofen group developed pyelonephritis compared with one in the antibiotic-treated group (P = .12).

An important limitation of the study was that nonparticipants had higher symptom scores, which may mean that the results are not generalizable to women who have recurrent urinary tract infections, longer duration of symptoms, or symptoms that are more severe. The strengths of the study were that more than half of all potentially eligible women were enrolled, and baseline data were collected from nonparticipants.

Can our patient avoid antibiotics?

Given the mild nature of her symptoms, the clinician should discuss with her the risks vs benefits of delaying antibiotics, once it has been determined that she has no risk factors for severe urinary tract infection. Her symptoms are likely to resolve within 1 week even if she declines antibiotic treatment, though they may last a day longer with ibuprofen alone than if she had received antibiotics. She should watch for symptoms of pyelonephritis (eg, flank pain, fever, chills, vomiting) and should seek prompt medical care if such symptoms occur.

DISCONTINUING BISPHOSPHONATES

A 64-year-old woman has taken alendronate for her osteoporosis for 5 years. She has no history of fractures. Her original bone density scans showed a T-score of –2.6 at the spine and –1.5 at the hip. Since she started to take alendronate, there has been no further loss in bone mineral density. She is tolerating the drug well and does not take any other medications. Should she continue the bisphosphonate?

Optimal duration of therapy unknown

The risks and benefits of long-term bisphosphonate use are debated.

In the Fracture Intervention Trial (FIT),¹² women with low bone mineral density of the femoral neck were randomized to receive alendronate or placebo and were followed for 36 months. The alendronate group had significantly fewer vertebral fractures and clinical fractures overall. Then, in the FIT Long-term Extension (FLEX) study,¹³ 1,009 alendronate-treated women in the FIT study were rerandomized to receive 5 years of additional treatment or to stop treatment. Bone density in the untreated women decreased, although not to the level it was before treatment. At the end of the study, there was no difference in hip fracture rate between the two groups (3% of each group had had a hip fracture), although women in the treated group had a lower rate of clinical vertebral fracture (2% vs 5%, relative risk 0.5, 95% CI 0.2–0.8).

In addition, rare but serious risks have been associated with bisphosphonate use, specifically atypical femoral fracture and osteonecrosis of the jaw. A US Food and Drug Administration (FDA) evaluation of long-term bisphosphonate use concluded that there was evidence of an increased risk of osteonecrosis of the jaw with longer duration of use, but causality was not established. The evaluation also noted conflicting results about the association with atypical femoral fracture.¹⁴

Based on this report and focusing on the absence of nonspine benefit after 5 years, the FDA suggested that bisphosphonates may be safely discontinued in some patients without compromising therapeutic gains, but no adequate clinical trial has yet delineated how long the benefits of treatment are maintained after cessation. A periodic reevaluation of continued need was recommended.¹⁴

New recommendations from the American Society for Bone and Mineral Research

Age is the greatest risk factor for fracture.¹⁵ Therefore, deciding whether to discontinue a bisphosphonate when a woman is older, and hence at higher risk, is a challenge.

A task force of the American Society for Bone and Mineral Research (ASBMR) has developed an evidence-based guideline on managing osteoporosis in patients on long-term bisphosphonate treatment.¹⁶ The goal was to provide guidance on the duration of bisphosphonate therapy from the perspective of risk vs benefit. The authors conducted a systematic review focusing on two randomized controlled trials (FLEX¹³ and the Health Outcomes and Reduced Incidence With Zoledronic Acid Once Yearly Pivotal Fracture Trial¹⁷) that provided data on long-term bisphosphonate use.

The task force recommended¹⁶ that after 5 years of oral bisphosphonates or 3 years of intravenous bisphosphonates, risk should be reassessed. In women at high fracture risk, they recommended continuing the oral bisphosphonate for 10 years or the intravenous bisphosphonate for 6 years. Factors that favored continuation of bisphosphonate therapy were as follows:

• An osteoporotic fracture before or during therapy
• A hip bone mineral density T-score ≤ –2.5
• High risk of fracture, defined as age older than 70 or 75, other strong risk factors for fracture, or a FRAX fracture risk score¹⁸ above a country-specific threshold.

(The FRAX score is based on age, sex, weight, height, previous fracture, hip fracture in a parent, current smoking, use of glucocorticoids, rheumatoid arthritis, secondary osteoporosis, alcohol use, and bone mineral density in the femoral neck. It gives an estimate of the 10-year risk of major osteoporotic fracture and hip fracture. High risk would be a 10-year risk of major osteoporotic fracture greater than 20% or a 10-year risk of hip fracture greater than 3%.)

For women at high risk, the risks of atypical femoral fracture and osteonecrosis of the jaw are outweighed by the benefit of a reduction in vertebral fracture risk. For women not at high risk of fracture, a drug holiday of 2 to 3 years can be considered after 3 to 5 years of treatment.

Although the task force recommended reassessment after 2 to 3 years of drug holiday, how best to do this is not clear. The task force did not recommend a specific approach to reassessment, so decisions about when to restart therapy after a drug holiday could potentially be informed by subsequent bone mineral density testing if it were to show persistent bone loss. Another option could be to restart bisphosphonates after a defined amount of time (eg, 3–5 years) for women who have previously experienced benefit.

The task force recommendations are in line with those of other societies, the FDA, and expert opinion.^19–23

The American Association of Clinical Endocrinologists recommends considering a drug holiday in low-risk patients after 4 to 5 years of treatment. For high-risk patients, they recommend 1 to 2 years of drug holiday after 10 years of treatment. They encourage restarting treatment if bone mineral density decreases, bone turnover markers rise, or fracture occurs.¹⁹ This is a grade C recommendation, meaning the advice is based on descriptive studies and expert opinion.

Although some clinicians restart bisphosphonates when markers of bone turnover such as NTX (N-telopeptide of type 1 collagen) rise to premenopausal levels, there is no evidence to support this strategy.²⁴

The task force recommendations are based on limited evidence that primarily comes from white postmenopausal women. Another important limitation is that the outcomes are primarily vertebral fractures. However, until additional evidence is available, these guidelines can be useful in guiding decision-making.

Should our patient continue therapy?

Our patient is relatively young and does not have any of the high-risk features noted within the task force recommendations. She has responded well to bisphosphonate treatment and so can consider a drug holiday at this time.

OVARIAN CANCER SCREENING

A 50-year-old woman requests screening for ovarian cancer. She is postmenopausal and has no personal or family history of cancer. She is concerned because a friend forwarded an e-mail stating, “Please tell all your female friends and relatives to insist on a cancer antigen (CA) 125 blood test every year as part of their annual exam. This is an inexpensive and simple blood test. Don’t take no for an answer. If I had known then what I know now, we would have caught my cancer much earlier, before it was stage III!” What should you tell the patient?

Ovarian cancer is the most deadly of female reproductive cancers, largely because in most patients the cancer has already spread beyond the ovary by the time of clinical detection. Death rates from ovarian cancer have decreased only slightly in the past 30 years.

Little benefit and considerable harm of screening

In 2011, the Prostate Lung Colorectal Ovarian (PLCO) Cancer Screening trial²⁵ randomized more than 68,000 women ages 55 to 74 from the general US population to annual screening with CA 125 testing and transvaginal ultrasonography compared with usual care. They were followed for a median of 12.4 years.

Screening did not affect stage at diagnosis (77%–78% were in stage III or IV in both the screening and usual care groups), nor did it reduce the rate of death from ovarian cancer. In addition, false-positive findings led to some harm: nearly one in three women who had a positive screening test underwent surgery. Of 3,285 women with false-positive results, 1,080 underwent surgery, and 15% of these had at least one serious complication. The trial was stopped early due to evidence of futility.

A new UK study also found no benefit from screening

In the PLCO study, a CA 125 result of 35 U/mL or greater was classified as abnormal. However, researchers in the United Kingdom postulated that instead of using a single cutoff for a normal or abnormal CA 125 level, it would be better to interpret the CA 125 result according to a somewhat complicated (and proprietary) algorithm called the Risk of Ovarian Cancer Algorithm (ROCA).^26,27 The ROCA takes into account a woman’s age, menopausal status, known genetic mutations (BRCA 1 or 2 or Lynch syndrome), Ashkenazi Jewish descent, and family history of ovarian or breast cancer, as well as any change in CA 125 level over time.

In a 2016 UK study,²⁶ 202,638 postmenopausal women ages 50 to 74 were randomized to no screening, annual screening with transvaginal ultrasonography, or multimodal screening with an annual CA 125 blood test interpreted with the ROCA algorithm, adding transvaginal ultrasonography as a second-line test when needed if the CA 125 level was abnormal based on the ROCA. Women with abnormal findings on multimodal screening or ultrasonography had repeat tests, and women with persistent abnormalities underwent clinical evaluation and, when appropriate, surgery.

Participants were at average risk of ovarian cancer; those with suspected familial ovarian cancer syndrome were excluded, as were those with a personal history of ovarian cancer or other active cancer.

Results. At a median follow-up of 11.1 years, the percentage of women who were diagnosed with ovarian cancer was 0.7% in the multimodal screening group, 0.6% in the screening ultrasonography group, and 0.6% in the no-screening group. Comparing either multimodal or screening ultrasonography with no screening, there was no statistically significant reduction in mortality rate over 14 years of follow-up.

Screening had significant costs and potential harms. For every ovarian or peritoneal cancer detected by screening, an additional 2 women in the multimodal screening group and 10 women in the ultrasonography group underwent needless surgery.

Strengths of this trial included its large size, allowing adequate power to detect differences in outcomes, its multicenter setting, its high compliance rate, and the low crossover rate in the no-screening group. However, the design of the study makes it difficult to anticipate the late effects of screening. Also, the patient must purchase ROCA testing online and must also pay a consultation fee. Insurance providers do not cover this test.

Should our patient proceed with ovarian cancer screening?

No. Current evidence shows no clear benefit to ovarian cancer screening for average-risk women, and we should not recommend yearly ultrasonography and CA 125 level testing, as they are likely to cause harm without providing benefit. The US Preventive Services Task Force recommends against screening for ovarian cancer.²⁸ For premenopausal women, pregnancy, hormonal contraception, and breastfeeding all significantly decrease ovarian cancer risk by suppressing ovulation.^29–31

REPRODUCTIVE FACTORS AND THE RISK OF DEATH

A 26-year-old woman comes in to discuss her contraceptive options. She has been breastfeeding since the birth of her first baby 6 months ago, and wonders how lactation and contraception may affect her long-term health.

Questions about the safety of contraceptive options are common, especially in breastfeeding mothers.

In 2010, the long-term Royal College of General Practitioners’ Oral Contraceptive Study reported that the all-cause mortality rate was actually lower in women who used oral contraceptives.³² Similarly, in 2013, an Oxford study that followed 17,032 women for over 30 years reported no association between oral contraceptives and breast cancer.³³

However, in 2014, results from the Nurses’ Health Study indicated that breast cancer rates were higher in oral contraceptive users, although reassuringly, the study found no difference in all-cause mortality rates in women who had used oral contraception.³⁴

The European Prospective Investigation Into Cancer and Nutrition

To further characterize relationships between reproductive characteristics and mortality rates, investigators analyzed data from the European Prospective Investigation Into Cancer and Nutrition,³⁵ which recruited 322,972 women from 10 countries between 1992 and 2000. Analyses were stratified by study center and participant age and were adjusted for body mass index, physical activity, education level, smoking, and menopausal status; alcohol intake was examined as a potential confounder but was excluded from final models.

Findings. Over an average 13 years of follow-up, the rate of all-cause mortality was 20% lower in parous than in nulliparous women. In parous women, the all-cause mortality rate was additionally 18% lower in those who had breastfed vs those who had never breastfed, although breastfeeding duration was not associated with mortality. Use of oral contraceptives lowered all-cause mortality by 10% among nonsmokers; in smokers, no association with all-cause mortality was seen for oral contraceptive use, as smoking is such a powerful risk factor for mortality. The primary contributor to all-cause mortality appeared to be ischemic heart disease, the incidence of which was significantly lower in parous women (by 14%) and those who breastfed (by 20%) and was not related to oral contraceptive use.³⁵

Strengths of this study included the large sample size recruited from countries across Europe, with varying rates of breastfeeding and contraceptive use. However, as with all observational studies, it remains subject to the possibility of residual confounding.

What should we tell this patient?

After congratulating her for breastfeeding, we can reassure her about the safety of all available contraceptives. According to the US Centers for Disease Control and Prevention (CDC),³⁶ after 42 days postpartum most women can use combined hormonal contraception. All other methods can be used immediately postpartum, including progestin-only pills.

As lactational amenorrhea is only effective while mothers are exclusively breastfeeding, and short interpregnancy intervals have been associated with higher rates of adverse pregnancy outcomes,³⁷ this patient will likely benefit from promptly starting a prescription contraceptive.

HIGHLY EFFECTIVE REVERSIBLE CONTRACEPTION

This same 26-year-old patient is concerned that she will not remember to take an oral contraceptive every day, and expresses interest in a more convenient method of contraception. However, she is concerned about the potential risks.

Although intrauterine contraceptives (IUCs) are typically 20 times more effective than oral contraceptives³⁸ and have been used by millions of women worldwide, rates of use in the United States have been lower than in many other countries.³⁹

A study of intrauterine contraception

To clarify the safety of IUCs, researchers followed 61,448 women who underwent IUC placement in six European countries between 2006 and 2013.⁴⁰ Most participants received an IUC containing levonorgestrel, while 30% received a copper IUC.

Findings. Overall, rates of uterine perforation were low (approximately 1 per 1,000 insertions). The most significant risk factors for perforation were breastfeeding at the time of insertion and insertion less than 36 weeks after the last delivery. None of the perforations in the study led to serious illness or injury of intra-abdominal or pelvic structures. Interestingly, women using a levonorgestrel IUC were considerably less likely to experience a contraceptive failure than those using a copper IUC.⁴¹

Strengths of this study included the prospective data collection and power to examine rare clinical outcomes. However, it was industry-funded.

The risk of pelvic infection with an IUC is so low that the CDC does not recommend prophylactic antibiotics with the insertion procedure. If women have other indications for testing for sexually transmitted disease, an IUC can be placed the same day as testing, and before results are available.⁴² If a woman is found to have a sexually transmitted disease while she has an IUC in place, she should be treated with antibiotics, and there is no need to remove the IUC.⁴³

Subdermal implants

Another highly effective contraceptive option for this patient is the progestin-only subdermal contraceptive implant (marketed in the United States as Nexplanon). Implants have been well-studied and found to have no adverse effect on lactation.⁴⁴

Learning to place a subdermal contraceptive is far easier than learning to place an IUC, but it requires a few hours of FDA-mandated in-person training. Unfortunately, relatively few clinicians have obtained this training.⁴⁵ As placing a subdermal contraceptive is like placing an intravenous line without needing to hit the vein, this procedure can easily be incorporated into a primary care practice. Training from the manufacturer is available to providers who request it.

What should we tell this patient?

An IUC is a great option for many women. When pregnancy is desired, the device is easily removed. Of the three IUCs now available in the United States, those containing 52 mg of levonorgestrel (marketed in the United States as Mirena and Liletta) are the most effective.

The only option more effective than these IUCs is subdermal contraception.⁴⁶ These reversible contraceptives are typically more effective than permanent contraceptives (ie, tubal ligation)⁴⁷ and can be removed at any time if a patient wishes to switch to another method or to become pregnant.

Pregnancy rates following attempts at “sterilization” are higher than many realize. There are a variety of approaches to “tying tubes,” some of which may not result in complete tubal occlusion. The failure rate of the laparoscopic approach, according to the US Collaborative Review of Sterilization, ranges from 7.5 per 1,000 procedures for unipolar coagulation to a high of 36.5 per 1,000 for the spring clip.⁴⁸ The relatively commonly used Filshie clip was not included in this study, but its failure rate is reported to be between 1% and 2%.

Women's health encompasses a variety of topics relevant to the daily practice of internists. Staying up to date with the evidence in this wide field is a challenge.

This article reviews important studies published in 2015 and early 2016 on treatment of urinary tract infections, the optimal duration of bisphosphonate use, ovarian cancer screening, the impact of oral contraceptives and lactation on mortality rates, and the risks and benefits of intrauterine contraception. We critically appraised the studies and judged that their methodology was strong and appropriate for inclusion in this review.

IBUPROFEN FOR URINARY TRACT INFECTIONS

A 36-year-old woman reports 4 days of mild to moderate dysuria, frequency, and urgency. She denies fever, nausea, or back pain. Her last urinary tract infection was 2 years ago. Office urinalysis reveals leukocyte esterase and nitrites. She has read an article about antibiotic resistance and Clostridium difficile infection and asks you if antibiotics are truly necessary. What do you recommend?

Urinary tract infections are often self-limited

Uncomplicated urinary tract infections account for 25% of antibiotic prescriptions in primary care.¹

Several small studies have suggested that many of these infections are self-limited, resolving within 3 to 14 days without antibiotics (Table 1).^2–6 A potential disadvantage of withholding treatment is slower bacterial clearance and resolution of symptoms, but reducing the number of antibiotic prescriptions may help slow antibiotic resistance.^7,8 Surveys and qualitative studies have suggested that women are concerned about the harms of antibiotic treatment and so may be willing to avoid or postpone antibiotic use.^9–11

Ibuprofen vs fosfomycin

Gágyor et al⁶ conducted a double-blind, randomized multicenter trial in 42 general practices in Germany to assess whether treating the symptoms of uncomplicated urinary tract infection with ibuprofen would reduce antibiotic use without worsening outcomes.

Of the 779 eligible women with suspected urinary tract infection, 281 declined to participate in the study, 4 did not participate for reasons not specified, 246 received a single dose of fosfomycin 3 g, and 248 were treated with ibuprofen 400 mg three times a day for 3 days. Participants scored their daily symptoms and activity impairment, and safety data were collected for adverse events and relapses up to day 28 and within 6 and 12 months. In both groups, if symptoms worsened or persisted, antibiotic therapy was initiated at the discretion of the treating physician.

Exclusion criteria included fever, “loin” (back) tenderness, pregnancy, renal disease, a previous urinary tract infection within 2 weeks, urinary catheterization, and a contraindication to nonsteroidal anti-inflammatory medications.

Results. Within 28 days of symptom onset, women in the ibuprofen group had received 81 courses of antibiotics for symptoms of urinary tract infection (plus another 13 courses for other reasons), compared with 277 courses for urinary tract infection in the fosfomycin group (plus 6 courses for other reasons), for a relative rate reduction in antibiotic use of 66.5% (95% confidence interval [CI] 58.8%–74.4%, P < .001). The women who received ibuprofen were more likely to need antibiotics after initial treatment because of refractory symptoms but were still less likely to receive antibiotics overall (Table 1).

The mean duration of symptoms was slightly shorter in the fosfomycin group (4.6 vs 5.6 days, P < .001). However, the percentage of patients who had a recurrent urinary tract infection within 2 to 4 weeks was higher in the fosfomycin-treated patients (11% vs 6% P = .049).

Although the study was not powered to show significant differences in pyelonephritis, five patients in the ibuprofen group developed pyelonephritis compared with one in the antibiotic-treated group (P = .12).

An important limitation of the study was that nonparticipants had higher symptom scores, which may mean that the results are not generalizable to women who have recurrent urinary tract infections, longer duration of symptoms, or symptoms that are more severe. The strengths of the study were that more than half of all potentially eligible women were enrolled, and baseline data were collected from nonparticipants.

Can our patient avoid antibiotics?

Given the mild nature of her symptoms, the clinician should discuss with her the risks vs benefits of delaying antibiotics, once it has been determined that she has no risk factors for severe urinary tract infection. Her symptoms are likely to resolve within 1 week even if she declines antibiotic treatment, though they may last a day longer with ibuprofen alone than if she had received antibiotics. She should watch for symptoms of pyelonephritis (eg, flank pain, fever, chills, vomiting) and should seek prompt medical care if such symptoms occur.

DISCONTINUING BISPHOSPHONATES

A 64-year-old woman has taken alendronate for her osteoporosis for 5 years. She has no history of fractures. Her original bone density scans showed a T-score of –2.6 at the spine and –1.5 at the hip. Since she started to take alendronate, there has been no further loss in bone mineral density. She is tolerating the drug well and does not take any other medications. Should she continue the bisphosphonate?

Optimal duration of therapy unknown

The risks and benefits of long-term bisphosphonate use are debated.

In the Fracture Intervention Trial (FIT),¹² women with low bone mineral density of the femoral neck were randomized to receive alendronate or placebo and were followed for 36 months. The alendronate group had significantly fewer vertebral fractures and clinical fractures overall. Then, in the FIT Long-term Extension (FLEX) study,¹³ 1,009 alendronate-treated women in the FIT study were rerandomized to receive 5 years of additional treatment or to stop treatment. Bone density in the untreated women decreased, although not to the level it was before treatment. At the end of the study, there was no difference in hip fracture rate between the two groups (3% of each group had had a hip fracture), although women in the treated group had a lower rate of clinical vertebral fracture (2% vs 5%, relative risk 0.5, 95% CI 0.2–0.8).

In addition, rare but serious risks have been associated with bisphosphonate use, specifically atypical femoral fracture and osteonecrosis of the jaw. A US Food and Drug Administration (FDA) evaluation of long-term bisphosphonate use concluded that there was evidence of an increased risk of osteonecrosis of the jaw with longer duration of use, but causality was not established. The evaluation also noted conflicting results about the association with atypical femoral fracture.¹⁴

Based on this report and focusing on the absence of nonspine benefit after 5 years, the FDA suggested that bisphosphonates may be safely discontinued in some patients without compromising therapeutic gains, but no adequate clinical trial has yet delineated how long the benefits of treatment are maintained after cessation. A periodic reevaluation of continued need was recommended.¹⁴

New recommendations from the American Society for Bone and Mineral Research

Age is the greatest risk factor for fracture.¹⁵ Therefore, deciding whether to discontinue a bisphosphonate when a woman is older, and hence at higher risk, is a challenge.

A task force of the American Society for Bone and Mineral Research (ASBMR) has developed an evidence-based guideline on managing osteoporosis in patients on long-term bisphosphonate treatment.¹⁶ The goal was to provide guidance on the duration of bisphosphonate therapy from the perspective of risk vs benefit. The authors conducted a systematic review focusing on two randomized controlled trials (FLEX¹³ and the Health Outcomes and Reduced Incidence With Zoledronic Acid Once Yearly Pivotal Fracture Trial¹⁷) that provided data on long-term bisphosphonate use.

The task force recommended¹⁶ that after 5 years of oral bisphosphonates or 3 years of intravenous bisphosphonates, risk should be reassessed. In women at high fracture risk, they recommended continuing the oral bisphosphonate for 10 years or the intravenous bisphosphonate for 6 years. Factors that favored continuation of bisphosphonate therapy were as follows:

• An osteoporotic fracture before or during therapy
• A hip bone mineral density T-score ≤ –2.5
• High risk of fracture, defined as age older than 70 or 75, other strong risk factors for fracture, or a FRAX fracture risk score¹⁸ above a country-specific threshold.

(The FRAX score is based on age, sex, weight, height, previous fracture, hip fracture in a parent, current smoking, use of glucocorticoids, rheumatoid arthritis, secondary osteoporosis, alcohol use, and bone mineral density in the femoral neck. It gives an estimate of the 10-year risk of major osteoporotic fracture and hip fracture. High risk would be a 10-year risk of major osteoporotic fracture greater than 20% or a 10-year risk of hip fracture greater than 3%.)

For women at high risk, the risks of atypical femoral fracture and osteonecrosis of the jaw are outweighed by the benefit of a reduction in vertebral fracture risk. For women not at high risk of fracture, a drug holiday of 2 to 3 years can be considered after 3 to 5 years of treatment.

Although the task force recommended reassessment after 2 to 3 years of drug holiday, how best to do this is not clear. The task force did not recommend a specific approach to reassessment, so decisions about when to restart therapy after a drug holiday could potentially be informed by subsequent bone mineral density testing if it were to show persistent bone loss. Another option could be to restart bisphosphonates after a defined amount of time (eg, 3–5 years) for women who have previously experienced benefit.

The task force recommendations are in line with those of other societies, the FDA, and expert opinion.^19–23

The American Association of Clinical Endocrinologists recommends considering a drug holiday in low-risk patients after 4 to 5 years of treatment. For high-risk patients, they recommend 1 to 2 years of drug holiday after 10 years of treatment. They encourage restarting treatment if bone mineral density decreases, bone turnover markers rise, or fracture occurs.¹⁹ This is a grade C recommendation, meaning the advice is based on descriptive studies and expert opinion.

Although some clinicians restart bisphosphonates when markers of bone turnover such as NTX (N-telopeptide of type 1 collagen) rise to premenopausal levels, there is no evidence to support this strategy.²⁴

The task force recommendations are based on limited evidence that primarily comes from white postmenopausal women. Another important limitation is that the outcomes are primarily vertebral fractures. However, until additional evidence is available, these guidelines can be useful in guiding decision-making.

Should our patient continue therapy?

Our patient is relatively young and does not have any of the high-risk features noted within the task force recommendations. She has responded well to bisphosphonate treatment and so can consider a drug holiday at this time.

OVARIAN CANCER SCREENING

A 50-year-old woman requests screening for ovarian cancer. She is postmenopausal and has no personal or family history of cancer. She is concerned because a friend forwarded an e-mail stating, “Please tell all your female friends and relatives to insist on a cancer antigen (CA) 125 blood test every year as part of their annual exam. This is an inexpensive and simple blood test. Don’t take no for an answer. If I had known then what I know now, we would have caught my cancer much earlier, before it was stage III!” What should you tell the patient?

Ovarian cancer is the most deadly of female reproductive cancers, largely because in most patients the cancer has already spread beyond the ovary by the time of clinical detection. Death rates from ovarian cancer have decreased only slightly in the past 30 years.

Little benefit and considerable harm of screening

In 2011, the Prostate Lung Colorectal Ovarian (PLCO) Cancer Screening trial²⁵ randomized more than 68,000 women ages 55 to 74 from the general US population to annual screening with CA 125 testing and transvaginal ultrasonography compared with usual care. They were followed for a median of 12.4 years.

Screening did not affect stage at diagnosis (77%–78% were in stage III or IV in both the screening and usual care groups), nor did it reduce the rate of death from ovarian cancer. In addition, false-positive findings led to some harm: nearly one in three women who had a positive screening test underwent surgery. Of 3,285 women with false-positive results, 1,080 underwent surgery, and 15% of these had at least one serious complication. The trial was stopped early due to evidence of futility.

A new UK study also found no benefit from screening

In the PLCO study, a CA 125 result of 35 U/mL or greater was classified as abnormal. However, researchers in the United Kingdom postulated that instead of using a single cutoff for a normal or abnormal CA 125 level, it would be better to interpret the CA 125 result according to a somewhat complicated (and proprietary) algorithm called the Risk of Ovarian Cancer Algorithm (ROCA).^26,27 The ROCA takes into account a woman’s age, menopausal status, known genetic mutations (BRCA 1 or 2 or Lynch syndrome), Ashkenazi Jewish descent, and family history of ovarian or breast cancer, as well as any change in CA 125 level over time.

In a 2016 UK study,²⁶ 202,638 postmenopausal women ages 50 to 74 were randomized to no screening, annual screening with transvaginal ultrasonography, or multimodal screening with an annual CA 125 blood test interpreted with the ROCA algorithm, adding transvaginal ultrasonography as a second-line test when needed if the CA 125 level was abnormal based on the ROCA. Women with abnormal findings on multimodal screening or ultrasonography had repeat tests, and women with persistent abnormalities underwent clinical evaluation and, when appropriate, surgery.

Participants were at average risk of ovarian cancer; those with suspected familial ovarian cancer syndrome were excluded, as were those with a personal history of ovarian cancer or other active cancer.

Results. At a median follow-up of 11.1 years, the percentage of women who were diagnosed with ovarian cancer was 0.7% in the multimodal screening group, 0.6% in the screening ultrasonography group, and 0.6% in the no-screening group. Comparing either multimodal or screening ultrasonography with no screening, there was no statistically significant reduction in mortality rate over 14 years of follow-up.

Screening had significant costs and potential harms. For every ovarian or peritoneal cancer detected by screening, an additional 2 women in the multimodal screening group and 10 women in the ultrasonography group underwent needless surgery.

Strengths of this trial included its large size, allowing adequate power to detect differences in outcomes, its multicenter setting, its high compliance rate, and the low crossover rate in the no-screening group. However, the design of the study makes it difficult to anticipate the late effects of screening. Also, the patient must purchase ROCA testing online and must also pay a consultation fee. Insurance providers do not cover this test.

Should our patient proceed with ovarian cancer screening?

No. Current evidence shows no clear benefit to ovarian cancer screening for average-risk women, and we should not recommend yearly ultrasonography and CA 125 level testing, as they are likely to cause harm without providing benefit. The US Preventive Services Task Force recommends against screening for ovarian cancer.²⁸ For premenopausal women, pregnancy, hormonal contraception, and breastfeeding all significantly decrease ovarian cancer risk by suppressing ovulation.^29–31

REPRODUCTIVE FACTORS AND THE RISK OF DEATH

A 26-year-old woman comes in to discuss her contraceptive options. She has been breastfeeding since the birth of her first baby 6 months ago, and wonders how lactation and contraception may affect her long-term health.

Questions about the safety of contraceptive options are common, especially in breastfeeding mothers.

In 2010, the long-term Royal College of General Practitioners’ Oral Contraceptive Study reported that the all-cause mortality rate was actually lower in women who used oral contraceptives.³² Similarly, in 2013, an Oxford study that followed 17,032 women for over 30 years reported no association between oral contraceptives and breast cancer.³³

However, in 2014, results from the Nurses’ Health Study indicated that breast cancer rates were higher in oral contraceptive users, although reassuringly, the study found no difference in all-cause mortality rates in women who had used oral contraception.³⁴

The European Prospective Investigation Into Cancer and Nutrition

To further characterize relationships between reproductive characteristics and mortality rates, investigators analyzed data from the European Prospective Investigation Into Cancer and Nutrition,³⁵ which recruited 322,972 women from 10 countries between 1992 and 2000. Analyses were stratified by study center and participant age and were adjusted for body mass index, physical activity, education level, smoking, and menopausal status; alcohol intake was examined as a potential confounder but was excluded from final models.

Findings. Over an average 13 years of follow-up, the rate of all-cause mortality was 20% lower in parous than in nulliparous women. In parous women, the all-cause mortality rate was additionally 18% lower in those who had breastfed vs those who had never breastfed, although breastfeeding duration was not associated with mortality. Use of oral contraceptives lowered all-cause mortality by 10% among nonsmokers; in smokers, no association with all-cause mortality was seen for oral contraceptive use, as smoking is such a powerful risk factor for mortality. The primary contributor to all-cause mortality appeared to be ischemic heart disease, the incidence of which was significantly lower in parous women (by 14%) and those who breastfed (by 20%) and was not related to oral contraceptive use.³⁵

Strengths of this study included the large sample size recruited from countries across Europe, with varying rates of breastfeeding and contraceptive use. However, as with all observational studies, it remains subject to the possibility of residual confounding.

What should we tell this patient?

After congratulating her for breastfeeding, we can reassure her about the safety of all available contraceptives. According to the US Centers for Disease Control and Prevention (CDC),³⁶ after 42 days postpartum most women can use combined hormonal contraception. All other methods can be used immediately postpartum, including progestin-only pills.

As lactational amenorrhea is only effective while mothers are exclusively breastfeeding, and short interpregnancy intervals have been associated with higher rates of adverse pregnancy outcomes,³⁷ this patient will likely benefit from promptly starting a prescription contraceptive.

HIGHLY EFFECTIVE REVERSIBLE CONTRACEPTION

This same 26-year-old patient is concerned that she will not remember to take an oral contraceptive every day, and expresses interest in a more convenient method of contraception. However, she is concerned about the potential risks.

Although intrauterine contraceptives (IUCs) are typically 20 times more effective than oral contraceptives³⁸ and have been used by millions of women worldwide, rates of use in the United States have been lower than in many other countries.³⁹

A study of intrauterine contraception

To clarify the safety of IUCs, researchers followed 61,448 women who underwent IUC placement in six European countries between 2006 and 2013.⁴⁰ Most participants received an IUC containing levonorgestrel, while 30% received a copper IUC.

Findings. Overall, rates of uterine perforation were low (approximately 1 per 1,000 insertions). The most significant risk factors for perforation were breastfeeding at the time of insertion and insertion less than 36 weeks after the last delivery. None of the perforations in the study led to serious illness or injury of intra-abdominal or pelvic structures. Interestingly, women using a levonorgestrel IUC were considerably less likely to experience a contraceptive failure than those using a copper IUC.⁴¹

Strengths of this study included the prospective data collection and power to examine rare clinical outcomes. However, it was industry-funded.

The risk of pelvic infection with an IUC is so low that the CDC does not recommend prophylactic antibiotics with the insertion procedure. If women have other indications for testing for sexually transmitted disease, an IUC can be placed the same day as testing, and before results are available.⁴² If a woman is found to have a sexually transmitted disease while she has an IUC in place, she should be treated with antibiotics, and there is no need to remove the IUC.⁴³

Subdermal implants

Another highly effective contraceptive option for this patient is the progestin-only subdermal contraceptive implant (marketed in the United States as Nexplanon). Implants have been well-studied and found to have no adverse effect on lactation.⁴⁴

Learning to place a subdermal contraceptive is far easier than learning to place an IUC, but it requires a few hours of FDA-mandated in-person training. Unfortunately, relatively few clinicians have obtained this training.⁴⁵ As placing a subdermal contraceptive is like placing an intravenous line without needing to hit the vein, this procedure can easily be incorporated into a primary care practice. Training from the manufacturer is available to providers who request it.

What should we tell this patient?

An IUC is a great option for many women. When pregnancy is desired, the device is easily removed. Of the three IUCs now available in the United States, those containing 52 mg of levonorgestrel (marketed in the United States as Mirena and Liletta) are the most effective.

The only option more effective than these IUCs is subdermal contraception.⁴⁶ These reversible contraceptives are typically more effective than permanent contraceptives (ie, tubal ligation)⁴⁷ and can be removed at any time if a patient wishes to switch to another method or to become pregnant.

Pregnancy rates following attempts at “sterilization” are higher than many realize. There are a variety of approaches to “tying tubes,” some of which may not result in complete tubal occlusion. The failure rate of the laparoscopic approach, according to the US Collaborative Review of Sterilization, ranges from 7.5 per 1,000 procedures for unipolar coagulation to a high of 36.5 per 1,000 for the spring clip.⁴⁸ The relatively commonly used Filshie clip was not included in this study, but its failure rate is reported to be between 1% and 2%.

Women's health encompasses a variety of topics relevant to the daily practice of internists. Staying up to date with the evidence in this wide field is a challenge.

This article reviews important studies published in 2015 and early 2016 on treatment of urinary tract infections, the optimal duration of bisphosphonate use, ovarian cancer screening, the impact of oral contraceptives and lactation on mortality rates, and the risks and benefits of intrauterine contraception. We critically appraised the studies and judged that their methodology was strong and appropriate for inclusion in this review.

IBUPROFEN FOR URINARY TRACT INFECTIONS

A 36-year-old woman reports 4 days of mild to moderate dysuria, frequency, and urgency. She denies fever, nausea, or back pain. Her last urinary tract infection was 2 years ago. Office urinalysis reveals leukocyte esterase and nitrites. She has read an article about antibiotic resistance and Clostridium difficile infection and asks you if antibiotics are truly necessary. What do you recommend?

Urinary tract infections are often self-limited

Uncomplicated urinary tract infections account for 25% of antibiotic prescriptions in primary care.¹

Several small studies have suggested that many of these infections are self-limited, resolving within 3 to 14 days without antibiotics (Table 1).^2–6 A potential disadvantage of withholding treatment is slower bacterial clearance and resolution of symptoms, but reducing the number of antibiotic prescriptions may help slow antibiotic resistance.^7,8 Surveys and qualitative studies have suggested that women are concerned about the harms of antibiotic treatment and so may be willing to avoid or postpone antibiotic use.^9–11

Ibuprofen vs fosfomycin

Gágyor et al⁶ conducted a double-blind, randomized multicenter trial in 42 general practices in Germany to assess whether treating the symptoms of uncomplicated urinary tract infection with ibuprofen would reduce antibiotic use without worsening outcomes.

Of the 779 eligible women with suspected urinary tract infection, 281 declined to participate in the study, 4 did not participate for reasons not specified, 246 received a single dose of fosfomycin 3 g, and 248 were treated with ibuprofen 400 mg three times a day for 3 days. Participants scored their daily symptoms and activity impairment, and safety data were collected for adverse events and relapses up to day 28 and within 6 and 12 months. In both groups, if symptoms worsened or persisted, antibiotic therapy was initiated at the discretion of the treating physician.

Exclusion criteria included fever, “loin” (back) tenderness, pregnancy, renal disease, a previous urinary tract infection within 2 weeks, urinary catheterization, and a contraindication to nonsteroidal anti-inflammatory medications.

Results. Within 28 days of symptom onset, women in the ibuprofen group had received 81 courses of antibiotics for symptoms of urinary tract infection (plus another 13 courses for other reasons), compared with 277 courses for urinary tract infection in the fosfomycin group (plus 6 courses for other reasons), for a relative rate reduction in antibiotic use of 66.5% (95% confidence interval [CI] 58.8%–74.4%, P < .001). The women who received ibuprofen were more likely to need antibiotics after initial treatment because of refractory symptoms but were still less likely to receive antibiotics overall (Table 1).

The mean duration of symptoms was slightly shorter in the fosfomycin group (4.6 vs 5.6 days, P < .001). However, the percentage of patients who had a recurrent urinary tract infection within 2 to 4 weeks was higher in the fosfomycin-treated patients (11% vs 6% P = .049).

Although the study was not powered to show significant differences in pyelonephritis, five patients in the ibuprofen group developed pyelonephritis compared with one in the antibiotic-treated group (P = .12).

An important limitation of the study was that nonparticipants had higher symptom scores, which may mean that the results are not generalizable to women who have recurrent urinary tract infections, longer duration of symptoms, or symptoms that are more severe. The strengths of the study were that more than half of all potentially eligible women were enrolled, and baseline data were collected from nonparticipants.

Can our patient avoid antibiotics?

Given the mild nature of her symptoms, the clinician should discuss with her the risks vs benefits of delaying antibiotics, once it has been determined that she has no risk factors for severe urinary tract infection. Her symptoms are likely to resolve within 1 week even if she declines antibiotic treatment, though they may last a day longer with ibuprofen alone than if she had received antibiotics. She should watch for symptoms of pyelonephritis (eg, flank pain, fever, chills, vomiting) and should seek prompt medical care if such symptoms occur.

DISCONTINUING BISPHOSPHONATES

A 64-year-old woman has taken alendronate for her osteoporosis for 5 years. She has no history of fractures. Her original bone density scans showed a T-score of –2.6 at the spine and –1.5 at the hip. Since she started to take alendronate, there has been no further loss in bone mineral density. She is tolerating the drug well and does not take any other medications. Should she continue the bisphosphonate?

Optimal duration of therapy unknown

The risks and benefits of long-term bisphosphonate use are debated.

In the Fracture Intervention Trial (FIT),¹² women with low bone mineral density of the femoral neck were randomized to receive alendronate or placebo and were followed for 36 months. The alendronate group had significantly fewer vertebral fractures and clinical fractures overall. Then, in the FIT Long-term Extension (FLEX) study,¹³ 1,009 alendronate-treated women in the FIT study were rerandomized to receive 5 years of additional treatment or to stop treatment. Bone density in the untreated women decreased, although not to the level it was before treatment. At the end of the study, there was no difference in hip fracture rate between the two groups (3% of each group had had a hip fracture), although women in the treated group had a lower rate of clinical vertebral fracture (2% vs 5%, relative risk 0.5, 95% CI 0.2–0.8).

In addition, rare but serious risks have been associated with bisphosphonate use, specifically atypical femoral fracture and osteonecrosis of the jaw. A US Food and Drug Administration (FDA) evaluation of long-term bisphosphonate use concluded that there was evidence of an increased risk of osteonecrosis of the jaw with longer duration of use, but causality was not established. The evaluation also noted conflicting results about the association with atypical femoral fracture.¹⁴

Based on this report and focusing on the absence of nonspine benefit after 5 years, the FDA suggested that bisphosphonates may be safely discontinued in some patients without compromising therapeutic gains, but no adequate clinical trial has yet delineated how long the benefits of treatment are maintained after cessation. A periodic reevaluation of continued need was recommended.¹⁴

New recommendations from the American Society for Bone and Mineral Research

Age is the greatest risk factor for fracture.¹⁵ Therefore, deciding whether to discontinue a bisphosphonate when a woman is older, and hence at higher risk, is a challenge.

A task force of the American Society for Bone and Mineral Research (ASBMR) has developed an evidence-based guideline on managing osteoporosis in patients on long-term bisphosphonate treatment.¹⁶ The goal was to provide guidance on the duration of bisphosphonate therapy from the perspective of risk vs benefit. The authors conducted a systematic review focusing on two randomized controlled trials (FLEX¹³ and the Health Outcomes and Reduced Incidence With Zoledronic Acid Once Yearly Pivotal Fracture Trial¹⁷) that provided data on long-term bisphosphonate use.

The task force recommended¹⁶ that after 5 years of oral bisphosphonates or 3 years of intravenous bisphosphonates, risk should be reassessed. In women at high fracture risk, they recommended continuing the oral bisphosphonate for 10 years or the intravenous bisphosphonate for 6 years. Factors that favored continuation of bisphosphonate therapy were as follows:

• An osteoporotic fracture before or during therapy
• A hip bone mineral density T-score ≤ –2.5
• High risk of fracture, defined as age older than 70 or 75, other strong risk factors for fracture, or a FRAX fracture risk score¹⁸ above a country-specific threshold.

(The FRAX score is based on age, sex, weight, height, previous fracture, hip fracture in a parent, current smoking, use of glucocorticoids, rheumatoid arthritis, secondary osteoporosis, alcohol use, and bone mineral density in the femoral neck. It gives an estimate of the 10-year risk of major osteoporotic fracture and hip fracture. High risk would be a 10-year risk of major osteoporotic fracture greater than 20% or a 10-year risk of hip fracture greater than 3%.)

For women at high risk, the risks of atypical femoral fracture and osteonecrosis of the jaw are outweighed by the benefit of a reduction in vertebral fracture risk. For women not at high risk of fracture, a drug holiday of 2 to 3 years can be considered after 3 to 5 years of treatment.

Although the task force recommended reassessment after 2 to 3 years of drug holiday, how best to do this is not clear. The task force did not recommend a specific approach to reassessment, so decisions about when to restart therapy after a drug holiday could potentially be informed by subsequent bone mineral density testing if it were to show persistent bone loss. Another option could be to restart bisphosphonates after a defined amount of time (eg, 3–5 years) for women who have previously experienced benefit.

The task force recommendations are in line with those of other societies, the FDA, and expert opinion.^19–23

The American Association of Clinical Endocrinologists recommends considering a drug holiday in low-risk patients after 4 to 5 years of treatment. For high-risk patients, they recommend 1 to 2 years of drug holiday after 10 years of treatment. They encourage restarting treatment if bone mineral density decreases, bone turnover markers rise, or fracture occurs.¹⁹ This is a grade C recommendation, meaning the advice is based on descriptive studies and expert opinion.

Although some clinicians restart bisphosphonates when markers of bone turnover such as NTX (N-telopeptide of type 1 collagen) rise to premenopausal levels, there is no evidence to support this strategy.²⁴

The task force recommendations are based on limited evidence that primarily comes from white postmenopausal women. Another important limitation is that the outcomes are primarily vertebral fractures. However, until additional evidence is available, these guidelines can be useful in guiding decision-making.

Should our patient continue therapy?

Our patient is relatively young and does not have any of the high-risk features noted within the task force recommendations. She has responded well to bisphosphonate treatment and so can consider a drug holiday at this time.

OVARIAN CANCER SCREENING

A 50-year-old woman requests screening for ovarian cancer. She is postmenopausal and has no personal or family history of cancer. She is concerned because a friend forwarded an e-mail stating, “Please tell all your female friends and relatives to insist on a cancer antigen (CA) 125 blood test every year as part of their annual exam. This is an inexpensive and simple blood test. Don’t take no for an answer. If I had known then what I know now, we would have caught my cancer much earlier, before it was stage III!” What should you tell the patient?

Ovarian cancer is the most deadly of female reproductive cancers, largely because in most patients the cancer has already spread beyond the ovary by the time of clinical detection. Death rates from ovarian cancer have decreased only slightly in the past 30 years.

Little benefit and considerable harm of screening

In 2011, the Prostate Lung Colorectal Ovarian (PLCO) Cancer Screening trial²⁵ randomized more than 68,000 women ages 55 to 74 from the general US population to annual screening with CA 125 testing and transvaginal ultrasonography compared with usual care. They were followed for a median of 12.4 years.

Screening did not affect stage at diagnosis (77%–78% were in stage III or IV in both the screening and usual care groups), nor did it reduce the rate of death from ovarian cancer. In addition, false-positive findings led to some harm: nearly one in three women who had a positive screening test underwent surgery. Of 3,285 women with false-positive results, 1,080 underwent surgery, and 15% of these had at least one serious complication. The trial was stopped early due to evidence of futility.

A new UK study also found no benefit from screening

In the PLCO study, a CA 125 result of 35 U/mL or greater was classified as abnormal. However, researchers in the United Kingdom postulated that instead of using a single cutoff for a normal or abnormal CA 125 level, it would be better to interpret the CA 125 result according to a somewhat complicated (and proprietary) algorithm called the Risk of Ovarian Cancer Algorithm (ROCA).^26,27 The ROCA takes into account a woman’s age, menopausal status, known genetic mutations (BRCA 1 or 2 or Lynch syndrome), Ashkenazi Jewish descent, and family history of ovarian or breast cancer, as well as any change in CA 125 level over time.

In a 2016 UK study,²⁶ 202,638 postmenopausal women ages 50 to 74 were randomized to no screening, annual screening with transvaginal ultrasonography, or multimodal screening with an annual CA 125 blood test interpreted with the ROCA algorithm, adding transvaginal ultrasonography as a second-line test when needed if the CA 125 level was abnormal based on the ROCA. Women with abnormal findings on multimodal screening or ultrasonography had repeat tests, and women with persistent abnormalities underwent clinical evaluation and, when appropriate, surgery.

Participants were at average risk of ovarian cancer; those with suspected familial ovarian cancer syndrome were excluded, as were those with a personal history of ovarian cancer or other active cancer.

Results. At a median follow-up of 11.1 years, the percentage of women who were diagnosed with ovarian cancer was 0.7% in the multimodal screening group, 0.6% in the screening ultrasonography group, and 0.6% in the no-screening group. Comparing either multimodal or screening ultrasonography with no screening, there was no statistically significant reduction in mortality rate over 14 years of follow-up.

Screening had significant costs and potential harms. For every ovarian or peritoneal cancer detected by screening, an additional 2 women in the multimodal screening group and 10 women in the ultrasonography group underwent needless surgery.

Strengths of this trial included its large size, allowing adequate power to detect differences in outcomes, its multicenter setting, its high compliance rate, and the low crossover rate in the no-screening group. However, the design of the study makes it difficult to anticipate the late effects of screening. Also, the patient must purchase ROCA testing online and must also pay a consultation fee. Insurance providers do not cover this test.

Should our patient proceed with ovarian cancer screening?

No. Current evidence shows no clear benefit to ovarian cancer screening for average-risk women, and we should not recommend yearly ultrasonography and CA 125 level testing, as they are likely to cause harm without providing benefit. The US Preventive Services Task Force recommends against screening for ovarian cancer.²⁸ For premenopausal women, pregnancy, hormonal contraception, and breastfeeding all significantly decrease ovarian cancer risk by suppressing ovulation.^29–31

REPRODUCTIVE FACTORS AND THE RISK OF DEATH

A 26-year-old woman comes in to discuss her contraceptive options. She has been breastfeeding since the birth of her first baby 6 months ago, and wonders how lactation and contraception may affect her long-term health.

Questions about the safety of contraceptive options are common, especially in breastfeeding mothers.

In 2010, the long-term Royal College of General Practitioners’ Oral Contraceptive Study reported that the all-cause mortality rate was actually lower in women who used oral contraceptives.³² Similarly, in 2013, an Oxford study that followed 17,032 women for over 30 years reported no association between oral contraceptives and breast cancer.³³

However, in 2014, results from the Nurses’ Health Study indicated that breast cancer rates were higher in oral contraceptive users, although reassuringly, the study found no difference in all-cause mortality rates in women who had used oral contraception.³⁴

The European Prospective Investigation Into Cancer and Nutrition

To further characterize relationships between reproductive characteristics and mortality rates, investigators analyzed data from the European Prospective Investigation Into Cancer and Nutrition,³⁵ which recruited 322,972 women from 10 countries between 1992 and 2000. Analyses were stratified by study center and participant age and were adjusted for body mass index, physical activity, education level, smoking, and menopausal status; alcohol intake was examined as a potential confounder but was excluded from final models.

Findings. Over an average 13 years of follow-up, the rate of all-cause mortality was 20% lower in parous than in nulliparous women. In parous women, the all-cause mortality rate was additionally 18% lower in those who had breastfed vs those who had never breastfed, although breastfeeding duration was not associated with mortality. Use of oral contraceptives lowered all-cause mortality by 10% among nonsmokers; in smokers, no association with all-cause mortality was seen for oral contraceptive use, as smoking is such a powerful risk factor for mortality. The primary contributor to all-cause mortality appeared to be ischemic heart disease, the incidence of which was significantly lower in parous women (by 14%) and those who breastfed (by 20%) and was not related to oral contraceptive use.³⁵

Strengths of this study included the large sample size recruited from countries across Europe, with varying rates of breastfeeding and contraceptive use. However, as with all observational studies, it remains subject to the possibility of residual confounding.

What should we tell this patient?

After congratulating her for breastfeeding, we can reassure her about the safety of all available contraceptives. According to the US Centers for Disease Control and Prevention (CDC),³⁶ after 42 days postpartum most women can use combined hormonal contraception. All other methods can be used immediately postpartum, including progestin-only pills.

As lactational amenorrhea is only effective while mothers are exclusively breastfeeding, and short interpregnancy intervals have been associated with higher rates of adverse pregnancy outcomes,³⁷ this patient will likely benefit from promptly starting a prescription contraceptive.

HIGHLY EFFECTIVE REVERSIBLE CONTRACEPTION

This same 26-year-old patient is concerned that she will not remember to take an oral contraceptive every day, and expresses interest in a more convenient method of contraception. However, she is concerned about the potential risks.

Although intrauterine contraceptives (IUCs) are typically 20 times more effective than oral contraceptives³⁸ and have been used by millions of women worldwide, rates of use in the United States have been lower than in many other countries.³⁹

A study of intrauterine contraception

To clarify the safety of IUCs, researchers followed 61,448 women who underwent IUC placement in six European countries between 2006 and 2013.⁴⁰ Most participants received an IUC containing levonorgestrel, while 30% received a copper IUC.

Findings. Overall, rates of uterine perforation were low (approximately 1 per 1,000 insertions). The most significant risk factors for perforation were breastfeeding at the time of insertion and insertion less than 36 weeks after the last delivery. None of the perforations in the study led to serious illness or injury of intra-abdominal or pelvic structures. Interestingly, women using a levonorgestrel IUC were considerably less likely to experience a contraceptive failure than those using a copper IUC.⁴¹

Strengths of this study included the prospective data collection and power to examine rare clinical outcomes. However, it was industry-funded.

The risk of pelvic infection with an IUC is so low that the CDC does not recommend prophylactic antibiotics with the insertion procedure. If women have other indications for testing for sexually transmitted disease, an IUC can be placed the same day as testing, and before results are available.⁴² If a woman is found to have a sexually transmitted disease while she has an IUC in place, she should be treated with antibiotics, and there is no need to remove the IUC.⁴³

Subdermal implants

Another highly effective contraceptive option for this patient is the progestin-only subdermal contraceptive implant (marketed in the United States as Nexplanon). Implants have been well-studied and found to have no adverse effect on lactation.⁴⁴

Learning to place a subdermal contraceptive is far easier than learning to place an IUC, but it requires a few hours of FDA-mandated in-person training. Unfortunately, relatively few clinicians have obtained this training.⁴⁵ As placing a subdermal contraceptive is like placing an intravenous line without needing to hit the vein, this procedure can easily be incorporated into a primary care practice. Training from the manufacturer is available to providers who request it.

What should we tell this patient?

An IUC is a great option for many women. When pregnancy is desired, the device is easily removed. Of the three IUCs now available in the United States, those containing 52 mg of levonorgestrel (marketed in the United States as Mirena and Liletta) are the most effective.

The only option more effective than these IUCs is subdermal contraception.⁴⁶ These reversible contraceptives are typically more effective than permanent contraceptives (ie, tubal ligation)⁴⁷ and can be removed at any time if a patient wishes to switch to another method or to become pregnant.

Pregnancy rates following attempts at “sterilization” are higher than many realize. There are a variety of approaches to “tying tubes,” some of which may not result in complete tubal occlusion. The failure rate of the laparoscopic approach, according to the US Collaborative Review of Sterilization, ranges from 7.5 per 1,000 procedures for unipolar coagulation to a high of 36.5 per 1,000 for the spring clip.⁴⁸ The relatively commonly used Filshie clip was not included in this study, but its failure rate is reported to be between 1% and 2%.

Taurine—an amino acid found in abundance in the human brain, retina, heart, and reproductive organs, as well as in meat and seafood—is also a major ingredient in “energy drinks” (Table 1).^1,2 Given the tremendous popularity of these drinks in the United States, it would seem important to know and to recognize taurine’s neuroendocrine effects. Unfortunately, little is known about the effects of taurine supplementation in humans.

This paper reviews the sparse data to provide clinicians some background on the structure, synthesis, distribution, metabolism, mechanisms, effects, safety, and proposed therapeutic targets of taurine.

TAURINE’S THERAPEUTIC POTENTIAL

Taurine has been reported to have widespread anti-inflammatory actions.^3,4 Taurine supplementation has been proposed to have beneficial effects in the treatment of epilepsy,⁵ heart failure,^6,7 cystic fibrosis,⁸ and diabetes⁹ and has been shown in animal studies to protect against neurotoxic insults from alcohol, ammonia, lead, and other substances.^10–16

In addition, taurine analogues such as homotaurine and N-acetyl-homotaurine (acamprosate) have been probed for possible therapeutic applications. Homotaurine has been shown to have antiamyloid activity that could in theory protect against the progression of Alzheimer disease,¹⁷ and acam­prosate is approved by the US Food and Drug Administration (FDA) for the treatment of alcohol use disorders.¹⁸

TAURINE CONSUMPTION

Energy drinks are widely consumed in the United States, with an estimated 354 million gallons sold in 2009, or approximately 5.25 L/year per person over age 10.¹ In 2012, US sales of energy drinks exceeded $12 billion,¹⁹ with young men, particularly those in the military deployed in war zones, being the biggest consumers.^20–22 Analyses have found that of 49 nonalcoholic energy drinks tested, the average concentration of taurine was 3,180 mg/L, or approximately 750 mg per 8-oz serving.^23,24 Popular brands include Red Bull, Monster, Rockstar (Table 1), NOS, Amp, and Full Throttle.

Taurine is plentiful in the human body, which contains up to 1 g of taurine per kg.²⁵ Foods such as poultry, beef, pork, seafood, and processed meats have a high taurine content (Table 2).^26–29 People who eat meat and seafood have plentiful taurine intake, whereas vegetarians and vegans consume much less and have significantly lower circulating levels³⁰ because plants do not contain taurine in appreciable amounts.^26,29

The typical American diet provides between 123 and 178 mg of taurine daily.²⁶ Consumption of one 8-oz energy drink can increase the average intake 6 to 16 times. A lacto-ovo vegetarian diet provides only about 17 mg of taurine daily, and an 8-oz energy drink can increase the average intake by 44 to 117 mg.²⁶ And since a vegan diet provides essentially no taurine,³⁰ energy drink intake in any amount would constitute a major relative increase in taurine consumption.

ATTEMPTS TO STUDY TAURINE'S EFFECTS

Since most clinical trials to date have looked at the effects of taurine in combination with other ingredients such as caffeine, creatine, and glucose^31–35 in drinks such as Red Bull, these studies cannot be used to determine the effects of taurine alone. In the few clinical trials that have tested isolated taurine consumption, data are not sufficient to make a conclusion on direct effects on energy metabolism.

Rutherford et al³⁶ tested the effect of oral taurine supplementation (1,660 mg) on endurance in trained male cyclists 1 hour before exercise, but observed no effect on fluid intake, heart rate, subjective exertion, or time-trial performance. A small increase (16%) in total fat oxidation was observed during the 90-minute exercise period. Since mitochondria are the main location of fatty acid degradation, this effect may be attributed to taurine supplementation, with subsequent improvement in mitochondrial function.

Zhang et al³⁷ found a 30-second increase in cycling energy capacity after 7 days of 6 g oral taurine supplementation, but the study was neither blinded nor placebo-controlled.

Kammerer et al³⁸ tested the effect of 1 g of taurine supplementation on physical and mental performance in young adult soldiers 45 minutes before physical fitness and cognitive testing. This double-blind, placebo-controlled randomized trial found no effect of taurine on cardiorespiratory fitness indices, concentration, or immediate memory, nor did it find any effect of an 80-mg dose of caffeine.

In sum, the available data are far from sufficient to determine the direct effect of taurine consumption on energy metabolism in healthy people.

PHARMACOLOGY OF TAURINE

Chemical structure

Taurine, or 2-aminoethane sulfonic acid, is a conditionally essential amino acid, ie, we can usually make enough in our own bodies. It was first prepared on a large scale for physiologic investigation almost 90 years ago, through the purification of ox bile.³⁹ It can be obtained either exogenously through dietary sources or endogenously through biosynthesis from methionine and cysteine precursors, both essential sulfur-containing alpha-amino acids.⁴⁰ Both sources are important to maintain physiologic levels of taurine, and either can help compensate for the other in cases of deficiency.⁴¹

The structure of taurine has two main differences from the essential amino acids. First, taurine’s amino group is attached to the beta-carbon rather than the alpha-carbon, making it a beta-amino acid instead of an alpha-amino acid.⁴² Second, the acid group in taurine is sulfonic acid, whereas the essential amino acids have a carboxylic acid.⁴³ Because of its distinctive structure, taurine is not used as a structural unit in proteins,⁴³ existing mostly as a free amino acid within cells, readily positioned to perform several unique functions.

Synthesis

De novo synthesis of taurine involves several enzymes and at least five pathways,⁴⁴ mostly differing by the order in which sulfur is oxidized and decarboxylated.⁴⁵

The rate-limiting enzyme of the predominant pathway is thought to be cysteine sulfinate decarboxylase (CSD), and its presence within an organ indicates involvement in taurine production.⁴⁴ CSD has been found in the liver,⁴⁶ the primary site of taurine biosynthesis, as well as in the retina,⁴⁷ brain,⁴⁸ kidney,⁴⁹ mammary glands,^50,51 and reproductive organs.⁵²

Distribution

Taurine levels are highest in electrically excitable tissues such as the central nervous system, retina, and heart; in secretory structures such as the pineal gland and the pituitary gland (including the posterior lobe or neurohypophysis); and in platelets²⁵ and neutrophils.⁵³

In the fetal brain, the taurine concentration is higher than that of any other amino acid,⁵⁴ but the concentration in the brain decreases with advancing age, whereas glutamate levels increase over time to make it the predominant amino acid in the adult brain.⁵⁴ Regardless, taurine is still the second most prevalent amino acid in the adult brain, its levels comparable to those of gamma-aminobutyric acid (GABA).⁵⁵

Taurine has also been found in variable amounts in the liver, muscle, kidney, pancreas, spleen, small intestine, and lungs,⁵⁶ as well as in several other locations.^45,57

Taurine is also present in the male and female reproductive organs. In male rats, taurine and taurine biosynthesis have been localized to Leydig cells of the testes, the cellular source of testosterone in males, as well as the cremaster muscle, efferent ducts, and peritubular myoid cells surrounding seminiferous tubules.⁵⁸ More recently, taurine has been detected in the testes of humans⁵⁹ and is also found in sperm and seminal fluid.⁶⁰ Levels of taurine in spermatozoa are correlated with sperm quality, presumably by protecting against lipid peroxidation through taurine’s antioxidant effects,^61,62 as well as through contribution to the spermatozoa maturation process by facilitating the capacitation, motility, and acrosomal reaction of sperm.⁶³

In female rats, taurine has been found in uterine tissue,⁶⁴ oviducts,⁶⁵ uterine fluid (where it is the predominant amino acid),⁶⁶ and thecal cells of developing follicles of ovaries, cells responsible for the synthesis of androgens such as testosterone and androstenedione.⁶⁵ Taurine is also a major component of human breast milk⁶⁷ and is important for proper neonatal nutrition.⁶⁸

Metabolism and excretion

Ninety-five percent of taurine is excreted in urine, about 70% as taurine itself, and the rest as sulfate. Most of the sulfate derived from taurine is produced by bacterial metabolism in the gut and then absorbed.⁶⁹ However, taurine can also be conjugated with bile acids to act as a detergent in lipid emulsification.⁷⁰ In this form, it may be subjected to the enterohepatic circulation, which gives bacteria another chance to convert it into inorganic sulfate for excretion in urine.⁶⁹

MECHANISMS AND NEUROENDOCRINE EFFECTS

As a free amino acid, taurine has widespread distribution and unique biochemical and physiologic properties and exhibits several organ-specific functions; however, indisputable evidence of a taurine-specific receptor is lacking, and its putative existence⁷¹ is controversial.⁷² Nonetheless, taurine is a neuromodulator with a variety of actions.

Neurotransmission

Taurine is known to be an inhibitory neurotransmitter and neuromodulator.⁷³ It is structurally analogous to GABA, the main inhibitory neurotransmitter in the brain.⁴⁵ Accordingly, it binds to GABA receptors to serve as an agonist,^74,75 causing neuronal hyperpolarization and inhibition. Taurine has an even higher affinity for glycine receptors⁷⁵ where it has long been known to act as an agonist.⁷⁶ GABA and glycine receptors both belong to the Cys-loop receptor superfamily,⁷⁷ with conservation of subunits that allows taurine to bind each receptor, albeit at different affinities. The binding effects of taurine on GABA and glycine receptors have not been well documented quantitatively; however, it is known that taurine has a substantially lower affinity than GABA and glycine for their respective receptors.⁷⁶

Catecholamines and the sympathetic nervous system

Surprisingly little is known about the effects of taurine on norepinephrine, dopamine, and the human sympathetic nervous system.⁷⁸ Humans with borderline hypertension given 6 g of taurine orally for 7 days⁷⁹ experienced decreases in epinephrine secretion and blood pressure, but normotensive study participants did not experience similar results, possibly because of a better ability to regulate sympathetic tone. Mizushima et al⁸⁰ showed that a longer period of taurine intake (6 g orally for 3 weeks) could elicit a decrease in norepinephrine in healthy men with normal blood pressure. Other similar studies^81–83 also suggested interplay between taurine and catecholamines, but the extent is still undetermined.

Growth hormone, prolactin, sex hormones, and cortisol

Taurine appears to have a complex relationship with several hormones, although its direct effects on hormone secretion remain obscure. Clinical studies of the acute and chronic neuroendocrine effects of taurine loading in humans are needed.

In female rats, secretion of prolactin is increased by the intraventricular injection of 5 μL of 2.0 μmol taurine over a 10-minute period.⁸⁴ Ikuyama et al⁸⁵ found an increase in prolactin and growth hormone secretion in adult male rats given 10 μL of 0.25 μmol and 1.0 μmol taurine intraventricularly, yet a higher dose of 4.0 μmol had no effect on either hormone. Furthermore, prolactin receptor deficiency is seen in CSD knockout mice, but the receptor is restored with taurine supplementation.⁸⁶

Mantovani and DeVivo⁸⁷ reported that 375 to 8,000 mg/day of taurine given orally for 4 to 6 months to epileptic patients stimulated the secretion of growth hormone. However, in another study, a single 75-mg/kg dose of oral taurine did not trigger an acute increase in levels of growth hormone or prolactin in humans.⁸⁸ Energy drinks may contain up to 1,000 mg of taurine per 8-oz serving, but the effects of larger doses on growth hormone, which is banned as a supplement by major athletic organizations because of its anabolic and possible performance-enhancing effects, remain to be determined.

Taurine may have effects on human sex hormones, based on the limited observations in rodents.^89–94

Although human salivary cortisol concentrations were purportedly assessed in response to 2,000 mg of oral taurine,⁹⁵ the methods and reported data are not adequate to draw any conclusions.

Energy metabolism

Mammals are unable to directly use taurine in energy production because they cannot directly reduce it.²⁵ Instead, bacteria in the gut use it as a source of energy, carbon, nitrogen, and sulfur.⁹⁶ However, taurine deficiency appears to impair the cellular respiratory chain, resulting in diminished production of adenosine triphosphate and diminished uptake of long-chain fatty acids by mitochondria, at least in the heart.⁹⁷

Taurine is present in human mitochondria and regulates mitochondrial function. For example, taurine in mitochondria assists in conjugation of transfer RNA for leucine, lysine, glutamate, and glutamine.⁹⁸ In TauT knockout mice, deficiency of taurine causes mitochondrial dysfunction, triggering a greater than 80% decrease in exercise capacity.⁹⁹ Several studies in rodents have shown increased exercise capacity after taurine supplementation.^100–102 In addition, taurine is critical for the growth of blastocytes, skeletal muscle, and myocardium; it is necessary for mitochondrial development and is also important for muscular endurance.^103,104

Antioxidation, anti-inflammation, and other functions

Taurine is a major antioxidant, scavenging reactive oxygen and protecting against oxidative stress to organs including the brain,^97,105,106 where it increasingly appears to have neuroprotective effects.^107,108

Cellular taurine also has anti-inflammatory actions.³ One of the proposed mechanisms is taurine inhibition of NF-kappa B, an important transcription factor for the synthesis of pro-inflammatory cytokines.⁴ This function may be important in protecting polyunsaturated fatty acids from oxidative stress—helping to maintain and stabilize the structure and function of plasma membranes within the lungs,¹⁰⁹ heart,¹¹⁰ brain,¹¹¹ liver,¹¹² and spermatozoa.^61,62

Taurine is also conjugated to bile acids synthesized in the liver, forming bile salts⁷⁰ that act as detergents to help emulsify and digest lipids in the body. In addition, taurine facilitates xenobiotic detoxification in the liver by conjugating with several drugs to aid in their excretion.²⁵ Taurine is also implicated in calcium modulation¹¹³ and homeostasis.¹¹⁴ Through inhibition of several types of calcium channels, taurine has been shown to decrease calcium influx into cells, effectively serving a cytoprotective role against calcium overload.^115,116

TAURINE DEFICIENCY

Fetal and neonatal deficiency

Though taurine is considered nonessential in adults because it can be readily synthesized endogenously, it is thought to be conditionally essential in neonatal nutrition.⁶⁸ It is the second most abundant free amino acid in human breast milk¹¹⁷ and the most abundant free amino acid in fetal brain.¹¹⁸ In cases of long-term parenteral nutrition, neonates can become drastically taurine deficient¹¹⁹ due to suboptimal CSD activity,¹¹⁸ leading to retinal dysfunction.⁴¹ Taurine deficiencies can lead to functional and structural brain damage.¹¹⁸ Moreover, maternal taurine deficiency results in neurologic abnormalities in offspring¹²⁰ and may lead to oxidative stress throughout life.¹²¹

In 1984, the FDA approved the inclusion of taurine in infant formulas based on research showing that taurine-deficient infants had impaired fat absorption, bile acid secretion, retinal function, and hepatic function.¹²² But still under debate are the amount and duration of taurine supplementation required by preterm and low-birth-weight infants, as several randomized controlled trials failed to show statistically significant effects on growth.¹²³ Nonetheless, given the alleged detrimental ramifications of a lack of taurine supplementation, as well as the ethical dilemma of performing additional research trials on infants, it is presumed that infant formulas and parenteral nutrition for preterm and low-birth-weight infants will continue to contain taurine.

Age- and disease-related deficiency

Although taurine deficiency is rare in neonates, it is perhaps inevitable with advancing age. Healthy elderly patients ages 61 to 81 have up to a 49% decrease in plasma taurine concentration compared with healthy individuals ages 27 to 57.¹²⁴ While reduced renal retention¹²⁵ and taurine intake¹²⁶ can account for depressed taurine levels, Eppler and Dawson¹²⁷ found that tissue and circulating taurine concentrations decrease over the human life span primarily due to an age-dependent depletion of CSD activity in the liver. This effectively impairs the biosynthesis of endogenous taurine from cysteine or methionine or both, forcing a greater reliance on exogenous sources.

While specific mechanisms have not been fully elucidated, taurine deficiency has also been identified in patients suffering from diseases including but not limited to disorders of bone (osteogenesis imperfecta, osteoporosis),¹²⁸ blood (acute myelogenous leukemia),¹²⁹ central nervous system (schizophrenia, Friedreich ataxia-spinocerebellar degeneration),^130,131 retina (retinitis pigmentosa),¹³² circulatory system and heart (essential hypertension, atherosclerosis),¹³³ digestion (Gaucher disease),¹³⁴ absorption (short-bowel syndrome),¹³⁵ cellular proliferation (cancer),¹³⁶ and membrane channels (cystic fibrosis),¹³⁷ as well as in patients restricted to long-term parenteral nutrition.¹³⁸ However, the apparent correlation between taurine deficiency and these conditions does not necessarily mean causation; more study is needed to elucidate a direct connection.

SAFETY AND TOXICITY OF TAURINE SUPPLEMENTATION

An upper safe level of intake for taurine has not been established. To date, several studies have involved heavy taurine supplementation without serious adverse effects. While the largest dosage of taurine tested in humans appears to be 10 g/day for 6 months,¹³⁹ a number of studies have used 1 to 6 g/day for periods of 1 week to 1 year.¹⁴⁰ However, the assessment of potential acute, subacute, and chronic adverse effects has not been comprehensive. The Scientific Committee on Food of the European Commission¹⁴¹ reviewed several toxicologic studies on taurine through 2003 and were unable to expose any carcinogenic or teratogenic potential. Nevertheless, based on the available data from trials in humans and lower animals, Shao and Hathcock¹⁴⁰ suggested an observed safe level of taurine of 3 g/day, a conservatively smaller dose that carries a higher level of confidence. Because there is no “observed adverse effect level” for daily taurine intake,¹⁴¹ more research must be done to ensure safety of higher amounts of taurine administration and to define a tolerable upper limit of intake.

Interactions with medications

To date, the literature is scarce regarding potential interactions between taurine and commonly used medications.

Although no evidence specifically links taurine with adverse effects when used concurrently with other medications, there may be a link between taurine supplementation and various cytochrome P450 systems responsible for hepatic drug metabolism. Specifically, taurine inhibits cytochrome P450 2E1, a highly conserved xenobiotic-metabolizing P450 responsible for the breakdown of more than 70 substrates, including several commonly used anesthetics, analgesics, antidepressants, antibacterials, and antiepileptics.¹⁴² Of note, taurine may contribute to the attenuation of oxidative stress in the liver in the presence of alcohol¹⁴³ and acetaminophen,¹⁴⁴ two substances frequently used and abused. Since the P450 2E1 system catalyzes comparable reactions in rodents and humans,¹⁴² rodents should plausibly serve as a model for further testing of the effects of taurine on various substrates.

POTENTIAL THERAPEUTIC APPLICATIONS

More analysis is needed to fully unlock and understand taurine’s potential value in healthcare.

Correction of late-life taurine decline in humans could be beneficial for cognitive performance, energy metabolism, sexual function, and vision, but clinical studies remain to be performed. While a decline in taurine with age may intensify the stress caused by reactive oxygen species, taurine supplementation has been shown to decrease the presence of oxidative markers¹²⁷ and to serve a neuroprotective role in rodents.^145,146 Taurine levels increase in the hippocampus after experimentally induced gliosis¹⁴⁷ and are neuroprotective against glutamate excitotoxicity.^148,149 Furthermore, data in Alzheimer disease, Huntington disease, and brain ischemia experimental models show that taurine inhibits neuronal death (apoptosis).^13,150,151 Taurine has even been proposed as a potential preventive treatment for Alzheimer dementia, as it stabilizes protein conformations to prevent their aggregation and subsequent dysfunction.¹⁵² Although improvement in memory and cognitive performance has been linked to taurine supplementation in old mice,^145,153 similar results have not been found in adult mice whose taurine levels are within normal limits. Taurine also has transient anticonvulsant effects in some epileptic humans.¹⁵⁴

Within the male reproductive organs, the age-related decline in taurine may or may not have implications regarding sexuality, as only very limited rat data are available.^89–91

In cats, taurine supplementation has been found to prevent the progressive degeneration of retinal photoreceptors seen in retinitis pigmentosa, a genetic disease that causes the loss of vision.¹⁵⁵

While several energy drink companies have advertised that taurine plays a role in improving cognitive and physical performance, there are few human studies that examine this contention in the absence of confounding factors such as caffeine or glucose.^36,37,95 Taurine supplementation in patients with heart failure has been shown to increase exercise capacity vs placebo.¹⁵⁶ This supports the idea that in cases of taurine deficiency, such as those seen in cardiomyopathy,¹⁵⁷ taurine supplementation could have restorative effects. However, we are not aware of any double-blind, placebo-controlled clinical trial of taurine alone in healthy patients that measured energy parameters as clinical outcomes.

Although it remains possible that acute supraphysiologic taurine levels achieved by supplementation could transiently trigger various psychoneuroendocrine responses in healthy people, clinical research is needed in which taurine is the sole intervention. At present, the most compelling clinical reason to prescribe or recommend taurine supplementation is taurine deficiency.

Taurine—an amino acid found in abundance in the human brain, retina, heart, and reproductive organs, as well as in meat and seafood—is also a major ingredient in “energy drinks” (Table 1).^1,2 Given the tremendous popularity of these drinks in the United States, it would seem important to know and to recognize taurine’s neuroendocrine effects. Unfortunately, little is known about the effects of taurine supplementation in humans.

This paper reviews the sparse data to provide clinicians some background on the structure, synthesis, distribution, metabolism, mechanisms, effects, safety, and proposed therapeutic targets of taurine.

TAURINE’S THERAPEUTIC POTENTIAL

Taurine has been reported to have widespread anti-inflammatory actions.^3,4 Taurine supplementation has been proposed to have beneficial effects in the treatment of epilepsy,⁵ heart failure,^6,7 cystic fibrosis,⁸ and diabetes⁹ and has been shown in animal studies to protect against neurotoxic insults from alcohol, ammonia, lead, and other substances.^10–16

In addition, taurine analogues such as homotaurine and N-acetyl-homotaurine (acamprosate) have been probed for possible therapeutic applications. Homotaurine has been shown to have antiamyloid activity that could in theory protect against the progression of Alzheimer disease,¹⁷ and acam­prosate is approved by the US Food and Drug Administration (FDA) for the treatment of alcohol use disorders.¹⁸

TAURINE CONSUMPTION

Energy drinks are widely consumed in the United States, with an estimated 354 million gallons sold in 2009, or approximately 5.25 L/year per person over age 10.¹ In 2012, US sales of energy drinks exceeded $12 billion,¹⁹ with young men, particularly those in the military deployed in war zones, being the biggest consumers.^20–22 Analyses have found that of 49 nonalcoholic energy drinks tested, the average concentration of taurine was 3,180 mg/L, or approximately 750 mg per 8-oz serving.^23,24 Popular brands include Red Bull, Monster, Rockstar (Table 1), NOS, Amp, and Full Throttle.

Taurine is plentiful in the human body, which contains up to 1 g of taurine per kg.²⁵ Foods such as poultry, beef, pork, seafood, and processed meats have a high taurine content (Table 2).^26–29 People who eat meat and seafood have plentiful taurine intake, whereas vegetarians and vegans consume much less and have significantly lower circulating levels³⁰ because plants do not contain taurine in appreciable amounts.^26,29

The typical American diet provides between 123 and 178 mg of taurine daily.²⁶ Consumption of one 8-oz energy drink can increase the average intake 6 to 16 times. A lacto-ovo vegetarian diet provides only about 17 mg of taurine daily, and an 8-oz energy drink can increase the average intake by 44 to 117 mg.²⁶ And since a vegan diet provides essentially no taurine,³⁰ energy drink intake in any amount would constitute a major relative increase in taurine consumption.

ATTEMPTS TO STUDY TAURINE'S EFFECTS

Since most clinical trials to date have looked at the effects of taurine in combination with other ingredients such as caffeine, creatine, and glucose^31–35 in drinks such as Red Bull, these studies cannot be used to determine the effects of taurine alone. In the few clinical trials that have tested isolated taurine consumption, data are not sufficient to make a conclusion on direct effects on energy metabolism.

Rutherford et al³⁶ tested the effect of oral taurine supplementation (1,660 mg) on endurance in trained male cyclists 1 hour before exercise, but observed no effect on fluid intake, heart rate, subjective exertion, or time-trial performance. A small increase (16%) in total fat oxidation was observed during the 90-minute exercise period. Since mitochondria are the main location of fatty acid degradation, this effect may be attributed to taurine supplementation, with subsequent improvement in mitochondrial function.

Zhang et al³⁷ found a 30-second increase in cycling energy capacity after 7 days of 6 g oral taurine supplementation, but the study was neither blinded nor placebo-controlled.

Kammerer et al³⁸ tested the effect of 1 g of taurine supplementation on physical and mental performance in young adult soldiers 45 minutes before physical fitness and cognitive testing. This double-blind, placebo-controlled randomized trial found no effect of taurine on cardiorespiratory fitness indices, concentration, or immediate memory, nor did it find any effect of an 80-mg dose of caffeine.

In sum, the available data are far from sufficient to determine the direct effect of taurine consumption on energy metabolism in healthy people.

PHARMACOLOGY OF TAURINE

Chemical structure

Taurine, or 2-aminoethane sulfonic acid, is a conditionally essential amino acid, ie, we can usually make enough in our own bodies. It was first prepared on a large scale for physiologic investigation almost 90 years ago, through the purification of ox bile.³⁹ It can be obtained either exogenously through dietary sources or endogenously through biosynthesis from methionine and cysteine precursors, both essential sulfur-containing alpha-amino acids.⁴⁰ Both sources are important to maintain physiologic levels of taurine, and either can help compensate for the other in cases of deficiency.⁴¹

The structure of taurine has two main differences from the essential amino acids. First, taurine’s amino group is attached to the beta-carbon rather than the alpha-carbon, making it a beta-amino acid instead of an alpha-amino acid.⁴² Second, the acid group in taurine is sulfonic acid, whereas the essential amino acids have a carboxylic acid.⁴³ Because of its distinctive structure, taurine is not used as a structural unit in proteins,⁴³ existing mostly as a free amino acid within cells, readily positioned to perform several unique functions.

Synthesis

De novo synthesis of taurine involves several enzymes and at least five pathways,⁴⁴ mostly differing by the order in which sulfur is oxidized and decarboxylated.⁴⁵

The rate-limiting enzyme of the predominant pathway is thought to be cysteine sulfinate decarboxylase (CSD), and its presence within an organ indicates involvement in taurine production.⁴⁴ CSD has been found in the liver,⁴⁶ the primary site of taurine biosynthesis, as well as in the retina,⁴⁷ brain,⁴⁸ kidney,⁴⁹ mammary glands,^50,51 and reproductive organs.⁵²

Distribution

Taurine levels are highest in electrically excitable tissues such as the central nervous system, retina, and heart; in secretory structures such as the pineal gland and the pituitary gland (including the posterior lobe or neurohypophysis); and in platelets²⁵ and neutrophils.⁵³

In the fetal brain, the taurine concentration is higher than that of any other amino acid,⁵⁴ but the concentration in the brain decreases with advancing age, whereas glutamate levels increase over time to make it the predominant amino acid in the adult brain.⁵⁴ Regardless, taurine is still the second most prevalent amino acid in the adult brain, its levels comparable to those of gamma-aminobutyric acid (GABA).⁵⁵

Taurine has also been found in variable amounts in the liver, muscle, kidney, pancreas, spleen, small intestine, and lungs,⁵⁶ as well as in several other locations.^45,57

Taurine is also present in the male and female reproductive organs. In male rats, taurine and taurine biosynthesis have been localized to Leydig cells of the testes, the cellular source of testosterone in males, as well as the cremaster muscle, efferent ducts, and peritubular myoid cells surrounding seminiferous tubules.⁵⁸ More recently, taurine has been detected in the testes of humans⁵⁹ and is also found in sperm and seminal fluid.⁶⁰ Levels of taurine in spermatozoa are correlated with sperm quality, presumably by protecting against lipid peroxidation through taurine’s antioxidant effects,^61,62 as well as through contribution to the spermatozoa maturation process by facilitating the capacitation, motility, and acrosomal reaction of sperm.⁶³

In female rats, taurine has been found in uterine tissue,⁶⁴ oviducts,⁶⁵ uterine fluid (where it is the predominant amino acid),⁶⁶ and thecal cells of developing follicles of ovaries, cells responsible for the synthesis of androgens such as testosterone and androstenedione.⁶⁵ Taurine is also a major component of human breast milk⁶⁷ and is important for proper neonatal nutrition.⁶⁸

Metabolism and excretion

Ninety-five percent of taurine is excreted in urine, about 70% as taurine itself, and the rest as sulfate. Most of the sulfate derived from taurine is produced by bacterial metabolism in the gut and then absorbed.⁶⁹ However, taurine can also be conjugated with bile acids to act as a detergent in lipid emulsification.⁷⁰ In this form, it may be subjected to the enterohepatic circulation, which gives bacteria another chance to convert it into inorganic sulfate for excretion in urine.⁶⁹

MECHANISMS AND NEUROENDOCRINE EFFECTS

As a free amino acid, taurine has widespread distribution and unique biochemical and physiologic properties and exhibits several organ-specific functions; however, indisputable evidence of a taurine-specific receptor is lacking, and its putative existence⁷¹ is controversial.⁷² Nonetheless, taurine is a neuromodulator with a variety of actions.

Neurotransmission

Taurine is known to be an inhibitory neurotransmitter and neuromodulator.⁷³ It is structurally analogous to GABA, the main inhibitory neurotransmitter in the brain.⁴⁵ Accordingly, it binds to GABA receptors to serve as an agonist,^74,75 causing neuronal hyperpolarization and inhibition. Taurine has an even higher affinity for glycine receptors⁷⁵ where it has long been known to act as an agonist.⁷⁶ GABA and glycine receptors both belong to the Cys-loop receptor superfamily,⁷⁷ with conservation of subunits that allows taurine to bind each receptor, albeit at different affinities. The binding effects of taurine on GABA and glycine receptors have not been well documented quantitatively; however, it is known that taurine has a substantially lower affinity than GABA and glycine for their respective receptors.⁷⁶

Catecholamines and the sympathetic nervous system

Surprisingly little is known about the effects of taurine on norepinephrine, dopamine, and the human sympathetic nervous system.⁷⁸ Humans with borderline hypertension given 6 g of taurine orally for 7 days⁷⁹ experienced decreases in epinephrine secretion and blood pressure, but normotensive study participants did not experience similar results, possibly because of a better ability to regulate sympathetic tone. Mizushima et al⁸⁰ showed that a longer period of taurine intake (6 g orally for 3 weeks) could elicit a decrease in norepinephrine in healthy men with normal blood pressure. Other similar studies^81–83 also suggested interplay between taurine and catecholamines, but the extent is still undetermined.

Growth hormone, prolactin, sex hormones, and cortisol

Taurine appears to have a complex relationship with several hormones, although its direct effects on hormone secretion remain obscure. Clinical studies of the acute and chronic neuroendocrine effects of taurine loading in humans are needed.

In female rats, secretion of prolactin is increased by the intraventricular injection of 5 μL of 2.0 μmol taurine over a 10-minute period.⁸⁴ Ikuyama et al⁸⁵ found an increase in prolactin and growth hormone secretion in adult male rats given 10 μL of 0.25 μmol and 1.0 μmol taurine intraventricularly, yet a higher dose of 4.0 μmol had no effect on either hormone. Furthermore, prolactin receptor deficiency is seen in CSD knockout mice, but the receptor is restored with taurine supplementation.⁸⁶

Mantovani and DeVivo⁸⁷ reported that 375 to 8,000 mg/day of taurine given orally for 4 to 6 months to epileptic patients stimulated the secretion of growth hormone. However, in another study, a single 75-mg/kg dose of oral taurine did not trigger an acute increase in levels of growth hormone or prolactin in humans.⁸⁸ Energy drinks may contain up to 1,000 mg of taurine per 8-oz serving, but the effects of larger doses on growth hormone, which is banned as a supplement by major athletic organizations because of its anabolic and possible performance-enhancing effects, remain to be determined.

Taurine may have effects on human sex hormones, based on the limited observations in rodents.^89–94

Although human salivary cortisol concentrations were purportedly assessed in response to 2,000 mg of oral taurine,⁹⁵ the methods and reported data are not adequate to draw any conclusions.

Energy metabolism

Mammals are unable to directly use taurine in energy production because they cannot directly reduce it.²⁵ Instead, bacteria in the gut use it as a source of energy, carbon, nitrogen, and sulfur.⁹⁶ However, taurine deficiency appears to impair the cellular respiratory chain, resulting in diminished production of adenosine triphosphate and diminished uptake of long-chain fatty acids by mitochondria, at least in the heart.⁹⁷

Taurine is present in human mitochondria and regulates mitochondrial function. For example, taurine in mitochondria assists in conjugation of transfer RNA for leucine, lysine, glutamate, and glutamine.⁹⁸ In TauT knockout mice, deficiency of taurine causes mitochondrial dysfunction, triggering a greater than 80% decrease in exercise capacity.⁹⁹ Several studies in rodents have shown increased exercise capacity after taurine supplementation.^100–102 In addition, taurine is critical for the growth of blastocytes, skeletal muscle, and myocardium; it is necessary for mitochondrial development and is also important for muscular endurance.^103,104

Antioxidation, anti-inflammation, and other functions

Taurine is a major antioxidant, scavenging reactive oxygen and protecting against oxidative stress to organs including the brain,^97,105,106 where it increasingly appears to have neuroprotective effects.^107,108

Cellular taurine also has anti-inflammatory actions.³ One of the proposed mechanisms is taurine inhibition of NF-kappa B, an important transcription factor for the synthesis of pro-inflammatory cytokines.⁴ This function may be important in protecting polyunsaturated fatty acids from oxidative stress—helping to maintain and stabilize the structure and function of plasma membranes within the lungs,¹⁰⁹ heart,¹¹⁰ brain,¹¹¹ liver,¹¹² and spermatozoa.^61,62

Taurine is also conjugated to bile acids synthesized in the liver, forming bile salts⁷⁰ that act as detergents to help emulsify and digest lipids in the body. In addition, taurine facilitates xenobiotic detoxification in the liver by conjugating with several drugs to aid in their excretion.²⁵ Taurine is also implicated in calcium modulation¹¹³ and homeostasis.¹¹⁴ Through inhibition of several types of calcium channels, taurine has been shown to decrease calcium influx into cells, effectively serving a cytoprotective role against calcium overload.^115,116

TAURINE DEFICIENCY

Fetal and neonatal deficiency

Though taurine is considered nonessential in adults because it can be readily synthesized endogenously, it is thought to be conditionally essential in neonatal nutrition.⁶⁸ It is the second most abundant free amino acid in human breast milk¹¹⁷ and the most abundant free amino acid in fetal brain.¹¹⁸ In cases of long-term parenteral nutrition, neonates can become drastically taurine deficient¹¹⁹ due to suboptimal CSD activity,¹¹⁸ leading to retinal dysfunction.⁴¹ Taurine deficiencies can lead to functional and structural brain damage.¹¹⁸ Moreover, maternal taurine deficiency results in neurologic abnormalities in offspring¹²⁰ and may lead to oxidative stress throughout life.¹²¹

In 1984, the FDA approved the inclusion of taurine in infant formulas based on research showing that taurine-deficient infants had impaired fat absorption, bile acid secretion, retinal function, and hepatic function.¹²² But still under debate are the amount and duration of taurine supplementation required by preterm and low-birth-weight infants, as several randomized controlled trials failed to show statistically significant effects on growth.¹²³ Nonetheless, given the alleged detrimental ramifications of a lack of taurine supplementation, as well as the ethical dilemma of performing additional research trials on infants, it is presumed that infant formulas and parenteral nutrition for preterm and low-birth-weight infants will continue to contain taurine.

Age- and disease-related deficiency

Although taurine deficiency is rare in neonates, it is perhaps inevitable with advancing age. Healthy elderly patients ages 61 to 81 have up to a 49% decrease in plasma taurine concentration compared with healthy individuals ages 27 to 57.¹²⁴ While reduced renal retention¹²⁵ and taurine intake¹²⁶ can account for depressed taurine levels, Eppler and Dawson¹²⁷ found that tissue and circulating taurine concentrations decrease over the human life span primarily due to an age-dependent depletion of CSD activity in the liver. This effectively impairs the biosynthesis of endogenous taurine from cysteine or methionine or both, forcing a greater reliance on exogenous sources.

While specific mechanisms have not been fully elucidated, taurine deficiency has also been identified in patients suffering from diseases including but not limited to disorders of bone (osteogenesis imperfecta, osteoporosis),¹²⁸ blood (acute myelogenous leukemia),¹²⁹ central nervous system (schizophrenia, Friedreich ataxia-spinocerebellar degeneration),^130,131 retina (retinitis pigmentosa),¹³² circulatory system and heart (essential hypertension, atherosclerosis),¹³³ digestion (Gaucher disease),¹³⁴ absorption (short-bowel syndrome),¹³⁵ cellular proliferation (cancer),¹³⁶ and membrane channels (cystic fibrosis),¹³⁷ as well as in patients restricted to long-term parenteral nutrition.¹³⁸ However, the apparent correlation between taurine deficiency and these conditions does not necessarily mean causation; more study is needed to elucidate a direct connection.

SAFETY AND TOXICITY OF TAURINE SUPPLEMENTATION

An upper safe level of intake for taurine has not been established. To date, several studies have involved heavy taurine supplementation without serious adverse effects. While the largest dosage of taurine tested in humans appears to be 10 g/day for 6 months,¹³⁹ a number of studies have used 1 to 6 g/day for periods of 1 week to 1 year.¹⁴⁰ However, the assessment of potential acute, subacute, and chronic adverse effects has not been comprehensive. The Scientific Committee on Food of the European Commission¹⁴¹ reviewed several toxicologic studies on taurine through 2003 and were unable to expose any carcinogenic or teratogenic potential. Nevertheless, based on the available data from trials in humans and lower animals, Shao and Hathcock¹⁴⁰ suggested an observed safe level of taurine of 3 g/day, a conservatively smaller dose that carries a higher level of confidence. Because there is no “observed adverse effect level” for daily taurine intake,¹⁴¹ more research must be done to ensure safety of higher amounts of taurine administration and to define a tolerable upper limit of intake.

Interactions with medications

To date, the literature is scarce regarding potential interactions between taurine and commonly used medications.

Although no evidence specifically links taurine with adverse effects when used concurrently with other medications, there may be a link between taurine supplementation and various cytochrome P450 systems responsible for hepatic drug metabolism. Specifically, taurine inhibits cytochrome P450 2E1, a highly conserved xenobiotic-metabolizing P450 responsible for the breakdown of more than 70 substrates, including several commonly used anesthetics, analgesics, antidepressants, antibacterials, and antiepileptics.¹⁴² Of note, taurine may contribute to the attenuation of oxidative stress in the liver in the presence of alcohol¹⁴³ and acetaminophen,¹⁴⁴ two substances frequently used and abused. Since the P450 2E1 system catalyzes comparable reactions in rodents and humans,¹⁴² rodents should plausibly serve as a model for further testing of the effects of taurine on various substrates.

POTENTIAL THERAPEUTIC APPLICATIONS

More analysis is needed to fully unlock and understand taurine’s potential value in healthcare.

Correction of late-life taurine decline in humans could be beneficial for cognitive performance, energy metabolism, sexual function, and vision, but clinical studies remain to be performed. While a decline in taurine with age may intensify the stress caused by reactive oxygen species, taurine supplementation has been shown to decrease the presence of oxidative markers¹²⁷ and to serve a neuroprotective role in rodents.^145,146 Taurine levels increase in the hippocampus after experimentally induced gliosis¹⁴⁷ and are neuroprotective against glutamate excitotoxicity.^148,149 Furthermore, data in Alzheimer disease, Huntington disease, and brain ischemia experimental models show that taurine inhibits neuronal death (apoptosis).^13,150,151 Taurine has even been proposed as a potential preventive treatment for Alzheimer dementia, as it stabilizes protein conformations to prevent their aggregation and subsequent dysfunction.¹⁵² Although improvement in memory and cognitive performance has been linked to taurine supplementation in old mice,^145,153 similar results have not been found in adult mice whose taurine levels are within normal limits. Taurine also has transient anticonvulsant effects in some epileptic humans.¹⁵⁴

Within the male reproductive organs, the age-related decline in taurine may or may not have implications regarding sexuality, as only very limited rat data are available.^89–91

In cats, taurine supplementation has been found to prevent the progressive degeneration of retinal photoreceptors seen in retinitis pigmentosa, a genetic disease that causes the loss of vision.¹⁵⁵

While several energy drink companies have advertised that taurine plays a role in improving cognitive and physical performance, there are few human studies that examine this contention in the absence of confounding factors such as caffeine or glucose.^36,37,95 Taurine supplementation in patients with heart failure has been shown to increase exercise capacity vs placebo.¹⁵⁶ This supports the idea that in cases of taurine deficiency, such as those seen in cardiomyopathy,¹⁵⁷ taurine supplementation could have restorative effects. However, we are not aware of any double-blind, placebo-controlled clinical trial of taurine alone in healthy patients that measured energy parameters as clinical outcomes.

Although it remains possible that acute supraphysiologic taurine levels achieved by supplementation could transiently trigger various psychoneuroendocrine responses in healthy people, clinical research is needed in which taurine is the sole intervention. At present, the most compelling clinical reason to prescribe or recommend taurine supplementation is taurine deficiency.

Taurine—an amino acid found in abundance in the human brain, retina, heart, and reproductive organs, as well as in meat and seafood—is also a major ingredient in “energy drinks” (Table 1).^1,2 Given the tremendous popularity of these drinks in the United States, it would seem important to know and to recognize taurine’s neuroendocrine effects. Unfortunately, little is known about the effects of taurine supplementation in humans.

This paper reviews the sparse data to provide clinicians some background on the structure, synthesis, distribution, metabolism, mechanisms, effects, safety, and proposed therapeutic targets of taurine.

TAURINE’S THERAPEUTIC POTENTIAL

Taurine has been reported to have widespread anti-inflammatory actions.^3,4 Taurine supplementation has been proposed to have beneficial effects in the treatment of epilepsy,⁵ heart failure,^6,7 cystic fibrosis,⁸ and diabetes⁹ and has been shown in animal studies to protect against neurotoxic insults from alcohol, ammonia, lead, and other substances.^10–16

In addition, taurine analogues such as homotaurine and N-acetyl-homotaurine (acamprosate) have been probed for possible therapeutic applications. Homotaurine has been shown to have antiamyloid activity that could in theory protect against the progression of Alzheimer disease,¹⁷ and acam­prosate is approved by the US Food and Drug Administration (FDA) for the treatment of alcohol use disorders.¹⁸

TAURINE CONSUMPTION

Energy drinks are widely consumed in the United States, with an estimated 354 million gallons sold in 2009, or approximately 5.25 L/year per person over age 10.¹ In 2012, US sales of energy drinks exceeded $12 billion,¹⁹ with young men, particularly those in the military deployed in war zones, being the biggest consumers.^20–22 Analyses have found that of 49 nonalcoholic energy drinks tested, the average concentration of taurine was 3,180 mg/L, or approximately 750 mg per 8-oz serving.^23,24 Popular brands include Red Bull, Monster, Rockstar (Table 1), NOS, Amp, and Full Throttle.

Taurine is plentiful in the human body, which contains up to 1 g of taurine per kg.²⁵ Foods such as poultry, beef, pork, seafood, and processed meats have a high taurine content (Table 2).^26–29 People who eat meat and seafood have plentiful taurine intake, whereas vegetarians and vegans consume much less and have significantly lower circulating levels³⁰ because plants do not contain taurine in appreciable amounts.^26,29

The typical American diet provides between 123 and 178 mg of taurine daily.²⁶ Consumption of one 8-oz energy drink can increase the average intake 6 to 16 times. A lacto-ovo vegetarian diet provides only about 17 mg of taurine daily, and an 8-oz energy drink can increase the average intake by 44 to 117 mg.²⁶ And since a vegan diet provides essentially no taurine,³⁰ energy drink intake in any amount would constitute a major relative increase in taurine consumption.

ATTEMPTS TO STUDY TAURINE'S EFFECTS

Since most clinical trials to date have looked at the effects of taurine in combination with other ingredients such as caffeine, creatine, and glucose^31–35 in drinks such as Red Bull, these studies cannot be used to determine the effects of taurine alone. In the few clinical trials that have tested isolated taurine consumption, data are not sufficient to make a conclusion on direct effects on energy metabolism.

Rutherford et al³⁶ tested the effect of oral taurine supplementation (1,660 mg) on endurance in trained male cyclists 1 hour before exercise, but observed no effect on fluid intake, heart rate, subjective exertion, or time-trial performance. A small increase (16%) in total fat oxidation was observed during the 90-minute exercise period. Since mitochondria are the main location of fatty acid degradation, this effect may be attributed to taurine supplementation, with subsequent improvement in mitochondrial function.

Zhang et al³⁷ found a 30-second increase in cycling energy capacity after 7 days of 6 g oral taurine supplementation, but the study was neither blinded nor placebo-controlled.

Kammerer et al³⁸ tested the effect of 1 g of taurine supplementation on physical and mental performance in young adult soldiers 45 minutes before physical fitness and cognitive testing. This double-blind, placebo-controlled randomized trial found no effect of taurine on cardiorespiratory fitness indices, concentration, or immediate memory, nor did it find any effect of an 80-mg dose of caffeine.

In sum, the available data are far from sufficient to determine the direct effect of taurine consumption on energy metabolism in healthy people.

PHARMACOLOGY OF TAURINE

Chemical structure

Taurine, or 2-aminoethane sulfonic acid, is a conditionally essential amino acid, ie, we can usually make enough in our own bodies. It was first prepared on a large scale for physiologic investigation almost 90 years ago, through the purification of ox bile.³⁹ It can be obtained either exogenously through dietary sources or endogenously through biosynthesis from methionine and cysteine precursors, both essential sulfur-containing alpha-amino acids.⁴⁰ Both sources are important to maintain physiologic levels of taurine, and either can help compensate for the other in cases of deficiency.⁴¹

The structure of taurine has two main differences from the essential amino acids. First, taurine’s amino group is attached to the beta-carbon rather than the alpha-carbon, making it a beta-amino acid instead of an alpha-amino acid.⁴² Second, the acid group in taurine is sulfonic acid, whereas the essential amino acids have a carboxylic acid.⁴³ Because of its distinctive structure, taurine is not used as a structural unit in proteins,⁴³ existing mostly as a free amino acid within cells, readily positioned to perform several unique functions.

Synthesis

De novo synthesis of taurine involves several enzymes and at least five pathways,⁴⁴ mostly differing by the order in which sulfur is oxidized and decarboxylated.⁴⁵

The rate-limiting enzyme of the predominant pathway is thought to be cysteine sulfinate decarboxylase (CSD), and its presence within an organ indicates involvement in taurine production.⁴⁴ CSD has been found in the liver,⁴⁶ the primary site of taurine biosynthesis, as well as in the retina,⁴⁷ brain,⁴⁸ kidney,⁴⁹ mammary glands,^50,51 and reproductive organs.⁵²

Distribution

Taurine levels are highest in electrically excitable tissues such as the central nervous system, retina, and heart; in secretory structures such as the pineal gland and the pituitary gland (including the posterior lobe or neurohypophysis); and in platelets²⁵ and neutrophils.⁵³

In the fetal brain, the taurine concentration is higher than that of any other amino acid,⁵⁴ but the concentration in the brain decreases with advancing age, whereas glutamate levels increase over time to make it the predominant amino acid in the adult brain.⁵⁴ Regardless, taurine is still the second most prevalent amino acid in the adult brain, its levels comparable to those of gamma-aminobutyric acid (GABA).⁵⁵

Taurine has also been found in variable amounts in the liver, muscle, kidney, pancreas, spleen, small intestine, and lungs,⁵⁶ as well as in several other locations.^45,57

Taurine is also present in the male and female reproductive organs. In male rats, taurine and taurine biosynthesis have been localized to Leydig cells of the testes, the cellular source of testosterone in males, as well as the cremaster muscle, efferent ducts, and peritubular myoid cells surrounding seminiferous tubules.⁵⁸ More recently, taurine has been detected in the testes of humans⁵⁹ and is also found in sperm and seminal fluid.⁶⁰ Levels of taurine in spermatozoa are correlated with sperm quality, presumably by protecting against lipid peroxidation through taurine’s antioxidant effects,^61,62 as well as through contribution to the spermatozoa maturation process by facilitating the capacitation, motility, and acrosomal reaction of sperm.⁶³

In female rats, taurine has been found in uterine tissue,⁶⁴ oviducts,⁶⁵ uterine fluid (where it is the predominant amino acid),⁶⁶ and thecal cells of developing follicles of ovaries, cells responsible for the synthesis of androgens such as testosterone and androstenedione.⁶⁵ Taurine is also a major component of human breast milk⁶⁷ and is important for proper neonatal nutrition.⁶⁸

Metabolism and excretion

Ninety-five percent of taurine is excreted in urine, about 70% as taurine itself, and the rest as sulfate. Most of the sulfate derived from taurine is produced by bacterial metabolism in the gut and then absorbed.⁶⁹ However, taurine can also be conjugated with bile acids to act as a detergent in lipid emulsification.⁷⁰ In this form, it may be subjected to the enterohepatic circulation, which gives bacteria another chance to convert it into inorganic sulfate for excretion in urine.⁶⁹

MECHANISMS AND NEUROENDOCRINE EFFECTS

As a free amino acid, taurine has widespread distribution and unique biochemical and physiologic properties and exhibits several organ-specific functions; however, indisputable evidence of a taurine-specific receptor is lacking, and its putative existence⁷¹ is controversial.⁷² Nonetheless, taurine is a neuromodulator with a variety of actions.

Neurotransmission

Taurine is known to be an inhibitory neurotransmitter and neuromodulator.⁷³ It is structurally analogous to GABA, the main inhibitory neurotransmitter in the brain.⁴⁵ Accordingly, it binds to GABA receptors to serve as an agonist,^74,75 causing neuronal hyperpolarization and inhibition. Taurine has an even higher affinity for glycine receptors⁷⁵ where it has long been known to act as an agonist.⁷⁶ GABA and glycine receptors both belong to the Cys-loop receptor superfamily,⁷⁷ with conservation of subunits that allows taurine to bind each receptor, albeit at different affinities. The binding effects of taurine on GABA and glycine receptors have not been well documented quantitatively; however, it is known that taurine has a substantially lower affinity than GABA and glycine for their respective receptors.⁷⁶

Catecholamines and the sympathetic nervous system

Surprisingly little is known about the effects of taurine on norepinephrine, dopamine, and the human sympathetic nervous system.⁷⁸ Humans with borderline hypertension given 6 g of taurine orally for 7 days⁷⁹ experienced decreases in epinephrine secretion and blood pressure, but normotensive study participants did not experience similar results, possibly because of a better ability to regulate sympathetic tone. Mizushima et al⁸⁰ showed that a longer period of taurine intake (6 g orally for 3 weeks) could elicit a decrease in norepinephrine in healthy men with normal blood pressure. Other similar studies^81–83 also suggested interplay between taurine and catecholamines, but the extent is still undetermined.

Growth hormone, prolactin, sex hormones, and cortisol

Taurine appears to have a complex relationship with several hormones, although its direct effects on hormone secretion remain obscure. Clinical studies of the acute and chronic neuroendocrine effects of taurine loading in humans are needed.

In female rats, secretion of prolactin is increased by the intraventricular injection of 5 μL of 2.0 μmol taurine over a 10-minute period.⁸⁴ Ikuyama et al⁸⁵ found an increase in prolactin and growth hormone secretion in adult male rats given 10 μL of 0.25 μmol and 1.0 μmol taurine intraventricularly, yet a higher dose of 4.0 μmol had no effect on either hormone. Furthermore, prolactin receptor deficiency is seen in CSD knockout mice, but the receptor is restored with taurine supplementation.⁸⁶

Mantovani and DeVivo⁸⁷ reported that 375 to 8,000 mg/day of taurine given orally for 4 to 6 months to epileptic patients stimulated the secretion of growth hormone. However, in another study, a single 75-mg/kg dose of oral taurine did not trigger an acute increase in levels of growth hormone or prolactin in humans.⁸⁸ Energy drinks may contain up to 1,000 mg of taurine per 8-oz serving, but the effects of larger doses on growth hormone, which is banned as a supplement by major athletic organizations because of its anabolic and possible performance-enhancing effects, remain to be determined.

Taurine may have effects on human sex hormones, based on the limited observations in rodents.^89–94

Although human salivary cortisol concentrations were purportedly assessed in response to 2,000 mg of oral taurine,⁹⁵ the methods and reported data are not adequate to draw any conclusions.

Energy metabolism

Mammals are unable to directly use taurine in energy production because they cannot directly reduce it.²⁵ Instead, bacteria in the gut use it as a source of energy, carbon, nitrogen, and sulfur.⁹⁶ However, taurine deficiency appears to impair the cellular respiratory chain, resulting in diminished production of adenosine triphosphate and diminished uptake of long-chain fatty acids by mitochondria, at least in the heart.⁹⁷

Taurine is present in human mitochondria and regulates mitochondrial function. For example, taurine in mitochondria assists in conjugation of transfer RNA for leucine, lysine, glutamate, and glutamine.⁹⁸ In TauT knockout mice, deficiency of taurine causes mitochondrial dysfunction, triggering a greater than 80% decrease in exercise capacity.⁹⁹ Several studies in rodents have shown increased exercise capacity after taurine supplementation.^100–102 In addition, taurine is critical for the growth of blastocytes, skeletal muscle, and myocardium; it is necessary for mitochondrial development and is also important for muscular endurance.^103,104

Antioxidation, anti-inflammation, and other functions

Taurine is a major antioxidant, scavenging reactive oxygen and protecting against oxidative stress to organs including the brain,^97,105,106 where it increasingly appears to have neuroprotective effects.^107,108

Cellular taurine also has anti-inflammatory actions.³ One of the proposed mechanisms is taurine inhibition of NF-kappa B, an important transcription factor for the synthesis of pro-inflammatory cytokines.⁴ This function may be important in protecting polyunsaturated fatty acids from oxidative stress—helping to maintain and stabilize the structure and function of plasma membranes within the lungs,¹⁰⁹ heart,¹¹⁰ brain,¹¹¹ liver,¹¹² and spermatozoa.^61,62

Taurine is also conjugated to bile acids synthesized in the liver, forming bile salts⁷⁰ that act as detergents to help emulsify and digest lipids in the body. In addition, taurine facilitates xenobiotic detoxification in the liver by conjugating with several drugs to aid in their excretion.²⁵ Taurine is also implicated in calcium modulation¹¹³ and homeostasis.¹¹⁴ Through inhibition of several types of calcium channels, taurine has been shown to decrease calcium influx into cells, effectively serving a cytoprotective role against calcium overload.^115,116

TAURINE DEFICIENCY

Fetal and neonatal deficiency

Though taurine is considered nonessential in adults because it can be readily synthesized endogenously, it is thought to be conditionally essential in neonatal nutrition.⁶⁸ It is the second most abundant free amino acid in human breast milk¹¹⁷ and the most abundant free amino acid in fetal brain.¹¹⁸ In cases of long-term parenteral nutrition, neonates can become drastically taurine deficient¹¹⁹ due to suboptimal CSD activity,¹¹⁸ leading to retinal dysfunction.⁴¹ Taurine deficiencies can lead to functional and structural brain damage.¹¹⁸ Moreover, maternal taurine deficiency results in neurologic abnormalities in offspring¹²⁰ and may lead to oxidative stress throughout life.¹²¹

In 1984, the FDA approved the inclusion of taurine in infant formulas based on research showing that taurine-deficient infants had impaired fat absorption, bile acid secretion, retinal function, and hepatic function.¹²² But still under debate are the amount and duration of taurine supplementation required by preterm and low-birth-weight infants, as several randomized controlled trials failed to show statistically significant effects on growth.¹²³ Nonetheless, given the alleged detrimental ramifications of a lack of taurine supplementation, as well as the ethical dilemma of performing additional research trials on infants, it is presumed that infant formulas and parenteral nutrition for preterm and low-birth-weight infants will continue to contain taurine.

Age- and disease-related deficiency

Although taurine deficiency is rare in neonates, it is perhaps inevitable with advancing age. Healthy elderly patients ages 61 to 81 have up to a 49% decrease in plasma taurine concentration compared with healthy individuals ages 27 to 57.¹²⁴ While reduced renal retention¹²⁵ and taurine intake¹²⁶ can account for depressed taurine levels, Eppler and Dawson¹²⁷ found that tissue and circulating taurine concentrations decrease over the human life span primarily due to an age-dependent depletion of CSD activity in the liver. This effectively impairs the biosynthesis of endogenous taurine from cysteine or methionine or both, forcing a greater reliance on exogenous sources.

While specific mechanisms have not been fully elucidated, taurine deficiency has also been identified in patients suffering from diseases including but not limited to disorders of bone (osteogenesis imperfecta, osteoporosis),¹²⁸ blood (acute myelogenous leukemia),¹²⁹ central nervous system (schizophrenia, Friedreich ataxia-spinocerebellar degeneration),^130,131 retina (retinitis pigmentosa),¹³² circulatory system and heart (essential hypertension, atherosclerosis),¹³³ digestion (Gaucher disease),¹³⁴ absorption (short-bowel syndrome),¹³⁵ cellular proliferation (cancer),¹³⁶ and membrane channels (cystic fibrosis),¹³⁷ as well as in patients restricted to long-term parenteral nutrition.¹³⁸ However, the apparent correlation between taurine deficiency and these conditions does not necessarily mean causation; more study is needed to elucidate a direct connection.

SAFETY AND TOXICITY OF TAURINE SUPPLEMENTATION

An upper safe level of intake for taurine has not been established. To date, several studies have involved heavy taurine supplementation without serious adverse effects. While the largest dosage of taurine tested in humans appears to be 10 g/day for 6 months,¹³⁹ a number of studies have used 1 to 6 g/day for periods of 1 week to 1 year.¹⁴⁰ However, the assessment of potential acute, subacute, and chronic adverse effects has not been comprehensive. The Scientific Committee on Food of the European Commission¹⁴¹ reviewed several toxicologic studies on taurine through 2003 and were unable to expose any carcinogenic or teratogenic potential. Nevertheless, based on the available data from trials in humans and lower animals, Shao and Hathcock¹⁴⁰ suggested an observed safe level of taurine of 3 g/day, a conservatively smaller dose that carries a higher level of confidence. Because there is no “observed adverse effect level” for daily taurine intake,¹⁴¹ more research must be done to ensure safety of higher amounts of taurine administration and to define a tolerable upper limit of intake.

Interactions with medications

To date, the literature is scarce regarding potential interactions between taurine and commonly used medications.

Although no evidence specifically links taurine with adverse effects when used concurrently with other medications, there may be a link between taurine supplementation and various cytochrome P450 systems responsible for hepatic drug metabolism. Specifically, taurine inhibits cytochrome P450 2E1, a highly conserved xenobiotic-metabolizing P450 responsible for the breakdown of more than 70 substrates, including several commonly used anesthetics, analgesics, antidepressants, antibacterials, and antiepileptics.¹⁴² Of note, taurine may contribute to the attenuation of oxidative stress in the liver in the presence of alcohol¹⁴³ and acetaminophen,¹⁴⁴ two substances frequently used and abused. Since the P450 2E1 system catalyzes comparable reactions in rodents and humans,¹⁴² rodents should plausibly serve as a model for further testing of the effects of taurine on various substrates.

POTENTIAL THERAPEUTIC APPLICATIONS

More analysis is needed to fully unlock and understand taurine’s potential value in healthcare.

Correction of late-life taurine decline in humans could be beneficial for cognitive performance, energy metabolism, sexual function, and vision, but clinical studies remain to be performed. While a decline in taurine with age may intensify the stress caused by reactive oxygen species, taurine supplementation has been shown to decrease the presence of oxidative markers¹²⁷ and to serve a neuroprotective role in rodents.^145,146 Taurine levels increase in the hippocampus after experimentally induced gliosis¹⁴⁷ and are neuroprotective against glutamate excitotoxicity.^148,149 Furthermore, data in Alzheimer disease, Huntington disease, and brain ischemia experimental models show that taurine inhibits neuronal death (apoptosis).^13,150,151 Taurine has even been proposed as a potential preventive treatment for Alzheimer dementia, as it stabilizes protein conformations to prevent their aggregation and subsequent dysfunction.¹⁵² Although improvement in memory and cognitive performance has been linked to taurine supplementation in old mice,^145,153 similar results have not been found in adult mice whose taurine levels are within normal limits. Taurine also has transient anticonvulsant effects in some epileptic humans.¹⁵⁴

Within the male reproductive organs, the age-related decline in taurine may or may not have implications regarding sexuality, as only very limited rat data are available.^89–91

In cats, taurine supplementation has been found to prevent the progressive degeneration of retinal photoreceptors seen in retinitis pigmentosa, a genetic disease that causes the loss of vision.¹⁵⁵

While several energy drink companies have advertised that taurine plays a role in improving cognitive and physical performance, there are few human studies that examine this contention in the absence of confounding factors such as caffeine or glucose.^36,37,95 Taurine supplementation in patients with heart failure has been shown to increase exercise capacity vs placebo.¹⁵⁶ This supports the idea that in cases of taurine deficiency, such as those seen in cardiomyopathy,¹⁵⁷ taurine supplementation could have restorative effects. However, we are not aware of any double-blind, placebo-controlled clinical trial of taurine alone in healthy patients that measured energy parameters as clinical outcomes.

Although it remains possible that acute supraphysiologic taurine levels achieved by supplementation could transiently trigger various psychoneuroendocrine responses in healthy people, clinical research is needed in which taurine is the sole intervention. At present, the most compelling clinical reason to prescribe or recommend taurine supplementation is taurine deficiency.

Once thought to only be associated with depression, self-criticism is a transdiagnostic risk factor for diverse forms of psychopathology.^1,2 However, research has shown that self-compassion is a robust resilience factor when faced with feelings of personal inadequacy.^3,4

Self-critical individuals experience feelings of unworthiness, inferiority, failure, and guilt. They engage in constant and harsh self-scrutiny and evaluation, and fear being disapproved and criticized and losing the approval and acceptance of others.⁵ Self-compassion involves treating oneself with care and concern when confronted with personal inadequacies, mistakes, failures, and painful life situations.^6,7Although self-criticism is the aspect of perfectionism most associated with maladjustment,⁸ one can be harshly self-critical without being a perfectionist. Most studies of self-criticism have not measured shame; however, this self-conscious emotion has been implicated in diverse forms of psychopathology.⁹ In contrast to guilt, which results from acknowledging bad behavior, shame results from seeing oneself as a bad or inadequate person.

Although self-criticism is destructive across clinical disorders and interpersonal relationships, self-compassion is associated with healthy relationships, emotional well-being, and better treatment outcomes.

Recent research shows how clinicians can teach their patients how to be less self-critical and more self-compassionate. Neff^6,7 proposes that self-compassion involves treating yourself with care and concern when being confronted with personal inadequacies, mistakes, failures, and painful life situations. It consists of 3 interacting components, each of which has a positive and negative pole:

• self-kindness vs self-judgment
• a sense of common humanity vs isolation
• mindfulness vs over-identification.

Self-kindness refers to being caring and understanding with oneself rather than harshly judgmental. Instead of attacking and berating oneself for personal shortcomings, the self is offered warmth and unconditional acceptance.

Humanity involves recognizing that humans are imperfect, that all people fail, make mistakes, and have serious life challenges. By remembering that imperfection is part of life, we feel less isolated when we are in pain.

Mindfulness in the context of self-compassion involves being aware of one’s painful experiences in a balanced way that neither ignores and avoids nor exaggerates painful thoughts and emotions.

Self-compassion is more than the absence of self-judgment, although a defining feature of self-compassion is the lack of self-judgment, and self-judgment overlaps with self-criticism. Rather, self-compassion provides several access points for reducing self-criticism. For example, being kind and understanding when confronting personal inadequacies (eg, “it’s okay not to be perfect”) can counter harsh self-talk (eg, “I’m not defective”). Mindfulness of emotional pain (eg, “this is hard”) can facilitate a kind and warm response (eg, “what can I do to take care of myself right now?”) and therefore lessen self-blame (eg, “blaming myself is just causing me more suffering”). Similarly, remembering that failure is part of the human experience (eg, “it’s normal to mess up sometimes”) can lessen egocentric feelings of isolation (eg, “it’s not just me”) and over-identification (eg, “it’s not the end of the world”), resulting in lessened self-criticism (eg, “maybe it’s not just because I’m a bad person”).

Depression

Several studies have found that self-criticism predicts depression. In 3 epidemiological studies, “feeling worthless” was among the top 2 symptoms predicting a depression diagnosis and later depressive episodes.¹⁰ Self-criticism in fourth-year medical students predicted depression 2 years later, and—in males—10 years later in their medical careers better than a history of depression.¹¹ Self-critical perfectionism also is associated with suicidal ideation and lethality of suicide attempts.¹²

Self-criticism has been shown to predict depressive relapse and residual self-devaluative symptoms in recovered depressed patients.¹³ In one study, currently depressed and remitted depressed patients had higher self-criticism and lower self-compassion compared with healthy controls. Both factors were more strongly associated with depression status than higher perfectionistic beliefs and cognitions, rumination, and maladaptive emotional regulation.¹⁴

Self-criticism and response to treatment. In the National Institute of Mental Health Treatment of Depression Collaborative Research Program,¹⁵ self-critical perfectionism predicted a poorer outcome across all 4 treatments (cognitive-behavioral therapy [CBT], interpersonal psychotherapy [IPT], pharmacotherapy plus clinical management, and placebo plus clinical management). Subsequent studies found that self-criticism predicted poorer response to CBT¹⁶ and IPT.¹⁷ The authors suggest that self-criticism could interfere with treatment because self-critical patients might have difficulty developing a strong therapeutic alliance.^18,19

Anxiety disorders

Self-criticism is common across psychiatric disorders. In a study of 5,877 respondents in the National Comorbidity Survey (NCS), self-criticism was associated with social phobia, findings that were significant after controlling for current emotional distress, neuroticism, and lifetime history of mood, anxiety, and substance use disorders.²⁰ Further, in a CBT treatment study, baseline self-criticism was associated with severity of social phobia and changes in self-criticism predicted treatment outcome.²¹ Self-criticism might be an important core psychological process in the development, maintenance, and course of social phobia. Patients with social anxiety disorder have less self-compassion than healthy controls and greater fear of negative evaluation.

In the NCS, self-criticism was associated with posttraumatic stress disorder (PTSD) even after controlling for lifetime history of affective and anxiety disorders.²⁰ Self-criticism predicted greater severity of combat-related PTSD in hospitalized male veterans,²² and those with PTSD had higher scores on self-criticism scales than those with major depressive disorder.²³ In a study of Holocaust survivors, those with PTSD scored higher on self-criticism than survivors without PTSD.²⁴ Self-criticism also distinguished between female victims of domestic violence with and without PTSD.²⁵

Self-compassion could be a protective factor for posttraumatic stress.²⁶ Combat veterans with higher levels of self-compassion showed lower levels of psychopathology, better functioning in daily life, and fewer symptoms of posttraumatic stress.²⁷ In fact, self-compassion has been found to be a stronger predictor of PTSD than level of combat exposure.²⁸

In an early study, self-criticism scores were higher in patients with panic disorder than in healthy controls, but lower than in patients with depression.²⁹ In a study of a mixed sample of anxiety disorder patients, symptoms of generalized anxiety disorder were associated with shame proneness.³⁰ Consistent with these results, Hoge et al³¹ found that self-compassion was lower in generalized anxiety disorder patients compared with healthy controls with elevated stress. Low self-compassion has been associated with severity of obsessive-compulsive disorder.³²

Eating disorders

Self-criticism is correlated with eating disorder severity.³³ In a study of patients with binge eating disorder, Dunkley and Grilo³⁴ found that self-criticism was associated with the over-evaluation of shape and weight independently of self-esteem and depression. Self-criticism also is associated with body dissatisfaction, independent of self-esteem and depression. Dunkley et al³⁵ found that self-criticism, but not global self-esteem, in patients with binge eating disorder mediated the relationship between childhood abuse and body dissatisfaction and depression. Numerous studies have shown that shame is associated with more severe eating disorder pathology.³³

Self-compassion seems to buffer against body image concerns. It is associated with less body dissatisfaction, body preoccupation, and weight worries,³⁶ greater body appreciation³⁷ and less disordered eating.^37-39 Early decreases in shame during eating disorder treatment was associated with more rapid reduction in eating disorder symptoms.⁴⁰

Interpersonal relationships

Several studies have shown that self-criticism has negative effects on interpersonal relationships throughout life.^5,41,42

• Self-criticism at age 12 predicted less involvement in high school activities and, at age 31, personal and social maladjustment.⁴³
• High school students with high self-criticism reported more interpersonal problems.⁴⁴
• Self-criticism was associated with loneliness, depression, and lack of intimacy with opposite sex friends or partners during the transition to college.⁴⁵
• In a study of college roommates,⁴⁶ self-criticism was associated with increased likelihood of rejection.
• Whiffen and Aube⁴⁷ found that self-criticism was associated with marital dissatisfaction and depression.
• Self-critical mothers with postpartum depression were less satisfied with social support and were more vulnerable to depression.⁴⁸

Self-compassion appears to enhance interpersonal relationships. In a study of heterosexual couples,⁴⁹ self-compassionate individuals were described by their partners as being more emotionally connected, as well as accepting and supporting autonomy, while being less detached, controlling, and verbally or physically aggressive than those lacking self-compassion. Because self-compassionate people give themselves care and support, they seem to have more emotional resources available to give to others.

See the Box examining the evidence on the role of self-compassion in borderline personality disorder and non-suicidal self-injury.

Achieving goals

Powers et al⁵⁰ suggest that self-critics approach goals based on motivation to avoid failure and disapproval, rather than on intrinsic interest and personal meaning. In studies of college students pursuing academic, social, or weight loss goals, self-criticism was associated with less progress to that goal. Self-criticism was associated with rumination and procrastination, which the authors suggest might have focused the self-critic on potential failure, negative evaluation from others, and loss of self-esteem. Additional studies showed the deleterious effects of self-criticism on college students’ progress on obtaining academic or music performance goals and on community residents’ weight loss goals.⁵¹

Not surprisingly, self-compassion is associated with successful goal pursuit and resilience when goals are not met⁵² and less procrastination and academic worry.⁵³ Self-compassion also is associated with intrinsic motivation, goals based on mastery rather than performance, and less fear of academic failure.⁵⁴

How self-criticism and self-compassion develop

Studies have explored the impact of early relationships with parents and development of self-criticism. Parental overcontrol and restrictiveness and lack of warmth consistently have been identified as parenting styles associated with development of self-criticism in children.⁵⁵ One study found that self-criticism fully mediated the relationship between childhood verbal abuse from parents and depression and anxiety in adulthood.⁵⁶ Reports from parents on their current parenting styles are consistent with these studies.⁵⁷ Amitay et al⁵⁷ states that “[s]elf-critics’ negative childhood experiences thus seem to contribute to a pattern of entering, creating, or manipulating subsequent interpersonal environments in ways that perpetuate their negative self-image and increase vulnerability to depression.” Not surprisingly, self-criticism is associated with a fearful avoidant attachment style.⁵⁸ Review of the developmental origins of self-criticism confirms these factors and presents findings that peer relationships also are important factors in the development of self-criticism.^59,60

Early positive relationships with caregivers are associated with self-compassion. Recollections of maternal support are correlated with self-compassion and secure attachment styles in adolescents and adults.⁶¹ Pepping et al⁶² found that retrospective reports of parental rejection, overprotection, and low parental warmth was associated with low self-compassion.

Benefits of self-compassion

A growing body of research suggests that self-compassion is strongly linked to mental health. Greater self-compassion consistently has been associated with lower levels of depression and anxiety,³ with a large effect size.⁴ Of course, central to self-compassion is the lack of self-criticism, but self-compassion still protects against anxiety and depression when controlling for self-criticism and negative affect.^6,63 Self-compassion is a strong predictor of symptom severity and quality of life among individuals with anxious distress.⁶⁴

The benefits of self-compassion stem partly from a greater ability to cope with negative emotions.^6,63,65 Self-compassionate people are less likely to ruminate on their negative thoughts and emotions or suppress them,^6,66 which helps to explain why self-compassion is a negative predictor of depression.⁶⁷

Self-compassion also enhances positive mind states. A number of studies have found links between self-compassion and positive psychological qualities, such as happiness, optimism, wisdom, curiosity, and exploration, and personal initiative.^63,65,68,69 By embracing one’s suffering with compassion, negative states are ameliorated when positive emotions of kindness, connectedness, and mindful presence are generated.

Misconceptions about self-compassion

A common misconception is that abandoning self-criticism in favor of self-compassion will undermine motivation⁷⁰; however, research indicates the opposite. Although self-compassion is negatively associated with maladaptive perfectionism, it is not correlated with self-adopted performance standards.⁶ Self-compassionate people have less fear of failure⁵⁴ and, when they do fail, they are more likely to try again.⁷¹ Breines and Chen⁷² found in a series of experimental studies that engendering feelings of self-compassion for personal weaknesses, failures, and past transgressions resulted in more motivation to change, to try harder to learn, and to avoid repeating past mistakes.

Another common misunderstanding is that self-compassion is a weakness. In fact, research suggests that self-compassion is a powerful way to cope with life challenges.⁷³

Although some fear that self-compassion leads to self-indulgence, there is evidence that self-compassion promotes health-related behaviors. Self-compassionate individuals are more likely to seek medical treatment when needed,⁷⁴ exercise for intrinsic reasons,⁷⁵ and drink less alcohol.⁷⁶ Inducing self-compassion has been found to help people stick to their diets⁷⁷ and quit smoking.⁷⁸

Self-compassion interventions

Individuals can develop self-compassion. Shapira and Mongrain⁷⁹ found that adults who wrote a compassionate letter to themselves once a day for a week about the distressing events they were experiencing showed significant reductions in depression up to 3 months and significant increases in happiness up to 6 months compared with a control group who wrote about early memories. Albertson et al⁸⁰ found that, compared with a wait-list control group, 3 weeks of self-compassion meditation training improved body dissatisfaction, body shame, and body appreciation among women with body image concerns. Similarly, Smeets et al⁸¹ found that 3 weeks of self-compassion training for female college students led to significantly greater increases in mindfulness, optimism, and self-efficacy, as well as greater decreases in rumination compared with a time management control group.

The Box^6,70,82-86 describes rating scales that can measure self-compassion and self-criticism.

Mindful self-compassion (MSC), developed by Neff and Germer,⁸⁷ is an 8-week group intervention designed to teach people how to be more self-compassionate through meditation and informal practices in daily life. Results of a randomized controlled trial found that, compared with a wait-list control group, participants using MSC reported significantly greater increases in self-compassion, compassion for others, mindfulness, and life satisfaction, and greater decreases in depression, anxiety, stress, and emotional avoidance, with large effect sizes indicated. These results were maintained up to 1 year.

Compassion-focused therapy (CFT) is designed to enhance self-compassion in clinical populations.⁸⁸ The approach uses a number of imagery and experiential exercises to enhance patients’ abilities to extend feelings of reassurance, safeness, and understanding toward themselves. CFT has shown promise in treating a diverse group of clinical disorders such as depression and shame,^8,89 social anxiety and shame,⁹⁰ eating disorders,⁹¹ psychosis,⁹² and patients with acquired brain injury.⁹³ A group-based CFT intervention with a heterogeneous group of community mental health patients led to significant reductions in depression, anxiety, stress, and self-criticism.⁹⁴ See Leaviss and Utley⁹⁵ for a review of the benefits of CFT.

Fears of developing self-compassion

It is important to note that some people can access self-compassion more easily than others. Highly self-critical patients could feel anxious when learning to be compassionate to themselves, a phenomenon known as “fear of compassion”⁹⁶ or “backdraft.”⁹⁷ Backdraft occurs when a firefighter opens a door with a hot fire behind it. Oxygen rushes in, causing a burst of flame. Similarly, when the door of the heart is opened with compassion, intense pain could be released. Unconditional love reveals the conditions under which we were unloved in the past. Some individuals, especially those with a history of childhood abuse or neglect, are fearful of compassion because it activates grief associated with feelings of wanting, but not receiving, affection and care from significant others in childhood.

Clinicians should be aware that anxiety could arise and should help patients learn how to go slowly and stabilize themselves if overwhelming emotions occur as a part of self-compassion practice. Both CFT and MSC have processes to deal with fear of compassion in their protocols,^98,99 with the focus on explaining to individuals that although such fears may occur, they are a normal and necessary part of the healing process. Individuals also are taught to focus on the breath, feeling the sensations in the soles of their feet, or other mindfulness practices to ground and stabilize attention when overwhelming feelings arise.

Clinical interventions

Self-compassion interventions that I (R.W.) find most helpful, in the order I administer them, are:

• exploring perceived advantages and disadvantages of self-criticism
• presenting self-compassion as a way to get the perceived advantages of self-criticism without the disadvantages
• discussing what it means to be compassionate for someone else who is suffering, and then asking what it would be like if they treated themselves with the same compassion
• exploring patients’ misconceptions and fears of self-compassion
• directing patients to the self-compassion Web site to get an understanding of what self-compassion is and how it differs from self-esteem
• taking an example of a recent situation in which the patient was self-critical and exploring how a self-compassionate response would differ.

Asking what they would say to a friend often is an effective way to get at this. In a later therapy session, self-compassionate imagery is a useful way to get the patient to experience self-compassion on an emotional level. See Neff¹⁰⁰ and Gilbert⁹⁸ for other techniques to enhance self-compassion.

Once thought to only be associated with depression, self-criticism is a transdiagnostic risk factor for diverse forms of psychopathology.^1,2 However, research has shown that self-compassion is a robust resilience factor when faced with feelings of personal inadequacy.^3,4

Self-critical individuals experience feelings of unworthiness, inferiority, failure, and guilt. They engage in constant and harsh self-scrutiny and evaluation, and fear being disapproved and criticized and losing the approval and acceptance of others.⁵ Self-compassion involves treating oneself with care and concern when confronted with personal inadequacies, mistakes, failures, and painful life situations.^6,7Although self-criticism is the aspect of perfectionism most associated with maladjustment,⁸ one can be harshly self-critical without being a perfectionist. Most studies of self-criticism have not measured shame; however, this self-conscious emotion has been implicated in diverse forms of psychopathology.⁹ In contrast to guilt, which results from acknowledging bad behavior, shame results from seeing oneself as a bad or inadequate person.

Although self-criticism is destructive across clinical disorders and interpersonal relationships, self-compassion is associated with healthy relationships, emotional well-being, and better treatment outcomes.

Recent research shows how clinicians can teach their patients how to be less self-critical and more self-compassionate. Neff^6,7 proposes that self-compassion involves treating yourself with care and concern when being confronted with personal inadequacies, mistakes, failures, and painful life situations. It consists of 3 interacting components, each of which has a positive and negative pole:

• self-kindness vs self-judgment
• a sense of common humanity vs isolation
• mindfulness vs over-identification.

Self-kindness refers to being caring and understanding with oneself rather than harshly judgmental. Instead of attacking and berating oneself for personal shortcomings, the self is offered warmth and unconditional acceptance.

Humanity involves recognizing that humans are imperfect, that all people fail, make mistakes, and have serious life challenges. By remembering that imperfection is part of life, we feel less isolated when we are in pain.

Mindfulness in the context of self-compassion involves being aware of one’s painful experiences in a balanced way that neither ignores and avoids nor exaggerates painful thoughts and emotions.

Self-compassion is more than the absence of self-judgment, although a defining feature of self-compassion is the lack of self-judgment, and self-judgment overlaps with self-criticism. Rather, self-compassion provides several access points for reducing self-criticism. For example, being kind and understanding when confronting personal inadequacies (eg, “it’s okay not to be perfect”) can counter harsh self-talk (eg, “I’m not defective”). Mindfulness of emotional pain (eg, “this is hard”) can facilitate a kind and warm response (eg, “what can I do to take care of myself right now?”) and therefore lessen self-blame (eg, “blaming myself is just causing me more suffering”). Similarly, remembering that failure is part of the human experience (eg, “it’s normal to mess up sometimes”) can lessen egocentric feelings of isolation (eg, “it’s not just me”) and over-identification (eg, “it’s not the end of the world”), resulting in lessened self-criticism (eg, “maybe it’s not just because I’m a bad person”).

Depression

Several studies have found that self-criticism predicts depression. In 3 epidemiological studies, “feeling worthless” was among the top 2 symptoms predicting a depression diagnosis and later depressive episodes.¹⁰ Self-criticism in fourth-year medical students predicted depression 2 years later, and—in males—10 years later in their medical careers better than a history of depression.¹¹ Self-critical perfectionism also is associated with suicidal ideation and lethality of suicide attempts.¹²

Self-criticism has been shown to predict depressive relapse and residual self-devaluative symptoms in recovered depressed patients.¹³ In one study, currently depressed and remitted depressed patients had higher self-criticism and lower self-compassion compared with healthy controls. Both factors were more strongly associated with depression status than higher perfectionistic beliefs and cognitions, rumination, and maladaptive emotional regulation.¹⁴

Self-criticism and response to treatment. In the National Institute of Mental Health Treatment of Depression Collaborative Research Program,¹⁵ self-critical perfectionism predicted a poorer outcome across all 4 treatments (cognitive-behavioral therapy [CBT], interpersonal psychotherapy [IPT], pharmacotherapy plus clinical management, and placebo plus clinical management). Subsequent studies found that self-criticism predicted poorer response to CBT¹⁶ and IPT.¹⁷ The authors suggest that self-criticism could interfere with treatment because self-critical patients might have difficulty developing a strong therapeutic alliance.^18,19

Anxiety disorders

Self-criticism is common across psychiatric disorders. In a study of 5,877 respondents in the National Comorbidity Survey (NCS), self-criticism was associated with social phobia, findings that were significant after controlling for current emotional distress, neuroticism, and lifetime history of mood, anxiety, and substance use disorders.²⁰ Further, in a CBT treatment study, baseline self-criticism was associated with severity of social phobia and changes in self-criticism predicted treatment outcome.²¹ Self-criticism might be an important core psychological process in the development, maintenance, and course of social phobia. Patients with social anxiety disorder have less self-compassion than healthy controls and greater fear of negative evaluation.

In the NCS, self-criticism was associated with posttraumatic stress disorder (PTSD) even after controlling for lifetime history of affective and anxiety disorders.²⁰ Self-criticism predicted greater severity of combat-related PTSD in hospitalized male veterans,²² and those with PTSD had higher scores on self-criticism scales than those with major depressive disorder.²³ In a study of Holocaust survivors, those with PTSD scored higher on self-criticism than survivors without PTSD.²⁴ Self-criticism also distinguished between female victims of domestic violence with and without PTSD.²⁵

Self-compassion could be a protective factor for posttraumatic stress.²⁶ Combat veterans with higher levels of self-compassion showed lower levels of psychopathology, better functioning in daily life, and fewer symptoms of posttraumatic stress.²⁷ In fact, self-compassion has been found to be a stronger predictor of PTSD than level of combat exposure.²⁸

In an early study, self-criticism scores were higher in patients with panic disorder than in healthy controls, but lower than in patients with depression.²⁹ In a study of a mixed sample of anxiety disorder patients, symptoms of generalized anxiety disorder were associated with shame proneness.³⁰ Consistent with these results, Hoge et al³¹ found that self-compassion was lower in generalized anxiety disorder patients compared with healthy controls with elevated stress. Low self-compassion has been associated with severity of obsessive-compulsive disorder.³²

Eating disorders

Self-criticism is correlated with eating disorder severity.³³ In a study of patients with binge eating disorder, Dunkley and Grilo³⁴ found that self-criticism was associated with the over-evaluation of shape and weight independently of self-esteem and depression. Self-criticism also is associated with body dissatisfaction, independent of self-esteem and depression. Dunkley et al³⁵ found that self-criticism, but not global self-esteem, in patients with binge eating disorder mediated the relationship between childhood abuse and body dissatisfaction and depression. Numerous studies have shown that shame is associated with more severe eating disorder pathology.³³

Self-compassion seems to buffer against body image concerns. It is associated with less body dissatisfaction, body preoccupation, and weight worries,³⁶ greater body appreciation³⁷ and less disordered eating.^37-39 Early decreases in shame during eating disorder treatment was associated with more rapid reduction in eating disorder symptoms.⁴⁰

Interpersonal relationships

Several studies have shown that self-criticism has negative effects on interpersonal relationships throughout life.^5,41,42

• Self-criticism at age 12 predicted less involvement in high school activities and, at age 31, personal and social maladjustment.⁴³
• High school students with high self-criticism reported more interpersonal problems.⁴⁴
• Self-criticism was associated with loneliness, depression, and lack of intimacy with opposite sex friends or partners during the transition to college.⁴⁵
• In a study of college roommates,⁴⁶ self-criticism was associated with increased likelihood of rejection.
• Whiffen and Aube⁴⁷ found that self-criticism was associated with marital dissatisfaction and depression.
• Self-critical mothers with postpartum depression were less satisfied with social support and were more vulnerable to depression.⁴⁸

Self-compassion appears to enhance interpersonal relationships. In a study of heterosexual couples,⁴⁹ self-compassionate individuals were described by their partners as being more emotionally connected, as well as accepting and supporting autonomy, while being less detached, controlling, and verbally or physically aggressive than those lacking self-compassion. Because self-compassionate people give themselves care and support, they seem to have more emotional resources available to give to others.

See the Box examining the evidence on the role of self-compassion in borderline personality disorder and non-suicidal self-injury.

Achieving goals

Powers et al⁵⁰ suggest that self-critics approach goals based on motivation to avoid failure and disapproval, rather than on intrinsic interest and personal meaning. In studies of college students pursuing academic, social, or weight loss goals, self-criticism was associated with less progress to that goal. Self-criticism was associated with rumination and procrastination, which the authors suggest might have focused the self-critic on potential failure, negative evaluation from others, and loss of self-esteem. Additional studies showed the deleterious effects of self-criticism on college students’ progress on obtaining academic or music performance goals and on community residents’ weight loss goals.⁵¹

Not surprisingly, self-compassion is associated with successful goal pursuit and resilience when goals are not met⁵² and less procrastination and academic worry.⁵³ Self-compassion also is associated with intrinsic motivation, goals based on mastery rather than performance, and less fear of academic failure.⁵⁴

How self-criticism and self-compassion develop

Studies have explored the impact of early relationships with parents and development of self-criticism. Parental overcontrol and restrictiveness and lack of warmth consistently have been identified as parenting styles associated with development of self-criticism in children.⁵⁵ One study found that self-criticism fully mediated the relationship between childhood verbal abuse from parents and depression and anxiety in adulthood.⁵⁶ Reports from parents on their current parenting styles are consistent with these studies.⁵⁷ Amitay et al⁵⁷ states that “[s]elf-critics’ negative childhood experiences thus seem to contribute to a pattern of entering, creating, or manipulating subsequent interpersonal environments in ways that perpetuate their negative self-image and increase vulnerability to depression.” Not surprisingly, self-criticism is associated with a fearful avoidant attachment style.⁵⁸ Review of the developmental origins of self-criticism confirms these factors and presents findings that peer relationships also are important factors in the development of self-criticism.^59,60

Early positive relationships with caregivers are associated with self-compassion. Recollections of maternal support are correlated with self-compassion and secure attachment styles in adolescents and adults.⁶¹ Pepping et al⁶² found that retrospective reports of parental rejection, overprotection, and low parental warmth was associated with low self-compassion.

Benefits of self-compassion

A growing body of research suggests that self-compassion is strongly linked to mental health. Greater self-compassion consistently has been associated with lower levels of depression and anxiety,³ with a large effect size.⁴ Of course, central to self-compassion is the lack of self-criticism, but self-compassion still protects against anxiety and depression when controlling for self-criticism and negative affect.^6,63 Self-compassion is a strong predictor of symptom severity and quality of life among individuals with anxious distress.⁶⁴

The benefits of self-compassion stem partly from a greater ability to cope with negative emotions.^6,63,65 Self-compassionate people are less likely to ruminate on their negative thoughts and emotions or suppress them,^6,66 which helps to explain why self-compassion is a negative predictor of depression.⁶⁷

Self-compassion also enhances positive mind states. A number of studies have found links between self-compassion and positive psychological qualities, such as happiness, optimism, wisdom, curiosity, and exploration, and personal initiative.^63,65,68,69 By embracing one’s suffering with compassion, negative states are ameliorated when positive emotions of kindness, connectedness, and mindful presence are generated.

Misconceptions about self-compassion

A common misconception is that abandoning self-criticism in favor of self-compassion will undermine motivation⁷⁰; however, research indicates the opposite. Although self-compassion is negatively associated with maladaptive perfectionism, it is not correlated with self-adopted performance standards.⁶ Self-compassionate people have less fear of failure⁵⁴ and, when they do fail, they are more likely to try again.⁷¹ Breines and Chen⁷² found in a series of experimental studies that engendering feelings of self-compassion for personal weaknesses, failures, and past transgressions resulted in more motivation to change, to try harder to learn, and to avoid repeating past mistakes.

Another common misunderstanding is that self-compassion is a weakness. In fact, research suggests that self-compassion is a powerful way to cope with life challenges.⁷³

Although some fear that self-compassion leads to self-indulgence, there is evidence that self-compassion promotes health-related behaviors. Self-compassionate individuals are more likely to seek medical treatment when needed,⁷⁴ exercise for intrinsic reasons,⁷⁵ and drink less alcohol.⁷⁶ Inducing self-compassion has been found to help people stick to their diets⁷⁷ and quit smoking.⁷⁸

Self-compassion interventions

Individuals can develop self-compassion. Shapira and Mongrain⁷⁹ found that adults who wrote a compassionate letter to themselves once a day for a week about the distressing events they were experiencing showed significant reductions in depression up to 3 months and significant increases in happiness up to 6 months compared with a control group who wrote about early memories. Albertson et al⁸⁰ found that, compared with a wait-list control group, 3 weeks of self-compassion meditation training improved body dissatisfaction, body shame, and body appreciation among women with body image concerns. Similarly, Smeets et al⁸¹ found that 3 weeks of self-compassion training for female college students led to significantly greater increases in mindfulness, optimism, and self-efficacy, as well as greater decreases in rumination compared with a time management control group.

The Box^6,70,82-86 describes rating scales that can measure self-compassion and self-criticism.

Mindful self-compassion (MSC), developed by Neff and Germer,⁸⁷ is an 8-week group intervention designed to teach people how to be more self-compassionate through meditation and informal practices in daily life. Results of a randomized controlled trial found that, compared with a wait-list control group, participants using MSC reported significantly greater increases in self-compassion, compassion for others, mindfulness, and life satisfaction, and greater decreases in depression, anxiety, stress, and emotional avoidance, with large effect sizes indicated. These results were maintained up to 1 year.

Compassion-focused therapy (CFT) is designed to enhance self-compassion in clinical populations.⁸⁸ The approach uses a number of imagery and experiential exercises to enhance patients’ abilities to extend feelings of reassurance, safeness, and understanding toward themselves. CFT has shown promise in treating a diverse group of clinical disorders such as depression and shame,^8,89 social anxiety and shame,⁹⁰ eating disorders,⁹¹ psychosis,⁹² and patients with acquired brain injury.⁹³ A group-based CFT intervention with a heterogeneous group of community mental health patients led to significant reductions in depression, anxiety, stress, and self-criticism.⁹⁴ See Leaviss and Utley⁹⁵ for a review of the benefits of CFT.

Fears of developing self-compassion

It is important to note that some people can access self-compassion more easily than others. Highly self-critical patients could feel anxious when learning to be compassionate to themselves, a phenomenon known as “fear of compassion”⁹⁶ or “backdraft.”⁹⁷ Backdraft occurs when a firefighter opens a door with a hot fire behind it. Oxygen rushes in, causing a burst of flame. Similarly, when the door of the heart is opened with compassion, intense pain could be released. Unconditional love reveals the conditions under which we were unloved in the past. Some individuals, especially those with a history of childhood abuse or neglect, are fearful of compassion because it activates grief associated with feelings of wanting, but not receiving, affection and care from significant others in childhood.

Clinicians should be aware that anxiety could arise and should help patients learn how to go slowly and stabilize themselves if overwhelming emotions occur as a part of self-compassion practice. Both CFT and MSC have processes to deal with fear of compassion in their protocols,^98,99 with the focus on explaining to individuals that although such fears may occur, they are a normal and necessary part of the healing process. Individuals also are taught to focus on the breath, feeling the sensations in the soles of their feet, or other mindfulness practices to ground and stabilize attention when overwhelming feelings arise.

Clinical interventions

Self-compassion interventions that I (R.W.) find most helpful, in the order I administer them, are:

• exploring perceived advantages and disadvantages of self-criticism
• presenting self-compassion as a way to get the perceived advantages of self-criticism without the disadvantages
• discussing what it means to be compassionate for someone else who is suffering, and then asking what it would be like if they treated themselves with the same compassion
• exploring patients’ misconceptions and fears of self-compassion
• directing patients to the self-compassion Web site to get an understanding of what self-compassion is and how it differs from self-esteem
• taking an example of a recent situation in which the patient was self-critical and exploring how a self-compassionate response would differ.

Asking what they would say to a friend often is an effective way to get at this. In a later therapy session, self-compassionate imagery is a useful way to get the patient to experience self-compassion on an emotional level. See Neff¹⁰⁰ and Gilbert⁹⁸ for other techniques to enhance self-compassion.

Once thought to only be associated with depression, self-criticism is a transdiagnostic risk factor for diverse forms of psychopathology.^1,2 However, research has shown that self-compassion is a robust resilience factor when faced with feelings of personal inadequacy.^3,4

Self-critical individuals experience feelings of unworthiness, inferiority, failure, and guilt. They engage in constant and harsh self-scrutiny and evaluation, and fear being disapproved and criticized and losing the approval and acceptance of others.⁵ Self-compassion involves treating oneself with care and concern when confronted with personal inadequacies, mistakes, failures, and painful life situations.^6,7Although self-criticism is the aspect of perfectionism most associated with maladjustment,⁸ one can be harshly self-critical without being a perfectionist. Most studies of self-criticism have not measured shame; however, this self-conscious emotion has been implicated in diverse forms of psychopathology.⁹ In contrast to guilt, which results from acknowledging bad behavior, shame results from seeing oneself as a bad or inadequate person.

Although self-criticism is destructive across clinical disorders and interpersonal relationships, self-compassion is associated with healthy relationships, emotional well-being, and better treatment outcomes.

Recent research shows how clinicians can teach their patients how to be less self-critical and more self-compassionate. Neff^6,7 proposes that self-compassion involves treating yourself with care and concern when being confronted with personal inadequacies, mistakes, failures, and painful life situations. It consists of 3 interacting components, each of which has a positive and negative pole:

• self-kindness vs self-judgment
• a sense of common humanity vs isolation
• mindfulness vs over-identification.

Self-kindness refers to being caring and understanding with oneself rather than harshly judgmental. Instead of attacking and berating oneself for personal shortcomings, the self is offered warmth and unconditional acceptance.

Humanity involves recognizing that humans are imperfect, that all people fail, make mistakes, and have serious life challenges. By remembering that imperfection is part of life, we feel less isolated when we are in pain.

Mindfulness in the context of self-compassion involves being aware of one’s painful experiences in a balanced way that neither ignores and avoids nor exaggerates painful thoughts and emotions.

Self-compassion is more than the absence of self-judgment, although a defining feature of self-compassion is the lack of self-judgment, and self-judgment overlaps with self-criticism. Rather, self-compassion provides several access points for reducing self-criticism. For example, being kind and understanding when confronting personal inadequacies (eg, “it’s okay not to be perfect”) can counter harsh self-talk (eg, “I’m not defective”). Mindfulness of emotional pain (eg, “this is hard”) can facilitate a kind and warm response (eg, “what can I do to take care of myself right now?”) and therefore lessen self-blame (eg, “blaming myself is just causing me more suffering”). Similarly, remembering that failure is part of the human experience (eg, “it’s normal to mess up sometimes”) can lessen egocentric feelings of isolation (eg, “it’s not just me”) and over-identification (eg, “it’s not the end of the world”), resulting in lessened self-criticism (eg, “maybe it’s not just because I’m a bad person”).

Depression

Several studies have found that self-criticism predicts depression. In 3 epidemiological studies, “feeling worthless” was among the top 2 symptoms predicting a depression diagnosis and later depressive episodes.¹⁰ Self-criticism in fourth-year medical students predicted depression 2 years later, and—in males—10 years later in their medical careers better than a history of depression.¹¹ Self-critical perfectionism also is associated with suicidal ideation and lethality of suicide attempts.¹²

Self-criticism has been shown to predict depressive relapse and residual self-devaluative symptoms in recovered depressed patients.¹³ In one study, currently depressed and remitted depressed patients had higher self-criticism and lower self-compassion compared with healthy controls. Both factors were more strongly associated with depression status than higher perfectionistic beliefs and cognitions, rumination, and maladaptive emotional regulation.¹⁴

Self-criticism and response to treatment. In the National Institute of Mental Health Treatment of Depression Collaborative Research Program,¹⁵ self-critical perfectionism predicted a poorer outcome across all 4 treatments (cognitive-behavioral therapy [CBT], interpersonal psychotherapy [IPT], pharmacotherapy plus clinical management, and placebo plus clinical management). Subsequent studies found that self-criticism predicted poorer response to CBT¹⁶ and IPT.¹⁷ The authors suggest that self-criticism could interfere with treatment because self-critical patients might have difficulty developing a strong therapeutic alliance.^18,19

Anxiety disorders

Self-criticism is common across psychiatric disorders. In a study of 5,877 respondents in the National Comorbidity Survey (NCS), self-criticism was associated with social phobia, findings that were significant after controlling for current emotional distress, neuroticism, and lifetime history of mood, anxiety, and substance use disorders.²⁰ Further, in a CBT treatment study, baseline self-criticism was associated with severity of social phobia and changes in self-criticism predicted treatment outcome.²¹ Self-criticism might be an important core psychological process in the development, maintenance, and course of social phobia. Patients with social anxiety disorder have less self-compassion than healthy controls and greater fear of negative evaluation.

In the NCS, self-criticism was associated with posttraumatic stress disorder (PTSD) even after controlling for lifetime history of affective and anxiety disorders.²⁰ Self-criticism predicted greater severity of combat-related PTSD in hospitalized male veterans,²² and those with PTSD had higher scores on self-criticism scales than those with major depressive disorder.²³ In a study of Holocaust survivors, those with PTSD scored higher on self-criticism than survivors without PTSD.²⁴ Self-criticism also distinguished between female victims of domestic violence with and without PTSD.²⁵

Self-compassion could be a protective factor for posttraumatic stress.²⁶ Combat veterans with higher levels of self-compassion showed lower levels of psychopathology, better functioning in daily life, and fewer symptoms of posttraumatic stress.²⁷ In fact, self-compassion has been found to be a stronger predictor of PTSD than level of combat exposure.²⁸

In an early study, self-criticism scores were higher in patients with panic disorder than in healthy controls, but lower than in patients with depression.²⁹ In a study of a mixed sample of anxiety disorder patients, symptoms of generalized anxiety disorder were associated with shame proneness.³⁰ Consistent with these results, Hoge et al³¹ found that self-compassion was lower in generalized anxiety disorder patients compared with healthy controls with elevated stress. Low self-compassion has been associated with severity of obsessive-compulsive disorder.³²

Eating disorders

Self-criticism is correlated with eating disorder severity.³³ In a study of patients with binge eating disorder, Dunkley and Grilo³⁴ found that self-criticism was associated with the over-evaluation of shape and weight independently of self-esteem and depression. Self-criticism also is associated with body dissatisfaction, independent of self-esteem and depression. Dunkley et al³⁵ found that self-criticism, but not global self-esteem, in patients with binge eating disorder mediated the relationship between childhood abuse and body dissatisfaction and depression. Numerous studies have shown that shame is associated with more severe eating disorder pathology.³³

Self-compassion seems to buffer against body image concerns. It is associated with less body dissatisfaction, body preoccupation, and weight worries,³⁶ greater body appreciation³⁷ and less disordered eating.^37-39 Early decreases in shame during eating disorder treatment was associated with more rapid reduction in eating disorder symptoms.⁴⁰

Interpersonal relationships

Several studies have shown that self-criticism has negative effects on interpersonal relationships throughout life.^5,41,42

• Self-criticism at age 12 predicted less involvement in high school activities and, at age 31, personal and social maladjustment.⁴³
• High school students with high self-criticism reported more interpersonal problems.⁴⁴
• Self-criticism was associated with loneliness, depression, and lack of intimacy with opposite sex friends or partners during the transition to college.⁴⁵
• In a study of college roommates,⁴⁶ self-criticism was associated with increased likelihood of rejection.
• Whiffen and Aube⁴⁷ found that self-criticism was associated with marital dissatisfaction and depression.
• Self-critical mothers with postpartum depression were less satisfied with social support and were more vulnerable to depression.⁴⁸

Self-compassion appears to enhance interpersonal relationships. In a study of heterosexual couples,⁴⁹ self-compassionate individuals were described by their partners as being more emotionally connected, as well as accepting and supporting autonomy, while being less detached, controlling, and verbally or physically aggressive than those lacking self-compassion. Because self-compassionate people give themselves care and support, they seem to have more emotional resources available to give to others.

See the Box examining the evidence on the role of self-compassion in borderline personality disorder and non-suicidal self-injury.

Achieving goals

Powers et al⁵⁰ suggest that self-critics approach goals based on motivation to avoid failure and disapproval, rather than on intrinsic interest and personal meaning. In studies of college students pursuing academic, social, or weight loss goals, self-criticism was associated with less progress to that goal. Self-criticism was associated with rumination and procrastination, which the authors suggest might have focused the self-critic on potential failure, negative evaluation from others, and loss of self-esteem. Additional studies showed the deleterious effects of self-criticism on college students’ progress on obtaining academic or music performance goals and on community residents’ weight loss goals.⁵¹

Not surprisingly, self-compassion is associated with successful goal pursuit and resilience when goals are not met⁵² and less procrastination and academic worry.⁵³ Self-compassion also is associated with intrinsic motivation, goals based on mastery rather than performance, and less fear of academic failure.⁵⁴

How self-criticism and self-compassion develop

Studies have explored the impact of early relationships with parents and development of self-criticism. Parental overcontrol and restrictiveness and lack of warmth consistently have been identified as parenting styles associated with development of self-criticism in children.⁵⁵ One study found that self-criticism fully mediated the relationship between childhood verbal abuse from parents and depression and anxiety in adulthood.⁵⁶ Reports from parents on their current parenting styles are consistent with these studies.⁵⁷ Amitay et al⁵⁷ states that “[s]elf-critics’ negative childhood experiences thus seem to contribute to a pattern of entering, creating, or manipulating subsequent interpersonal environments in ways that perpetuate their negative self-image and increase vulnerability to depression.” Not surprisingly, self-criticism is associated with a fearful avoidant attachment style.⁵⁸ Review of the developmental origins of self-criticism confirms these factors and presents findings that peer relationships also are important factors in the development of self-criticism.^59,60

Early positive relationships with caregivers are associated with self-compassion. Recollections of maternal support are correlated with self-compassion and secure attachment styles in adolescents and adults.⁶¹ Pepping et al⁶² found that retrospective reports of parental rejection, overprotection, and low parental warmth was associated with low self-compassion.

Benefits of self-compassion

A growing body of research suggests that self-compassion is strongly linked to mental health. Greater self-compassion consistently has been associated with lower levels of depression and anxiety,³ with a large effect size.⁴ Of course, central to self-compassion is the lack of self-criticism, but self-compassion still protects against anxiety and depression when controlling for self-criticism and negative affect.^6,63 Self-compassion is a strong predictor of symptom severity and quality of life among individuals with anxious distress.⁶⁴

The benefits of self-compassion stem partly from a greater ability to cope with negative emotions.^6,63,65 Self-compassionate people are less likely to ruminate on their negative thoughts and emotions or suppress them,^6,66 which helps to explain why self-compassion is a negative predictor of depression.⁶⁷

Self-compassion also enhances positive mind states. A number of studies have found links between self-compassion and positive psychological qualities, such as happiness, optimism, wisdom, curiosity, and exploration, and personal initiative.^63,65,68,69 By embracing one’s suffering with compassion, negative states are ameliorated when positive emotions of kindness, connectedness, and mindful presence are generated.

Misconceptions about self-compassion

A common misconception is that abandoning self-criticism in favor of self-compassion will undermine motivation⁷⁰; however, research indicates the opposite. Although self-compassion is negatively associated with maladaptive perfectionism, it is not correlated with self-adopted performance standards.⁶ Self-compassionate people have less fear of failure⁵⁴ and, when they do fail, they are more likely to try again.⁷¹ Breines and Chen⁷² found in a series of experimental studies that engendering feelings of self-compassion for personal weaknesses, failures, and past transgressions resulted in more motivation to change, to try harder to learn, and to avoid repeating past mistakes.

Another common misunderstanding is that self-compassion is a weakness. In fact, research suggests that self-compassion is a powerful way to cope with life challenges.⁷³

Although some fear that self-compassion leads to self-indulgence, there is evidence that self-compassion promotes health-related behaviors. Self-compassionate individuals are more likely to seek medical treatment when needed,⁷⁴ exercise for intrinsic reasons,⁷⁵ and drink less alcohol.⁷⁶ Inducing self-compassion has been found to help people stick to their diets⁷⁷ and quit smoking.⁷⁸

Self-compassion interventions

Individuals can develop self-compassion. Shapira and Mongrain⁷⁹ found that adults who wrote a compassionate letter to themselves once a day for a week about the distressing events they were experiencing showed significant reductions in depression up to 3 months and significant increases in happiness up to 6 months compared with a control group who wrote about early memories. Albertson et al⁸⁰ found that, compared with a wait-list control group, 3 weeks of self-compassion meditation training improved body dissatisfaction, body shame, and body appreciation among women with body image concerns. Similarly, Smeets et al⁸¹ found that 3 weeks of self-compassion training for female college students led to significantly greater increases in mindfulness, optimism, and self-efficacy, as well as greater decreases in rumination compared with a time management control group.

The Box^6,70,82-86 describes rating scales that can measure self-compassion and self-criticism.

Mindful self-compassion (MSC), developed by Neff and Germer,⁸⁷ is an 8-week group intervention designed to teach people how to be more self-compassionate through meditation and informal practices in daily life. Results of a randomized controlled trial found that, compared with a wait-list control group, participants using MSC reported significantly greater increases in self-compassion, compassion for others, mindfulness, and life satisfaction, and greater decreases in depression, anxiety, stress, and emotional avoidance, with large effect sizes indicated. These results were maintained up to 1 year.

Compassion-focused therapy (CFT) is designed to enhance self-compassion in clinical populations.⁸⁸ The approach uses a number of imagery and experiential exercises to enhance patients’ abilities to extend feelings of reassurance, safeness, and understanding toward themselves. CFT has shown promise in treating a diverse group of clinical disorders such as depression and shame,^8,89 social anxiety and shame,⁹⁰ eating disorders,⁹¹ psychosis,⁹² and patients with acquired brain injury.⁹³ A group-based CFT intervention with a heterogeneous group of community mental health patients led to significant reductions in depression, anxiety, stress, and self-criticism.⁹⁴ See Leaviss and Utley⁹⁵ for a review of the benefits of CFT.

Fears of developing self-compassion

It is important to note that some people can access self-compassion more easily than others. Highly self-critical patients could feel anxious when learning to be compassionate to themselves, a phenomenon known as “fear of compassion”⁹⁶ or “backdraft.”⁹⁷ Backdraft occurs when a firefighter opens a door with a hot fire behind it. Oxygen rushes in, causing a burst of flame. Similarly, when the door of the heart is opened with compassion, intense pain could be released. Unconditional love reveals the conditions under which we were unloved in the past. Some individuals, especially those with a history of childhood abuse or neglect, are fearful of compassion because it activates grief associated with feelings of wanting, but not receiving, affection and care from significant others in childhood.

Clinicians should be aware that anxiety could arise and should help patients learn how to go slowly and stabilize themselves if overwhelming emotions occur as a part of self-compassion practice. Both CFT and MSC have processes to deal with fear of compassion in their protocols,^98,99 with the focus on explaining to individuals that although such fears may occur, they are a normal and necessary part of the healing process. Individuals also are taught to focus on the breath, feeling the sensations in the soles of their feet, or other mindfulness practices to ground and stabilize attention when overwhelming feelings arise.

Clinical interventions

Self-compassion interventions that I (R.W.) find most helpful, in the order I administer them, are:

• exploring perceived advantages and disadvantages of self-criticism
• presenting self-compassion as a way to get the perceived advantages of self-criticism without the disadvantages
• discussing what it means to be compassionate for someone else who is suffering, and then asking what it would be like if they treated themselves with the same compassion
• exploring patients’ misconceptions and fears of self-compassion
• directing patients to the self-compassion Web site to get an understanding of what self-compassion is and how it differs from self-esteem
• taking an example of a recent situation in which the patient was self-critical and exploring how a self-compassionate response would differ.

Asking what they would say to a friend often is an effective way to get at this. In a later therapy session, self-compassionate imagery is a useful way to get the patient to experience self-compassion on an emotional level. See Neff¹⁰⁰ and Gilbert⁹⁸ for other techniques to enhance self-compassion.

Alcohol withdrawal is an uncomfortable and potentially life-threatening condition that must be treated before patients can achieve sobriety. Benzodiazepines remain the first-line treatment for alcohol withdrawal; however, these agents could:

• exacerbate agitation
• interact adversely with other medications, particularly opioids
• be unsafe for outpatients at risk of drinking again.
  

Off-label use of anticonvulsants could reduce these risks. In our emergency department, we routinely use these agents as monotherapy for patients discharging to outpatient detoxification or as adjunctive treatment for patients who require admission for severe withdrawal (Table^1,2).

Gabapentin is safe for patients with liver disease and has few drug–drug interactions.¹ Dosages of at least 1,200 mg/d seems to be comparable to lorazepam for alcohol withdrawal and could help prevent relapse after the withdrawal period.¹ Many patients report that gabapentin helps them sleep. Gabapentin could cause gastrointestinal upset or slight dizziness; patients with severe renal disease might require dosage adjustments.

Carbamazepine. In a randomized double-blind trial, carbamazepine was superior to lorazepam in preventing rebound withdrawal symptoms and reducing post-treatment drinking, although both agents were effective in decreasing withdrawal symptoms.² Avoid this agent in patients with serum liver enzymes 3 times higher than normal values, renal disease, neuropathy, thrombocytopenia, or leukopenia. Drug–drug interactions typically are not of concern unless a patient takes carbamazepine for several weeks.

Divalproex with as-needed benzodiazepines reduces the duration of withdrawal and risk of medical complications.³ Avoid using divalproex in patients with thrombocytopenia, leukopenia, or severe liver disease.

Alcohol withdrawal is an uncomfortable and potentially life-threatening condition that must be treated before patients can achieve sobriety. Benzodiazepines remain the first-line treatment for alcohol withdrawal; however, these agents could:

• exacerbate agitation
• interact adversely with other medications, particularly opioids
• be unsafe for outpatients at risk of drinking again.
  

Off-label use of anticonvulsants could reduce these risks. In our emergency department, we routinely use these agents as monotherapy for patients discharging to outpatient detoxification or as adjunctive treatment for patients who require admission for severe withdrawal (Table^1,2).

Gabapentin is safe for patients with liver disease and has few drug–drug interactions.¹ Dosages of at least 1,200 mg/d seems to be comparable to lorazepam for alcohol withdrawal and could help prevent relapse after the withdrawal period.¹ Many patients report that gabapentin helps them sleep. Gabapentin could cause gastrointestinal upset or slight dizziness; patients with severe renal disease might require dosage adjustments.

Carbamazepine. In a randomized double-blind trial, carbamazepine was superior to lorazepam in preventing rebound withdrawal symptoms and reducing post-treatment drinking, although both agents were effective in decreasing withdrawal symptoms.² Avoid this agent in patients with serum liver enzymes 3 times higher than normal values, renal disease, neuropathy, thrombocytopenia, or leukopenia. Drug–drug interactions typically are not of concern unless a patient takes carbamazepine for several weeks.

Divalproex with as-needed benzodiazepines reduces the duration of withdrawal and risk of medical complications.³ Avoid using divalproex in patients with thrombocytopenia, leukopenia, or severe liver disease.

Alcohol withdrawal is an uncomfortable and potentially life-threatening condition that must be treated before patients can achieve sobriety. Benzodiazepines remain the first-line treatment for alcohol withdrawal; however, these agents could:

• exacerbate agitation
• interact adversely with other medications, particularly opioids
• be unsafe for outpatients at risk of drinking again.
  

Off-label use of anticonvulsants could reduce these risks. In our emergency department, we routinely use these agents as monotherapy for patients discharging to outpatient detoxification or as adjunctive treatment for patients who require admission for severe withdrawal (Table^1,2).

Gabapentin is safe for patients with liver disease and has few drug–drug interactions.¹ Dosages of at least 1,200 mg/d seems to be comparable to lorazepam for alcohol withdrawal and could help prevent relapse after the withdrawal period.¹ Many patients report that gabapentin helps them sleep. Gabapentin could cause gastrointestinal upset or slight dizziness; patients with severe renal disease might require dosage adjustments.

Carbamazepine. In a randomized double-blind trial, carbamazepine was superior to lorazepam in preventing rebound withdrawal symptoms and reducing post-treatment drinking, although both agents were effective in decreasing withdrawal symptoms.² Avoid this agent in patients with serum liver enzymes 3 times higher than normal values, renal disease, neuropathy, thrombocytopenia, or leukopenia. Drug–drug interactions typically are not of concern unless a patient takes carbamazepine for several weeks.

Divalproex with as-needed benzodiazepines reduces the duration of withdrawal and risk of medical complications.³ Avoid using divalproex in patients with thrombocytopenia, leukopenia, or severe liver disease.

Earlier this year, the Centers for Disease Control and Prevention (CDC) published a clinical practice guideline aimed at decreasing opioid use in the treatment of chronic pain.¹ It developed this guideline in response to the increasing problem of opioid abuse and opioid-related mortality in the United States.

The CDC notes that an estimated 1.9 million people abused or were dependent on prescription opioid pain medication in 2013.¹ Between 1999 and 2014, more than 165,000 people in the United States died from an overdose of opioid pain medication, with that rate increasing markedly in the past decade.¹ In 2011, an estimated 420,000 emergency department visits were related to the abuse of narcotic pain relievers.²

While the problem of increasing opioid-related abuse and deaths has been apparent for some time, effective interventions have been elusive. Evidence remains sparse on the benefits and harms of long-term opioid therapy for chronic pain, except for those at the end of life. Evidence has been insufficient to determine long-term benefits of opioid therapy vs no opioid therapy, although the potential for harms from high doses of opioids are documented. There is not much evidence comparing nonpharmacologic and non-opioid pharmacologic treatments with long-term opioid therapy.

This lack of an evidence base is reflected in the CDC guideline. Of the guideline’s 12 recommendations, not one has high-level supporting evidence and only one has even moderate-level evidence behind it. Four recommendations are supported by low-level evidence, and 7 by very-low-level evidence. Yet 11 of the 12 are given an A recommendation, meaning that the guideline panel feels that most patients should receive this course of action.

Methodology used to create the guideline

The guideline committee used a modified GRADE approach (Grading of Recommendations Assessment, Development, and Evaluation) to develop the guideline. It is the same system the Advisory Committee on Immunization Practices adopted to assess and make recommendations on vaccines.³ The system’s classification of levels of evidence and recommendation categories are described in FIGURE 1.¹

The committee started by assessing evidence with a report on the long-term effectiveness of opioids for chronic pain, produced by the Agency for Health Care Research and Quality in 2014;⁴ it then augmented that report by performing an updated search for new evidence published since the report came out.⁵ The committee then conducted a “contextual evidence review”⁶ on the following 4 areas:

1. the effectiveness of nonpharmacologic (cognitive behavioral therapy, exercise therapy, interventional treatments, multimodal pain treatment) and non-opioid pharmacologic treatments (acetaminophen, nonsteroidal anti-inflammatory drugs, antidepressants, anticonvulsants)
2. the benefits and harms of opioid therapy
3. clinician and patient values and preferences related to opioids and medication risks, benefits, and use
4. resource allocation, including costs and economic analyses.

The guideline wording indicates that, for this contextual analysis, the committee used a rapid systematic review methodology, in part because of time constraints given the imperative to produce a guideline to address a pressing problem, and because of a recognition that evidence on the questions would be scant and not of high quality.¹ The 12 recommendations are categorized under 3 main headings.

Determining when to initiate or continue opioids for chronic pain

1. Nonpharmacologic therapy and non-opioid pharmacologic therapy are preferred for chronic pain. Consider opioid therapy only if you anticipate that benefits for both pain and function will outweigh risks to the patient. If opioids are used, combine them as appropriate with nonpharmacologic therapy and non-opioid pharmacologic therapy. (Recommendation category: A; evidence type: 3)

Review your state's prescription drug monitoring program to determine whether a patient is receiving opioid dosages, or dangerous combinations, that increase the risk for overdose.2. Before starting opioid therapy for chronic pain, establish treatment goals with the patient, including realistic goals for pain and function, and consider how therapy will be discontinued if the benefits do not outweigh the risks. Continue opioid therapy only if there is clinically meaningful improvement in pain and function that outweighs risks to patient safety. (Recommendation category: A; evidence type: 4)

3. Before starting opioid therapy, and periodically during its course, discuss with patients known risks and realistic benefits of opioid therapy and patient and clinician responsibilities for managing therapy. (Recommendation category: A; evidence type: 3)

Opioid selection, dosage, duration, follow-up, and discontinuation

4. When starting opioid therapy for chronic pain, prescribe immediate-release opioids instead of extended-release/long-acting (ER/LA) agents. (Recommendation category: A; evidence type: 4)

5. When starting opioids, prescribe the lowest effective dosage. Use caution when prescribing opioids at any dosage; carefully reassess the evidence for individual benefits and risks when increasing the dosage to ≥50 morphine milligram equivalents (MME)/d; and avoid increasing the dosage to ≥90 MME/d (or carefully justify such a decision, if made). (Recommendation category: A; evidence type: 3)

When starting opioid therapy for chronic pain, prescribe immediate-release opioids instead of extended-release/long-acting agents.6. Long-term opioid use often begins with treatment of acute pain. When opioids are used for acute pain, prescribe the lowest effective dose of immediate-release opioids at a quantity no greater than is needed for the expected duration of pain severe enough to require opioids. Three days or less will often be sufficient; more than 7 days will rarely be needed. (Recommendation category: A; evidence type: 4)

7. In monitoring opioid therapy for chronic pain, reevaluate benefits and harms with patients within one to 4 weeks of starting opioid therapy or escalating the dose. Also, evaluate the benefits and harms of continued therapy with patients every 3 months or more frequently. If the benefits of continued opioid therapy do not outweigh the harms, optimize other therapies and work with patients to taper opioids to lower dosages or to taper and discontinue them. (Recommendation category: A; evidence type: 4)

Assessing risk and addressing harms of opioid use

8. Before starting opioid therapy, and periodically during its continuation, evaluate risk factors for opioid-related harms. Incorporate strategies into the management plan to mitigate risk; consider offering naloxone when factors are present that increase the risk for opioid overdose—eg, a history of overdose, history of substance use disorder, higher opioid dosages (≥50 MME/d), or concurrent benzodiazepine use. (Recommendation category: A; evidence type: 4)

9. Review the patient’s history of controlled substance prescriptions. Use data from the state prescription drug monitoring program (PDMP) to determine whether the patient is receiving opioid dosages or dangerous combinations that put him or her at high risk for overdose. (State Web sites are available at http://www.pdmpassist.org/content/state-pdmp-websites.) Review PDMP data when starting opioid therapy for chronic pain and periodically during its continuation, at least every 3 months and with each new prescription. (Recommendation category: A; evidence type: 4)

10. Before prescribing opioids for chronic pain, use urine drug testing to assess for prescribed medications, as well as other controlled prescription drugs and illicit drugs, and consider urine drug testing at least annually. (Recommendation category: B; evidence type: 4)

11. Avoid prescribing opioid pain medication and benzodiazepines concurrently whenever possible. (Recommendation category: A; evidence type: 3)

See JFP's "3 in 3" video on urin drug testing at: http://bit.ly/2eL7Ptz.12. For patients with opioid use disorder, offer or arrange for evidence-based treatment (usually medication-assisted treatment with buprenorphine or methadone in combination with behavioral therapies). (Recommendation category: A; evidence type: 2)

Aids for guideline implementation

The CDC has produced materials to assist physicians in implementing this guideline, including checklists for prescribing or continuing opioids. The checklist for initiation of opioids is reproduced in FIGURE 2.⁷

The CDC is addressing a severe public health problem and doing so by using contemporary evidence-based methodology and guideline development processes. The lack of high-quality evidence on the topic and the use of a less-than-optimal evidence review process for some key questions may hamper this effort. However, given the prominence of the CDC, this clinical guideline will likely be considered the standard of care for family physicians.

Earlier this year, the Centers for Disease Control and Prevention (CDC) published a clinical practice guideline aimed at decreasing opioid use in the treatment of chronic pain.¹ It developed this guideline in response to the increasing problem of opioid abuse and opioid-related mortality in the United States.

The CDC notes that an estimated 1.9 million people abused or were dependent on prescription opioid pain medication in 2013.¹ Between 1999 and 2014, more than 165,000 people in the United States died from an overdose of opioid pain medication, with that rate increasing markedly in the past decade.¹ In 2011, an estimated 420,000 emergency department visits were related to the abuse of narcotic pain relievers.²

While the problem of increasing opioid-related abuse and deaths has been apparent for some time, effective interventions have been elusive. Evidence remains sparse on the benefits and harms of long-term opioid therapy for chronic pain, except for those at the end of life. Evidence has been insufficient to determine long-term benefits of opioid therapy vs no opioid therapy, although the potential for harms from high doses of opioids are documented. There is not much evidence comparing nonpharmacologic and non-opioid pharmacologic treatments with long-term opioid therapy.

This lack of an evidence base is reflected in the CDC guideline. Of the guideline’s 12 recommendations, not one has high-level supporting evidence and only one has even moderate-level evidence behind it. Four recommendations are supported by low-level evidence, and 7 by very-low-level evidence. Yet 11 of the 12 are given an A recommendation, meaning that the guideline panel feels that most patients should receive this course of action.

Methodology used to create the guideline

The guideline committee used a modified GRADE approach (Grading of Recommendations Assessment, Development, and Evaluation) to develop the guideline. It is the same system the Advisory Committee on Immunization Practices adopted to assess and make recommendations on vaccines.³ The system’s classification of levels of evidence and recommendation categories are described in FIGURE 1.¹

The committee started by assessing evidence with a report on the long-term effectiveness of opioids for chronic pain, produced by the Agency for Health Care Research and Quality in 2014;⁴ it then augmented that report by performing an updated search for new evidence published since the report came out.⁵ The committee then conducted a “contextual evidence review”⁶ on the following 4 areas:

1. the effectiveness of nonpharmacologic (cognitive behavioral therapy, exercise therapy, interventional treatments, multimodal pain treatment) and non-opioid pharmacologic treatments (acetaminophen, nonsteroidal anti-inflammatory drugs, antidepressants, anticonvulsants)
2. the benefits and harms of opioid therapy
3. clinician and patient values and preferences related to opioids and medication risks, benefits, and use
4. resource allocation, including costs and economic analyses.

The guideline wording indicates that, for this contextual analysis, the committee used a rapid systematic review methodology, in part because of time constraints given the imperative to produce a guideline to address a pressing problem, and because of a recognition that evidence on the questions would be scant and not of high quality.¹ The 12 recommendations are categorized under 3 main headings.

Determining when to initiate or continue opioids for chronic pain

1. Nonpharmacologic therapy and non-opioid pharmacologic therapy are preferred for chronic pain. Consider opioid therapy only if you anticipate that benefits for both pain and function will outweigh risks to the patient. If opioids are used, combine them as appropriate with nonpharmacologic therapy and non-opioid pharmacologic therapy. (Recommendation category: A; evidence type: 3)

Review your state's prescription drug monitoring program to determine whether a patient is receiving opioid dosages, or dangerous combinations, that increase the risk for overdose.2. Before starting opioid therapy for chronic pain, establish treatment goals with the patient, including realistic goals for pain and function, and consider how therapy will be discontinued if the benefits do not outweigh the risks. Continue opioid therapy only if there is clinically meaningful improvement in pain and function that outweighs risks to patient safety. (Recommendation category: A; evidence type: 4)

3. Before starting opioid therapy, and periodically during its course, discuss with patients known risks and realistic benefits of opioid therapy and patient and clinician responsibilities for managing therapy. (Recommendation category: A; evidence type: 3)

Opioid selection, dosage, duration, follow-up, and discontinuation

4. When starting opioid therapy for chronic pain, prescribe immediate-release opioids instead of extended-release/long-acting (ER/LA) agents. (Recommendation category: A; evidence type: 4)

5. When starting opioids, prescribe the lowest effective dosage. Use caution when prescribing opioids at any dosage; carefully reassess the evidence for individual benefits and risks when increasing the dosage to ≥50 morphine milligram equivalents (MME)/d; and avoid increasing the dosage to ≥90 MME/d (or carefully justify such a decision, if made). (Recommendation category: A; evidence type: 3)

When starting opioid therapy for chronic pain, prescribe immediate-release opioids instead of extended-release/long-acting agents.6. Long-term opioid use often begins with treatment of acute pain. When opioids are used for acute pain, prescribe the lowest effective dose of immediate-release opioids at a quantity no greater than is needed for the expected duration of pain severe enough to require opioids. Three days or less will often be sufficient; more than 7 days will rarely be needed. (Recommendation category: A; evidence type: 4)

7. In monitoring opioid therapy for chronic pain, reevaluate benefits and harms with patients within one to 4 weeks of starting opioid therapy or escalating the dose. Also, evaluate the benefits and harms of continued therapy with patients every 3 months or more frequently. If the benefits of continued opioid therapy do not outweigh the harms, optimize other therapies and work with patients to taper opioids to lower dosages or to taper and discontinue them. (Recommendation category: A; evidence type: 4)

Assessing risk and addressing harms of opioid use

8. Before starting opioid therapy, and periodically during its continuation, evaluate risk factors for opioid-related harms. Incorporate strategies into the management plan to mitigate risk; consider offering naloxone when factors are present that increase the risk for opioid overdose—eg, a history of overdose, history of substance use disorder, higher opioid dosages (≥50 MME/d), or concurrent benzodiazepine use. (Recommendation category: A; evidence type: 4)

9. Review the patient’s history of controlled substance prescriptions. Use data from the state prescription drug monitoring program (PDMP) to determine whether the patient is receiving opioid dosages or dangerous combinations that put him or her at high risk for overdose. (State Web sites are available at http://www.pdmpassist.org/content/state-pdmp-websites.) Review PDMP data when starting opioid therapy for chronic pain and periodically during its continuation, at least every 3 months and with each new prescription. (Recommendation category: A; evidence type: 4)

10. Before prescribing opioids for chronic pain, use urine drug testing to assess for prescribed medications, as well as other controlled prescription drugs and illicit drugs, and consider urine drug testing at least annually. (Recommendation category: B; evidence type: 4)

11. Avoid prescribing opioid pain medication and benzodiazepines concurrently whenever possible. (Recommendation category: A; evidence type: 3)

See JFP's "3 in 3" video on urin drug testing at: http://bit.ly/2eL7Ptz.12. For patients with opioid use disorder, offer or arrange for evidence-based treatment (usually medication-assisted treatment with buprenorphine or methadone in combination with behavioral therapies). (Recommendation category: A; evidence type: 2)

Aids for guideline implementation

The CDC has produced materials to assist physicians in implementing this guideline, including checklists for prescribing or continuing opioids. The checklist for initiation of opioids is reproduced in FIGURE 2.⁷

The CDC is addressing a severe public health problem and doing so by using contemporary evidence-based methodology and guideline development processes. The lack of high-quality evidence on the topic and the use of a less-than-optimal evidence review process for some key questions may hamper this effort. However, given the prominence of the CDC, this clinical guideline will likely be considered the standard of care for family physicians.

Earlier this year, the Centers for Disease Control and Prevention (CDC) published a clinical practice guideline aimed at decreasing opioid use in the treatment of chronic pain.¹ It developed this guideline in response to the increasing problem of opioid abuse and opioid-related mortality in the United States.

The CDC notes that an estimated 1.9 million people abused or were dependent on prescription opioid pain medication in 2013.¹ Between 1999 and 2014, more than 165,000 people in the United States died from an overdose of opioid pain medication, with that rate increasing markedly in the past decade.¹ In 2011, an estimated 420,000 emergency department visits were related to the abuse of narcotic pain relievers.²

While the problem of increasing opioid-related abuse and deaths has been apparent for some time, effective interventions have been elusive. Evidence remains sparse on the benefits and harms of long-term opioid therapy for chronic pain, except for those at the end of life. Evidence has been insufficient to determine long-term benefits of opioid therapy vs no opioid therapy, although the potential for harms from high doses of opioids are documented. There is not much evidence comparing nonpharmacologic and non-opioid pharmacologic treatments with long-term opioid therapy.

This lack of an evidence base is reflected in the CDC guideline. Of the guideline’s 12 recommendations, not one has high-level supporting evidence and only one has even moderate-level evidence behind it. Four recommendations are supported by low-level evidence, and 7 by very-low-level evidence. Yet 11 of the 12 are given an A recommendation, meaning that the guideline panel feels that most patients should receive this course of action.

Methodology used to create the guideline

The guideline committee used a modified GRADE approach (Grading of Recommendations Assessment, Development, and Evaluation) to develop the guideline. It is the same system the Advisory Committee on Immunization Practices adopted to assess and make recommendations on vaccines.³ The system’s classification of levels of evidence and recommendation categories are described in FIGURE 1.¹

The committee started by assessing evidence with a report on the long-term effectiveness of opioids for chronic pain, produced by the Agency for Health Care Research and Quality in 2014;⁴ it then augmented that report by performing an updated search for new evidence published since the report came out.⁵ The committee then conducted a “contextual evidence review”⁶ on the following 4 areas:

1. the effectiveness of nonpharmacologic (cognitive behavioral therapy, exercise therapy, interventional treatments, multimodal pain treatment) and non-opioid pharmacologic treatments (acetaminophen, nonsteroidal anti-inflammatory drugs, antidepressants, anticonvulsants)
2. the benefits and harms of opioid therapy
3. clinician and patient values and preferences related to opioids and medication risks, benefits, and use
4. resource allocation, including costs and economic analyses.

The guideline wording indicates that, for this contextual analysis, the committee used a rapid systematic review methodology, in part because of time constraints given the imperative to produce a guideline to address a pressing problem, and because of a recognition that evidence on the questions would be scant and not of high quality.¹ The 12 recommendations are categorized under 3 main headings.

Determining when to initiate or continue opioids for chronic pain

1. Nonpharmacologic therapy and non-opioid pharmacologic therapy are preferred for chronic pain. Consider opioid therapy only if you anticipate that benefits for both pain and function will outweigh risks to the patient. If opioids are used, combine them as appropriate with nonpharmacologic therapy and non-opioid pharmacologic therapy. (Recommendation category: A; evidence type: 3)

Review your state's prescription drug monitoring program to determine whether a patient is receiving opioid dosages, or dangerous combinations, that increase the risk for overdose.2. Before starting opioid therapy for chronic pain, establish treatment goals with the patient, including realistic goals for pain and function, and consider how therapy will be discontinued if the benefits do not outweigh the risks. Continue opioid therapy only if there is clinically meaningful improvement in pain and function that outweighs risks to patient safety. (Recommendation category: A; evidence type: 4)

3. Before starting opioid therapy, and periodically during its course, discuss with patients known risks and realistic benefits of opioid therapy and patient and clinician responsibilities for managing therapy. (Recommendation category: A; evidence type: 3)

Opioid selection, dosage, duration, follow-up, and discontinuation

4. When starting opioid therapy for chronic pain, prescribe immediate-release opioids instead of extended-release/long-acting (ER/LA) agents. (Recommendation category: A; evidence type: 4)

5. When starting opioids, prescribe the lowest effective dosage. Use caution when prescribing opioids at any dosage; carefully reassess the evidence for individual benefits and risks when increasing the dosage to ≥50 morphine milligram equivalents (MME)/d; and avoid increasing the dosage to ≥90 MME/d (or carefully justify such a decision, if made). (Recommendation category: A; evidence type: 3)

When starting opioid therapy for chronic pain, prescribe immediate-release opioids instead of extended-release/long-acting agents.6. Long-term opioid use often begins with treatment of acute pain. When opioids are used for acute pain, prescribe the lowest effective dose of immediate-release opioids at a quantity no greater than is needed for the expected duration of pain severe enough to require opioids. Three days or less will often be sufficient; more than 7 days will rarely be needed. (Recommendation category: A; evidence type: 4)

7. In monitoring opioid therapy for chronic pain, reevaluate benefits and harms with patients within one to 4 weeks of starting opioid therapy or escalating the dose. Also, evaluate the benefits and harms of continued therapy with patients every 3 months or more frequently. If the benefits of continued opioid therapy do not outweigh the harms, optimize other therapies and work with patients to taper opioids to lower dosages or to taper and discontinue them. (Recommendation category: A; evidence type: 4)

Assessing risk and addressing harms of opioid use

8. Before starting opioid therapy, and periodically during its continuation, evaluate risk factors for opioid-related harms. Incorporate strategies into the management plan to mitigate risk; consider offering naloxone when factors are present that increase the risk for opioid overdose—eg, a history of overdose, history of substance use disorder, higher opioid dosages (≥50 MME/d), or concurrent benzodiazepine use. (Recommendation category: A; evidence type: 4)

9. Review the patient’s history of controlled substance prescriptions. Use data from the state prescription drug monitoring program (PDMP) to determine whether the patient is receiving opioid dosages or dangerous combinations that put him or her at high risk for overdose. (State Web sites are available at http://www.pdmpassist.org/content/state-pdmp-websites.) Review PDMP data when starting opioid therapy for chronic pain and periodically during its continuation, at least every 3 months and with each new prescription. (Recommendation category: A; evidence type: 4)

10. Before prescribing opioids for chronic pain, use urine drug testing to assess for prescribed medications, as well as other controlled prescription drugs and illicit drugs, and consider urine drug testing at least annually. (Recommendation category: B; evidence type: 4)

11. Avoid prescribing opioid pain medication and benzodiazepines concurrently whenever possible. (Recommendation category: A; evidence type: 3)

See JFP's "3 in 3" video on urin drug testing at: http://bit.ly/2eL7Ptz.12. For patients with opioid use disorder, offer or arrange for evidence-based treatment (usually medication-assisted treatment with buprenorphine or methadone in combination with behavioral therapies). (Recommendation category: A; evidence type: 2)

Aids for guideline implementation

The CDC has produced materials to assist physicians in implementing this guideline, including checklists for prescribing or continuing opioids. The checklist for initiation of opioids is reproduced in FIGURE 2.⁷

The CDC is addressing a severe public health problem and doing so by using contemporary evidence-based methodology and guideline development processes. The lack of high-quality evidence on the topic and the use of a less-than-optimal evidence review process for some key questions may hamper this effort. However, given the prominence of the CDC, this clinical guideline will likely be considered the standard of care for family physicians.

Intrusive musical imagery (IMI) is characterized by recalling pieces of music,¹ usually repetitions of 15 to 30 seconds,² without pathology of the ear or nervous system.¹ Also known as earworm—ohrwurm in German—or involuntary musical imagery, bits of music can become a constant cause of distress.¹

IMI is prevalent in the general population; in an internet survey >85% of respondents reported experiencing IMI at least weekly.² IMI can be generated by:

• hearing music
• reading song lyrics
• being in contact with an environment or people who are linked to specific song, such as department stores that play holiday music.^2,3

IMI also is associated with stressful situations or neurological insult.¹

Any song or segment of music can be the basis of IMI. The content of IMI change over time (ie, a new song can become a source of IMI).³ The frequency of experiencing IMI is correlated to how much music a person is exposed to and the importance a person places on music.² Most episodes are intermittent; however, continuous musical episodes are known to occur.³ Episodes of IMI with obsessive-compulsive features can be classified as musical obsessions (MO).¹ MO may be part of obsessive-compulsive symptoms, including washing, checking, aggression, sexual obsessions, and religious obsessions or other obsessions.¹

Diagnosing musical obsessions

No current measures are adequate to diagnose MO. The Yale-Brown Obsessive Compulsive Scale does not distinguish MO from other intrusive auditory imagery.¹

It is important to differentiate MO from:

• Musical preoccupations or recollections in which an individual repeatedly listens or recalls a particular song or part of a song, but does not have the urge to listen or recall music in an obsessive-compulsive pattern.¹ These individuals do not display fear and avoidant behaviors that could be seen in patients with MO.¹
• Musical hallucinations lack an input stimulus and the patient believes the music comes from an outside source and interprets it as reality. Misdiagnosing MO as a psychotic symptom is common and can result in improper treatment.¹

Management

Pharmacotherapy. MO responds to the same medications used to treat obsessive-compulsive disorder, such as selective serotonin reuptake inhibitors and clomipramine.¹ Cognitive-behavioral interventions could help patients address dysfunctional beliefs, without trying to suppress them.¹

Distraction. Encourage patients to sing a different song that does not have obsessive quality¹ or engage in a task that uses working memory.³

Exposure and response prevention therapy. Some case reports have reported efficacy in treating MO.¹

Intrusive musical imagery (IMI) is characterized by recalling pieces of music,¹ usually repetitions of 15 to 30 seconds,² without pathology of the ear or nervous system.¹ Also known as earworm—ohrwurm in German—or involuntary musical imagery, bits of music can become a constant cause of distress.¹

IMI is prevalent in the general population; in an internet survey >85% of respondents reported experiencing IMI at least weekly.² IMI can be generated by:

• hearing music
• reading song lyrics
• being in contact with an environment or people who are linked to specific song, such as department stores that play holiday music.^2,3

IMI also is associated with stressful situations or neurological insult.¹

Any song or segment of music can be the basis of IMI. The content of IMI change over time (ie, a new song can become a source of IMI).³ The frequency of experiencing IMI is correlated to how much music a person is exposed to and the importance a person places on music.² Most episodes are intermittent; however, continuous musical episodes are known to occur.³ Episodes of IMI with obsessive-compulsive features can be classified as musical obsessions (MO).¹ MO may be part of obsessive-compulsive symptoms, including washing, checking, aggression, sexual obsessions, and religious obsessions or other obsessions.¹

Diagnosing musical obsessions

No current measures are adequate to diagnose MO. The Yale-Brown Obsessive Compulsive Scale does not distinguish MO from other intrusive auditory imagery.¹

It is important to differentiate MO from:

• Musical preoccupations or recollections in which an individual repeatedly listens or recalls a particular song or part of a song, but does not have the urge to listen or recall music in an obsessive-compulsive pattern.¹ These individuals do not display fear and avoidant behaviors that could be seen in patients with MO.¹
• Musical hallucinations lack an input stimulus and the patient believes the music comes from an outside source and interprets it as reality. Misdiagnosing MO as a psychotic symptom is common and can result in improper treatment.¹

Management

Pharmacotherapy. MO responds to the same medications used to treat obsessive-compulsive disorder, such as selective serotonin reuptake inhibitors and clomipramine.¹ Cognitive-behavioral interventions could help patients address dysfunctional beliefs, without trying to suppress them.¹

Distraction. Encourage patients to sing a different song that does not have obsessive quality¹ or engage in a task that uses working memory.³

Exposure and response prevention therapy. Some case reports have reported efficacy in treating MO.¹

Intrusive musical imagery (IMI) is characterized by recalling pieces of music,¹ usually repetitions of 15 to 30 seconds,² without pathology of the ear or nervous system.¹ Also known as earworm—ohrwurm in German—or involuntary musical imagery, bits of music can become a constant cause of distress.¹

IMI is prevalent in the general population; in an internet survey >85% of respondents reported experiencing IMI at least weekly.² IMI can be generated by:

• hearing music
• reading song lyrics
• being in contact with an environment or people who are linked to specific song, such as department stores that play holiday music.^2,3

IMI also is associated with stressful situations or neurological insult.¹

Any song or segment of music can be the basis of IMI. The content of IMI change over time (ie, a new song can become a source of IMI).³ The frequency of experiencing IMI is correlated to how much music a person is exposed to and the importance a person places on music.² Most episodes are intermittent; however, continuous musical episodes are known to occur.³ Episodes of IMI with obsessive-compulsive features can be classified as musical obsessions (MO).¹ MO may be part of obsessive-compulsive symptoms, including washing, checking, aggression, sexual obsessions, and religious obsessions or other obsessions.¹

Diagnosing musical obsessions

No current measures are adequate to diagnose MO. The Yale-Brown Obsessive Compulsive Scale does not distinguish MO from other intrusive auditory imagery.¹

It is important to differentiate MO from:

• Musical preoccupations or recollections in which an individual repeatedly listens or recalls a particular song or part of a song, but does not have the urge to listen or recall music in an obsessive-compulsive pattern.¹ These individuals do not display fear and avoidant behaviors that could be seen in patients with MO.¹
• Musical hallucinations lack an input stimulus and the patient believes the music comes from an outside source and interprets it as reality. Misdiagnosing MO as a psychotic symptom is common and can result in improper treatment.¹

Management

Pharmacotherapy. MO responds to the same medications used to treat obsessive-compulsive disorder, such as selective serotonin reuptake inhibitors and clomipramine.¹ Cognitive-behavioral interventions could help patients address dysfunctional beliefs, without trying to suppress them.¹

Distraction. Encourage patients to sing a different song that does not have obsessive quality¹ or engage in a task that uses working memory.³

Exposure and response prevention therapy. Some case reports have reported efficacy in treating MO.¹

It is much more important to know what sort of a patient has a disease than what sort of a disease a patient has.

—Attributed to Sir William Osler¹

Recent years have seen an increase in people  traveling away from their home region for healthcare, often for care that is less expensive or unavailable where they live.^2–4 Many Americans seek care abroad (engaging in “medical tourism”); conversely, the United States annually receives thousands of foreign travelers for medical evaluations, a trend projected to increase.^2,3,5 Additionally, US healthcare providers often see foreign travelers for unexpected ailments that develop during their time here.

See related editorial

Traveling for healthcare can be stressful for patients, and caring for international patients may pose challenges for providers and medical centers. On the other hand, such encounters also provide many mutual benefits. Unfortunately, there is little published guidance addressing these issues.² In this article, we therefore discuss many of the benefits and challenges, with the hope of improving the quality of care delivered and the clinical experience for both providers and patients.

CHALLENGES FOR INTERNATIONAL PATIENTS AND THEIR PROVIDERS

Some scenarios that illustrate challenges faced by international patients and their healthcare providers are presented in Table 1.

For patients, heightened anxiety

Many international patients feel anxious, isolated, and vulnerable, particularly if they have never been away from home before. These feelings arise from multiple factors, including the stress of traveling, lack of family or social support, an unfamiliar environment, contrasting cultural practices, and high expectations.^3,4 Language barriers, especially for patients who speak uncommon dialects, and lack of continuously available interpretive services often augment the unsettled emotions of international patients.

Cultural differences

International patients may quickly notice significant differences from their home country in how healthcare is practiced and culturally applied.^4,6 Such differences may include dress codes and the comparatively equal role of women vis-à-vis men in the Western medical profession.

For cultural, personal, or religious reasons, some patients feel uncomfortable with healthcare providers of the opposite sex. This discomfort can be heightened if the patient needs a potentially uncomfortable and humiliating procedure such as a gynecologic or rectal examination.

The multidisciplinary team approach to healthcare, which can include trainees, nurses, and pharmacists, may leave patients confused about who their primary health provider is.

Decision-making also has cultural implications. In Western medicine, we respect individual autonomy and expect patients to participate in decisions about their care. However, in many areas of the world, medical decision-making is deferred to extended family members or cultural leaders.² Additional and often repeated conversations may be needed with both the patient and family members to ensure appropriate understanding and ethical consent for care.

Some international patients may have expectations that are quite different from those of the healthcare provider and that are sometimes unrealistic.^2,6

Institutional challenges

Many medical conditions require prolonged treatment and longitudinal care, a notable challenge when that care is delivered outside of one’s home country. Practice models within a clinic may not allow for prolonged subsequent visits, which may be needed to accommodate language-translation services. Complex multidisciplinary plans of care must somehow effectively utilize available appointment slots and be time-efficient.

Criteria for hospitalization differ widely among different countries, often based on resources, and may necessitate additional dialogue between the patient and healthcare provider.

Obtaining, interpreting the patient’s record

Medical records from foreign institutions are often unavailable, incomplete, or illegible. Further, depending on the country, it may be difficult to contact local providers for supplemental information. Differences in time zones, limited access to technology, language barriers, and handwritten notes all pose problems when trying to obtain additional information.

Many under-resourced foreign medical centers cannot duplicate medical records and radiographic films for the patient to bring to the United States. Medical records from foreign laboratories often raise questions about the quality, accuracy, and methodology of the testing platform used.² Thus, the provider may need to start over and repeat the entire clinical, radiologic, and laboratory evaluation.

Communicating with the patient

Difficulties in communication between patients and providers can hinder the development of a positive and productive relationship, reducing patient autonomy and complicating informed consent.² Obtaining a medical history from non–English-speaking patients can be arduous and time-consuming. Colloquial language may further alter interpretation and understanding, even for formally trained interpreters. Language differences may make it more difficult to explain differential diagnoses, diagnostic approaches, and management plans.

Many US medical centers provide interpreters for many languages, but the great number of languages spoken around the world ensures that barriers in communication persist. Telephone language lines and other commercial language services are available but may feel less personal to patients or evoke concerns about medical confidentiality. For less commonly spoken languages and dialects, appropriate translation services may not even be available.⁶

Filling in information gaps

Medical conditions, medications, and treatments may have different names in different countries. The quality of pharmaceuticals in some regions may be questionable, and herbal supplements may be unique to a particular location. Many medications available abroad are not available in the United States, potentially confusing US providers as to medication appropriateness, efficacy, and potential toxicities.

Lacking adequate medical records and trying to obtain a new medical history from patients and their family members, providers may struggle with continued gaps of information, hindering a timely diagnosis and composition of an appropriate management plan.

A culturally sensitive but complete physical examination

Every effort should be made to complete a thorough and comprehensive physical examination, even if the patient’s culture differs on this point. This may require a “chaperone” to be present or, if available, a clinician of the same sex as the patient to perform the examination. A compromised examination will impede making the correct diagnosis.

Religious, cultural, and other patient-specific attitudes and beliefs that may affect a medical evaluation should ideally be addressed before scheduling the appointment. A preexamination discussion with the patient and family can help avert unintentional actions and behavior misperceived as offensive, while strengthening the level of trust between patient and provider.²

Money matters

Foreign patients typically have limited or no medical insurance coverage and thus may be paying out of pocket or through limited governmental subsidies. Many refugees and asylum-seekers have no insurance or money to pay for care. (A full discussion of refugee care is beyond the scope of this article). Thus, it is necessary to ascertain in advance who will pay for the care.

Clinicians must be sensitive to the exorbitant costs of medical care and medications in the United States, particularly from the perspective of foreign patients. We strive to provide the best cost-effective care, but what is considered cost-effective and standard care for a patient with US health insurance may be viewed differently by international patients. For some foreign patients, some tests and treatments may be just too expensive, raising personal and institutional ethical concerns regarding how best to evaluate and manage these patients. Ideally, these issues should also be addressed before the patient’s appointment is scheduled.

Clinicians must optimize diagnostic and medical management while minimizing unnecessary testing. This principle further underscores the importance of obtaining a complete medical history and physical examination within a time-sensitive and well-coordinated plan of care.^2,4

Continuity of care after the patient leaves

As the medical evaluation and care plan approach completion, ensuring some form of continued medical care can become challenging. Some foreign patients may have the financial or legal means (eg, through an extended medical visa) to remain for further care and follow-up, but most do not.

Finding an available, willing health provider in the patient’s native country for continued management may be difficult and time-consuming. Most US medical centers have no established system to identify available foreign health providers, and usually the patient and family are responsible for arranging continued healthcare back in their home country.

Opportunities for possible improvement of care are noted in Table 2.

ADVANTAGES OF CARING FOR INTERNATIONAL PATIENTS

Despite the possible challenges, there are many benefits of caring for international patients.

Gaining medical knowledge

In US medical centers caring for both regional and referred patients, providers are often exposed to medical conditions that range from common ailments to the rare conditions (or “zebras”) taught during residency training. From the medical education standpoint, international patients provide US health providers heightened opportunities to encounter diseases not commonly seen in the United States (eg, infections such as malaria, schistosomiasis, drug-resistant tuberculosis, and advanced or end-stage forms of noncommunicable diseases). Although not limited to international patients, chronically neglected diseases often give providers first-hand experience in the natural history of select disease progression.

Gaining cultural knowledge

Caring for international patients also enables health providers to learn about different cultures, societal norms, and regional beliefs affecting healthcare. In essence, international patients enable US providers to become more diversified and enlightened with communication skills and assorted managerial strategies on a global scale.

These patients remind us of the stark differences regarding access and quality of medical care globally, particularly in lesser-resourced locations. In a busy domestic medical practice with its own daily challenges, many of us forget these international healthcare disparities, and often take for granted the comparative abundance of healthcare resources available in the United States. Provider frustrations about domestic policies and concerns for a “broken” healthcare system often blind us to the available resources we are fortunate to have at our disposal.

Further, as members of the global community, we have the opportunity to learn from international patients while broadening our view of humanity, thereby enhancing our awareness and empathy toward patients and communities struggling with under-resourced healthcare systems. Healthcare providers are often touched by the gratitude of patients for the opportunity to receive treatments that may otherwise be unavailable. Such experiences may motivate many US health providers to become more engaged in coordinated strategies for global health improvement.

Reimbursement is possible

Caring for international patients should not financially deter US health care centers. Complex, multidisciplinary care evaluations may incur notable expenses; however, alternative and more lucrative payer systems, including government subsidies, can be involved to maintain revenue, reimbursements, and even possibly lead to increased donations.^3–5 Given the potential for high costs to be incurred, US providers and institutions need to continually ensure appropriate evidence-based use of resources and cost-effective care without compromising the quality of care provided. The price of certain drugs has been rising astonishingly in the United States, and some patients may therefore prefer to obtain them for long-term use upon return to their home country.

High-quality cost-effective care is satisfying to the patient, provider, and institution, and also may save money that can be reallocated.⁴ Providers also may find personal fulfillment in striving for and achieving such goals, despite the potential challenges throughout the course of care.

Opportunities for improvement

Regardless of the challenges presented by international patients, participating medical centers often enjoy the prestige and credibility of becoming an “international healthcare center.”^4,7 From the standpoint of medical education, these centers have the potential to train providers with increased clinical and cultural competencies along with expanding healthcare services to include clinical, educational and research opportunities abroad.

Research is needed to provide evidence-based guidance on best strategies for patients, clinicians, and healthcare systems to effectively care for international patients.

Suggested opportunities for maximizing advantages are noted in Table 3.

It is much more important to know what sort of a patient has a disease than what sort of a disease a patient has.

—Attributed to Sir William Osler¹

Recent years have seen an increase in people  traveling away from their home region for healthcare, often for care that is less expensive or unavailable where they live.^2–4 Many Americans seek care abroad (engaging in “medical tourism”); conversely, the United States annually receives thousands of foreign travelers for medical evaluations, a trend projected to increase.^2,3,5 Additionally, US healthcare providers often see foreign travelers for unexpected ailments that develop during their time here.

See related editorial

Traveling for healthcare can be stressful for patients, and caring for international patients may pose challenges for providers and medical centers. On the other hand, such encounters also provide many mutual benefits. Unfortunately, there is little published guidance addressing these issues.² In this article, we therefore discuss many of the benefits and challenges, with the hope of improving the quality of care delivered and the clinical experience for both providers and patients.

CHALLENGES FOR INTERNATIONAL PATIENTS AND THEIR PROVIDERS

Some scenarios that illustrate challenges faced by international patients and their healthcare providers are presented in Table 1.

For patients, heightened anxiety

Many international patients feel anxious, isolated, and vulnerable, particularly if they have never been away from home before. These feelings arise from multiple factors, including the stress of traveling, lack of family or social support, an unfamiliar environment, contrasting cultural practices, and high expectations.^3,4 Language barriers, especially for patients who speak uncommon dialects, and lack of continuously available interpretive services often augment the unsettled emotions of international patients.

Cultural differences

International patients may quickly notice significant differences from their home country in how healthcare is practiced and culturally applied.^4,6 Such differences may include dress codes and the comparatively equal role of women vis-à-vis men in the Western medical profession.

For cultural, personal, or religious reasons, some patients feel uncomfortable with healthcare providers of the opposite sex. This discomfort can be heightened if the patient needs a potentially uncomfortable and humiliating procedure such as a gynecologic or rectal examination.

The multidisciplinary team approach to healthcare, which can include trainees, nurses, and pharmacists, may leave patients confused about who their primary health provider is.

Decision-making also has cultural implications. In Western medicine, we respect individual autonomy and expect patients to participate in decisions about their care. However, in many areas of the world, medical decision-making is deferred to extended family members or cultural leaders.² Additional and often repeated conversations may be needed with both the patient and family members to ensure appropriate understanding and ethical consent for care.

Some international patients may have expectations that are quite different from those of the healthcare provider and that are sometimes unrealistic.^2,6

Institutional challenges

Many medical conditions require prolonged treatment and longitudinal care, a notable challenge when that care is delivered outside of one’s home country. Practice models within a clinic may not allow for prolonged subsequent visits, which may be needed to accommodate language-translation services. Complex multidisciplinary plans of care must somehow effectively utilize available appointment slots and be time-efficient.

Criteria for hospitalization differ widely among different countries, often based on resources, and may necessitate additional dialogue between the patient and healthcare provider.

Obtaining, interpreting the patient’s record

Medical records from foreign institutions are often unavailable, incomplete, or illegible. Further, depending on the country, it may be difficult to contact local providers for supplemental information. Differences in time zones, limited access to technology, language barriers, and handwritten notes all pose problems when trying to obtain additional information.

Many under-resourced foreign medical centers cannot duplicate medical records and radiographic films for the patient to bring to the United States. Medical records from foreign laboratories often raise questions about the quality, accuracy, and methodology of the testing platform used.² Thus, the provider may need to start over and repeat the entire clinical, radiologic, and laboratory evaluation.

Communicating with the patient

Difficulties in communication between patients and providers can hinder the development of a positive and productive relationship, reducing patient autonomy and complicating informed consent.² Obtaining a medical history from non–English-speaking patients can be arduous and time-consuming. Colloquial language may further alter interpretation and understanding, even for formally trained interpreters. Language differences may make it more difficult to explain differential diagnoses, diagnostic approaches, and management plans.

Many US medical centers provide interpreters for many languages, but the great number of languages spoken around the world ensures that barriers in communication persist. Telephone language lines and other commercial language services are available but may feel less personal to patients or evoke concerns about medical confidentiality. For less commonly spoken languages and dialects, appropriate translation services may not even be available.⁶

Filling in information gaps

Medical conditions, medications, and treatments may have different names in different countries. The quality of pharmaceuticals in some regions may be questionable, and herbal supplements may be unique to a particular location. Many medications available abroad are not available in the United States, potentially confusing US providers as to medication appropriateness, efficacy, and potential toxicities.

Lacking adequate medical records and trying to obtain a new medical history from patients and their family members, providers may struggle with continued gaps of information, hindering a timely diagnosis and composition of an appropriate management plan.

A culturally sensitive but complete physical examination

Every effort should be made to complete a thorough and comprehensive physical examination, even if the patient’s culture differs on this point. This may require a “chaperone” to be present or, if available, a clinician of the same sex as the patient to perform the examination. A compromised examination will impede making the correct diagnosis.

Religious, cultural, and other patient-specific attitudes and beliefs that may affect a medical evaluation should ideally be addressed before scheduling the appointment. A preexamination discussion with the patient and family can help avert unintentional actions and behavior misperceived as offensive, while strengthening the level of trust between patient and provider.²

Money matters

Foreign patients typically have limited or no medical insurance coverage and thus may be paying out of pocket or through limited governmental subsidies. Many refugees and asylum-seekers have no insurance or money to pay for care. (A full discussion of refugee care is beyond the scope of this article). Thus, it is necessary to ascertain in advance who will pay for the care.

Clinicians must be sensitive to the exorbitant costs of medical care and medications in the United States, particularly from the perspective of foreign patients. We strive to provide the best cost-effective care, but what is considered cost-effective and standard care for a patient with US health insurance may be viewed differently by international patients. For some foreign patients, some tests and treatments may be just too expensive, raising personal and institutional ethical concerns regarding how best to evaluate and manage these patients. Ideally, these issues should also be addressed before the patient’s appointment is scheduled.

Clinicians must optimize diagnostic and medical management while minimizing unnecessary testing. This principle further underscores the importance of obtaining a complete medical history and physical examination within a time-sensitive and well-coordinated plan of care.^2,4

Continuity of care after the patient leaves

As the medical evaluation and care plan approach completion, ensuring some form of continued medical care can become challenging. Some foreign patients may have the financial or legal means (eg, through an extended medical visa) to remain for further care and follow-up, but most do not.

Finding an available, willing health provider in the patient’s native country for continued management may be difficult and time-consuming. Most US medical centers have no established system to identify available foreign health providers, and usually the patient and family are responsible for arranging continued healthcare back in their home country.

Opportunities for possible improvement of care are noted in Table 2.

ADVANTAGES OF CARING FOR INTERNATIONAL PATIENTS

Despite the possible challenges, there are many benefits of caring for international patients.

Gaining medical knowledge

In US medical centers caring for both regional and referred patients, providers are often exposed to medical conditions that range from common ailments to the rare conditions (or “zebras”) taught during residency training. From the medical education standpoint, international patients provide US health providers heightened opportunities to encounter diseases not commonly seen in the United States (eg, infections such as malaria, schistosomiasis, drug-resistant tuberculosis, and advanced or end-stage forms of noncommunicable diseases). Although not limited to international patients, chronically neglected diseases often give providers first-hand experience in the natural history of select disease progression.

Gaining cultural knowledge

Caring for international patients also enables health providers to learn about different cultures, societal norms, and regional beliefs affecting healthcare. In essence, international patients enable US providers to become more diversified and enlightened with communication skills and assorted managerial strategies on a global scale.

These patients remind us of the stark differences regarding access and quality of medical care globally, particularly in lesser-resourced locations. In a busy domestic medical practice with its own daily challenges, many of us forget these international healthcare disparities, and often take for granted the comparative abundance of healthcare resources available in the United States. Provider frustrations about domestic policies and concerns for a “broken” healthcare system often blind us to the available resources we are fortunate to have at our disposal.

Further, as members of the global community, we have the opportunity to learn from international patients while broadening our view of humanity, thereby enhancing our awareness and empathy toward patients and communities struggling with under-resourced healthcare systems. Healthcare providers are often touched by the gratitude of patients for the opportunity to receive treatments that may otherwise be unavailable. Such experiences may motivate many US health providers to become more engaged in coordinated strategies for global health improvement.

Reimbursement is possible

Caring for international patients should not financially deter US health care centers. Complex, multidisciplinary care evaluations may incur notable expenses; however, alternative and more lucrative payer systems, including government subsidies, can be involved to maintain revenue, reimbursements, and even possibly lead to increased donations.^3–5 Given the potential for high costs to be incurred, US providers and institutions need to continually ensure appropriate evidence-based use of resources and cost-effective care without compromising the quality of care provided. The price of certain drugs has been rising astonishingly in the United States, and some patients may therefore prefer to obtain them for long-term use upon return to their home country.

High-quality cost-effective care is satisfying to the patient, provider, and institution, and also may save money that can be reallocated.⁴ Providers also may find personal fulfillment in striving for and achieving such goals, despite the potential challenges throughout the course of care.

Opportunities for improvement

Regardless of the challenges presented by international patients, participating medical centers often enjoy the prestige and credibility of becoming an “international healthcare center.”^4,7 From the standpoint of medical education, these centers have the potential to train providers with increased clinical and cultural competencies along with expanding healthcare services to include clinical, educational and research opportunities abroad.

Research is needed to provide evidence-based guidance on best strategies for patients, clinicians, and healthcare systems to effectively care for international patients.

Suggested opportunities for maximizing advantages are noted in Table 3.

It is much more important to know what sort of a patient has a disease than what sort of a disease a patient has.

—Attributed to Sir William Osler¹

Recent years have seen an increase in people  traveling away from their home region for healthcare, often for care that is less expensive or unavailable where they live.^2–4 Many Americans seek care abroad (engaging in “medical tourism”); conversely, the United States annually receives thousands of foreign travelers for medical evaluations, a trend projected to increase.^2,3,5 Additionally, US healthcare providers often see foreign travelers for unexpected ailments that develop during their time here.

See related editorial

Traveling for healthcare can be stressful for patients, and caring for international patients may pose challenges for providers and medical centers. On the other hand, such encounters also provide many mutual benefits. Unfortunately, there is little published guidance addressing these issues.² In this article, we therefore discuss many of the benefits and challenges, with the hope of improving the quality of care delivered and the clinical experience for both providers and patients.

CHALLENGES FOR INTERNATIONAL PATIENTS AND THEIR PROVIDERS

Some scenarios that illustrate challenges faced by international patients and their healthcare providers are presented in Table 1.

For patients, heightened anxiety

Many international patients feel anxious, isolated, and vulnerable, particularly if they have never been away from home before. These feelings arise from multiple factors, including the stress of traveling, lack of family or social support, an unfamiliar environment, contrasting cultural practices, and high expectations.^3,4 Language barriers, especially for patients who speak uncommon dialects, and lack of continuously available interpretive services often augment the unsettled emotions of international patients.

Cultural differences

International patients may quickly notice significant differences from their home country in how healthcare is practiced and culturally applied.^4,6 Such differences may include dress codes and the comparatively equal role of women vis-à-vis men in the Western medical profession.

For cultural, personal, or religious reasons, some patients feel uncomfortable with healthcare providers of the opposite sex. This discomfort can be heightened if the patient needs a potentially uncomfortable and humiliating procedure such as a gynecologic or rectal examination.

The multidisciplinary team approach to healthcare, which can include trainees, nurses, and pharmacists, may leave patients confused about who their primary health provider is.

Decision-making also has cultural implications. In Western medicine, we respect individual autonomy and expect patients to participate in decisions about their care. However, in many areas of the world, medical decision-making is deferred to extended family members or cultural leaders.² Additional and often repeated conversations may be needed with both the patient and family members to ensure appropriate understanding and ethical consent for care.

Some international patients may have expectations that are quite different from those of the healthcare provider and that are sometimes unrealistic.^2,6

Institutional challenges

Many medical conditions require prolonged treatment and longitudinal care, a notable challenge when that care is delivered outside of one’s home country. Practice models within a clinic may not allow for prolonged subsequent visits, which may be needed to accommodate language-translation services. Complex multidisciplinary plans of care must somehow effectively utilize available appointment slots and be time-efficient.

Criteria for hospitalization differ widely among different countries, often based on resources, and may necessitate additional dialogue between the patient and healthcare provider.

Obtaining, interpreting the patient’s record

Medical records from foreign institutions are often unavailable, incomplete, or illegible. Further, depending on the country, it may be difficult to contact local providers for supplemental information. Differences in time zones, limited access to technology, language barriers, and handwritten notes all pose problems when trying to obtain additional information.

Many under-resourced foreign medical centers cannot duplicate medical records and radiographic films for the patient to bring to the United States. Medical records from foreign laboratories often raise questions about the quality, accuracy, and methodology of the testing platform used.² Thus, the provider may need to start over and repeat the entire clinical, radiologic, and laboratory evaluation.

Communicating with the patient

Difficulties in communication between patients and providers can hinder the development of a positive and productive relationship, reducing patient autonomy and complicating informed consent.² Obtaining a medical history from non–English-speaking patients can be arduous and time-consuming. Colloquial language may further alter interpretation and understanding, even for formally trained interpreters. Language differences may make it more difficult to explain differential diagnoses, diagnostic approaches, and management plans.

Many US medical centers provide interpreters for many languages, but the great number of languages spoken around the world ensures that barriers in communication persist. Telephone language lines and other commercial language services are available but may feel less personal to patients or evoke concerns about medical confidentiality. For less commonly spoken languages and dialects, appropriate translation services may not even be available.⁶

Filling in information gaps

Medical conditions, medications, and treatments may have different names in different countries. The quality of pharmaceuticals in some regions may be questionable, and herbal supplements may be unique to a particular location. Many medications available abroad are not available in the United States, potentially confusing US providers as to medication appropriateness, efficacy, and potential toxicities.

Lacking adequate medical records and trying to obtain a new medical history from patients and their family members, providers may struggle with continued gaps of information, hindering a timely diagnosis and composition of an appropriate management plan.

A culturally sensitive but complete physical examination

Every effort should be made to complete a thorough and comprehensive physical examination, even if the patient’s culture differs on this point. This may require a “chaperone” to be present or, if available, a clinician of the same sex as the patient to perform the examination. A compromised examination will impede making the correct diagnosis.

Religious, cultural, and other patient-specific attitudes and beliefs that may affect a medical evaluation should ideally be addressed before scheduling the appointment. A preexamination discussion with the patient and family can help avert unintentional actions and behavior misperceived as offensive, while strengthening the level of trust between patient and provider.²

Money matters

Foreign patients typically have limited or no medical insurance coverage and thus may be paying out of pocket or through limited governmental subsidies. Many refugees and asylum-seekers have no insurance or money to pay for care. (A full discussion of refugee care is beyond the scope of this article). Thus, it is necessary to ascertain in advance who will pay for the care.

Clinicians must be sensitive to the exorbitant costs of medical care and medications in the United States, particularly from the perspective of foreign patients. We strive to provide the best cost-effective care, but what is considered cost-effective and standard care for a patient with US health insurance may be viewed differently by international patients. For some foreign patients, some tests and treatments may be just too expensive, raising personal and institutional ethical concerns regarding how best to evaluate and manage these patients. Ideally, these issues should also be addressed before the patient’s appointment is scheduled.

Clinicians must optimize diagnostic and medical management while minimizing unnecessary testing. This principle further underscores the importance of obtaining a complete medical history and physical examination within a time-sensitive and well-coordinated plan of care.^2,4

Continuity of care after the patient leaves

As the medical evaluation and care plan approach completion, ensuring some form of continued medical care can become challenging. Some foreign patients may have the financial or legal means (eg, through an extended medical visa) to remain for further care and follow-up, but most do not.

Finding an available, willing health provider in the patient’s native country for continued management may be difficult and time-consuming. Most US medical centers have no established system to identify available foreign health providers, and usually the patient and family are responsible for arranging continued healthcare back in their home country.

Opportunities for possible improvement of care are noted in Table 2.

ADVANTAGES OF CARING FOR INTERNATIONAL PATIENTS

Despite the possible challenges, there are many benefits of caring for international patients.

Gaining medical knowledge

In US medical centers caring for both regional and referred patients, providers are often exposed to medical conditions that range from common ailments to the rare conditions (or “zebras”) taught during residency training. From the medical education standpoint, international patients provide US health providers heightened opportunities to encounter diseases not commonly seen in the United States (eg, infections such as malaria, schistosomiasis, drug-resistant tuberculosis, and advanced or end-stage forms of noncommunicable diseases). Although not limited to international patients, chronically neglected diseases often give providers first-hand experience in the natural history of select disease progression.

Gaining cultural knowledge

Caring for international patients also enables health providers to learn about different cultures, societal norms, and regional beliefs affecting healthcare. In essence, international patients enable US providers to become more diversified and enlightened with communication skills and assorted managerial strategies on a global scale.

These patients remind us of the stark differences regarding access and quality of medical care globally, particularly in lesser-resourced locations. In a busy domestic medical practice with its own daily challenges, many of us forget these international healthcare disparities, and often take for granted the comparative abundance of healthcare resources available in the United States. Provider frustrations about domestic policies and concerns for a “broken” healthcare system often blind us to the available resources we are fortunate to have at our disposal.

Further, as members of the global community, we have the opportunity to learn from international patients while broadening our view of humanity, thereby enhancing our awareness and empathy toward patients and communities struggling with under-resourced healthcare systems. Healthcare providers are often touched by the gratitude of patients for the opportunity to receive treatments that may otherwise be unavailable. Such experiences may motivate many US health providers to become more engaged in coordinated strategies for global health improvement.

Reimbursement is possible

Caring for international patients should not financially deter US health care centers. Complex, multidisciplinary care evaluations may incur notable expenses; however, alternative and more lucrative payer systems, including government subsidies, can be involved to maintain revenue, reimbursements, and even possibly lead to increased donations.^3–5 Given the potential for high costs to be incurred, US providers and institutions need to continually ensure appropriate evidence-based use of resources and cost-effective care without compromising the quality of care provided. The price of certain drugs has been rising astonishingly in the United States, and some patients may therefore prefer to obtain them for long-term use upon return to their home country.

High-quality cost-effective care is satisfying to the patient, provider, and institution, and also may save money that can be reallocated.⁴ Providers also may find personal fulfillment in striving for and achieving such goals, despite the potential challenges throughout the course of care.

Opportunities for improvement

Regardless of the challenges presented by international patients, participating medical centers often enjoy the prestige and credibility of becoming an “international healthcare center.”^4,7 From the standpoint of medical education, these centers have the potential to train providers with increased clinical and cultural competencies along with expanding healthcare services to include clinical, educational and research opportunities abroad.

Research is needed to provide evidence-based guidance on best strategies for patients, clinicians, and healthcare systems to effectively care for international patients.

Suggested opportunities for maximizing advantages are noted in Table 3.

With a substantial increase in antidepressant use in the United States over the last 2 decades, serotonin syndrome has become an increasingly common and significant clinical concern. In 1999, 6.5% of adults age 18 and older were taking antidepressants; by 2010, the percentage had increased to 10.4%.¹ Though the true incidence of serotonin syndrome is difficult to determine, the number of ingestions of selective serotonin reuptake inhibitors (SSRIs) associated with moderate to major effects reported to US poison control centers increased from 7,349 in 2002² to 8,585 in 2005.³

Though the clinical manifestations are often mild to moderate, patients with serotonin syndrome can deteriorate rapidly and require intensive care. Unlike neuroleptic malignant syndrome, serotonin syndrome should not be considered an extremely rare idiosyncratic reaction to medication, but rather a progression of serotonergic toxicity based on increasing concentration levels that can occur in any patient regardless of age.⁴

Because it has a nonspecific prodrome and protean manifestations, serotonin syndrome can easily be overlooked, misdiagnosed, or exacerbated if not carefully assessed. Diagnosis requires a low threshold for suspicion and a meticulous history and physical examination. In the syndrome’s mildest stage, symptoms are often misattributed to other causes, and in its most severe form, it can easily be mistaken for neuroleptic malignant syndrome.

WHAT IS SEROTONIN SYNDROME?

Serotonin syndrome classically presents as the triad of autonomic dysfunction, neuromuscular excitation, and altered mental status. These symptoms are a result of increased serotonin levels affecting the central and peripheral nervous systems. Serotonin affects a family of receptors that has seven members, of which 5-HT1A and 5-HT2A are most often responsible for serotonin syndrome.⁵

Conditions that can alter the regulation of serotonin include therapeutic doses, drug interactions, intentional or unintentional overdoses, and overlapping transitions between medications. As a result, drugs that have been associated with serotonin syndrome can be classified into the following five categories as shown below and in Table 1:

Drugs that decrease serotonin breakdown include monoamine oxidase inhibitors (MAOIs), linezolid,⁶ methylene blue, procarbazine, and Syrian rue.

Drugs that decrease serotonin reuptake include SSRIs, serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, opioids (meperidine, buprenorphine, tramadol, tapentadol, dextromethorphan), antiepileptics (carbamazepine, valproate), and antiemetics (ondansetron, granisetron, metoclopramide), and the herbal preparation St. John’s wort.

Drugs that increase serotonin precursors or agonists include tryptophan, lithium, fentanyl, and lysergic acid diethylamide (LSD).

Drugs that increase serotonin release include fenfluramine, amphetamines, and methylenedioxymethamphetamine (ecstasy).

Drugs that prevent breakdown of the agents listed above are CYP2D6 and CYP3A4 inhibitors, eg, erythromycin,⁷ ciprofloxacin, fluconazole, ritonavir, and grapefruit juice.

However, the only drugs that have been reliably confirmed to precipitate serotonin syndrome are MAOIs, SSRIs, SNRIs, and serotonin releasers. Other listed drug interactions are based on case reports and have not been thoroughly evaluated.^6–9

Currently, SSRIs are the most commonly prescribed antidepressant medications and, consequently, they are the ones most often implicated in serotonergic toxicity.^1,10 An estimated 15% of SSRI overdoses lead to mild or moderate serotonin toxicity.¹¹ Serotonergic agents used in conjunction can increase the risk for severe serotonin syndrome; an SSRI and an MAOI in combination poses the greatest risk.⁵

Ultimately, the incidence of serotonin syndrome is difficult to assess, but it is believed to be underreported because it is easy to misdiagnose and mild symptoms may be dismissed.

WHO IS AT RISK OF SEROTONIN SYNDROME?

Long-term antidepressant use has disproportionately increased in middle-aged and older adults and non-Hispanic whites.^1,12,13 Intuitively, as the risk for depression increases dramatically in patients with chronic medical conditions, serotonin syndrome should be more prevalent among the elderly. In addition, patients with multiple comorbidities take more medications, increasing the risk of polypharmacy and adverse drug reactions.¹⁴

Although the epidemiology of serotonin syndrome has yet to be extensively studied, the combination of age and comorbidities may increase the risk for this condition.

HOW DOES IT PRESENT?

Serotonin syndrome characteristically presents as the triad of autonomic dysfunction, neuromuscular excitation, and altered mental status. However, these symptoms may not occur simultaneously: autonomic dysfunction is present in 40% of patients, neuromuscular excitation in 50%, and altered mental status in 40%.¹⁵ The symptoms can range from mild to life-threatening (Table 2).¹⁶

Autonomic dysfunction. Diaphoresis is present in 48.8% of cases, tachycardia in 44%, nausea and vomiting in 26.8%, and mydriasis in 19.5%. Other signs are hyperactive bowel sounds, diarrhea, and flushing.¹⁶

Neuromuscular excitation. Myoclonus is present in 48.8%, hyperreflexia in 41%, hyperthermia in 26.8%, and hypertonicity and rigidity in 19.5%. Other signs are spontaneous or inducible clonus, ocular clonus (continuous rhythmic oscillations of gaze), and tremor.

Altered mental status. Confusion is present in 41.2% and agitation in 36.5%. Other signs are anxiety, lethargy, and coma.

Symptoms of serotonin toxicity arise within an hour of a precipitating event (eg, ingestion) in approximately 28% of patients, and within 6 hours in 61%.¹⁶ Highly diagnostic features include hyperreflexia and induced or spontaneous clonus that are generally more pronounced in the lower limbs.¹¹ Clonus can be elicited with ankle dorsiflexion.

In mild toxicity, patients may present with tremor or twitching and anxiety, as well as with hyperreflexia, tachycardia, diaphoresis, and mydriasis. Further investigation may uncover a recently initiated antidepressant or a cold-and-cough medication that contains dextromethorphan.^15,17

In moderate toxicity, patients present in significant distress, with agitation and restlessness. Features may include hyperreflexia and clonus of the lower extremities, opsoclonus, hyperactive bowel sounds, diarrhea, nausea, vomiting, tachycardia, hypertension, diaphoresis, mydriasis, and hyperthermia (< 40°C, 104°F). The patient’s history may reveal use of ecstasy or combined treatment with serotonin-potentiating agents such as an antidepressant with a proserotonergic opioid, antiepileptic, or CYP2D6 or CYP3A4 inhibitor.¹⁵

Severe serotonin toxicity is a life-threatening condition that can lead to multiorgan failure within hours. It can be characterized by muscle rigidity, which can cause the body temperature to elevate rapidly to over 40°C. This hypertonicity can mask the classic and diagnostic signs of hyperreflexia and clonus. Patients may have unstable and dynamic vital signs with confusion or delirium and can experience tonic-clonic seizures.

If the muscle rigidity and resulting hyperthermia are not managed properly, patients can develop cellular damage and enzyme dysfunction leading to rhabdomyolysis, myoglobinuria, renal failure, metabolic acidosis, acute respiratory distress syndrome, and disseminated intravascular coagulation.^16,18

Serotonin crisis is usually caused by the co-ingestion of multiple serotonergic agents, such as an antidepressant with an aforementioned opioid and antiemetic¹⁹; combining an SSRI and an MAOI poses the greatest risk. Alternatively, patients may have recently switched antidepressants without observing a safe washout period, leading to an overlap of serotonin levels.¹⁶

HOW DO WE DIAGNOSE SEROTONIN SYNDROME?

Serotonin syndrome is a clinical diagnosis and therefore requires a thorough review of medications and physical examination. Serum serotonin levels are an unreliable indicator of toxicity and do not correlate well with the clinical presentation.¹⁶

Currently, there are two clinical tools for diagnosing serotonin syndrome: the Hunter serotonin toxicity criteria (Figure 1) and the Sternbach criteria.

The Hunter criteria are based more heavily on physical findings. The patient must have taken a serotonergic agent and have one of the following:

• Spontaneous clonus
• Inducible clonus plus agitation or diaphoresis
• Ocular clonus plus agitation or diaphoresis
• Inducible clonus or ocular clonus, plus hypertonia and hyperthermia
• Tremor plus hyperreflexia.

The Sternbach criteria. The patient must be using a serotonergic agent, must have no other causes of symptoms, must not have recently used a neuroleptic agent, and must have three of the following:

• Mental status changes
• Agitation
• Hyperreflexia
• Myoclonus
• Diaphoresis
• Shivering
• Tremor
• Diarrhea
• Incoordination
• Fever

The Hunter criteria are recommended and are more specific (97% vs 96%) and more sensitive (84% vs 75%) than the Sternbach criteria when compared with the gold standard of diagnosis by a clinical toxicologist.¹ The Hunter criteria are also less likely to yield false-positive results.¹¹

Differential diagnosis

The differential diagnosis for serotonin syndrome includes neuroleptic malignant syndrome, anticholinergic poisoning (Table 3), metastatic carcinoma, central nervous system infection, gastroenteritis, and sepsis.

Neuroleptic malignant syndrome, the disorder most often misdiagnosed as serotonin syndrome, is an idiosyncratic reaction to a dopamine antagonist (eg, haloperidol, fluphenazine) that develops over days to weeks.²⁰ In 70% of patients, agitated delirium with confusion appears first, followed by lead pipe rigidity and cogwheel tremor, then hyperthermia with body temperature greater than 40°C, and finally, profuse diaphoresis, tachycardia, hypertension, and tachypnea.²¹

Key elements that distinguish neuroleptic malignant syndrome are the timeline of the clinical course, bradyreflexia, and the absence of clonus. Prodromal symptoms of nausea, vomiting, and diarrhea are also rare in neuroleptic malignant syndrome. Neuroleptic malignant syndrome typically requires an average of 9 days to resolve.

Anticholinergic poisoning usually develops within 1 to 2 hours of oral ingestion. Symptoms include flushing, anhidrosis, anhidrotic hyperthermia, mydriasis, urinary retention, decreased bowel sounds, agitated delirium, and visual hallucinations. In contrast to serotonin syndrome, reflexes and muscle tone are normal with anticholinergic poisoning.

HOW CAN WE TREAT SEROTONIN SYNDROME?

The two mainstays of serotonin syndrome management are to discontinue the serotonergic agent and to give supportive care. Most patients improve within 24 hours of stopping the precipitating drug and starting therapy.¹⁶

For mild serotonin syndrome, treatment involves discontinuing the offending agent and supportive therapy with intravenous fluids, correction of vital signs, and symptomatic treatment with a benzodiazepine. Patients should be admitted and observed for 12 to 24 hours to prevent exacerbation.

For moderate serotonin syndrome, treatment also involves stopping the serotonergic agent and giving supportive care. Symptomatic treatment with a benzodiazepine and nonserotonergic antiemetics is recommended, and standard cooling measures should be implemented for hyperthermia. Patients should be admitted and observed for 12 to 24 hours to prevent exacerbation.

For severe serotonin toxicity, treatment should focus on management of airway, breathing, and circulation—ie, the “ABCs.” The two primary life-threatening concerns are hyperthermia (temperature > 40°C or 104°F) and rigidity, which can lead to hypoventilation.^1,22 Controlling hyperthermia and rigidity can prevent other grave complications. Patients with severe serotonin toxicity should be sedated, paralyzed, and intubated.²¹ This will reverse ventilatory hypertonia and allow for mechanical ventilation. Paralysis will also prevent the exacerbation of hyperthermia, which is caused by muscle rigidity. Antipyretics have no role in the treatment of serotonin syndrome since the hyperthermia is not caused by a change in the hypothalamic temperature set point.²¹ Standard cooling measures should be used to manage hyperthermia.

Serotonin antagonists

Serotonin antagonists have had some success in case reports, but further studies are needed to confirm this.^4,23,24

Cyproheptadine is a potent 5-HT2A antagonist; patients usually respond within 1 to 2 hours of administration. Signs and symptoms have resolved completely within times ranging from 20 minutes to 48 hours, depending on the severity of toxicity.

The recommended initial dose of cyproheptadine is 12 mg, followed by 2 mg every 2 hours if symptoms continue.¹⁶ Maintenance dosing with 8 mg every 6 hours should be prescribed once stabilization is achieved. The total daily dose for adults should not exceed 0.5 mg/kg/day. Cyproheptadine is available only in oral form but can be crushed and administered via a nasogastric tube.²¹

Chlorpromazine is a 5-HT1A and 5-HT2A antagonist and can be given intramuscularly. Despite case reports citing its effectiveness, the risk of hypotension, dystonic reactions, and neuroleptic malignant syndrome may make it a less desirable option.^4,25

Cyproheptadine, chlorpromazine, and other serotonin receptor antagonists require further investigation beyond individual case reports to determine their effectiveness and reliability in treating serotonin syndrome.

Other agents

Benzodiazepines are considered a mainstay for symptomatic relief because of their anxiolytic and muscle relaxant effects.²⁶ However, animal studies showed that treatment with benzodiazepines attenuated hyperthermia but had no effect on time to recovery or outcome.²⁷

Neuromuscular blocking agents. The suggested neuromuscular blocking agent for severe toxicity is a nondepolarizing agent such as vecuronium. Succinylcholine should be avoided, as it can exacerbate rhabdomyolysis and hyperkalemia.²¹

Dantrolene has also been suggested for its muscle-relaxing effects and use in malignant hyperthermia. However, this treatment has not been successful in isolated case reports and has been ineffective in animal models.^4,28

Physical restraints are ill-advised, since isometric muscle contractions can exacerbate hyperthermia and lactic acidosis in agitated patients.²¹ If physical restraints are necessary to deliver medications, they should be removed as soon as possible.

HOW CAN WE PREVENT SEROTONIN SYNDROME?

Prevention of serotonin syndrome begins with improving education and awareness in patients and healthcare providers. Patients should be primarily concerned with taking their medications carefully as prescribed and recognizing early signs and symptoms of serotonin toxicity.

As use of antidepressants among an aging population continues to increase, and as physicians in multiple disciplines prescribe them for evolving indications (eg, duloxetine to treat osteoarthritis, diabetic neuropathy, fibromyalgia, and chemotherapy-induced peripheral neuropathy), healthcare providers need to be prepared to see more cases of serotonin syndrome and its deleterious effects.^29–31 Physicians should be vigilant in minimizing unnecessary use of serotonergic agents and reviewing drug regimens regularly to limit polypharmacy.

Electronic ordering systems should be designed to detect and alert the prescriber to possible interactions that can potentiate serotonin syndrome, and to not place the order until the prescriber overrides the alert. Combinations of SSRIs and MAOIs have the highest risk for inducing severe serotonin syndrome and should always be avoided.

If a patient is transitioning between serotonergic agents, physicians should observe a safe washout period to prevent overlap.^16,32 Washout periods may differ among medications depending on their half-lives. For example, sertraline has a washout period of 2 weeks, while fluoxetine requires a washout period of 5 to 6 weeks.³³ Consulting a pharmacist may be helpful when considering half-lives and washout periods.

We believe that educating both patients and physicians regarding prevention will help minimize the risk for serotonergic syndrome and will improve efficiency in assessment and management should toxicity develop.

With a substantial increase in antidepressant use in the United States over the last 2 decades, serotonin syndrome has become an increasingly common and significant clinical concern. In 1999, 6.5% of adults age 18 and older were taking antidepressants; by 2010, the percentage had increased to 10.4%.¹ Though the true incidence of serotonin syndrome is difficult to determine, the number of ingestions of selective serotonin reuptake inhibitors (SSRIs) associated with moderate to major effects reported to US poison control centers increased from 7,349 in 2002² to 8,585 in 2005.³

Though the clinical manifestations are often mild to moderate, patients with serotonin syndrome can deteriorate rapidly and require intensive care. Unlike neuroleptic malignant syndrome, serotonin syndrome should not be considered an extremely rare idiosyncratic reaction to medication, but rather a progression of serotonergic toxicity based on increasing concentration levels that can occur in any patient regardless of age.⁴

Because it has a nonspecific prodrome and protean manifestations, serotonin syndrome can easily be overlooked, misdiagnosed, or exacerbated if not carefully assessed. Diagnosis requires a low threshold for suspicion and a meticulous history and physical examination. In the syndrome’s mildest stage, symptoms are often misattributed to other causes, and in its most severe form, it can easily be mistaken for neuroleptic malignant syndrome.

WHAT IS SEROTONIN SYNDROME?

Serotonin syndrome classically presents as the triad of autonomic dysfunction, neuromuscular excitation, and altered mental status. These symptoms are a result of increased serotonin levels affecting the central and peripheral nervous systems. Serotonin affects a family of receptors that has seven members, of which 5-HT1A and 5-HT2A are most often responsible for serotonin syndrome.⁵

Conditions that can alter the regulation of serotonin include therapeutic doses, drug interactions, intentional or unintentional overdoses, and overlapping transitions between medications. As a result, drugs that have been associated with serotonin syndrome can be classified into the following five categories as shown below and in Table 1:

Drugs that decrease serotonin breakdown include monoamine oxidase inhibitors (MAOIs), linezolid,⁶ methylene blue, procarbazine, and Syrian rue.

Drugs that decrease serotonin reuptake include SSRIs, serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, opioids (meperidine, buprenorphine, tramadol, tapentadol, dextromethorphan), antiepileptics (carbamazepine, valproate), and antiemetics (ondansetron, granisetron, metoclopramide), and the herbal preparation St. John’s wort.

Drugs that increase serotonin precursors or agonists include tryptophan, lithium, fentanyl, and lysergic acid diethylamide (LSD).

Drugs that increase serotonin release include fenfluramine, amphetamines, and methylenedioxymethamphetamine (ecstasy).

Drugs that prevent breakdown of the agents listed above are CYP2D6 and CYP3A4 inhibitors, eg, erythromycin,⁷ ciprofloxacin, fluconazole, ritonavir, and grapefruit juice.

However, the only drugs that have been reliably confirmed to precipitate serotonin syndrome are MAOIs, SSRIs, SNRIs, and serotonin releasers. Other listed drug interactions are based on case reports and have not been thoroughly evaluated.^6–9

Currently, SSRIs are the most commonly prescribed antidepressant medications and, consequently, they are the ones most often implicated in serotonergic toxicity.^1,10 An estimated 15% of SSRI overdoses lead to mild or moderate serotonin toxicity.¹¹ Serotonergic agents used in conjunction can increase the risk for severe serotonin syndrome; an SSRI and an MAOI in combination poses the greatest risk.⁵

Ultimately, the incidence of serotonin syndrome is difficult to assess, but it is believed to be underreported because it is easy to misdiagnose and mild symptoms may be dismissed.

WHO IS AT RISK OF SEROTONIN SYNDROME?

Long-term antidepressant use has disproportionately increased in middle-aged and older adults and non-Hispanic whites.^1,12,13 Intuitively, as the risk for depression increases dramatically in patients with chronic medical conditions, serotonin syndrome should be more prevalent among the elderly. In addition, patients with multiple comorbidities take more medications, increasing the risk of polypharmacy and adverse drug reactions.¹⁴

Although the epidemiology of serotonin syndrome has yet to be extensively studied, the combination of age and comorbidities may increase the risk for this condition.

HOW DOES IT PRESENT?

Serotonin syndrome characteristically presents as the triad of autonomic dysfunction, neuromuscular excitation, and altered mental status. However, these symptoms may not occur simultaneously: autonomic dysfunction is present in 40% of patients, neuromuscular excitation in 50%, and altered mental status in 40%.¹⁵ The symptoms can range from mild to life-threatening (Table 2).¹⁶

Autonomic dysfunction. Diaphoresis is present in 48.8% of cases, tachycardia in 44%, nausea and vomiting in 26.8%, and mydriasis in 19.5%. Other signs are hyperactive bowel sounds, diarrhea, and flushing.¹⁶

Neuromuscular excitation. Myoclonus is present in 48.8%, hyperreflexia in 41%, hyperthermia in 26.8%, and hypertonicity and rigidity in 19.5%. Other signs are spontaneous or inducible clonus, ocular clonus (continuous rhythmic oscillations of gaze), and tremor.

Altered mental status. Confusion is present in 41.2% and agitation in 36.5%. Other signs are anxiety, lethargy, and coma.

Symptoms of serotonin toxicity arise within an hour of a precipitating event (eg, ingestion) in approximately 28% of patients, and within 6 hours in 61%.¹⁶ Highly diagnostic features include hyperreflexia and induced or spontaneous clonus that are generally more pronounced in the lower limbs.¹¹ Clonus can be elicited with ankle dorsiflexion.

In mild toxicity, patients may present with tremor or twitching and anxiety, as well as with hyperreflexia, tachycardia, diaphoresis, and mydriasis. Further investigation may uncover a recently initiated antidepressant or a cold-and-cough medication that contains dextromethorphan.^15,17

In moderate toxicity, patients present in significant distress, with agitation and restlessness. Features may include hyperreflexia and clonus of the lower extremities, opsoclonus, hyperactive bowel sounds, diarrhea, nausea, vomiting, tachycardia, hypertension, diaphoresis, mydriasis, and hyperthermia (< 40°C, 104°F). The patient’s history may reveal use of ecstasy or combined treatment with serotonin-potentiating agents such as an antidepressant with a proserotonergic opioid, antiepileptic, or CYP2D6 or CYP3A4 inhibitor.¹⁵

Severe serotonin toxicity is a life-threatening condition that can lead to multiorgan failure within hours. It can be characterized by muscle rigidity, which can cause the body temperature to elevate rapidly to over 40°C. This hypertonicity can mask the classic and diagnostic signs of hyperreflexia and clonus. Patients may have unstable and dynamic vital signs with confusion or delirium and can experience tonic-clonic seizures.

If the muscle rigidity and resulting hyperthermia are not managed properly, patients can develop cellular damage and enzyme dysfunction leading to rhabdomyolysis, myoglobinuria, renal failure, metabolic acidosis, acute respiratory distress syndrome, and disseminated intravascular coagulation.^16,18

Serotonin crisis is usually caused by the co-ingestion of multiple serotonergic agents, such as an antidepressant with an aforementioned opioid and antiemetic¹⁹; combining an SSRI and an MAOI poses the greatest risk. Alternatively, patients may have recently switched antidepressants without observing a safe washout period, leading to an overlap of serotonin levels.¹⁶

HOW DO WE DIAGNOSE SEROTONIN SYNDROME?

Serotonin syndrome is a clinical diagnosis and therefore requires a thorough review of medications and physical examination. Serum serotonin levels are an unreliable indicator of toxicity and do not correlate well with the clinical presentation.¹⁶

Currently, there are two clinical tools for diagnosing serotonin syndrome: the Hunter serotonin toxicity criteria (Figure 1) and the Sternbach criteria.

The Hunter criteria are based more heavily on physical findings. The patient must have taken a serotonergic agent and have one of the following:

• Spontaneous clonus
• Inducible clonus plus agitation or diaphoresis
• Ocular clonus plus agitation or diaphoresis
• Inducible clonus or ocular clonus, plus hypertonia and hyperthermia
• Tremor plus hyperreflexia.

The Sternbach criteria. The patient must be using a serotonergic agent, must have no other causes of symptoms, must not have recently used a neuroleptic agent, and must have three of the following:

• Mental status changes
• Agitation
• Hyperreflexia
• Myoclonus
• Diaphoresis
• Shivering
• Tremor
• Diarrhea
• Incoordination
• Fever

The Hunter criteria are recommended and are more specific (97% vs 96%) and more sensitive (84% vs 75%) than the Sternbach criteria when compared with the gold standard of diagnosis by a clinical toxicologist.¹ The Hunter criteria are also less likely to yield false-positive results.¹¹

Differential diagnosis

The differential diagnosis for serotonin syndrome includes neuroleptic malignant syndrome, anticholinergic poisoning (Table 3), metastatic carcinoma, central nervous system infection, gastroenteritis, and sepsis.

Neuroleptic malignant syndrome, the disorder most often misdiagnosed as serotonin syndrome, is an idiosyncratic reaction to a dopamine antagonist (eg, haloperidol, fluphenazine) that develops over days to weeks.²⁰ In 70% of patients, agitated delirium with confusion appears first, followed by lead pipe rigidity and cogwheel tremor, then hyperthermia with body temperature greater than 40°C, and finally, profuse diaphoresis, tachycardia, hypertension, and tachypnea.²¹

Key elements that distinguish neuroleptic malignant syndrome are the timeline of the clinical course, bradyreflexia, and the absence of clonus. Prodromal symptoms of nausea, vomiting, and diarrhea are also rare in neuroleptic malignant syndrome. Neuroleptic malignant syndrome typically requires an average of 9 days to resolve.

Anticholinergic poisoning usually develops within 1 to 2 hours of oral ingestion. Symptoms include flushing, anhidrosis, anhidrotic hyperthermia, mydriasis, urinary retention, decreased bowel sounds, agitated delirium, and visual hallucinations. In contrast to serotonin syndrome, reflexes and muscle tone are normal with anticholinergic poisoning.

HOW CAN WE TREAT SEROTONIN SYNDROME?

The two mainstays of serotonin syndrome management are to discontinue the serotonergic agent and to give supportive care. Most patients improve within 24 hours of stopping the precipitating drug and starting therapy.¹⁶

For mild serotonin syndrome, treatment involves discontinuing the offending agent and supportive therapy with intravenous fluids, correction of vital signs, and symptomatic treatment with a benzodiazepine. Patients should be admitted and observed for 12 to 24 hours to prevent exacerbation.

For moderate serotonin syndrome, treatment also involves stopping the serotonergic agent and giving supportive care. Symptomatic treatment with a benzodiazepine and nonserotonergic antiemetics is recommended, and standard cooling measures should be implemented for hyperthermia. Patients should be admitted and observed for 12 to 24 hours to prevent exacerbation.

For severe serotonin toxicity, treatment should focus on management of airway, breathing, and circulation—ie, the “ABCs.” The two primary life-threatening concerns are hyperthermia (temperature > 40°C or 104°F) and rigidity, which can lead to hypoventilation.^1,22 Controlling hyperthermia and rigidity can prevent other grave complications. Patients with severe serotonin toxicity should be sedated, paralyzed, and intubated.²¹ This will reverse ventilatory hypertonia and allow for mechanical ventilation. Paralysis will also prevent the exacerbation of hyperthermia, which is caused by muscle rigidity. Antipyretics have no role in the treatment of serotonin syndrome since the hyperthermia is not caused by a change in the hypothalamic temperature set point.²¹ Standard cooling measures should be used to manage hyperthermia.

Serotonin antagonists

Serotonin antagonists have had some success in case reports, but further studies are needed to confirm this.^4,23,24

Cyproheptadine is a potent 5-HT2A antagonist; patients usually respond within 1 to 2 hours of administration. Signs and symptoms have resolved completely within times ranging from 20 minutes to 48 hours, depending on the severity of toxicity.

The recommended initial dose of cyproheptadine is 12 mg, followed by 2 mg every 2 hours if symptoms continue.¹⁶ Maintenance dosing with 8 mg every 6 hours should be prescribed once stabilization is achieved. The total daily dose for adults should not exceed 0.5 mg/kg/day. Cyproheptadine is available only in oral form but can be crushed and administered via a nasogastric tube.²¹

Chlorpromazine is a 5-HT1A and 5-HT2A antagonist and can be given intramuscularly. Despite case reports citing its effectiveness, the risk of hypotension, dystonic reactions, and neuroleptic malignant syndrome may make it a less desirable option.^4,25

Cyproheptadine, chlorpromazine, and other serotonin receptor antagonists require further investigation beyond individual case reports to determine their effectiveness and reliability in treating serotonin syndrome.

Other agents

Benzodiazepines are considered a mainstay for symptomatic relief because of their anxiolytic and muscle relaxant effects.²⁶ However, animal studies showed that treatment with benzodiazepines attenuated hyperthermia but had no effect on time to recovery or outcome.²⁷

Neuromuscular blocking agents. The suggested neuromuscular blocking agent for severe toxicity is a nondepolarizing agent such as vecuronium. Succinylcholine should be avoided, as it can exacerbate rhabdomyolysis and hyperkalemia.²¹

Dantrolene has also been suggested for its muscle-relaxing effects and use in malignant hyperthermia. However, this treatment has not been successful in isolated case reports and has been ineffective in animal models.^4,28

Physical restraints are ill-advised, since isometric muscle contractions can exacerbate hyperthermia and lactic acidosis in agitated patients.²¹ If physical restraints are necessary to deliver medications, they should be removed as soon as possible.

HOW CAN WE PREVENT SEROTONIN SYNDROME?

Prevention of serotonin syndrome begins with improving education and awareness in patients and healthcare providers. Patients should be primarily concerned with taking their medications carefully as prescribed and recognizing early signs and symptoms of serotonin toxicity.

As use of antidepressants among an aging population continues to increase, and as physicians in multiple disciplines prescribe them for evolving indications (eg, duloxetine to treat osteoarthritis, diabetic neuropathy, fibromyalgia, and chemotherapy-induced peripheral neuropathy), healthcare providers need to be prepared to see more cases of serotonin syndrome and its deleterious effects.^29–31 Physicians should be vigilant in minimizing unnecessary use of serotonergic agents and reviewing drug regimens regularly to limit polypharmacy.

Electronic ordering systems should be designed to detect and alert the prescriber to possible interactions that can potentiate serotonin syndrome, and to not place the order until the prescriber overrides the alert. Combinations of SSRIs and MAOIs have the highest risk for inducing severe serotonin syndrome and should always be avoided.

If a patient is transitioning between serotonergic agents, physicians should observe a safe washout period to prevent overlap.^16,32 Washout periods may differ among medications depending on their half-lives. For example, sertraline has a washout period of 2 weeks, while fluoxetine requires a washout period of 5 to 6 weeks.³³ Consulting a pharmacist may be helpful when considering half-lives and washout periods.

We believe that educating both patients and physicians regarding prevention will help minimize the risk for serotonergic syndrome and will improve efficiency in assessment and management should toxicity develop.

With a substantial increase in antidepressant use in the United States over the last 2 decades, serotonin syndrome has become an increasingly common and significant clinical concern. In 1999, 6.5% of adults age 18 and older were taking antidepressants; by 2010, the percentage had increased to 10.4%.¹ Though the true incidence of serotonin syndrome is difficult to determine, the number of ingestions of selective serotonin reuptake inhibitors (SSRIs) associated with moderate to major effects reported to US poison control centers increased from 7,349 in 2002² to 8,585 in 2005.³

Though the clinical manifestations are often mild to moderate, patients with serotonin syndrome can deteriorate rapidly and require intensive care. Unlike neuroleptic malignant syndrome, serotonin syndrome should not be considered an extremely rare idiosyncratic reaction to medication, but rather a progression of serotonergic toxicity based on increasing concentration levels that can occur in any patient regardless of age.⁴

Because it has a nonspecific prodrome and protean manifestations, serotonin syndrome can easily be overlooked, misdiagnosed, or exacerbated if not carefully assessed. Diagnosis requires a low threshold for suspicion and a meticulous history and physical examination. In the syndrome’s mildest stage, symptoms are often misattributed to other causes, and in its most severe form, it can easily be mistaken for neuroleptic malignant syndrome.

WHAT IS SEROTONIN SYNDROME?

Serotonin syndrome classically presents as the triad of autonomic dysfunction, neuromuscular excitation, and altered mental status. These symptoms are a result of increased serotonin levels affecting the central and peripheral nervous systems. Serotonin affects a family of receptors that has seven members, of which 5-HT1A and 5-HT2A are most often responsible for serotonin syndrome.⁵

Conditions that can alter the regulation of serotonin include therapeutic doses, drug interactions, intentional or unintentional overdoses, and overlapping transitions between medications. As a result, drugs that have been associated with serotonin syndrome can be classified into the following five categories as shown below and in Table 1:

Drugs that decrease serotonin breakdown include monoamine oxidase inhibitors (MAOIs), linezolid,⁶ methylene blue, procarbazine, and Syrian rue.

Drugs that decrease serotonin reuptake include SSRIs, serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, opioids (meperidine, buprenorphine, tramadol, tapentadol, dextromethorphan), antiepileptics (carbamazepine, valproate), and antiemetics (ondansetron, granisetron, metoclopramide), and the herbal preparation St. John’s wort.

Drugs that increase serotonin precursors or agonists include tryptophan, lithium, fentanyl, and lysergic acid diethylamide (LSD).

Drugs that increase serotonin release include fenfluramine, amphetamines, and methylenedioxymethamphetamine (ecstasy).

Drugs that prevent breakdown of the agents listed above are CYP2D6 and CYP3A4 inhibitors, eg, erythromycin,⁷ ciprofloxacin, fluconazole, ritonavir, and grapefruit juice.

However, the only drugs that have been reliably confirmed to precipitate serotonin syndrome are MAOIs, SSRIs, SNRIs, and serotonin releasers. Other listed drug interactions are based on case reports and have not been thoroughly evaluated.^6–9

Currently, SSRIs are the most commonly prescribed antidepressant medications and, consequently, they are the ones most often implicated in serotonergic toxicity.^1,10 An estimated 15% of SSRI overdoses lead to mild or moderate serotonin toxicity.¹¹ Serotonergic agents used in conjunction can increase the risk for severe serotonin syndrome; an SSRI and an MAOI in combination poses the greatest risk.⁵

Ultimately, the incidence of serotonin syndrome is difficult to assess, but it is believed to be underreported because it is easy to misdiagnose and mild symptoms may be dismissed.

WHO IS AT RISK OF SEROTONIN SYNDROME?

Long-term antidepressant use has disproportionately increased in middle-aged and older adults and non-Hispanic whites.^1,12,13 Intuitively, as the risk for depression increases dramatically in patients with chronic medical conditions, serotonin syndrome should be more prevalent among the elderly. In addition, patients with multiple comorbidities take more medications, increasing the risk of polypharmacy and adverse drug reactions.¹⁴

Although the epidemiology of serotonin syndrome has yet to be extensively studied, the combination of age and comorbidities may increase the risk for this condition.

HOW DOES IT PRESENT?

Serotonin syndrome characteristically presents as the triad of autonomic dysfunction, neuromuscular excitation, and altered mental status. However, these symptoms may not occur simultaneously: autonomic dysfunction is present in 40% of patients, neuromuscular excitation in 50%, and altered mental status in 40%.¹⁵ The symptoms can range from mild to life-threatening (Table 2).¹⁶

Autonomic dysfunction. Diaphoresis is present in 48.8% of cases, tachycardia in 44%, nausea and vomiting in 26.8%, and mydriasis in 19.5%. Other signs are hyperactive bowel sounds, diarrhea, and flushing.¹⁶

Neuromuscular excitation. Myoclonus is present in 48.8%, hyperreflexia in 41%, hyperthermia in 26.8%, and hypertonicity and rigidity in 19.5%. Other signs are spontaneous or inducible clonus, ocular clonus (continuous rhythmic oscillations of gaze), and tremor.

Altered mental status. Confusion is present in 41.2% and agitation in 36.5%. Other signs are anxiety, lethargy, and coma.

Symptoms of serotonin toxicity arise within an hour of a precipitating event (eg, ingestion) in approximately 28% of patients, and within 6 hours in 61%.¹⁶ Highly diagnostic features include hyperreflexia and induced or spontaneous clonus that are generally more pronounced in the lower limbs.¹¹ Clonus can be elicited with ankle dorsiflexion.

In mild toxicity, patients may present with tremor or twitching and anxiety, as well as with hyperreflexia, tachycardia, diaphoresis, and mydriasis. Further investigation may uncover a recently initiated antidepressant or a cold-and-cough medication that contains dextromethorphan.^15,17

In moderate toxicity, patients present in significant distress, with agitation and restlessness. Features may include hyperreflexia and clonus of the lower extremities, opsoclonus, hyperactive bowel sounds, diarrhea, nausea, vomiting, tachycardia, hypertension, diaphoresis, mydriasis, and hyperthermia (< 40°C, 104°F). The patient’s history may reveal use of ecstasy or combined treatment with serotonin-potentiating agents such as an antidepressant with a proserotonergic opioid, antiepileptic, or CYP2D6 or CYP3A4 inhibitor.¹⁵

Severe serotonin toxicity is a life-threatening condition that can lead to multiorgan failure within hours. It can be characterized by muscle rigidity, which can cause the body temperature to elevate rapidly to over 40°C. This hypertonicity can mask the classic and diagnostic signs of hyperreflexia and clonus. Patients may have unstable and dynamic vital signs with confusion or delirium and can experience tonic-clonic seizures.

If the muscle rigidity and resulting hyperthermia are not managed properly, patients can develop cellular damage and enzyme dysfunction leading to rhabdomyolysis, myoglobinuria, renal failure, metabolic acidosis, acute respiratory distress syndrome, and disseminated intravascular coagulation.^16,18

Serotonin crisis is usually caused by the co-ingestion of multiple serotonergic agents, such as an antidepressant with an aforementioned opioid and antiemetic¹⁹; combining an SSRI and an MAOI poses the greatest risk. Alternatively, patients may have recently switched antidepressants without observing a safe washout period, leading to an overlap of serotonin levels.¹⁶

HOW DO WE DIAGNOSE SEROTONIN SYNDROME?

Serotonin syndrome is a clinical diagnosis and therefore requires a thorough review of medications and physical examination. Serum serotonin levels are an unreliable indicator of toxicity and do not correlate well with the clinical presentation.¹⁶

Currently, there are two clinical tools for diagnosing serotonin syndrome: the Hunter serotonin toxicity criteria (Figure 1) and the Sternbach criteria.

The Hunter criteria are based more heavily on physical findings. The patient must have taken a serotonergic agent and have one of the following:

• Spontaneous clonus
• Inducible clonus plus agitation or diaphoresis
• Ocular clonus plus agitation or diaphoresis
• Inducible clonus or ocular clonus, plus hypertonia and hyperthermia
• Tremor plus hyperreflexia.

The Sternbach criteria. The patient must be using a serotonergic agent, must have no other causes of symptoms, must not have recently used a neuroleptic agent, and must have three of the following:

• Mental status changes
• Agitation
• Hyperreflexia
• Myoclonus
• Diaphoresis
• Shivering
• Tremor
• Diarrhea
• Incoordination
• Fever

The Hunter criteria are recommended and are more specific (97% vs 96%) and more sensitive (84% vs 75%) than the Sternbach criteria when compared with the gold standard of diagnosis by a clinical toxicologist.¹ The Hunter criteria are also less likely to yield false-positive results.¹¹

Differential diagnosis

The differential diagnosis for serotonin syndrome includes neuroleptic malignant syndrome, anticholinergic poisoning (Table 3), metastatic carcinoma, central nervous system infection, gastroenteritis, and sepsis.

Neuroleptic malignant syndrome, the disorder most often misdiagnosed as serotonin syndrome, is an idiosyncratic reaction to a dopamine antagonist (eg, haloperidol, fluphenazine) that develops over days to weeks.²⁰ In 70% of patients, agitated delirium with confusion appears first, followed by lead pipe rigidity and cogwheel tremor, then hyperthermia with body temperature greater than 40°C, and finally, profuse diaphoresis, tachycardia, hypertension, and tachypnea.²¹

Key elements that distinguish neuroleptic malignant syndrome are the timeline of the clinical course, bradyreflexia, and the absence of clonus. Prodromal symptoms of nausea, vomiting, and diarrhea are also rare in neuroleptic malignant syndrome. Neuroleptic malignant syndrome typically requires an average of 9 days to resolve.

Anticholinergic poisoning usually develops within 1 to 2 hours of oral ingestion. Symptoms include flushing, anhidrosis, anhidrotic hyperthermia, mydriasis, urinary retention, decreased bowel sounds, agitated delirium, and visual hallucinations. In contrast to serotonin syndrome, reflexes and muscle tone are normal with anticholinergic poisoning.

HOW CAN WE TREAT SEROTONIN SYNDROME?

The two mainstays of serotonin syndrome management are to discontinue the serotonergic agent and to give supportive care. Most patients improve within 24 hours of stopping the precipitating drug and starting therapy.¹⁶

For mild serotonin syndrome, treatment involves discontinuing the offending agent and supportive therapy with intravenous fluids, correction of vital signs, and symptomatic treatment with a benzodiazepine. Patients should be admitted and observed for 12 to 24 hours to prevent exacerbation.

For moderate serotonin syndrome, treatment also involves stopping the serotonergic agent and giving supportive care. Symptomatic treatment with a benzodiazepine and nonserotonergic antiemetics is recommended, and standard cooling measures should be implemented for hyperthermia. Patients should be admitted and observed for 12 to 24 hours to prevent exacerbation.

For severe serotonin toxicity, treatment should focus on management of airway, breathing, and circulation—ie, the “ABCs.” The two primary life-threatening concerns are hyperthermia (temperature > 40°C or 104°F) and rigidity, which can lead to hypoventilation.^1,22 Controlling hyperthermia and rigidity can prevent other grave complications. Patients with severe serotonin toxicity should be sedated, paralyzed, and intubated.²¹ This will reverse ventilatory hypertonia and allow for mechanical ventilation. Paralysis will also prevent the exacerbation of hyperthermia, which is caused by muscle rigidity. Antipyretics have no role in the treatment of serotonin syndrome since the hyperthermia is not caused by a change in the hypothalamic temperature set point.²¹ Standard cooling measures should be used to manage hyperthermia.

Serotonin antagonists

Serotonin antagonists have had some success in case reports, but further studies are needed to confirm this.^4,23,24

Cyproheptadine is a potent 5-HT2A antagonist; patients usually respond within 1 to 2 hours of administration. Signs and symptoms have resolved completely within times ranging from 20 minutes to 48 hours, depending on the severity of toxicity.

The recommended initial dose of cyproheptadine is 12 mg, followed by 2 mg every 2 hours if symptoms continue.¹⁶ Maintenance dosing with 8 mg every 6 hours should be prescribed once stabilization is achieved. The total daily dose for adults should not exceed 0.5 mg/kg/day. Cyproheptadine is available only in oral form but can be crushed and administered via a nasogastric tube.²¹

Chlorpromazine is a 5-HT1A and 5-HT2A antagonist and can be given intramuscularly. Despite case reports citing its effectiveness, the risk of hypotension, dystonic reactions, and neuroleptic malignant syndrome may make it a less desirable option.^4,25

Cyproheptadine, chlorpromazine, and other serotonin receptor antagonists require further investigation beyond individual case reports to determine their effectiveness and reliability in treating serotonin syndrome.

Other agents

Benzodiazepines are considered a mainstay for symptomatic relief because of their anxiolytic and muscle relaxant effects.²⁶ However, animal studies showed that treatment with benzodiazepines attenuated hyperthermia but had no effect on time to recovery or outcome.²⁷