Reviews

Asthma medications comprise several drug classes, including leukotriene antagonists and steroid-based inhalers. These drugs have been implicated in behavioral changes, such as increased hyperactivity, similar to symptoms of attention-deficit/hyperactivity disorder (ADHD) and oppositional defiant disorder (ODD)¹; this scenario is more of a concern in children than adults. This raises the question of whether these medications are physiologically linked to behavioral symptoms because of a suggested association with serotonin.^2,3 If this is the case, it is necessary to identify and evaluate possible psychiatric effects of these asthma agents.

How asthma medications work

Some asthma agents, such as montelukast, act as either leukotriene-related enzyme inhibitors (arachidonate 5-lipoxygenase) or leukotriene receptor antagonists. These drugs block production of inflammatory leukotrienes, which cause bronchoconstriction. Leukotrienes also can trigger cytokine synthesis, which can modulate leukotriene receptor function. Therefore, leukotriene antagonists could interfere with cytokine function.^3,4

Corticosteroid inhalers suppress inflammatory genes by reversing histone acetylation of inflammatory genes involved in asthma. These inhalers have been shown to reduce cytokine levels in patients with chronic lung disease and those with moderate to severe asthma.^5,6 Corticosteroids also have been associated with a decrease in serotonin levels, which could contribute to depression.⁷

Possible link between asthma and serotonin

Serotonin plays an integral role in observable, dysfunctional behaviors seen in disorders such as ADHD and ODD. In previous studies, serotonin modulated the cytokine network, and patients with asthma had elevated levels of plasma serotonin.^2,3 These findings imply that asthma medications could be involved in altering levels of both cytokines and serotonin. Pretorius² emphasized the importance of monitoring serotonin levels in children who exhibit behavioral dysfunction based on these observations:

• Persons with asthma presenting with medical symptoms have elevated serotonin levels.
• Decreased serotonin levels have been associated with ADHD and ODD; medications for ADHD have been shown to increase serotonin levels.
• Asthma medications have been shown to decrease serotonin levels.^2,3

Asthma medications might be partially responsible for behavioral disturbances, and therapeutic management should integrate the role of serotonin with asthma therapy.^2,3

Clinical considerations

Therapeutic management of asthma should consider psychiatric conditions and treatments. Future research should investigate the overall predisposition for behavioral dysfunction in persons with respiratory syncytial virus, a precursor for asthma. Once an asthma patient’s risk of a psychiatric disorder has been identified, the clinician can determine the most effective medications for treating the condition. If potential medications or genetic or environmental factors are identified, we might expect a move toward personalized care in the not too distant future.

Asthma medications comprise several drug classes, including leukotriene antagonists and steroid-based inhalers. These drugs have been implicated in behavioral changes, such as increased hyperactivity, similar to symptoms of attention-deficit/hyperactivity disorder (ADHD) and oppositional defiant disorder (ODD)¹; this scenario is more of a concern in children than adults. This raises the question of whether these medications are physiologically linked to behavioral symptoms because of a suggested association with serotonin.^2,3 If this is the case, it is necessary to identify and evaluate possible psychiatric effects of these asthma agents.

How asthma medications work

Some asthma agents, such as montelukast, act as either leukotriene-related enzyme inhibitors (arachidonate 5-lipoxygenase) or leukotriene receptor antagonists. These drugs block production of inflammatory leukotrienes, which cause bronchoconstriction. Leukotrienes also can trigger cytokine synthesis, which can modulate leukotriene receptor function. Therefore, leukotriene antagonists could interfere with cytokine function.^3,4

Corticosteroid inhalers suppress inflammatory genes by reversing histone acetylation of inflammatory genes involved in asthma. These inhalers have been shown to reduce cytokine levels in patients with chronic lung disease and those with moderate to severe asthma.^5,6 Corticosteroids also have been associated with a decrease in serotonin levels, which could contribute to depression.⁷

Possible link between asthma and serotonin

Serotonin plays an integral role in observable, dysfunctional behaviors seen in disorders such as ADHD and ODD. In previous studies, serotonin modulated the cytokine network, and patients with asthma had elevated levels of plasma serotonin.^2,3 These findings imply that asthma medications could be involved in altering levels of both cytokines and serotonin. Pretorius² emphasized the importance of monitoring serotonin levels in children who exhibit behavioral dysfunction based on these observations:

• Persons with asthma presenting with medical symptoms have elevated serotonin levels.
• Decreased serotonin levels have been associated with ADHD and ODD; medications for ADHD have been shown to increase serotonin levels.
• Asthma medications have been shown to decrease serotonin levels.^2,3

Asthma medications might be partially responsible for behavioral disturbances, and therapeutic management should integrate the role of serotonin with asthma therapy.^2,3

Clinical considerations

Therapeutic management of asthma should consider psychiatric conditions and treatments. Future research should investigate the overall predisposition for behavioral dysfunction in persons with respiratory syncytial virus, a precursor for asthma. Once an asthma patient’s risk of a psychiatric disorder has been identified, the clinician can determine the most effective medications for treating the condition. If potential medications or genetic or environmental factors are identified, we might expect a move toward personalized care in the not too distant future.

Asthma medications comprise several drug classes, including leukotriene antagonists and steroid-based inhalers. These drugs have been implicated in behavioral changes, such as increased hyperactivity, similar to symptoms of attention-deficit/hyperactivity disorder (ADHD) and oppositional defiant disorder (ODD)¹; this scenario is more of a concern in children than adults. This raises the question of whether these medications are physiologically linked to behavioral symptoms because of a suggested association with serotonin.^2,3 If this is the case, it is necessary to identify and evaluate possible psychiatric effects of these asthma agents.

How asthma medications work

Some asthma agents, such as montelukast, act as either leukotriene-related enzyme inhibitors (arachidonate 5-lipoxygenase) or leukotriene receptor antagonists. These drugs block production of inflammatory leukotrienes, which cause bronchoconstriction. Leukotrienes also can trigger cytokine synthesis, which can modulate leukotriene receptor function. Therefore, leukotriene antagonists could interfere with cytokine function.^3,4

Corticosteroid inhalers suppress inflammatory genes by reversing histone acetylation of inflammatory genes involved in asthma. These inhalers have been shown to reduce cytokine levels in patients with chronic lung disease and those with moderate to severe asthma.^5,6 Corticosteroids also have been associated with a decrease in serotonin levels, which could contribute to depression.⁷

Possible link between asthma and serotonin

Serotonin plays an integral role in observable, dysfunctional behaviors seen in disorders such as ADHD and ODD. In previous studies, serotonin modulated the cytokine network, and patients with asthma had elevated levels of plasma serotonin.^2,3 These findings imply that asthma medications could be involved in altering levels of both cytokines and serotonin. Pretorius² emphasized the importance of monitoring serotonin levels in children who exhibit behavioral dysfunction based on these observations:

• Persons with asthma presenting with medical symptoms have elevated serotonin levels.
• Decreased serotonin levels have been associated with ADHD and ODD; medications for ADHD have been shown to increase serotonin levels.
• Asthma medications have been shown to decrease serotonin levels.^2,3

Asthma medications might be partially responsible for behavioral disturbances, and therapeutic management should integrate the role of serotonin with asthma therapy.^2,3

Clinical considerations

Therapeutic management of asthma should consider psychiatric conditions and treatments. Future research should investigate the overall predisposition for behavioral dysfunction in persons with respiratory syncytial virus, a precursor for asthma. Once an asthma patient’s risk of a psychiatric disorder has been identified, the clinician can determine the most effective medications for treating the condition. If potential medications or genetic or environmental factors are identified, we might expect a move toward personalized care in the not too distant future.

Taking over the care of a patient with a complex medication regimen consisting of multiple psycho­tropics is a common experience for many practicing psychiatrists. Increasing attention has been paid to the risks of polypharmacy and the importance of “deprescribing”—reducing or stopping medication—when the risks of a drug outweigh the benefits.^1,2 However, successfully reducing medication burden can be a challenge, particularly when there is fear of decompensation or if the patient is psycho­logically attached to the complex medication regimen.

We describe a pragmatic approach to deprescribing, outlining 6 steps that we have used successfully in several treatment settings, which can assist prescribers facing similar challenges in their own practices.

1. Obtain a detailed history. First compile a comprehensive list of the patient’s medications, including psychotropics, other drugs, and supplements. If necessary, coordinate with your patient’s primary care provider. Then reassess the patient’s history of illness and efficacy of pharmacologic and non-pharmacologic treatments and how the current regimen has evolved. Understand the patient’s course of illness, coping styles, strengths, and vulnerabilities with an eye toward deprescribing.

2. Investigate underlying meaning. Even the most biologically oriented prescribers can benefit from exploring the underlying meaning the patient ascribes to the medication regimen. Common themes include:

• hesitation to relinquish a complex medication regimen because the patient fears decompensation (which could be either realistic or unrealistic)
• attachment to the “sick role”
• interpreting the complex regimen as evidence of the provider’s care and concern.

A series of sensitive conversations exploring these factors and addressing their underlying meaning can help increase a patient’s trust in the process of deprescribing.

3. Assess risk vs benefit. Weigh and educate the patient on the potential risks and benefits of each medication, as well as drug interactions and additive side effects.

4. Start with:
The most risky. Medications with significant risk for serious adverse effects (eg, high doses of a QTc-prolonging medication in a patient with elevated QTc) should be targeted early.

The least likely to be missed. If there are no high-risk medications that need to take priority, discontinuation of a “redundant” medication, such as a low-dose anti­histamine prescribed with multiple other sedating medications, can be an achievable first step. By starting with a medication that the patient is unlikely to miss, the provider can make efficient initial progress while building patient confidence in the deprescribing process.

Medication the patient is most motivated to discontinue. This strategy can enhance the therapeutic alliance and increase the likelihood of successful patient engagement for patients hesitant to decrease medications, so long as there are no significant contraindications to discontinuing the medication.

5. Go slowly. As long as there are no medications that put the patient at risk and require rapid discontinuation, going slowly increases the likelihood of long-term success by:

• permitting careful monitoring for any worsening symptoms
• allowing more time for physiologic readjustment
• enabling the patient and provider to build confidence in the process over time.

With slow discontinuation, normal emotions, such as transient, situationally appropriate anxiety about a life stressor, are less likely to be misinterpreted by the patient or provider as an inability to tolerate medication reduction because there is more opportunity to observe overall trends in symptoms.

6. Replace medications with alternatives. Offering non-pharmacological treatment when possible can greatly facilitate reducing the number of medications. Examples include:

• teaching a patient breathing exercises or mindfulness while preparing to decrease an as needed anxiolytic
• engaging the patient in cognitive-behavioral therapy for insomnia before reducing sleep medications
• working together to identify opportunities for behavioral activation and exercises that are the most achievable for the patient.

This replacement strategy can work in a physiologic sense and address a patient’s fear that medications are “taken away” without alternatives in place.

Although these strategies might not work for every patient and are not recommended for reducing medications that are medically necessary, using this approach will increase the likelihood of long-term success and maintain the patient–provider alliance when reducing unnecessary and potentially risky polypharmacy. An article by Gupta and Cahill¹ describes some similar approaches with additional discussion and considerations.

Taking over the care of a patient with a complex medication regimen consisting of multiple psycho­tropics is a common experience for many practicing psychiatrists. Increasing attention has been paid to the risks of polypharmacy and the importance of “deprescribing”—reducing or stopping medication—when the risks of a drug outweigh the benefits.^1,2 However, successfully reducing medication burden can be a challenge, particularly when there is fear of decompensation or if the patient is psycho­logically attached to the complex medication regimen.

We describe a pragmatic approach to deprescribing, outlining 6 steps that we have used successfully in several treatment settings, which can assist prescribers facing similar challenges in their own practices.

1. Obtain a detailed history. First compile a comprehensive list of the patient’s medications, including psychotropics, other drugs, and supplements. If necessary, coordinate with your patient’s primary care provider. Then reassess the patient’s history of illness and efficacy of pharmacologic and non-pharmacologic treatments and how the current regimen has evolved. Understand the patient’s course of illness, coping styles, strengths, and vulnerabilities with an eye toward deprescribing.

2. Investigate underlying meaning. Even the most biologically oriented prescribers can benefit from exploring the underlying meaning the patient ascribes to the medication regimen. Common themes include:

• hesitation to relinquish a complex medication regimen because the patient fears decompensation (which could be either realistic or unrealistic)
• attachment to the “sick role”
• interpreting the complex regimen as evidence of the provider’s care and concern.

A series of sensitive conversations exploring these factors and addressing their underlying meaning can help increase a patient’s trust in the process of deprescribing.

3. Assess risk vs benefit. Weigh and educate the patient on the potential risks and benefits of each medication, as well as drug interactions and additive side effects.

4. Start with:
The most risky. Medications with significant risk for serious adverse effects (eg, high doses of a QTc-prolonging medication in a patient with elevated QTc) should be targeted early.

The least likely to be missed. If there are no high-risk medications that need to take priority, discontinuation of a “redundant” medication, such as a low-dose anti­histamine prescribed with multiple other sedating medications, can be an achievable first step. By starting with a medication that the patient is unlikely to miss, the provider can make efficient initial progress while building patient confidence in the deprescribing process.

Medication the patient is most motivated to discontinue. This strategy can enhance the therapeutic alliance and increase the likelihood of successful patient engagement for patients hesitant to decrease medications, so long as there are no significant contraindications to discontinuing the medication.

5. Go slowly. As long as there are no medications that put the patient at risk and require rapid discontinuation, going slowly increases the likelihood of long-term success by:

• permitting careful monitoring for any worsening symptoms
• allowing more time for physiologic readjustment
• enabling the patient and provider to build confidence in the process over time.

With slow discontinuation, normal emotions, such as transient, situationally appropriate anxiety about a life stressor, are less likely to be misinterpreted by the patient or provider as an inability to tolerate medication reduction because there is more opportunity to observe overall trends in symptoms.

6. Replace medications with alternatives. Offering non-pharmacological treatment when possible can greatly facilitate reducing the number of medications. Examples include:

• teaching a patient breathing exercises or mindfulness while preparing to decrease an as needed anxiolytic
• engaging the patient in cognitive-behavioral therapy for insomnia before reducing sleep medications
• working together to identify opportunities for behavioral activation and exercises that are the most achievable for the patient.

This replacement strategy can work in a physiologic sense and address a patient’s fear that medications are “taken away” without alternatives in place.

Although these strategies might not work for every patient and are not recommended for reducing medications that are medically necessary, using this approach will increase the likelihood of long-term success and maintain the patient–provider alliance when reducing unnecessary and potentially risky polypharmacy. An article by Gupta and Cahill¹ describes some similar approaches with additional discussion and considerations.

Taking over the care of a patient with a complex medication regimen consisting of multiple psycho­tropics is a common experience for many practicing psychiatrists. Increasing attention has been paid to the risks of polypharmacy and the importance of “deprescribing”—reducing or stopping medication—when the risks of a drug outweigh the benefits.^1,2 However, successfully reducing medication burden can be a challenge, particularly when there is fear of decompensation or if the patient is psycho­logically attached to the complex medication regimen.

We describe a pragmatic approach to deprescribing, outlining 6 steps that we have used successfully in several treatment settings, which can assist prescribers facing similar challenges in their own practices.

1. Obtain a detailed history. First compile a comprehensive list of the patient’s medications, including psychotropics, other drugs, and supplements. If necessary, coordinate with your patient’s primary care provider. Then reassess the patient’s history of illness and efficacy of pharmacologic and non-pharmacologic treatments and how the current regimen has evolved. Understand the patient’s course of illness, coping styles, strengths, and vulnerabilities with an eye toward deprescribing.

2. Investigate underlying meaning. Even the most biologically oriented prescribers can benefit from exploring the underlying meaning the patient ascribes to the medication regimen. Common themes include:

• hesitation to relinquish a complex medication regimen because the patient fears decompensation (which could be either realistic or unrealistic)
• attachment to the “sick role”
• interpreting the complex regimen as evidence of the provider’s care and concern.

A series of sensitive conversations exploring these factors and addressing their underlying meaning can help increase a patient’s trust in the process of deprescribing.

3. Assess risk vs benefit. Weigh and educate the patient on the potential risks and benefits of each medication, as well as drug interactions and additive side effects.

4. Start with:
The most risky. Medications with significant risk for serious adverse effects (eg, high doses of a QTc-prolonging medication in a patient with elevated QTc) should be targeted early.

The least likely to be missed. If there are no high-risk medications that need to take priority, discontinuation of a “redundant” medication, such as a low-dose anti­histamine prescribed with multiple other sedating medications, can be an achievable first step. By starting with a medication that the patient is unlikely to miss, the provider can make efficient initial progress while building patient confidence in the deprescribing process.

Medication the patient is most motivated to discontinue. This strategy can enhance the therapeutic alliance and increase the likelihood of successful patient engagement for patients hesitant to decrease medications, so long as there are no significant contraindications to discontinuing the medication.

5. Go slowly. As long as there are no medications that put the patient at risk and require rapid discontinuation, going slowly increases the likelihood of long-term success by:

• permitting careful monitoring for any worsening symptoms
• allowing more time for physiologic readjustment
• enabling the patient and provider to build confidence in the process over time.

With slow discontinuation, normal emotions, such as transient, situationally appropriate anxiety about a life stressor, are less likely to be misinterpreted by the patient or provider as an inability to tolerate medication reduction because there is more opportunity to observe overall trends in symptoms.

6. Replace medications with alternatives. Offering non-pharmacological treatment when possible can greatly facilitate reducing the number of medications. Examples include:

• teaching a patient breathing exercises or mindfulness while preparing to decrease an as needed anxiolytic
• engaging the patient in cognitive-behavioral therapy for insomnia before reducing sleep medications
• working together to identify opportunities for behavioral activation and exercises that are the most achievable for the patient.

This replacement strategy can work in a physiologic sense and address a patient’s fear that medications are “taken away” without alternatives in place.

Although these strategies might not work for every patient and are not recommended for reducing medications that are medically necessary, using this approach will increase the likelihood of long-term success and maintain the patient–provider alliance when reducing unnecessary and potentially risky polypharmacy. An article by Gupta and Cahill¹ describes some similar approaches with additional discussion and considerations.

Hypertension is a widespread, under-recognized, and undertreated cause of morbidity and mortality in the United States and is associated with several psychiatric illnesses. Left untreated, hypertension can have significant consequences, including increased risk of stroke, coronary heart disease, heart failure, chronic kidney failure, and death. Approximately 70 million adults in the United States have hypertension, but only 60% of them have been diagnosed, and of those only 50% have their blood pressure under control.¹ In 2013, 360,000 deaths in the United States were attributed to hypertension.²

Hypertension is associated with major depressive disorder, generalized anxiety disorder, bipolar disorder, and schizophrenia.^3-5 Additionally, impulsive eating disorders, substance abuse, anxiety, and depression are associated with a hypertension diagnosis, although patients with panic disorder develop hypertension at a younger age.⁶ A 2007 study found a 61% prevalence of hypertension in those with bipolar disorder compared with 41% among the general population.⁷ The strong link between bipolar disorder and hypertension might be because of a common disease mechanism; both are associated with hyperactive cellular calcium signaling and increased platelet intracellular calcium ion concentrations.⁸

Hypertension not only is common among patients with psychiatric illness, it likely contributes to worse clinical outcomes. Studies across different cultures have found higher mortality rates in individuals with mental illness.^9-11 Persons with schizophrenia and other severe mental illnesses may lose ≥25 years of life expectancy, with the primary cause of death being cardiovascular disease, not suicide.¹² Patients with depression have a 50% greater risk of cardiovascular disease, which is equivalent to the risk of smoking.¹³ 

Schizophrenia is strongly associated with numerous comorbidities and has been linked significantly to an elevated 10-year cardiac risk after controlling for body mass index.⁵ The high rate of non-treatment of hypertension for patients with schizophrenia (62.4%) is especially concerning.¹⁴

Because of the well-documented morbidity and mortality of hypertension and its increased prevalence and undertreatment in the psychiatric population, mental health providers are in an important position to recognize hypertension and evaluate its inherent risks to direct their patients toward proper treatment. This article reviews:

• the signs and symptoms of hypertension
• the mental health provider’s role in the evaluation and diagnosis
• how psychotropic drugs influence blood pressure and drug–drug interactions
• the management of hypertension in psychiatric patients, including strategies for counseling and lifestyle management.

Diagnosing hypertension

Hypertension is defined as a blood pressure >140/90 mm Hg, the average of ≥2 properly measured readings at ≥2 visits in a medical setting.¹⁵ The proper equipment, including a well-fitting blood pressure cuff, and technique to measure blood pressure are essential to avoid misdiagnosis. The patient should be at rest for ≥5 minutes, without active pain or emotional distress.

Most cases of hypertension (90% to 95%) are primary, commonly called essential hypertension. However, the differential diagnosis also should consider secondary causes, which may include:

• obesity
• medications
• chronic alcohol use
• methamphetamine or cocaine use
• primary kidney disease
• atherosclerotic renal artery stenosis
• obstructive sleep apnea
• hypothyroidism
• primary hyperaldosteronism
• narrowing of the aorta
• Cushing syndrome
• primary hyperparathyroidism
• polycythemia
• pheochromocytoma.

Medical evaluation. Once the diagnosis of hypertension is made, a medical evaluation is indicated to determine if the patient has end-organ damage from the elevated pressures, such as renal disease or heart disease, to identify other modifiable cardiovascular risk factors, such as hyperlipidemia, and to screen for secondary causes of hypertension. This evaluation includes¹⁵:

• a physical exam
• review of medications
• lipid profile
• urinalysis to screen for proteinuria
• serum electrolytes and creatinine
• electrocardiogram to screen for left ventricular hypertrophy or prior infarction
• fasting glucose or hemoglobin A1_c to screen for type 2 diabetes mellitus.

Psychotropic drugs. In psychiatric patients, the evaluation must consider the potential impact psychotropic drug effects and drug–drug interactions can have on blood pressure (Table 2). For example, patients taking both diuretics and lithium are at increased risk for dehydration and increased serum lithium levels, which could cause severe neurologic symptoms and renal insufficiency.¹⁶ Several antihypertensives when taken with venlafaxine can increase blood pressure, but antihypertensives with α-1 blocking psychotropics can decrease blood pressure. Monoamine oxidase inhibitors can cause hypotension or hypertension with various classes of antihypertensives. Stimulants, such as methylphenidate, atomoxetine, dextroamphetamine, armodafinil, or modafinil, alone or combined with antihypertensives, can cause hypertension.¹⁷

Substance abuse, particularly alcohol, methamphetamine, and cocaine, can cause difficulty controlling blood pressure. Patients with refractory hypertension should have a reassessment of substance abuse as a potential cause.

Screening guidelines for mental health providers

For many patients with severe mental illness, visits to their mental health providers might be their only contact with the medical system. Therefore, screening in the mental health settings could detect cases that otherwise would be missed.

Screening recommendations. The U.S. Preventive Services Task Force recommends screening for hypertension in the general population beginning at age 18.¹⁸ Adults age 18 to 39 with normal blood pressure (<130/85 mm Hg) and no other risk factors (eg, overweight, obese, or African American) can be screened every 3 years. Those with risk factors or a blood pressure of 130/85 to 139/89 mm Hg and adults age ≥40 should have annual screenings.

Ideally, psychiatrists and other mental health providers should monitor blood pressure at each visit, especially in patients taking psychotropics because of their higher risk for hypertension.

Optimizing treatment. Once the diagnosis of essential hypertension is established, identifying psychiatric comorbidities and the severity of psychiatric symptoms are important to optimize treatment adherence. Patients with increased depressive symptoms are less likely to comply with antihypertensive medication,¹⁹ and patients with confirmed depression are 3 times more likely to not adhere to medical treatment recommendations than non-depressed patients.²⁰

Physicians’ attitudes toward hypertension also can affect patients’ compliance and blood pressure control.²¹ Psychiatrists should be empathetic and motivational toward patients attempting to control their blood pressure. The Seventh Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure states, “Motivation improves when patients have positive experiences with, and trust in, the clinician. Empathy builds trust and is a potent motivator.”²²

Treatment and management

Treatment of hypertension significantly reduces the risk of stroke, myocardial infarction, renal injury, heart failure, and premature death. Studies show that treatment that reduces systolic blood pressure by 12 mm Hg over 10 years will prevent 1 death for every 11 patients with essential hypertension. In those with concomitant cardiovascular disease or target organ damage, such a reduction would prevent death in 1 of every 9 patients treated.¹⁵Blood pressure goals. The 2014 Eighth Joint National Committee Guideline for Management of High Blood Pressure in Adults provides guidance on blood pressure goals depending on patients’ underlying medical history (Figure).²³ Based on expert opinion and randomized controlled studies, blood pressure goals for patients without diabetes or chronic kidney disease (CKD)—an estimated or measured glomerular filtration rate (GFR) of ≤60 mL/min/1.73 m²—depend on age: <140/90 mm Hg for age 18 to 59 and <150/90 mm Hg for age ≥60. For patients with diabetes or CKD, the blood pressure goal is <140/90 mm Hg, regardless of age.

However, not all experts agree on these specific blood pressure goals. A major trial (SPRINT) published in 2015 found that intensive blood pressure goals do benefit higher-risk, non-diabetic patients.²⁴ Specifically, the study randomized patients age ≥50 with systolic blood pressure of 130 to 180 mm Hg and increased cardiovascular risk to systolic blood pressure targets of <140 mm Hg (standard) or <120 mm Hg (intensive). Characteristics of increased cardiovascular risk were clinical or subclinical cardiovascular disease other than stroke, CKD with GFR of 20 to 60 mL/min/1.73 m², age ≥75, or Framingham 10-year coronary heart disease risk score ≥15%. Intensive treatment significantly reduced overall mortality and the rate of acute coronary syndrome, myocardial infarction, heart failure, stroke, or cardiovascular death. However, the results of this study have not been assimilated into any recent guidelines. Therefore, consider a goal of <120 mm Hg for non-diabetic patients age ≥50 with any of these factors.

Lifestyle modifications. Psychiatrists are well equipped to motivate and encourage behavioral modification in patients with hypertension. Counseling and structured training courses could help to effectively lower blood pressure.²⁵ Patients should receive education on lifestyle modifications including:

• weight reduction
• physical activity
• moderate alcohol consumption
• decreased sodium consumption
• implementation of the Dietary Approaches to Stop Hypertension (DASH) or Mediterranean diets.¹⁵

Maintaining a normal body weight is ideal, but weight reduction of 10 lb can reduce blood pressure in overweight patients. The DASH diet, consisting of fruits, vegetables, low-fat dairy products, high calcium and potassium intake, and reduced saturated and total fat intake can decrease systolic blood pressure from 8 to 14 mm Hg. Reduction of sodium intake to ≤2,400 mg/d can reduce systolic blood pressure from 2 to 8 mm Hg. Regular aerobic exercise of 30 minutes a day most days of the week can reduce systolic blood pressure up to 9 mm Hg. Patients also should be encouraged to quit smoking. Patients who implement ≥2 these modifications get better results.

Antihypertensive medications. Patients who do not reach their goals with lifestyle measures alone should receive antihypertensive medications. Most patients will require ≥2 agents to control their blood pressure. Clinical trials show that some patient subgroups have better outcomes with different first-line agents.

For example, in non-African American patients, thiazide diuretics, calcium channel blockers, angiotensin receptor blockers, and angiotensin-converting enzyme inhibitors are first-line treatments (Table 3). For African American patients without CKD, first-line treatments should be thiazide diuretics and calcium channel blockers, because angiotensin-converting enzyme inhibitors and angiotensin receptor blockers do not reduce cardiovascular events as effectively. African American patients with CKD and proteinuria, however, benefit from angiotensin-converting enzyme inhibitors or angiotensin receptor blockers and are preferred first-line agents. However, blood pressure control is a more important factor in improving outcomes than the choice of medication.

Psychiatrists’ role. Psychiatrists should aim to collaborate with the primary care provider when treating hypertension. However, when integrative care is not possible, they should start a first-line medication with follow-up in 1 month or sooner for patients with severe hypertension (>160/100 mm Hg) or significant comorbidities (eg, CKD, congestive heart failure, coronary disease). Patients with blood pressure >160/100 mm Hg often are started on a thiazide diuretic with one other medication because a single agent usually does not achieve goal blood pressure. Patients with CKD need close monitoring of potassium and creatinine when starting angiotensin-converting enzyme inhibitor or angiotensin receptor blocker therapy, usually within 1 to 2 days of starting or adjusting their medication. Adjust or add medication dosages monthly until blood pressure goals are reached.

A general internist, cardiologist, or nephrologist who has expertise in managing complex cases should oversee care of a psychiatric patient in any of the following scenarios:

• suspected secondary cause of hypertension
• adverse reaction to antihypertensive medications
• complicated comorbid conditions (ie, creatinine >1.8 mg/dL, worsening renal failure, hyperkalemia, heart failure, coronary disease)
• blood pressure >180/120 mm Hg
• requires ≥3 antihypertensive medications.

Summing up

Hypertension is a significant comorbidity in many psychiatric patients, but usually is asymptomatic. Often the psychiatrist or other mental health provider will diagnose hypertension because of their frequent contact with these patients. Once the diagnosis is made, an initial evaluation can direct lifestyle modifications. Patients who continue to have significant elevation of blood pressure should start pharmacotherapy, either by the psychiatrist or by ensuring follow-up with a primary care physician. The psychiatrist may be able to manage cases of essential hypertension, but always must be vigilant for potential drug–disease or drug–drug interactions during treatment. A team-based approach may improve health outcomes in psychiatric patients.

Hypertension is a widespread, under-recognized, and undertreated cause of morbidity and mortality in the United States and is associated with several psychiatric illnesses. Left untreated, hypertension can have significant consequences, including increased risk of stroke, coronary heart disease, heart failure, chronic kidney failure, and death. Approximately 70 million adults in the United States have hypertension, but only 60% of them have been diagnosed, and of those only 50% have their blood pressure under control.¹ In 2013, 360,000 deaths in the United States were attributed to hypertension.²

Hypertension is associated with major depressive disorder, generalized anxiety disorder, bipolar disorder, and schizophrenia.^3-5 Additionally, impulsive eating disorders, substance abuse, anxiety, and depression are associated with a hypertension diagnosis, although patients with panic disorder develop hypertension at a younger age.⁶ A 2007 study found a 61% prevalence of hypertension in those with bipolar disorder compared with 41% among the general population.⁷ The strong link between bipolar disorder and hypertension might be because of a common disease mechanism; both are associated with hyperactive cellular calcium signaling and increased platelet intracellular calcium ion concentrations.⁸

Hypertension not only is common among patients with psychiatric illness, it likely contributes to worse clinical outcomes. Studies across different cultures have found higher mortality rates in individuals with mental illness.^9-11 Persons with schizophrenia and other severe mental illnesses may lose ≥25 years of life expectancy, with the primary cause of death being cardiovascular disease, not suicide.¹² Patients with depression have a 50% greater risk of cardiovascular disease, which is equivalent to the risk of smoking.¹³ 

Schizophrenia is strongly associated with numerous comorbidities and has been linked significantly to an elevated 10-year cardiac risk after controlling for body mass index.⁵ The high rate of non-treatment of hypertension for patients with schizophrenia (62.4%) is especially concerning.¹⁴

Because of the well-documented morbidity and mortality of hypertension and its increased prevalence and undertreatment in the psychiatric population, mental health providers are in an important position to recognize hypertension and evaluate its inherent risks to direct their patients toward proper treatment. This article reviews:

• the signs and symptoms of hypertension
• the mental health provider’s role in the evaluation and diagnosis
• how psychotropic drugs influence blood pressure and drug–drug interactions
• the management of hypertension in psychiatric patients, including strategies for counseling and lifestyle management.

Diagnosing hypertension

Hypertension is defined as a blood pressure >140/90 mm Hg, the average of ≥2 properly measured readings at ≥2 visits in a medical setting.¹⁵ The proper equipment, including a well-fitting blood pressure cuff, and technique to measure blood pressure are essential to avoid misdiagnosis. The patient should be at rest for ≥5 minutes, without active pain or emotional distress.

Most cases of hypertension (90% to 95%) are primary, commonly called essential hypertension. However, the differential diagnosis also should consider secondary causes, which may include:

• obesity
• medications
• chronic alcohol use
• methamphetamine or cocaine use
• primary kidney disease
• atherosclerotic renal artery stenosis
• obstructive sleep apnea
• hypothyroidism
• primary hyperaldosteronism
• narrowing of the aorta
• Cushing syndrome
• primary hyperparathyroidism
• polycythemia
• pheochromocytoma.

Medical evaluation. Once the diagnosis of hypertension is made, a medical evaluation is indicated to determine if the patient has end-organ damage from the elevated pressures, such as renal disease or heart disease, to identify other modifiable cardiovascular risk factors, such as hyperlipidemia, and to screen for secondary causes of hypertension. This evaluation includes¹⁵:

• a physical exam
• review of medications
• lipid profile
• urinalysis to screen for proteinuria
• serum electrolytes and creatinine
• electrocardiogram to screen for left ventricular hypertrophy or prior infarction
• fasting glucose or hemoglobin A1_c to screen for type 2 diabetes mellitus.

Psychotropic drugs. In psychiatric patients, the evaluation must consider the potential impact psychotropic drug effects and drug–drug interactions can have on blood pressure (Table 2). For example, patients taking both diuretics and lithium are at increased risk for dehydration and increased serum lithium levels, which could cause severe neurologic symptoms and renal insufficiency.¹⁶ Several antihypertensives when taken with venlafaxine can increase blood pressure, but antihypertensives with α-1 blocking psychotropics can decrease blood pressure. Monoamine oxidase inhibitors can cause hypotension or hypertension with various classes of antihypertensives. Stimulants, such as methylphenidate, atomoxetine, dextroamphetamine, armodafinil, or modafinil, alone or combined with antihypertensives, can cause hypertension.¹⁷

Substance abuse, particularly alcohol, methamphetamine, and cocaine, can cause difficulty controlling blood pressure. Patients with refractory hypertension should have a reassessment of substance abuse as a potential cause.

Screening guidelines for mental health providers

For many patients with severe mental illness, visits to their mental health providers might be their only contact with the medical system. Therefore, screening in the mental health settings could detect cases that otherwise would be missed.

Screening recommendations. The U.S. Preventive Services Task Force recommends screening for hypertension in the general population beginning at age 18.¹⁸ Adults age 18 to 39 with normal blood pressure (<130/85 mm Hg) and no other risk factors (eg, overweight, obese, or African American) can be screened every 3 years. Those with risk factors or a blood pressure of 130/85 to 139/89 mm Hg and adults age ≥40 should have annual screenings.

Ideally, psychiatrists and other mental health providers should monitor blood pressure at each visit, especially in patients taking psychotropics because of their higher risk for hypertension.

Optimizing treatment. Once the diagnosis of essential hypertension is established, identifying psychiatric comorbidities and the severity of psychiatric symptoms are important to optimize treatment adherence. Patients with increased depressive symptoms are less likely to comply with antihypertensive medication,¹⁹ and patients with confirmed depression are 3 times more likely to not adhere to medical treatment recommendations than non-depressed patients.²⁰

Physicians’ attitudes toward hypertension also can affect patients’ compliance and blood pressure control.²¹ Psychiatrists should be empathetic and motivational toward patients attempting to control their blood pressure. The Seventh Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure states, “Motivation improves when patients have positive experiences with, and trust in, the clinician. Empathy builds trust and is a potent motivator.”²²

Treatment and management

Treatment of hypertension significantly reduces the risk of stroke, myocardial infarction, renal injury, heart failure, and premature death. Studies show that treatment that reduces systolic blood pressure by 12 mm Hg over 10 years will prevent 1 death for every 11 patients with essential hypertension. In those with concomitant cardiovascular disease or target organ damage, such a reduction would prevent death in 1 of every 9 patients treated.¹⁵Blood pressure goals. The 2014 Eighth Joint National Committee Guideline for Management of High Blood Pressure in Adults provides guidance on blood pressure goals depending on patients’ underlying medical history (Figure).²³ Based on expert opinion and randomized controlled studies, blood pressure goals for patients without diabetes or chronic kidney disease (CKD)—an estimated or measured glomerular filtration rate (GFR) of ≤60 mL/min/1.73 m²—depend on age: <140/90 mm Hg for age 18 to 59 and <150/90 mm Hg for age ≥60. For patients with diabetes or CKD, the blood pressure goal is <140/90 mm Hg, regardless of age.

However, not all experts agree on these specific blood pressure goals. A major trial (SPRINT) published in 2015 found that intensive blood pressure goals do benefit higher-risk, non-diabetic patients.²⁴ Specifically, the study randomized patients age ≥50 with systolic blood pressure of 130 to 180 mm Hg and increased cardiovascular risk to systolic blood pressure targets of <140 mm Hg (standard) or <120 mm Hg (intensive). Characteristics of increased cardiovascular risk were clinical or subclinical cardiovascular disease other than stroke, CKD with GFR of 20 to 60 mL/min/1.73 m², age ≥75, or Framingham 10-year coronary heart disease risk score ≥15%. Intensive treatment significantly reduced overall mortality and the rate of acute coronary syndrome, myocardial infarction, heart failure, stroke, or cardiovascular death. However, the results of this study have not been assimilated into any recent guidelines. Therefore, consider a goal of <120 mm Hg for non-diabetic patients age ≥50 with any of these factors.

Lifestyle modifications. Psychiatrists are well equipped to motivate and encourage behavioral modification in patients with hypertension. Counseling and structured training courses could help to effectively lower blood pressure.²⁵ Patients should receive education on lifestyle modifications including:

• weight reduction
• physical activity
• moderate alcohol consumption
• decreased sodium consumption
• implementation of the Dietary Approaches to Stop Hypertension (DASH) or Mediterranean diets.¹⁵

Maintaining a normal body weight is ideal, but weight reduction of 10 lb can reduce blood pressure in overweight patients. The DASH diet, consisting of fruits, vegetables, low-fat dairy products, high calcium and potassium intake, and reduced saturated and total fat intake can decrease systolic blood pressure from 8 to 14 mm Hg. Reduction of sodium intake to ≤2,400 mg/d can reduce systolic blood pressure from 2 to 8 mm Hg. Regular aerobic exercise of 30 minutes a day most days of the week can reduce systolic blood pressure up to 9 mm Hg. Patients also should be encouraged to quit smoking. Patients who implement ≥2 these modifications get better results.

Antihypertensive medications. Patients who do not reach their goals with lifestyle measures alone should receive antihypertensive medications. Most patients will require ≥2 agents to control their blood pressure. Clinical trials show that some patient subgroups have better outcomes with different first-line agents.

For example, in non-African American patients, thiazide diuretics, calcium channel blockers, angiotensin receptor blockers, and angiotensin-converting enzyme inhibitors are first-line treatments (Table 3). For African American patients without CKD, first-line treatments should be thiazide diuretics and calcium channel blockers, because angiotensin-converting enzyme inhibitors and angiotensin receptor blockers do not reduce cardiovascular events as effectively. African American patients with CKD and proteinuria, however, benefit from angiotensin-converting enzyme inhibitors or angiotensin receptor blockers and are preferred first-line agents. However, blood pressure control is a more important factor in improving outcomes than the choice of medication.

Psychiatrists’ role. Psychiatrists should aim to collaborate with the primary care provider when treating hypertension. However, when integrative care is not possible, they should start a first-line medication with follow-up in 1 month or sooner for patients with severe hypertension (>160/100 mm Hg) or significant comorbidities (eg, CKD, congestive heart failure, coronary disease). Patients with blood pressure >160/100 mm Hg often are started on a thiazide diuretic with one other medication because a single agent usually does not achieve goal blood pressure. Patients with CKD need close monitoring of potassium and creatinine when starting angiotensin-converting enzyme inhibitor or angiotensin receptor blocker therapy, usually within 1 to 2 days of starting or adjusting their medication. Adjust or add medication dosages monthly until blood pressure goals are reached.

A general internist, cardiologist, or nephrologist who has expertise in managing complex cases should oversee care of a psychiatric patient in any of the following scenarios:

• suspected secondary cause of hypertension
• adverse reaction to antihypertensive medications
• complicated comorbid conditions (ie, creatinine >1.8 mg/dL, worsening renal failure, hyperkalemia, heart failure, coronary disease)
• blood pressure >180/120 mm Hg
• requires ≥3 antihypertensive medications.

Summing up

Hypertension is a significant comorbidity in many psychiatric patients, but usually is asymptomatic. Often the psychiatrist or other mental health provider will diagnose hypertension because of their frequent contact with these patients. Once the diagnosis is made, an initial evaluation can direct lifestyle modifications. Patients who continue to have significant elevation of blood pressure should start pharmacotherapy, either by the psychiatrist or by ensuring follow-up with a primary care physician. The psychiatrist may be able to manage cases of essential hypertension, but always must be vigilant for potential drug–disease or drug–drug interactions during treatment. A team-based approach may improve health outcomes in psychiatric patients.

Hypertension is a widespread, under-recognized, and undertreated cause of morbidity and mortality in the United States and is associated with several psychiatric illnesses. Left untreated, hypertension can have significant consequences, including increased risk of stroke, coronary heart disease, heart failure, chronic kidney failure, and death. Approximately 70 million adults in the United States have hypertension, but only 60% of them have been diagnosed, and of those only 50% have their blood pressure under control.¹ In 2013, 360,000 deaths in the United States were attributed to hypertension.²

Hypertension is associated with major depressive disorder, generalized anxiety disorder, bipolar disorder, and schizophrenia.^3-5 Additionally, impulsive eating disorders, substance abuse, anxiety, and depression are associated with a hypertension diagnosis, although patients with panic disorder develop hypertension at a younger age.⁶ A 2007 study found a 61% prevalence of hypertension in those with bipolar disorder compared with 41% among the general population.⁷ The strong link between bipolar disorder and hypertension might be because of a common disease mechanism; both are associated with hyperactive cellular calcium signaling and increased platelet intracellular calcium ion concentrations.⁸

Hypertension not only is common among patients with psychiatric illness, it likely contributes to worse clinical outcomes. Studies across different cultures have found higher mortality rates in individuals with mental illness.^9-11 Persons with schizophrenia and other severe mental illnesses may lose ≥25 years of life expectancy, with the primary cause of death being cardiovascular disease, not suicide.¹² Patients with depression have a 50% greater risk of cardiovascular disease, which is equivalent to the risk of smoking.¹³ 

Schizophrenia is strongly associated with numerous comorbidities and has been linked significantly to an elevated 10-year cardiac risk after controlling for body mass index.⁵ The high rate of non-treatment of hypertension for patients with schizophrenia (62.4%) is especially concerning.¹⁴

Because of the well-documented morbidity and mortality of hypertension and its increased prevalence and undertreatment in the psychiatric population, mental health providers are in an important position to recognize hypertension and evaluate its inherent risks to direct their patients toward proper treatment. This article reviews:

• the signs and symptoms of hypertension
• the mental health provider’s role in the evaluation and diagnosis
• how psychotropic drugs influence blood pressure and drug–drug interactions
• the management of hypertension in psychiatric patients, including strategies for counseling and lifestyle management.

Diagnosing hypertension

Hypertension is defined as a blood pressure >140/90 mm Hg, the average of ≥2 properly measured readings at ≥2 visits in a medical setting.¹⁵ The proper equipment, including a well-fitting blood pressure cuff, and technique to measure blood pressure are essential to avoid misdiagnosis. The patient should be at rest for ≥5 minutes, without active pain or emotional distress.

Most cases of hypertension (90% to 95%) are primary, commonly called essential hypertension. However, the differential diagnosis also should consider secondary causes, which may include:

• obesity
• medications
• chronic alcohol use
• methamphetamine or cocaine use
• primary kidney disease
• atherosclerotic renal artery stenosis
• obstructive sleep apnea
• hypothyroidism
• primary hyperaldosteronism
• narrowing of the aorta
• Cushing syndrome
• primary hyperparathyroidism
• polycythemia
• pheochromocytoma.

Medical evaluation. Once the diagnosis of hypertension is made, a medical evaluation is indicated to determine if the patient has end-organ damage from the elevated pressures, such as renal disease or heart disease, to identify other modifiable cardiovascular risk factors, such as hyperlipidemia, and to screen for secondary causes of hypertension. This evaluation includes¹⁵:

• a physical exam
• review of medications
• lipid profile
• urinalysis to screen for proteinuria
• serum electrolytes and creatinine
• electrocardiogram to screen for left ventricular hypertrophy or prior infarction
• fasting glucose or hemoglobin A1_c to screen for type 2 diabetes mellitus.

Psychotropic drugs. In psychiatric patients, the evaluation must consider the potential impact psychotropic drug effects and drug–drug interactions can have on blood pressure (Table 2). For example, patients taking both diuretics and lithium are at increased risk for dehydration and increased serum lithium levels, which could cause severe neurologic symptoms and renal insufficiency.¹⁶ Several antihypertensives when taken with venlafaxine can increase blood pressure, but antihypertensives with α-1 blocking psychotropics can decrease blood pressure. Monoamine oxidase inhibitors can cause hypotension or hypertension with various classes of antihypertensives. Stimulants, such as methylphenidate, atomoxetine, dextroamphetamine, armodafinil, or modafinil, alone or combined with antihypertensives, can cause hypertension.¹⁷

Substance abuse, particularly alcohol, methamphetamine, and cocaine, can cause difficulty controlling blood pressure. Patients with refractory hypertension should have a reassessment of substance abuse as a potential cause.

Screening guidelines for mental health providers

For many patients with severe mental illness, visits to their mental health providers might be their only contact with the medical system. Therefore, screening in the mental health settings could detect cases that otherwise would be missed.

Screening recommendations. The U.S. Preventive Services Task Force recommends screening for hypertension in the general population beginning at age 18.¹⁸ Adults age 18 to 39 with normal blood pressure (<130/85 mm Hg) and no other risk factors (eg, overweight, obese, or African American) can be screened every 3 years. Those with risk factors or a blood pressure of 130/85 to 139/89 mm Hg and adults age ≥40 should have annual screenings.

Ideally, psychiatrists and other mental health providers should monitor blood pressure at each visit, especially in patients taking psychotropics because of their higher risk for hypertension.

Optimizing treatment. Once the diagnosis of essential hypertension is established, identifying psychiatric comorbidities and the severity of psychiatric symptoms are important to optimize treatment adherence. Patients with increased depressive symptoms are less likely to comply with antihypertensive medication,¹⁹ and patients with confirmed depression are 3 times more likely to not adhere to medical treatment recommendations than non-depressed patients.²⁰

Physicians’ attitudes toward hypertension also can affect patients’ compliance and blood pressure control.²¹ Psychiatrists should be empathetic and motivational toward patients attempting to control their blood pressure. The Seventh Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure states, “Motivation improves when patients have positive experiences with, and trust in, the clinician. Empathy builds trust and is a potent motivator.”²²

Treatment and management

Treatment of hypertension significantly reduces the risk of stroke, myocardial infarction, renal injury, heart failure, and premature death. Studies show that treatment that reduces systolic blood pressure by 12 mm Hg over 10 years will prevent 1 death for every 11 patients with essential hypertension. In those with concomitant cardiovascular disease or target organ damage, such a reduction would prevent death in 1 of every 9 patients treated.¹⁵Blood pressure goals. The 2014 Eighth Joint National Committee Guideline for Management of High Blood Pressure in Adults provides guidance on blood pressure goals depending on patients’ underlying medical history (Figure).²³ Based on expert opinion and randomized controlled studies, blood pressure goals for patients without diabetes or chronic kidney disease (CKD)—an estimated or measured glomerular filtration rate (GFR) of ≤60 mL/min/1.73 m²—depend on age: <140/90 mm Hg for age 18 to 59 and <150/90 mm Hg for age ≥60. For patients with diabetes or CKD, the blood pressure goal is <140/90 mm Hg, regardless of age.

However, not all experts agree on these specific blood pressure goals. A major trial (SPRINT) published in 2015 found that intensive blood pressure goals do benefit higher-risk, non-diabetic patients.²⁴ Specifically, the study randomized patients age ≥50 with systolic blood pressure of 130 to 180 mm Hg and increased cardiovascular risk to systolic blood pressure targets of <140 mm Hg (standard) or <120 mm Hg (intensive). Characteristics of increased cardiovascular risk were clinical or subclinical cardiovascular disease other than stroke, CKD with GFR of 20 to 60 mL/min/1.73 m², age ≥75, or Framingham 10-year coronary heart disease risk score ≥15%. Intensive treatment significantly reduced overall mortality and the rate of acute coronary syndrome, myocardial infarction, heart failure, stroke, or cardiovascular death. However, the results of this study have not been assimilated into any recent guidelines. Therefore, consider a goal of <120 mm Hg for non-diabetic patients age ≥50 with any of these factors.

Lifestyle modifications. Psychiatrists are well equipped to motivate and encourage behavioral modification in patients with hypertension. Counseling and structured training courses could help to effectively lower blood pressure.²⁵ Patients should receive education on lifestyle modifications including:

• weight reduction
• physical activity
• moderate alcohol consumption
• decreased sodium consumption
• implementation of the Dietary Approaches to Stop Hypertension (DASH) or Mediterranean diets.¹⁵

Maintaining a normal body weight is ideal, but weight reduction of 10 lb can reduce blood pressure in overweight patients. The DASH diet, consisting of fruits, vegetables, low-fat dairy products, high calcium and potassium intake, and reduced saturated and total fat intake can decrease systolic blood pressure from 8 to 14 mm Hg. Reduction of sodium intake to ≤2,400 mg/d can reduce systolic blood pressure from 2 to 8 mm Hg. Regular aerobic exercise of 30 minutes a day most days of the week can reduce systolic blood pressure up to 9 mm Hg. Patients also should be encouraged to quit smoking. Patients who implement ≥2 these modifications get better results.

Antihypertensive medications. Patients who do not reach their goals with lifestyle measures alone should receive antihypertensive medications. Most patients will require ≥2 agents to control their blood pressure. Clinical trials show that some patient subgroups have better outcomes with different first-line agents.

For example, in non-African American patients, thiazide diuretics, calcium channel blockers, angiotensin receptor blockers, and angiotensin-converting enzyme inhibitors are first-line treatments (Table 3). For African American patients without CKD, first-line treatments should be thiazide diuretics and calcium channel blockers, because angiotensin-converting enzyme inhibitors and angiotensin receptor blockers do not reduce cardiovascular events as effectively. African American patients with CKD and proteinuria, however, benefit from angiotensin-converting enzyme inhibitors or angiotensin receptor blockers and are preferred first-line agents. However, blood pressure control is a more important factor in improving outcomes than the choice of medication.

Psychiatrists’ role. Psychiatrists should aim to collaborate with the primary care provider when treating hypertension. However, when integrative care is not possible, they should start a first-line medication with follow-up in 1 month or sooner for patients with severe hypertension (>160/100 mm Hg) or significant comorbidities (eg, CKD, congestive heart failure, coronary disease). Patients with blood pressure >160/100 mm Hg often are started on a thiazide diuretic with one other medication because a single agent usually does not achieve goal blood pressure. Patients with CKD need close monitoring of potassium and creatinine when starting angiotensin-converting enzyme inhibitor or angiotensin receptor blocker therapy, usually within 1 to 2 days of starting or adjusting their medication. Adjust or add medication dosages monthly until blood pressure goals are reached.

A general internist, cardiologist, or nephrologist who has expertise in managing complex cases should oversee care of a psychiatric patient in any of the following scenarios:

• suspected secondary cause of hypertension
• adverse reaction to antihypertensive medications
• complicated comorbid conditions (ie, creatinine >1.8 mg/dL, worsening renal failure, hyperkalemia, heart failure, coronary disease)
• blood pressure >180/120 mm Hg
• requires ≥3 antihypertensive medications.

Summing up

Hypertension is a significant comorbidity in many psychiatric patients, but usually is asymptomatic. Often the psychiatrist or other mental health provider will diagnose hypertension because of their frequent contact with these patients. Once the diagnosis is made, an initial evaluation can direct lifestyle modifications. Patients who continue to have significant elevation of blood pressure should start pharmacotherapy, either by the psychiatrist or by ensuring follow-up with a primary care physician. The psychiatrist may be able to manage cases of essential hypertension, but always must be vigilant for potential drug–disease or drug–drug interactions during treatment. A team-based approach may improve health outcomes in psychiatric patients.

Mammalian target of rapamycin (mTOR), a serine–threonine protein kinase, operates in the phosphoinositide 3-kinase (PI3K)–protein kinase B (AKT)–mTOR signal transduction pathway regulating both normal and cancer cellular processes, including cell growth, proliferation, motility, survival, and protein and lipid synthesis.¹ Genetic alterations affecting this pathway, including mutations in receptor tyrosine kinases PI3K and AKT, occur frequently in human cancers,² supporting the rationale to develop drugs that target pathway components, such as mTOR inhibitors.

Two mTOR inhibitors are currently approved by the US Food and Drug Administration for cancer treatment: temsirolimus, for advanced renal cell carcinoma (RCC; approved 2007)³ and everolimus, for advanced RCC (approved 2009), advanced pancreatic neuroendocrine tumors (pNET; approved 2011), and hormone receptor-positive (HR-positive), human epidermal growth factor receptor-2 (HER2)-negative advanced breast cancer (approved 2012).⁴ Another mTOR inhibitor, sirolimus, is approved for use as an immunosuppressive agent and prophylactic against organ rejection after kidney transplant.⁵

Stomatitis, inflammation of the oral mucosa with contributing factors of genetic predisposition, nutritional deficiencies, infections, and immunological or hematologic dysfunction,⁶ occurs frequently as a side effect associated with mTOR inhibitor treatment.^7-9 Left untreated or managed unsatisfactorily, mTOR inhibitor-associated stomatitis (mIAS) may cause patients discomfort and trouble with maintaining adequate nutritional intake and proper oral hygiene, as well as strict adherence to cancer treatment. It is therefore important for health care providers of cancer patients receiving mTOR inhibitor treatment to be knowledgeable about this side effect. The purpose of the present systematic review of published literature is to provide a better understanding of the differential diagnosis of mIAS, the pathophysiology of mIAS, preventive strategies for patients initiating mTOR inhibitor treatment, and treatment options available to manage mIAS.

Method

The PubMed database was searched with the terms mTOR inhibitor and stomatitis (no date restriction); 79 articles were retrieved, and all abstracts were reviewed to select those relevant to the aims of this review article. To understand future directions for management and prevention of mIAS, a search of clinicaltrials.gov was performed with the terms temsirolimus everolimus stomatitis yielding 12 clinical trials, of which 4 were excluded: 1 trial was terminated due to slow accrual, the status of 1 trial had not been verified in >2 years, and 2 studies focused on efficacy outcomes. A search of the American Society of Clinical Oncology (ASCO) meeting abstracts database was performed to assess the availability of clinical trial data; the search was limited to 2011-2016 and terms were stomatitis in the title and mTOR in the abstract or title. Seven abstracts were retrieved; 2 discussed stomatitis prevention (1 as a “trial-in-progress” and 1 presented results of the trial); the other 5 abstracts presented meta-analyses or reviews of previous clinical studies to assess the risk, incidence, management, and resolution of mIAS.

Review findings

Incidence of mIAS in patients treated for cancer

Two recent meta-analyses quantified the rate of mIAS in patients receiving mTOR inhibitors. Shameem and colleagues¹⁰ identified 9 randomized studies of everolimus (8 phase 3, 1 phase 2) and 2 of temsirolimus (1 each phase 2 and 3) involving a total of 4752 patients with a variety of tumor types including angiomyolipoma, breast, gastric, giant cell astrocytoma, pNET, and RCC. Patients received everolimus monotherapy (n = 1,075) or in combination with exemestane (n = 485), tamoxifen (n = 54), letrozole (n = 137), or octreotide (n = 216). Temsirolimus was administered as monotherapy (n = 208) or in combination with interferon
(n = 210) or letrozole (n = 550). The incidence of all-grade stomatitis in the 11 studies ranged from 11%-63%, and the overall incidence of any grade stomatitis was 33.5% (95% confidence interval [CI], 21.9%-47.6%). The concurrent use of a second agent may have confounded these findings because, for example, stomatitis has been reported in pooled analyses and in postmarketing experience with letrozole.¹¹

Rugo and colleagues¹² evaluated the incidence of stomatitis in 1455 patients participating in 5 phase 3 randomized clinical trials of everolimus in breast cancer, carcinoid tumor, pNET, and RCC. Patients received everolimus monotherapy
(n = 478) or in combination with exemestane (n = 482), trastuzumab plus vinorelbine (n = 280), or octreotide
(n = 215). The incidence of stomatitis in patients receiving everolimus was 59%-71%, compared with 19%-29% in 1,071 patients of the comparator arms (placebo, and placebo–trastuzumab–vinorelbine). The overall incidence of any grade stomatitis was 67%; most events were mild (grade 1/2); 9% of stomatitis events were moderate to severe (grade 3/4).

Differential clinical presentation of mIAS and severity

Oral mucositis is a common significant adverse event (AE) that occurs in patients with cancer who receive standard chemotherapy regimens and/or radiation therapy,¹³ so it is important to recognize that the clinical presentation of mIAS differs from that of oral mucositis (Table 1, Figure ^14,15).¹⁶ mIAS shares some similarities with aphthous ulcers (also referred to as canker sores), a common oral condition with varied causes related to systemic disorders, gastrointestinal disorders, and infections, among others .¹⁷ In general, mIAS ulcers develop with a median onset of 10 days (range, 4-25 days) after initiation of mTOR inhibitor treatment and resolve in about 1-3 weeks after dose interruption/reduction of everolimus.^16,18,19 mIAS ulcers appear as distinct, oval lesions with a central gray area surrounded by peripheral erythema. They are usually localized to the movable mucosa of the mouth and oropharynx. Although mIAS lesions are usually small, they are quite painful and may cluster.

Differential diagnosis of mIAS should be made based on physical examination and medical history, with consideration given to appearance of lesions (number, size, and location), current infection status, and current medications. Specific diagnostic testing should be conducted to confirm a coexisting or alternative cause of oral lesions.¹⁷

Although there are many different scales for grading mIAS severity, the most commonly used are the National Cancer Institute Common Terminology Criteria for Adverse Events (based on patient function, symptoms, and intervention needs) and the World Health Organization oral mucositis scales (based on symptoms, clinical presentation, and interference with patient function).^20-22 These scales distinguish between mild lesions (grade 1/2) and moderate to severe lesions (grade 3/4) that cause significant pain or interfere with oral intake.

Pathophysiology of mIAS

The pathophysiology mIAS is incompletely understood. The ubiquitous role of the PI3K-AKT-mTOR pathway in regulating broad cellular functions suggests that mTOR inhibition is likely to have wide-ranging effects on many biological processes. It is not known whether disruption of one or more processes – or upsetting the balance of mTOR activities – underlies the formation of mIAS.

Differences between mIAS and oral mucositis, including clinical presentation and concomitant toxicities,^16,23 suggest that the two types of oral lesions are fundamentally distinct. This distinction is supported by animal studies in which mTOR inhibition was found to almost completely prevent the appearance of oral mucositis in irradiated mice. The protective effect of mTOR inhibition is mediated through suppression of oxidative stress generated by radiation therapy.²⁴

Although mIAS and recurrent aphthous ulcers share some similarities, it is not clear whether they also share a common pathophysiology. Recent studies suggest that patients with recurrent aphthous ulcers have immune dysfunction that leads to excessive immune response to normally innocuous substrates in the oral mucosa.²⁵ mTOR inhibition can have proinflammatory activity by promoting autophagy, a process that stimulates antigen presentation and activation of T cells that produce proinflammatory cytokines.²⁶ It is interesting to note that the incidence of stomatitis in patients receiving sirolimus after kidney transplant is relatively low, 3%-20%.⁵ Sirolimus is administered in combination with other immunosuppressants, namely cyclosporine and corticosteroids, so it suggests that concomitant use of a steroid-based regimen may have a preventive or therapeutic effect. However, posttransplant sirolimus is typically administered at relatively low doses, which might account in part for the lower incidence of mIAS observed. Ongoing clinical studies of steroid-based mouthwashes in patients receiving everolimus should shed light on this.

Other study findings have shown that inhibition of the PI3K-AKT-mTOR signaling pathway affects skin wound healing,^27,28 which raises the possibility that mIAS may stem from a diminished capacity to repair physical injuries to the oral mucosa. More research is needed to elucidate the pathophysiology of mIAS.

Preventive measures for patients initiating mTOR inhibitor treatment

There are preventive measures for mIAS that have not yet been backed up with evidence-based findings, although several clinical studies that are underway aim to address this gap (Table 2). The hypotheses about the pathophysiology of mIAS suggest that certain preventive and therapeutic interventions might be effective against mIAS. For example, two studies are evaluating the use of steroid-based mouthwashes in patients receiving everolimus, based on the hypothesis that mIAS may arise from an inflammatory process; another study will evaluate a mucoadhesive oral wound rinse, based on the hypothesis that wound protection might prevent mIAS. Glutamine suspension is also under evaluation as it is understood to have wound-preventative and tissue-repair properties, and another study is focused on dentist-guided oral management. Recent results of one of these trials (SWISH),²⁹ reported that preventative care with a dexamethasone mouthwash 3-4 times a day significantly minimized or prevented the incidence of all grades of stomatitis in women receiving everolimus plus exemestane therapy for advanced/metastatic breast cancer compared with the incidence of stomatitis observed in a previously published phase 3 trial (BOLERO-2)^30,31 of everolimus plus exemestane in the same patient population. Results from several other studies are expected soon.

Current approaches to mIAS prevention are based largely on clinical experience with chemotherapy- or radiation-induced oral mucositis (Table 3).^13,32 Preventive measures use three main strategies: establish and maintain good routine oral care; modify diet to avoid potentially damaging foods; and improve patient education about mIAS. In regard to patient education, numerous studies have reported that establishing an institutional protocol for oral care helped reduce the incidence of chemotherapy- or radiation-induced oral mucositis.^33-40 An ongoing clinical study that will randomize patients to receive oral care education from oral surgeons or instruction on brushing only (NCT02376985) is investigating whether having an oral care protocol holds for patients with mIAS. The hypothesis is that focusing attention on oral care and educating patients to recognize the onset of mIAS facilitates early detection and promotes early intervention.

Therapeutic measures for patients with mIAS

Therapeutic measures for mIAS are based largely on experience with chemotherapy- or radiation-induced oral mucositis or recurrent aphthous ulcers (Table 3) and vary in part by the severity of lesions. Treatments for mild mIAS aim to ameliorate symptoms (eg, topical analgesics for pain), protect the oral mucosa (eg, mucoadhesive gels or viscous solutions that coat the oral cavity), prevent potential sequelae (eg, prophylactic antibiotics to avoid secondary infections), and reduce inflammation/immune response (eg, steroid-based mouth rinses, topical steroids, or topical anti-inflammatory agents). Treatments for mild mIAS are generally local rather than systemic.

Treatment options for moderate to severe mIAS include systemic approaches that generally carry increased risk of AEs and, therefore, should be reserved for patients with multiple lesions, uncontrolled or poorly controlled pain, or greatly diminished oral food intake (Table 3).⁴¹ When mIAS cannot be controlled with the interventions described, the dose of the mTOR inhibitor can be reduced with the recognition that dose modification of anticancer therapy may affect disease outcomes.²⁹ The experience of reduction or interruption of treatment with everolimus in the BOLERO-2 trial as a strategy for management of AEs is discussed in a recent review.²⁹ Prescribing information for both temsirolimus and everolimus specify that grade 3 AEs be treated with temporary dose interruption, and with resolution (temsirolimus: grade ≤2; everolimus: grade ≤1), treatment may be resumed at lower doses (temsirolimus: reduce by 5 mg/week; no lower than 15 mg/week; everolimus: reduce by half the previously administered dose).^3,4 Grade 4 events due to treatment with temsirolimus may also be treated with dose interruption/reduction; the everolimus prescribing information advises treatment discontinuation for grade 4 stomatitis.

Summary and discussion

mTOR inhibitors can be effective treatments for patients with advanced cancer, specifically for advanced RCC, advanced pNET, and HR+, HER2-negative advanced breast cancer. Although mIAS may occur in many patients, it is usually grade 1 or 2 in severity. mIAS has an early onset, usually within the first 2 weeks of treatment^16,19,42 and a relatively rapid resolution, usually within 3 weeks.^16,19 Thus, most cases of mIAS are self-limiting.

The relatively recent emergence of mIAS poses short-term challenges regarding diagnosis, assessment, prevention, and treatment. Several clinical studies are underway to evaluate a range of interventions for their preventive and therapeutic efficacy in mIAS. Furthermore, our growing understanding of the underlying pathophysiology of mIAS can guide how mIAS is managed and what interventions patients receive.

Although mIAS is believed to differ from chemotherapy- or radiation-induced oral mucositis and aphthous ulcers, much can be learned from the treatment of both of these. Several strategies have been proposed to limit the occurrence of mIAS (Table 3). First, establish an oral care protocol. Educate patients who are initiating treatment with an mTOR inhibitor on implementation of the oral care protocol and emphasize adherence. Second, educate patients on the symptoms and timing of mIAS. Patients may hesitate to report mild symptoms or assume they are innocuous, so be clear that reporting all symptoms is important to allow timely clinical evaluation. Early recognition of mIAS facilitates early intervention and can prevent dose modification and interruption. Third, implement the preventive and treatment measures described. Many of the preventive measures can be incorporated into an oral care protocol.

The advent of mTOR inhibitors has clinically benefited many patients with cancer. Although side effects, like mIAS, may develop during treatment, they should not be considered insurmountable. Through education, vigilance, and aggressive management, health care providers and patients can work together to help patients maintain their quality of life while continuing to optimally address their disease.
 

Acknowledgment

The authors thank Anna Lau, PhD, and Patricia Segarini, PhD, of Percolation Communications LLC, for their editorial assistance. Funding for manuscript development was provided by Novartis Pharmaceuticals Corp.

Mammalian target of rapamycin (mTOR), a serine–threonine protein kinase, operates in the phosphoinositide 3-kinase (PI3K)–protein kinase B (AKT)–mTOR signal transduction pathway regulating both normal and cancer cellular processes, including cell growth, proliferation, motility, survival, and protein and lipid synthesis.¹ Genetic alterations affecting this pathway, including mutations in receptor tyrosine kinases PI3K and AKT, occur frequently in human cancers,² supporting the rationale to develop drugs that target pathway components, such as mTOR inhibitors.

Two mTOR inhibitors are currently approved by the US Food and Drug Administration for cancer treatment: temsirolimus, for advanced renal cell carcinoma (RCC; approved 2007)³ and everolimus, for advanced RCC (approved 2009), advanced pancreatic neuroendocrine tumors (pNET; approved 2011), and hormone receptor-positive (HR-positive), human epidermal growth factor receptor-2 (HER2)-negative advanced breast cancer (approved 2012).⁴ Another mTOR inhibitor, sirolimus, is approved for use as an immunosuppressive agent and prophylactic against organ rejection after kidney transplant.⁵

Stomatitis, inflammation of the oral mucosa with contributing factors of genetic predisposition, nutritional deficiencies, infections, and immunological or hematologic dysfunction,⁶ occurs frequently as a side effect associated with mTOR inhibitor treatment.^7-9 Left untreated or managed unsatisfactorily, mTOR inhibitor-associated stomatitis (mIAS) may cause patients discomfort and trouble with maintaining adequate nutritional intake and proper oral hygiene, as well as strict adherence to cancer treatment. It is therefore important for health care providers of cancer patients receiving mTOR inhibitor treatment to be knowledgeable about this side effect. The purpose of the present systematic review of published literature is to provide a better understanding of the differential diagnosis of mIAS, the pathophysiology of mIAS, preventive strategies for patients initiating mTOR inhibitor treatment, and treatment options available to manage mIAS.

Method

The PubMed database was searched with the terms mTOR inhibitor and stomatitis (no date restriction); 79 articles were retrieved, and all abstracts were reviewed to select those relevant to the aims of this review article. To understand future directions for management and prevention of mIAS, a search of clinicaltrials.gov was performed with the terms temsirolimus everolimus stomatitis yielding 12 clinical trials, of which 4 were excluded: 1 trial was terminated due to slow accrual, the status of 1 trial had not been verified in >2 years, and 2 studies focused on efficacy outcomes. A search of the American Society of Clinical Oncology (ASCO) meeting abstracts database was performed to assess the availability of clinical trial data; the search was limited to 2011-2016 and terms were stomatitis in the title and mTOR in the abstract or title. Seven abstracts were retrieved; 2 discussed stomatitis prevention (1 as a “trial-in-progress” and 1 presented results of the trial); the other 5 abstracts presented meta-analyses or reviews of previous clinical studies to assess the risk, incidence, management, and resolution of mIAS.

Review findings

Incidence of mIAS in patients treated for cancer

Two recent meta-analyses quantified the rate of mIAS in patients receiving mTOR inhibitors. Shameem and colleagues¹⁰ identified 9 randomized studies of everolimus (8 phase 3, 1 phase 2) and 2 of temsirolimus (1 each phase 2 and 3) involving a total of 4752 patients with a variety of tumor types including angiomyolipoma, breast, gastric, giant cell astrocytoma, pNET, and RCC. Patients received everolimus monotherapy (n = 1,075) or in combination with exemestane (n = 485), tamoxifen (n = 54), letrozole (n = 137), or octreotide (n = 216). Temsirolimus was administered as monotherapy (n = 208) or in combination with interferon
(n = 210) or letrozole (n = 550). The incidence of all-grade stomatitis in the 11 studies ranged from 11%-63%, and the overall incidence of any grade stomatitis was 33.5% (95% confidence interval [CI], 21.9%-47.6%). The concurrent use of a second agent may have confounded these findings because, for example, stomatitis has been reported in pooled analyses and in postmarketing experience with letrozole.¹¹

Rugo and colleagues¹² evaluated the incidence of stomatitis in 1455 patients participating in 5 phase 3 randomized clinical trials of everolimus in breast cancer, carcinoid tumor, pNET, and RCC. Patients received everolimus monotherapy
(n = 478) or in combination with exemestane (n = 482), trastuzumab plus vinorelbine (n = 280), or octreotide
(n = 215). The incidence of stomatitis in patients receiving everolimus was 59%-71%, compared with 19%-29% in 1,071 patients of the comparator arms (placebo, and placebo–trastuzumab–vinorelbine). The overall incidence of any grade stomatitis was 67%; most events were mild (grade 1/2); 9% of stomatitis events were moderate to severe (grade 3/4).

Differential clinical presentation of mIAS and severity

Oral mucositis is a common significant adverse event (AE) that occurs in patients with cancer who receive standard chemotherapy regimens and/or radiation therapy,¹³ so it is important to recognize that the clinical presentation of mIAS differs from that of oral mucositis (Table 1, Figure ^14,15).¹⁶ mIAS shares some similarities with aphthous ulcers (also referred to as canker sores), a common oral condition with varied causes related to systemic disorders, gastrointestinal disorders, and infections, among others .¹⁷ In general, mIAS ulcers develop with a median onset of 10 days (range, 4-25 days) after initiation of mTOR inhibitor treatment and resolve in about 1-3 weeks after dose interruption/reduction of everolimus.^16,18,19 mIAS ulcers appear as distinct, oval lesions with a central gray area surrounded by peripheral erythema. They are usually localized to the movable mucosa of the mouth and oropharynx. Although mIAS lesions are usually small, they are quite painful and may cluster.

Differential diagnosis of mIAS should be made based on physical examination and medical history, with consideration given to appearance of lesions (number, size, and location), current infection status, and current medications. Specific diagnostic testing should be conducted to confirm a coexisting or alternative cause of oral lesions.¹⁷

Although there are many different scales for grading mIAS severity, the most commonly used are the National Cancer Institute Common Terminology Criteria for Adverse Events (based on patient function, symptoms, and intervention needs) and the World Health Organization oral mucositis scales (based on symptoms, clinical presentation, and interference with patient function).^20-22 These scales distinguish between mild lesions (grade 1/2) and moderate to severe lesions (grade 3/4) that cause significant pain or interfere with oral intake.

Pathophysiology of mIAS

The pathophysiology mIAS is incompletely understood. The ubiquitous role of the PI3K-AKT-mTOR pathway in regulating broad cellular functions suggests that mTOR inhibition is likely to have wide-ranging effects on many biological processes. It is not known whether disruption of one or more processes – or upsetting the balance of mTOR activities – underlies the formation of mIAS.

Differences between mIAS and oral mucositis, including clinical presentation and concomitant toxicities,^16,23 suggest that the two types of oral lesions are fundamentally distinct. This distinction is supported by animal studies in which mTOR inhibition was found to almost completely prevent the appearance of oral mucositis in irradiated mice. The protective effect of mTOR inhibition is mediated through suppression of oxidative stress generated by radiation therapy.²⁴

Although mIAS and recurrent aphthous ulcers share some similarities, it is not clear whether they also share a common pathophysiology. Recent studies suggest that patients with recurrent aphthous ulcers have immune dysfunction that leads to excessive immune response to normally innocuous substrates in the oral mucosa.²⁵ mTOR inhibition can have proinflammatory activity by promoting autophagy, a process that stimulates antigen presentation and activation of T cells that produce proinflammatory cytokines.²⁶ It is interesting to note that the incidence of stomatitis in patients receiving sirolimus after kidney transplant is relatively low, 3%-20%.⁵ Sirolimus is administered in combination with other immunosuppressants, namely cyclosporine and corticosteroids, so it suggests that concomitant use of a steroid-based regimen may have a preventive or therapeutic effect. However, posttransplant sirolimus is typically administered at relatively low doses, which might account in part for the lower incidence of mIAS observed. Ongoing clinical studies of steroid-based mouthwashes in patients receiving everolimus should shed light on this.

Other study findings have shown that inhibition of the PI3K-AKT-mTOR signaling pathway affects skin wound healing,^27,28 which raises the possibility that mIAS may stem from a diminished capacity to repair physical injuries to the oral mucosa. More research is needed to elucidate the pathophysiology of mIAS.

Preventive measures for patients initiating mTOR inhibitor treatment

There are preventive measures for mIAS that have not yet been backed up with evidence-based findings, although several clinical studies that are underway aim to address this gap (Table 2). The hypotheses about the pathophysiology of mIAS suggest that certain preventive and therapeutic interventions might be effective against mIAS. For example, two studies are evaluating the use of steroid-based mouthwashes in patients receiving everolimus, based on the hypothesis that mIAS may arise from an inflammatory process; another study will evaluate a mucoadhesive oral wound rinse, based on the hypothesis that wound protection might prevent mIAS. Glutamine suspension is also under evaluation as it is understood to have wound-preventative and tissue-repair properties, and another study is focused on dentist-guided oral management. Recent results of one of these trials (SWISH),²⁹ reported that preventative care with a dexamethasone mouthwash 3-4 times a day significantly minimized or prevented the incidence of all grades of stomatitis in women receiving everolimus plus exemestane therapy for advanced/metastatic breast cancer compared with the incidence of stomatitis observed in a previously published phase 3 trial (BOLERO-2)^30,31 of everolimus plus exemestane in the same patient population. Results from several other studies are expected soon.

Current approaches to mIAS prevention are based largely on clinical experience with chemotherapy- or radiation-induced oral mucositis (Table 3).^13,32 Preventive measures use three main strategies: establish and maintain good routine oral care; modify diet to avoid potentially damaging foods; and improve patient education about mIAS. In regard to patient education, numerous studies have reported that establishing an institutional protocol for oral care helped reduce the incidence of chemotherapy- or radiation-induced oral mucositis.^33-40 An ongoing clinical study that will randomize patients to receive oral care education from oral surgeons or instruction on brushing only (NCT02376985) is investigating whether having an oral care protocol holds for patients with mIAS. The hypothesis is that focusing attention on oral care and educating patients to recognize the onset of mIAS facilitates early detection and promotes early intervention.

Therapeutic measures for patients with mIAS

Therapeutic measures for mIAS are based largely on experience with chemotherapy- or radiation-induced oral mucositis or recurrent aphthous ulcers (Table 3) and vary in part by the severity of lesions. Treatments for mild mIAS aim to ameliorate symptoms (eg, topical analgesics for pain), protect the oral mucosa (eg, mucoadhesive gels or viscous solutions that coat the oral cavity), prevent potential sequelae (eg, prophylactic antibiotics to avoid secondary infections), and reduce inflammation/immune response (eg, steroid-based mouth rinses, topical steroids, or topical anti-inflammatory agents). Treatments for mild mIAS are generally local rather than systemic.

Treatment options for moderate to severe mIAS include systemic approaches that generally carry increased risk of AEs and, therefore, should be reserved for patients with multiple lesions, uncontrolled or poorly controlled pain, or greatly diminished oral food intake (Table 3).⁴¹ When mIAS cannot be controlled with the interventions described, the dose of the mTOR inhibitor can be reduced with the recognition that dose modification of anticancer therapy may affect disease outcomes.²⁹ The experience of reduction or interruption of treatment with everolimus in the BOLERO-2 trial as a strategy for management of AEs is discussed in a recent review.²⁹ Prescribing information for both temsirolimus and everolimus specify that grade 3 AEs be treated with temporary dose interruption, and with resolution (temsirolimus: grade ≤2; everolimus: grade ≤1), treatment may be resumed at lower doses (temsirolimus: reduce by 5 mg/week; no lower than 15 mg/week; everolimus: reduce by half the previously administered dose).^3,4 Grade 4 events due to treatment with temsirolimus may also be treated with dose interruption/reduction; the everolimus prescribing information advises treatment discontinuation for grade 4 stomatitis.

Summary and discussion

mTOR inhibitors can be effective treatments for patients with advanced cancer, specifically for advanced RCC, advanced pNET, and HR+, HER2-negative advanced breast cancer. Although mIAS may occur in many patients, it is usually grade 1 or 2 in severity. mIAS has an early onset, usually within the first 2 weeks of treatment^16,19,42 and a relatively rapid resolution, usually within 3 weeks.^16,19 Thus, most cases of mIAS are self-limiting.

The relatively recent emergence of mIAS poses short-term challenges regarding diagnosis, assessment, prevention, and treatment. Several clinical studies are underway to evaluate a range of interventions for their preventive and therapeutic efficacy in mIAS. Furthermore, our growing understanding of the underlying pathophysiology of mIAS can guide how mIAS is managed and what interventions patients receive.

Although mIAS is believed to differ from chemotherapy- or radiation-induced oral mucositis and aphthous ulcers, much can be learned from the treatment of both of these. Several strategies have been proposed to limit the occurrence of mIAS (Table 3). First, establish an oral care protocol. Educate patients who are initiating treatment with an mTOR inhibitor on implementation of the oral care protocol and emphasize adherence. Second, educate patients on the symptoms and timing of mIAS. Patients may hesitate to report mild symptoms or assume they are innocuous, so be clear that reporting all symptoms is important to allow timely clinical evaluation. Early recognition of mIAS facilitates early intervention and can prevent dose modification and interruption. Third, implement the preventive and treatment measures described. Many of the preventive measures can be incorporated into an oral care protocol.

The advent of mTOR inhibitors has clinically benefited many patients with cancer. Although side effects, like mIAS, may develop during treatment, they should not be considered insurmountable. Through education, vigilance, and aggressive management, health care providers and patients can work together to help patients maintain their quality of life while continuing to optimally address their disease.
 

Acknowledgment

The authors thank Anna Lau, PhD, and Patricia Segarini, PhD, of Percolation Communications LLC, for their editorial assistance. Funding for manuscript development was provided by Novartis Pharmaceuticals Corp.

Mammalian target of rapamycin (mTOR), a serine–threonine protein kinase, operates in the phosphoinositide 3-kinase (PI3K)–protein kinase B (AKT)–mTOR signal transduction pathway regulating both normal and cancer cellular processes, including cell growth, proliferation, motility, survival, and protein and lipid synthesis.¹ Genetic alterations affecting this pathway, including mutations in receptor tyrosine kinases PI3K and AKT, occur frequently in human cancers,² supporting the rationale to develop drugs that target pathway components, such as mTOR inhibitors.

Two mTOR inhibitors are currently approved by the US Food and Drug Administration for cancer treatment: temsirolimus, for advanced renal cell carcinoma (RCC; approved 2007)³ and everolimus, for advanced RCC (approved 2009), advanced pancreatic neuroendocrine tumors (pNET; approved 2011), and hormone receptor-positive (HR-positive), human epidermal growth factor receptor-2 (HER2)-negative advanced breast cancer (approved 2012).⁴ Another mTOR inhibitor, sirolimus, is approved for use as an immunosuppressive agent and prophylactic against organ rejection after kidney transplant.⁵

Stomatitis, inflammation of the oral mucosa with contributing factors of genetic predisposition, nutritional deficiencies, infections, and immunological or hematologic dysfunction,⁶ occurs frequently as a side effect associated with mTOR inhibitor treatment.^7-9 Left untreated or managed unsatisfactorily, mTOR inhibitor-associated stomatitis (mIAS) may cause patients discomfort and trouble with maintaining adequate nutritional intake and proper oral hygiene, as well as strict adherence to cancer treatment. It is therefore important for health care providers of cancer patients receiving mTOR inhibitor treatment to be knowledgeable about this side effect. The purpose of the present systematic review of published literature is to provide a better understanding of the differential diagnosis of mIAS, the pathophysiology of mIAS, preventive strategies for patients initiating mTOR inhibitor treatment, and treatment options available to manage mIAS.

Method

The PubMed database was searched with the terms mTOR inhibitor and stomatitis (no date restriction); 79 articles were retrieved, and all abstracts were reviewed to select those relevant to the aims of this review article. To understand future directions for management and prevention of mIAS, a search of clinicaltrials.gov was performed with the terms temsirolimus everolimus stomatitis yielding 12 clinical trials, of which 4 were excluded: 1 trial was terminated due to slow accrual, the status of 1 trial had not been verified in >2 years, and 2 studies focused on efficacy outcomes. A search of the American Society of Clinical Oncology (ASCO) meeting abstracts database was performed to assess the availability of clinical trial data; the search was limited to 2011-2016 and terms were stomatitis in the title and mTOR in the abstract or title. Seven abstracts were retrieved; 2 discussed stomatitis prevention (1 as a “trial-in-progress” and 1 presented results of the trial); the other 5 abstracts presented meta-analyses or reviews of previous clinical studies to assess the risk, incidence, management, and resolution of mIAS.

Review findings

Incidence of mIAS in patients treated for cancer

Two recent meta-analyses quantified the rate of mIAS in patients receiving mTOR inhibitors. Shameem and colleagues¹⁰ identified 9 randomized studies of everolimus (8 phase 3, 1 phase 2) and 2 of temsirolimus (1 each phase 2 and 3) involving a total of 4752 patients with a variety of tumor types including angiomyolipoma, breast, gastric, giant cell astrocytoma, pNET, and RCC. Patients received everolimus monotherapy (n = 1,075) or in combination with exemestane (n = 485), tamoxifen (n = 54), letrozole (n = 137), or octreotide (n = 216). Temsirolimus was administered as monotherapy (n = 208) or in combination with interferon
(n = 210) or letrozole (n = 550). The incidence of all-grade stomatitis in the 11 studies ranged from 11%-63%, and the overall incidence of any grade stomatitis was 33.5% (95% confidence interval [CI], 21.9%-47.6%). The concurrent use of a second agent may have confounded these findings because, for example, stomatitis has been reported in pooled analyses and in postmarketing experience with letrozole.¹¹

Rugo and colleagues¹² evaluated the incidence of stomatitis in 1455 patients participating in 5 phase 3 randomized clinical trials of everolimus in breast cancer, carcinoid tumor, pNET, and RCC. Patients received everolimus monotherapy
(n = 478) or in combination with exemestane (n = 482), trastuzumab plus vinorelbine (n = 280), or octreotide
(n = 215). The incidence of stomatitis in patients receiving everolimus was 59%-71%, compared with 19%-29% in 1,071 patients of the comparator arms (placebo, and placebo–trastuzumab–vinorelbine). The overall incidence of any grade stomatitis was 67%; most events were mild (grade 1/2); 9% of stomatitis events were moderate to severe (grade 3/4).

Differential clinical presentation of mIAS and severity

Oral mucositis is a common significant adverse event (AE) that occurs in patients with cancer who receive standard chemotherapy regimens and/or radiation therapy,¹³ so it is important to recognize that the clinical presentation of mIAS differs from that of oral mucositis (Table 1, Figure ^14,15).¹⁶ mIAS shares some similarities with aphthous ulcers (also referred to as canker sores), a common oral condition with varied causes related to systemic disorders, gastrointestinal disorders, and infections, among others .¹⁷ In general, mIAS ulcers develop with a median onset of 10 days (range, 4-25 days) after initiation of mTOR inhibitor treatment and resolve in about 1-3 weeks after dose interruption/reduction of everolimus.^16,18,19 mIAS ulcers appear as distinct, oval lesions with a central gray area surrounded by peripheral erythema. They are usually localized to the movable mucosa of the mouth and oropharynx. Although mIAS lesions are usually small, they are quite painful and may cluster.

Differential diagnosis of mIAS should be made based on physical examination and medical history, with consideration given to appearance of lesions (number, size, and location), current infection status, and current medications. Specific diagnostic testing should be conducted to confirm a coexisting or alternative cause of oral lesions.¹⁷

Although there are many different scales for grading mIAS severity, the most commonly used are the National Cancer Institute Common Terminology Criteria for Adverse Events (based on patient function, symptoms, and intervention needs) and the World Health Organization oral mucositis scales (based on symptoms, clinical presentation, and interference with patient function).^20-22 These scales distinguish between mild lesions (grade 1/2) and moderate to severe lesions (grade 3/4) that cause significant pain or interfere with oral intake.

Pathophysiology of mIAS

The pathophysiology mIAS is incompletely understood. The ubiquitous role of the PI3K-AKT-mTOR pathway in regulating broad cellular functions suggests that mTOR inhibition is likely to have wide-ranging effects on many biological processes. It is not known whether disruption of one or more processes – or upsetting the balance of mTOR activities – underlies the formation of mIAS.

Differences between mIAS and oral mucositis, including clinical presentation and concomitant toxicities,^16,23 suggest that the two types of oral lesions are fundamentally distinct. This distinction is supported by animal studies in which mTOR inhibition was found to almost completely prevent the appearance of oral mucositis in irradiated mice. The protective effect of mTOR inhibition is mediated through suppression of oxidative stress generated by radiation therapy.²⁴

Although mIAS and recurrent aphthous ulcers share some similarities, it is not clear whether they also share a common pathophysiology. Recent studies suggest that patients with recurrent aphthous ulcers have immune dysfunction that leads to excessive immune response to normally innocuous substrates in the oral mucosa.²⁵ mTOR inhibition can have proinflammatory activity by promoting autophagy, a process that stimulates antigen presentation and activation of T cells that produce proinflammatory cytokines.²⁶ It is interesting to note that the incidence of stomatitis in patients receiving sirolimus after kidney transplant is relatively low, 3%-20%.⁵ Sirolimus is administered in combination with other immunosuppressants, namely cyclosporine and corticosteroids, so it suggests that concomitant use of a steroid-based regimen may have a preventive or therapeutic effect. However, posttransplant sirolimus is typically administered at relatively low doses, which might account in part for the lower incidence of mIAS observed. Ongoing clinical studies of steroid-based mouthwashes in patients receiving everolimus should shed light on this.

Other study findings have shown that inhibition of the PI3K-AKT-mTOR signaling pathway affects skin wound healing,^27,28 which raises the possibility that mIAS may stem from a diminished capacity to repair physical injuries to the oral mucosa. More research is needed to elucidate the pathophysiology of mIAS.

Preventive measures for patients initiating mTOR inhibitor treatment

There are preventive measures for mIAS that have not yet been backed up with evidence-based findings, although several clinical studies that are underway aim to address this gap (Table 2). The hypotheses about the pathophysiology of mIAS suggest that certain preventive and therapeutic interventions might be effective against mIAS. For example, two studies are evaluating the use of steroid-based mouthwashes in patients receiving everolimus, based on the hypothesis that mIAS may arise from an inflammatory process; another study will evaluate a mucoadhesive oral wound rinse, based on the hypothesis that wound protection might prevent mIAS. Glutamine suspension is also under evaluation as it is understood to have wound-preventative and tissue-repair properties, and another study is focused on dentist-guided oral management. Recent results of one of these trials (SWISH),²⁹ reported that preventative care with a dexamethasone mouthwash 3-4 times a day significantly minimized or prevented the incidence of all grades of stomatitis in women receiving everolimus plus exemestane therapy for advanced/metastatic breast cancer compared with the incidence of stomatitis observed in a previously published phase 3 trial (BOLERO-2)^30,31 of everolimus plus exemestane in the same patient population. Results from several other studies are expected soon.

Current approaches to mIAS prevention are based largely on clinical experience with chemotherapy- or radiation-induced oral mucositis (Table 3).^13,32 Preventive measures use three main strategies: establish and maintain good routine oral care; modify diet to avoid potentially damaging foods; and improve patient education about mIAS. In regard to patient education, numerous studies have reported that establishing an institutional protocol for oral care helped reduce the incidence of chemotherapy- or radiation-induced oral mucositis.^33-40 An ongoing clinical study that will randomize patients to receive oral care education from oral surgeons or instruction on brushing only (NCT02376985) is investigating whether having an oral care protocol holds for patients with mIAS. The hypothesis is that focusing attention on oral care and educating patients to recognize the onset of mIAS facilitates early detection and promotes early intervention.

Therapeutic measures for patients with mIAS

Therapeutic measures for mIAS are based largely on experience with chemotherapy- or radiation-induced oral mucositis or recurrent aphthous ulcers (Table 3) and vary in part by the severity of lesions. Treatments for mild mIAS aim to ameliorate symptoms (eg, topical analgesics for pain), protect the oral mucosa (eg, mucoadhesive gels or viscous solutions that coat the oral cavity), prevent potential sequelae (eg, prophylactic antibiotics to avoid secondary infections), and reduce inflammation/immune response (eg, steroid-based mouth rinses, topical steroids, or topical anti-inflammatory agents). Treatments for mild mIAS are generally local rather than systemic.

Treatment options for moderate to severe mIAS include systemic approaches that generally carry increased risk of AEs and, therefore, should be reserved for patients with multiple lesions, uncontrolled or poorly controlled pain, or greatly diminished oral food intake (Table 3).⁴¹ When mIAS cannot be controlled with the interventions described, the dose of the mTOR inhibitor can be reduced with the recognition that dose modification of anticancer therapy may affect disease outcomes.²⁹ The experience of reduction or interruption of treatment with everolimus in the BOLERO-2 trial as a strategy for management of AEs is discussed in a recent review.²⁹ Prescribing information for both temsirolimus and everolimus specify that grade 3 AEs be treated with temporary dose interruption, and with resolution (temsirolimus: grade ≤2; everolimus: grade ≤1), treatment may be resumed at lower doses (temsirolimus: reduce by 5 mg/week; no lower than 15 mg/week; everolimus: reduce by half the previously administered dose).^3,4 Grade 4 events due to treatment with temsirolimus may also be treated with dose interruption/reduction; the everolimus prescribing information advises treatment discontinuation for grade 4 stomatitis.

Summary and discussion

mTOR inhibitors can be effective treatments for patients with advanced cancer, specifically for advanced RCC, advanced pNET, and HR+, HER2-negative advanced breast cancer. Although mIAS may occur in many patients, it is usually grade 1 or 2 in severity. mIAS has an early onset, usually within the first 2 weeks of treatment^16,19,42 and a relatively rapid resolution, usually within 3 weeks.^16,19 Thus, most cases of mIAS are self-limiting.

The relatively recent emergence of mIAS poses short-term challenges regarding diagnosis, assessment, prevention, and treatment. Several clinical studies are underway to evaluate a range of interventions for their preventive and therapeutic efficacy in mIAS. Furthermore, our growing understanding of the underlying pathophysiology of mIAS can guide how mIAS is managed and what interventions patients receive.

Although mIAS is believed to differ from chemotherapy- or radiation-induced oral mucositis and aphthous ulcers, much can be learned from the treatment of both of these. Several strategies have been proposed to limit the occurrence of mIAS (Table 3). First, establish an oral care protocol. Educate patients who are initiating treatment with an mTOR inhibitor on implementation of the oral care protocol and emphasize adherence. Second, educate patients on the symptoms and timing of mIAS. Patients may hesitate to report mild symptoms or assume they are innocuous, so be clear that reporting all symptoms is important to allow timely clinical evaluation. Early recognition of mIAS facilitates early intervention and can prevent dose modification and interruption. Third, implement the preventive and treatment measures described. Many of the preventive measures can be incorporated into an oral care protocol.

The advent of mTOR inhibitors has clinically benefited many patients with cancer. Although side effects, like mIAS, may develop during treatment, they should not be considered insurmountable. Through education, vigilance, and aggressive management, health care providers and patients can work together to help patients maintain their quality of life while continuing to optimally address their disease.
 

Acknowledgment

The authors thank Anna Lau, PhD, and Patricia Segarini, PhD, of Percolation Communications LLC, for their editorial assistance. Funding for manuscript development was provided by Novartis Pharmaceuticals Corp.

The popularity of electronic cigarettes (E-cigs) and “vapes” has grown dramatically, spawning a new industry of electronic nicotine delivery systems (ENDS). With the increasing use of E-cigs not only for smoking cessation, but also as a primary nicotine source, it is important for mental health professionals to be prepared to discuss use of these devices with patients. In this article, we will describe:

• the composition of E-cigs and their current use
• evidence for their use for smoking cessation
• adverse health effects
• recommendations of major regulatory agencies.

Finally, we will provide recommendations for E-cig use in clinical populations.

What is an electronic nicotine delivery system?

ENDS produce an aerosol with or without nicotine that is inhaled and is thought to mimic the use of combustible cigarettes. ENDS evolved from basic E-cigs into a less “cigarette-like” and more customizable product (Figure 1). ENDS include a range of designs and go by various names, including “personal vaporizers,” “e-cigars,” and “e-hookahs” (in this article, we will use the term “ENDS” to refer to these devices).

The general design of ENDS is a plastic tubing system that contains a mouthpiece, battery, electronic heating element (“vaporizer”), and a cartridge with liquid solvent with or without nicotine or flavoring (Figure 2). One draw on the mouthpiece or press of a button activates the device, heats the solution, and delivers a vapor in a similar manner to taking a puff of a cigarette. Although studies have shown that ENDS result in significant increases in plasma nicotine concentrations in 5 minutes,¹ the plasma nicotine levels obtained with the first-generation “cigarette-like” ENDS are much lower than those caused by inhaling tobacco smoke.² Over time nicotine delivery capability has improved as ENDS have evolved such that the rate of nicotine delivery and peak concentration obtained with newer models more closely mirror tobacco cigarettes.³ Whether the rapid delivery of larger amounts of nicotine helps or hinders one’s efforts to break nicotine addiction remains to be determined because of the reinforcing properties of the drug.

The liquid in the E-cig cartridge typically contains not only nicotine but a number of chemical compounds with potentially deleterious or unknown health risks. The 3 main ingredients include:

• a solvent of glycerin and/or propylene glycol
• nicotine in various concentrations
• flavorings.

The glycerin or propylene glycol forms the basis for the aerosol. Nicotine concentrations vary from 0 (denicotinized) to 35 mcg per puff.⁴ A study reported 7,700 unique flavors available for vaping liquid.⁵ The liquid also contains impurities, such as anabasine, which has effects on the α-7 nicotinic acetylcholine receptor and its principal use is as an insecticide and β-nicotyrine, which inhibits cytochrome P450 2A.

Epidemiology and end-user perspectives

In 2014, 12.4% of U.S. adults classified themselves as “ever users” of ENDS (used at least once) and 3.7% of adults classified themselves as current users, according to the National Health Interview Study.⁶ Importantly, among E-cig users who had not used combustible cigarettes, young adults (age 18 to 24) were more likely to have tried ENDS than older adults. ENDS are becoming more popular across the globe. A study in the European Union found that ever users of ENDS most commonly were current cigarette smokers (31%) followed by former (10.8%) and never smokers (2.3%).⁷

ENDS use is relevant for mental health professionals because of the high rate of comorbid tobacco use disorder in individuals with psychiatric conditions. For example, 2 U.S. population surveys^8,9 revealed those with mental health conditions were 1.5 to 2 times more likely to have tried ENDS and 2 to 3 times more likely to be current users. Those with psychiatric illness reported similar reasons for ENDS use as other individuals, including “just because,” use as a smoking cessation aid, ease of use, and perceived safety vs combustible cigarettes.

A recent review that included 9 studies focusing on ENDS use in those with mental illness reported mixed findings on the utility of these devices to reduce or stop use of combustible cigarettes.¹⁰ Additionally, it is important to monitor the use of cigarettes and ENDS in patients with psychiatric illness because the byproducts of tobacco smoke can affect the metabolism of some psychotropic medications.¹¹ Although reduced use of combustible cigarettes could lead to lower dosing of some psychotropics, an unreported decrease in combustible cigarette use could lead to supratherapeutic drug levels. There are no data on the effect of ENDS on the metabolism of psychotropics.

ENDS are increasingly popular among adolescents. In 2015, there were an estimated 4.6 million current tobacco users among middle/high school youths in the United States and 3 million current ENDS users, according to the National Youth Tobacco Surveys.¹² The shift from combustible cigarettes to ENDS is notable, with an increase in the percentage of current E-cig users and a decrease in the percentage of exclusive combustible cigarette users. In addition, there has been no change in the prevalence of lifetime tobacco users.¹² This is a global issue, as reports of ever use of ENDS by adolescents range from 6.5% to 31% in the United States, 14.6% in Canada, and 4.7% to 38.5% in Europe.¹³ Based on these trends, the U.S. Surgeon General released a statement warning against the use of ENDS in youth because of the lack of safety data and strong association with use of tobacco products.¹⁴

There are a number of possible reasons for the increasing popularity of ENDS, including the product’s novelty, lack of regulations regarding their sale, availability of flavorings, and the perception that ENDS are safe alternatives to cigarettes. E-cig–using youths have described ENDS as “not at all harmful” and “not at all addictive” and believe that ENDS with flavoring are less harmful than those without.¹⁵ Although studies in adults show some users reporting that ENDS are less satisfying, they are seen as useful in decreasing craving and a safer alternative to cigarettes.^16,17

Are ENDS effective for smoking cessation?
The evidence for ENDS as aids to smoking cessation remains murky (Table 1^18-22). There is a paucity of randomized controlled clinical trials (RCTs) investigating ENDS for smoking cessation or reduction, and it is difficult to quantify the amount of nicotine used in ENDS because of the variety of delivery systems and cartridges. In a recent Cochrane review, those using ENDS to quit smoking were more likely to be abstinent from combustible cigarettes at 6 months vs those using nicotine-free ENDS (relative risk = 2.29; 95% CI, 1.05 to 4.96), but there was no significant difference in quit rates compared with nicotine patches.²³ However, the confidence in this finding was rated as low because of the limited number of RCTs. Of note, the authors found 15 ongoing RCTs at the time of publication that might be eligible for later evaluation.

Non-RCTs reveal mixed data. Positive results include 1 study with an odds ratio of 6.07 to quit for intensive ENDS users vs non-users,²⁴ and another with dual users of combustible and electronic cigarettes having a 46% quit rate at 1 year.²⁵ Additionally, in a pilot study providing ENDS to 14 patients with schizophrenia who had no previous desire to quit smoking, authors noted a reduction in the number of cigarettes smoked per day by 50% in one-half of participants and abstinence in 14% of participants at 52 weeks.²⁶ Studies with neutral or negative results include those showing ENDS users to be current combustible tobacco smokers, and use of ENDS not predicting smoking cessation.^4,27 Data also are mixed regarding the use of ENDS as a harm reduction strategy. One study found that ENDS decreased cigarette consumption, but did not increase the likelihood of quitting,²⁸ while another reported that daily use of ENDS increased the odds of reducing smoking by as much as 2.5 times compared with non-use of such aids.²⁹ In a 24-month prospective cohort study following tobacco users, there was no difference in the number of cigarettes smoked per day in those who started the trial as users of combustible cigarettes alone vs combustible cigarettes plus ENDS users.³⁰ Interestingly, those who started the study as combustible cigarette users and switched to ENDS and those who had continued dual use throughout the 24 months smoked fewer combustible cigarettes per day than those who never tried ENDS or quit during the study period.

Health effects

To better understand the adverse health effects of ENDS, one must consider potential short- and long-term consequences (Table 2). In the short-term, ENDS have been found to increase markers of inflammation and oxidative stress acutely as evidenced by in vivo laboratory studies.^31,32 ENDS also have been linked to upper respiratory irritation, in part, because of the transformation of glycerin in the nicotine cartridge to acrolein upon combustion.³³ Even 5 minutes of ad lib E-cig use has been found to significantly increase airflow resistance during pulmonary function tests³⁴—changes that have been shown to precede more persistent alterations in peak expiratory flow, such as those seen in chronic obstructive pulmonary disease. The more common patient-reported side effects include:

• daytime cough (27%)
• phlegm production (25%)
• headache (21%)
• dry mouth/throat (20%)
• vertigo, headache, or nausea (9%).^35,36

A RCT investigating efficacy of E-cigs vs nicotine patches vs denicotinized E-cigs found no difference among the groups in the number of reported adverse events.¹⁸ Interestingly, another RCT found a decrease in adverse events, such as dry cough, mouth irritation, throat irritation, shortness of breath, and headache, compared with baseline in combustible cigarette smokers who used regular or denicotinized E-cigs.¹⁹

Although no studies have directly investigated long-term health consequences of ENDS because of their relative novelty, one can extrapolate potential harmful long-term effects based on knowledge of the products’ chemical constituents. For example, propylene glycol can degrade into propylene oxide, a class 2B carcinogen.³⁷ Other potential carcinogens in the aerosol include formaldehyde and acetaldehyde. On a broader scale, many of the particulates have been shown to cause systemic inflammation, which is thought to increase cardiovascular and respiratory disease and death.³⁸ Flavorings in ENDS include a variety of components including, but not limited to, aldehydes, which are irritants, and other additives that have been associated with respiratory disease.³⁹

Second-hand exposure. There are no long-term studies of second-hand vapor exposure, but similar to long-term health on primary users, one can glean some observations from the literature. It is promising that compared with cigarettes, ENDS lack sidestream smoke and the vapor has not been found to contain carbon monoxide.⁴⁰ Some research has demonstrated that the size and spray of fine particles in the aerosol is as large or larger than combustible cigarettes.⁴¹ Formaldehyde, acetaldehyde, isoprene, and acetic acid have been found in ENDS vapor.⁴⁰ Interestingly, a simulated café study found elevated nicotine, glycerine, hydrocarbon, and other materials classified as carcinogens in the air.⁴²

Although it is popularly thought that ENDS are less toxic than tobacco cigarettes, there is not enough evidence to estimate precisely as to how much less toxic or the consequences of use. ENDS are increasingly popular and are being used by never smokers who should be educated on the potential harm that ENDS pose.

Recommendations from agencies and medical organizations

The World Health Organization (WHO) recommended prohibiting the use of ENDS in indoor spaces to minimize potential health risks to users and non-users. The WHO also aims to prevent dissemination of unproven health claims, including claims that ENDS are effective—or not—or that the devices are innocuous.³⁶ In the United States, the FDA has stated that ENDS are not recommended for safe quitting (2009). In August 2016, the FDA introduced regulations banning the sale of ENDS to individuals age <18 and required manufacturers to submit documents detailing all ingredients for review and possible approval.

The American Lung Association has stated its concerns about the use of ENDS but has not made any direct recommendations. The American Heart Association reports a potential negative public health impact and provides clinical guideline recommendations.⁴³ Prominent psychiatric organizations such as the American Psychiatric Association, American Academy of Addiction Psychiatry (AAAP), the Substance Abuse and Mental Health Services Administration (SAMHSA), and the National Institute of Drug Abuse do not have official statements supporting or rejecting the use of ENDS. However, they do note the potential harm and lack of substantial evidence for efficacy of ENDS as a smoking cessation tool, and the AAAP and SAMHSA state that they will work with regulatory agencies to reduce the use of toxic products with addictive potential including ENDS.^44-46

Clinical recommendations

We do not recommend ENDS as a first-line treatment for smoking cessation because there is no evidence they are superior to the FDA-approved nicotine replacement therapies (NRTs), the paucity of research into the potential short- and long-term health risks of ENDS, and the fact that these products are not regulated for use as smoking cessation aids. It is, however, advisable to discuss ENDS use with patients by:

• asking if they are using the products
• assessing whether the user also is a smoker
• advising the patient to quit.

It also is important to assess the patient’s knowledge and attitudes regarding ENDS use and provide education about the products. Some patients firmly believe that ENDS are the lesser of 2 evils, and they are decreasing the harms of smoking by using these devices. While the debate over a potential harm reduction strategy unfolds,⁴⁷ we think that because of the state of the evidence it is prudent to adopt a more precautionary stance and recommend that patients work toward abstinence from nicotine in any form.

For dual tobacco/ENDS users and for patients using ENDS who want to quit smoking, we recommend treatment with an approved pharmacotherapy (ie, NRTs, bupropion, and varenicline) combined with counseling. A 2013 Cochrane Review found that all pharamacotherapy options are more effective than placebo, and combination NRT and varenicline are superior to single NRT or bupropion (Box).^23,48

The popularity of electronic cigarettes (E-cigs) and “vapes” has grown dramatically, spawning a new industry of electronic nicotine delivery systems (ENDS). With the increasing use of E-cigs not only for smoking cessation, but also as a primary nicotine source, it is important for mental health professionals to be prepared to discuss use of these devices with patients. In this article, we will describe:

• the composition of E-cigs and their current use
• evidence for their use for smoking cessation
• adverse health effects
• recommendations of major regulatory agencies.

Finally, we will provide recommendations for E-cig use in clinical populations.

What is an electronic nicotine delivery system?

ENDS produce an aerosol with or without nicotine that is inhaled and is thought to mimic the use of combustible cigarettes. ENDS evolved from basic E-cigs into a less “cigarette-like” and more customizable product (Figure 1). ENDS include a range of designs and go by various names, including “personal vaporizers,” “e-cigars,” and “e-hookahs” (in this article, we will use the term “ENDS” to refer to these devices).

The general design of ENDS is a plastic tubing system that contains a mouthpiece, battery, electronic heating element (“vaporizer”), and a cartridge with liquid solvent with or without nicotine or flavoring (Figure 2). One draw on the mouthpiece or press of a button activates the device, heats the solution, and delivers a vapor in a similar manner to taking a puff of a cigarette. Although studies have shown that ENDS result in significant increases in plasma nicotine concentrations in 5 minutes,¹ the plasma nicotine levels obtained with the first-generation “cigarette-like” ENDS are much lower than those caused by inhaling tobacco smoke.² Over time nicotine delivery capability has improved as ENDS have evolved such that the rate of nicotine delivery and peak concentration obtained with newer models more closely mirror tobacco cigarettes.³ Whether the rapid delivery of larger amounts of nicotine helps or hinders one’s efforts to break nicotine addiction remains to be determined because of the reinforcing properties of the drug.

The liquid in the E-cig cartridge typically contains not only nicotine but a number of chemical compounds with potentially deleterious or unknown health risks. The 3 main ingredients include:

• a solvent of glycerin and/or propylene glycol
• nicotine in various concentrations
• flavorings.

The glycerin or propylene glycol forms the basis for the aerosol. Nicotine concentrations vary from 0 (denicotinized) to 35 mcg per puff.⁴ A study reported 7,700 unique flavors available for vaping liquid.⁵ The liquid also contains impurities, such as anabasine, which has effects on the α-7 nicotinic acetylcholine receptor and its principal use is as an insecticide and β-nicotyrine, which inhibits cytochrome P450 2A.

Epidemiology and end-user perspectives

In 2014, 12.4% of U.S. adults classified themselves as “ever users” of ENDS (used at least once) and 3.7% of adults classified themselves as current users, according to the National Health Interview Study.⁶ Importantly, among E-cig users who had not used combustible cigarettes, young adults (age 18 to 24) were more likely to have tried ENDS than older adults. ENDS are becoming more popular across the globe. A study in the European Union found that ever users of ENDS most commonly were current cigarette smokers (31%) followed by former (10.8%) and never smokers (2.3%).⁷

ENDS use is relevant for mental health professionals because of the high rate of comorbid tobacco use disorder in individuals with psychiatric conditions. For example, 2 U.S. population surveys^8,9 revealed those with mental health conditions were 1.5 to 2 times more likely to have tried ENDS and 2 to 3 times more likely to be current users. Those with psychiatric illness reported similar reasons for ENDS use as other individuals, including “just because,” use as a smoking cessation aid, ease of use, and perceived safety vs combustible cigarettes.

A recent review that included 9 studies focusing on ENDS use in those with mental illness reported mixed findings on the utility of these devices to reduce or stop use of combustible cigarettes.¹⁰ Additionally, it is important to monitor the use of cigarettes and ENDS in patients with psychiatric illness because the byproducts of tobacco smoke can affect the metabolism of some psychotropic medications.¹¹ Although reduced use of combustible cigarettes could lead to lower dosing of some psychotropics, an unreported decrease in combustible cigarette use could lead to supratherapeutic drug levels. There are no data on the effect of ENDS on the metabolism of psychotropics.

ENDS are increasingly popular among adolescents. In 2015, there were an estimated 4.6 million current tobacco users among middle/high school youths in the United States and 3 million current ENDS users, according to the National Youth Tobacco Surveys.¹² The shift from combustible cigarettes to ENDS is notable, with an increase in the percentage of current E-cig users and a decrease in the percentage of exclusive combustible cigarette users. In addition, there has been no change in the prevalence of lifetime tobacco users.¹² This is a global issue, as reports of ever use of ENDS by adolescents range from 6.5% to 31% in the United States, 14.6% in Canada, and 4.7% to 38.5% in Europe.¹³ Based on these trends, the U.S. Surgeon General released a statement warning against the use of ENDS in youth because of the lack of safety data and strong association with use of tobacco products.¹⁴

There are a number of possible reasons for the increasing popularity of ENDS, including the product’s novelty, lack of regulations regarding their sale, availability of flavorings, and the perception that ENDS are safe alternatives to cigarettes. E-cig–using youths have described ENDS as “not at all harmful” and “not at all addictive” and believe that ENDS with flavoring are less harmful than those without.¹⁵ Although studies in adults show some users reporting that ENDS are less satisfying, they are seen as useful in decreasing craving and a safer alternative to cigarettes.^16,17

Are ENDS effective for smoking cessation?
The evidence for ENDS as aids to smoking cessation remains murky (Table 1^18-22). There is a paucity of randomized controlled clinical trials (RCTs) investigating ENDS for smoking cessation or reduction, and it is difficult to quantify the amount of nicotine used in ENDS because of the variety of delivery systems and cartridges. In a recent Cochrane review, those using ENDS to quit smoking were more likely to be abstinent from combustible cigarettes at 6 months vs those using nicotine-free ENDS (relative risk = 2.29; 95% CI, 1.05 to 4.96), but there was no significant difference in quit rates compared with nicotine patches.²³ However, the confidence in this finding was rated as low because of the limited number of RCTs. Of note, the authors found 15 ongoing RCTs at the time of publication that might be eligible for later evaluation.

Non-RCTs reveal mixed data. Positive results include 1 study with an odds ratio of 6.07 to quit for intensive ENDS users vs non-users,²⁴ and another with dual users of combustible and electronic cigarettes having a 46% quit rate at 1 year.²⁵ Additionally, in a pilot study providing ENDS to 14 patients with schizophrenia who had no previous desire to quit smoking, authors noted a reduction in the number of cigarettes smoked per day by 50% in one-half of participants and abstinence in 14% of participants at 52 weeks.²⁶ Studies with neutral or negative results include those showing ENDS users to be current combustible tobacco smokers, and use of ENDS not predicting smoking cessation.^4,27 Data also are mixed regarding the use of ENDS as a harm reduction strategy. One study found that ENDS decreased cigarette consumption, but did not increase the likelihood of quitting,²⁸ while another reported that daily use of ENDS increased the odds of reducing smoking by as much as 2.5 times compared with non-use of such aids.²⁹ In a 24-month prospective cohort study following tobacco users, there was no difference in the number of cigarettes smoked per day in those who started the trial as users of combustible cigarettes alone vs combustible cigarettes plus ENDS users.³⁰ Interestingly, those who started the study as combustible cigarette users and switched to ENDS and those who had continued dual use throughout the 24 months smoked fewer combustible cigarettes per day than those who never tried ENDS or quit during the study period.

Health effects

To better understand the adverse health effects of ENDS, one must consider potential short- and long-term consequences (Table 2). In the short-term, ENDS have been found to increase markers of inflammation and oxidative stress acutely as evidenced by in vivo laboratory studies.^31,32 ENDS also have been linked to upper respiratory irritation, in part, because of the transformation of glycerin in the nicotine cartridge to acrolein upon combustion.³³ Even 5 minutes of ad lib E-cig use has been found to significantly increase airflow resistance during pulmonary function tests³⁴—changes that have been shown to precede more persistent alterations in peak expiratory flow, such as those seen in chronic obstructive pulmonary disease. The more common patient-reported side effects include:

• daytime cough (27%)
• phlegm production (25%)
• headache (21%)
• dry mouth/throat (20%)
• vertigo, headache, or nausea (9%).^35,36

A RCT investigating efficacy of E-cigs vs nicotine patches vs denicotinized E-cigs found no difference among the groups in the number of reported adverse events.¹⁸ Interestingly, another RCT found a decrease in adverse events, such as dry cough, mouth irritation, throat irritation, shortness of breath, and headache, compared with baseline in combustible cigarette smokers who used regular or denicotinized E-cigs.¹⁹

Although no studies have directly investigated long-term health consequences of ENDS because of their relative novelty, one can extrapolate potential harmful long-term effects based on knowledge of the products’ chemical constituents. For example, propylene glycol can degrade into propylene oxide, a class 2B carcinogen.³⁷ Other potential carcinogens in the aerosol include formaldehyde and acetaldehyde. On a broader scale, many of the particulates have been shown to cause systemic inflammation, which is thought to increase cardiovascular and respiratory disease and death.³⁸ Flavorings in ENDS include a variety of components including, but not limited to, aldehydes, which are irritants, and other additives that have been associated with respiratory disease.³⁹

Second-hand exposure. There are no long-term studies of second-hand vapor exposure, but similar to long-term health on primary users, one can glean some observations from the literature. It is promising that compared with cigarettes, ENDS lack sidestream smoke and the vapor has not been found to contain carbon monoxide.⁴⁰ Some research has demonstrated that the size and spray of fine particles in the aerosol is as large or larger than combustible cigarettes.⁴¹ Formaldehyde, acetaldehyde, isoprene, and acetic acid have been found in ENDS vapor.⁴⁰ Interestingly, a simulated café study found elevated nicotine, glycerine, hydrocarbon, and other materials classified as carcinogens in the air.⁴²

Although it is popularly thought that ENDS are less toxic than tobacco cigarettes, there is not enough evidence to estimate precisely as to how much less toxic or the consequences of use. ENDS are increasingly popular and are being used by never smokers who should be educated on the potential harm that ENDS pose.

Recommendations from agencies and medical organizations

The World Health Organization (WHO) recommended prohibiting the use of ENDS in indoor spaces to minimize potential health risks to users and non-users. The WHO also aims to prevent dissemination of unproven health claims, including claims that ENDS are effective—or not—or that the devices are innocuous.³⁶ In the United States, the FDA has stated that ENDS are not recommended for safe quitting (2009). In August 2016, the FDA introduced regulations banning the sale of ENDS to individuals age <18 and required manufacturers to submit documents detailing all ingredients for review and possible approval.

The American Lung Association has stated its concerns about the use of ENDS but has not made any direct recommendations. The American Heart Association reports a potential negative public health impact and provides clinical guideline recommendations.⁴³ Prominent psychiatric organizations such as the American Psychiatric Association, American Academy of Addiction Psychiatry (AAAP), the Substance Abuse and Mental Health Services Administration (SAMHSA), and the National Institute of Drug Abuse do not have official statements supporting or rejecting the use of ENDS. However, they do note the potential harm and lack of substantial evidence for efficacy of ENDS as a smoking cessation tool, and the AAAP and SAMHSA state that they will work with regulatory agencies to reduce the use of toxic products with addictive potential including ENDS.^44-46

Clinical recommendations

We do not recommend ENDS as a first-line treatment for smoking cessation because there is no evidence they are superior to the FDA-approved nicotine replacement therapies (NRTs), the paucity of research into the potential short- and long-term health risks of ENDS, and the fact that these products are not regulated for use as smoking cessation aids. It is, however, advisable to discuss ENDS use with patients by:

• asking if they are using the products
• assessing whether the user also is a smoker
• advising the patient to quit.

It also is important to assess the patient’s knowledge and attitudes regarding ENDS use and provide education about the products. Some patients firmly believe that ENDS are the lesser of 2 evils, and they are decreasing the harms of smoking by using these devices. While the debate over a potential harm reduction strategy unfolds,⁴⁷ we think that because of the state of the evidence it is prudent to adopt a more precautionary stance and recommend that patients work toward abstinence from nicotine in any form.

For dual tobacco/ENDS users and for patients using ENDS who want to quit smoking, we recommend treatment with an approved pharmacotherapy (ie, NRTs, bupropion, and varenicline) combined with counseling. A 2013 Cochrane Review found that all pharamacotherapy options are more effective than placebo, and combination NRT and varenicline are superior to single NRT or bupropion (Box).^23,48

The popularity of electronic cigarettes (E-cigs) and “vapes” has grown dramatically, spawning a new industry of electronic nicotine delivery systems (ENDS). With the increasing use of E-cigs not only for smoking cessation, but also as a primary nicotine source, it is important for mental health professionals to be prepared to discuss use of these devices with patients. In this article, we will describe:

• the composition of E-cigs and their current use
• evidence for their use for smoking cessation
• adverse health effects
• recommendations of major regulatory agencies.

Finally, we will provide recommendations for E-cig use in clinical populations.

What is an electronic nicotine delivery system?

ENDS produce an aerosol with or without nicotine that is inhaled and is thought to mimic the use of combustible cigarettes. ENDS evolved from basic E-cigs into a less “cigarette-like” and more customizable product (Figure 1). ENDS include a range of designs and go by various names, including “personal vaporizers,” “e-cigars,” and “e-hookahs” (in this article, we will use the term “ENDS” to refer to these devices).

The general design of ENDS is a plastic tubing system that contains a mouthpiece, battery, electronic heating element (“vaporizer”), and a cartridge with liquid solvent with or without nicotine or flavoring (Figure 2). One draw on the mouthpiece or press of a button activates the device, heats the solution, and delivers a vapor in a similar manner to taking a puff of a cigarette. Although studies have shown that ENDS result in significant increases in plasma nicotine concentrations in 5 minutes,¹ the plasma nicotine levels obtained with the first-generation “cigarette-like” ENDS are much lower than those caused by inhaling tobacco smoke.² Over time nicotine delivery capability has improved as ENDS have evolved such that the rate of nicotine delivery and peak concentration obtained with newer models more closely mirror tobacco cigarettes.³ Whether the rapid delivery of larger amounts of nicotine helps or hinders one’s efforts to break nicotine addiction remains to be determined because of the reinforcing properties of the drug.

The liquid in the E-cig cartridge typically contains not only nicotine but a number of chemical compounds with potentially deleterious or unknown health risks. The 3 main ingredients include:

• a solvent of glycerin and/or propylene glycol
• nicotine in various concentrations
• flavorings.

The glycerin or propylene glycol forms the basis for the aerosol. Nicotine concentrations vary from 0 (denicotinized) to 35 mcg per puff.⁴ A study reported 7,700 unique flavors available for vaping liquid.⁵ The liquid also contains impurities, such as anabasine, which has effects on the α-7 nicotinic acetylcholine receptor and its principal use is as an insecticide and β-nicotyrine, which inhibits cytochrome P450 2A.

Epidemiology and end-user perspectives

In 2014, 12.4% of U.S. adults classified themselves as “ever users” of ENDS (used at least once) and 3.7% of adults classified themselves as current users, according to the National Health Interview Study.⁶ Importantly, among E-cig users who had not used combustible cigarettes, young adults (age 18 to 24) were more likely to have tried ENDS than older adults. ENDS are becoming more popular across the globe. A study in the European Union found that ever users of ENDS most commonly were current cigarette smokers (31%) followed by former (10.8%) and never smokers (2.3%).⁷

ENDS use is relevant for mental health professionals because of the high rate of comorbid tobacco use disorder in individuals with psychiatric conditions. For example, 2 U.S. population surveys^8,9 revealed those with mental health conditions were 1.5 to 2 times more likely to have tried ENDS and 2 to 3 times more likely to be current users. Those with psychiatric illness reported similar reasons for ENDS use as other individuals, including “just because,” use as a smoking cessation aid, ease of use, and perceived safety vs combustible cigarettes.

A recent review that included 9 studies focusing on ENDS use in those with mental illness reported mixed findings on the utility of these devices to reduce or stop use of combustible cigarettes.¹⁰ Additionally, it is important to monitor the use of cigarettes and ENDS in patients with psychiatric illness because the byproducts of tobacco smoke can affect the metabolism of some psychotropic medications.¹¹ Although reduced use of combustible cigarettes could lead to lower dosing of some psychotropics, an unreported decrease in combustible cigarette use could lead to supratherapeutic drug levels. There are no data on the effect of ENDS on the metabolism of psychotropics.

ENDS are increasingly popular among adolescents. In 2015, there were an estimated 4.6 million current tobacco users among middle/high school youths in the United States and 3 million current ENDS users, according to the National Youth Tobacco Surveys.¹² The shift from combustible cigarettes to ENDS is notable, with an increase in the percentage of current E-cig users and a decrease in the percentage of exclusive combustible cigarette users. In addition, there has been no change in the prevalence of lifetime tobacco users.¹² This is a global issue, as reports of ever use of ENDS by adolescents range from 6.5% to 31% in the United States, 14.6% in Canada, and 4.7% to 38.5% in Europe.¹³ Based on these trends, the U.S. Surgeon General released a statement warning against the use of ENDS in youth because of the lack of safety data and strong association with use of tobacco products.¹⁴

There are a number of possible reasons for the increasing popularity of ENDS, including the product’s novelty, lack of regulations regarding their sale, availability of flavorings, and the perception that ENDS are safe alternatives to cigarettes. E-cig–using youths have described ENDS as “not at all harmful” and “not at all addictive” and believe that ENDS with flavoring are less harmful than those without.¹⁵ Although studies in adults show some users reporting that ENDS are less satisfying, they are seen as useful in decreasing craving and a safer alternative to cigarettes.^16,17

Are ENDS effective for smoking cessation?
The evidence for ENDS as aids to smoking cessation remains murky (Table 1^18-22). There is a paucity of randomized controlled clinical trials (RCTs) investigating ENDS for smoking cessation or reduction, and it is difficult to quantify the amount of nicotine used in ENDS because of the variety of delivery systems and cartridges. In a recent Cochrane review, those using ENDS to quit smoking were more likely to be abstinent from combustible cigarettes at 6 months vs those using nicotine-free ENDS (relative risk = 2.29; 95% CI, 1.05 to 4.96), but there was no significant difference in quit rates compared with nicotine patches.²³ However, the confidence in this finding was rated as low because of the limited number of RCTs. Of note, the authors found 15 ongoing RCTs at the time of publication that might be eligible for later evaluation.

Non-RCTs reveal mixed data. Positive results include 1 study with an odds ratio of 6.07 to quit for intensive ENDS users vs non-users,²⁴ and another with dual users of combustible and electronic cigarettes having a 46% quit rate at 1 year.²⁵ Additionally, in a pilot study providing ENDS to 14 patients with schizophrenia who had no previous desire to quit smoking, authors noted a reduction in the number of cigarettes smoked per day by 50% in one-half of participants and abstinence in 14% of participants at 52 weeks.²⁶ Studies with neutral or negative results include those showing ENDS users to be current combustible tobacco smokers, and use of ENDS not predicting smoking cessation.^4,27 Data also are mixed regarding the use of ENDS as a harm reduction strategy. One study found that ENDS decreased cigarette consumption, but did not increase the likelihood of quitting,²⁸ while another reported that daily use of ENDS increased the odds of reducing smoking by as much as 2.5 times compared with non-use of such aids.²⁹ In a 24-month prospective cohort study following tobacco users, there was no difference in the number of cigarettes smoked per day in those who started the trial as users of combustible cigarettes alone vs combustible cigarettes plus ENDS users.³⁰ Interestingly, those who started the study as combustible cigarette users and switched to ENDS and those who had continued dual use throughout the 24 months smoked fewer combustible cigarettes per day than those who never tried ENDS or quit during the study period.

Health effects

To better understand the adverse health effects of ENDS, one must consider potential short- and long-term consequences (Table 2). In the short-term, ENDS have been found to increase markers of inflammation and oxidative stress acutely as evidenced by in vivo laboratory studies.^31,32 ENDS also have been linked to upper respiratory irritation, in part, because of the transformation of glycerin in the nicotine cartridge to acrolein upon combustion.³³ Even 5 minutes of ad lib E-cig use has been found to significantly increase airflow resistance during pulmonary function tests³⁴—changes that have been shown to precede more persistent alterations in peak expiratory flow, such as those seen in chronic obstructive pulmonary disease. The more common patient-reported side effects include:

• daytime cough (27%)
• phlegm production (25%)
• headache (21%)
• dry mouth/throat (20%)
• vertigo, headache, or nausea (9%).^35,36

A RCT investigating efficacy of E-cigs vs nicotine patches vs denicotinized E-cigs found no difference among the groups in the number of reported adverse events.¹⁸ Interestingly, another RCT found a decrease in adverse events, such as dry cough, mouth irritation, throat irritation, shortness of breath, and headache, compared with baseline in combustible cigarette smokers who used regular or denicotinized E-cigs.¹⁹

Although no studies have directly investigated long-term health consequences of ENDS because of their relative novelty, one can extrapolate potential harmful long-term effects based on knowledge of the products’ chemical constituents. For example, propylene glycol can degrade into propylene oxide, a class 2B carcinogen.³⁷ Other potential carcinogens in the aerosol include formaldehyde and acetaldehyde. On a broader scale, many of the particulates have been shown to cause systemic inflammation, which is thought to increase cardiovascular and respiratory disease and death.³⁸ Flavorings in ENDS include a variety of components including, but not limited to, aldehydes, which are irritants, and other additives that have been associated with respiratory disease.³⁹

Second-hand exposure. There are no long-term studies of second-hand vapor exposure, but similar to long-term health on primary users, one can glean some observations from the literature. It is promising that compared with cigarettes, ENDS lack sidestream smoke and the vapor has not been found to contain carbon monoxide.⁴⁰ Some research has demonstrated that the size and spray of fine particles in the aerosol is as large or larger than combustible cigarettes.⁴¹ Formaldehyde, acetaldehyde, isoprene, and acetic acid have been found in ENDS vapor.⁴⁰ Interestingly, a simulated café study found elevated nicotine, glycerine, hydrocarbon, and other materials classified as carcinogens in the air.⁴²

Although it is popularly thought that ENDS are less toxic than tobacco cigarettes, there is not enough evidence to estimate precisely as to how much less toxic or the consequences of use. ENDS are increasingly popular and are being used by never smokers who should be educated on the potential harm that ENDS pose.

Recommendations from agencies and medical organizations

The World Health Organization (WHO) recommended prohibiting the use of ENDS in indoor spaces to minimize potential health risks to users and non-users. The WHO also aims to prevent dissemination of unproven health claims, including claims that ENDS are effective—or not—or that the devices are innocuous.³⁶ In the United States, the FDA has stated that ENDS are not recommended for safe quitting (2009). In August 2016, the FDA introduced regulations banning the sale of ENDS to individuals age <18 and required manufacturers to submit documents detailing all ingredients for review and possible approval.

The American Lung Association has stated its concerns about the use of ENDS but has not made any direct recommendations. The American Heart Association reports a potential negative public health impact and provides clinical guideline recommendations.⁴³ Prominent psychiatric organizations such as the American Psychiatric Association, American Academy of Addiction Psychiatry (AAAP), the Substance Abuse and Mental Health Services Administration (SAMHSA), and the National Institute of Drug Abuse do not have official statements supporting or rejecting the use of ENDS. However, they do note the potential harm and lack of substantial evidence for efficacy of ENDS as a smoking cessation tool, and the AAAP and SAMHSA state that they will work with regulatory agencies to reduce the use of toxic products with addictive potential including ENDS.^44-46

Clinical recommendations

We do not recommend ENDS as a first-line treatment for smoking cessation because there is no evidence they are superior to the FDA-approved nicotine replacement therapies (NRTs), the paucity of research into the potential short- and long-term health risks of ENDS, and the fact that these products are not regulated for use as smoking cessation aids. It is, however, advisable to discuss ENDS use with patients by:

• asking if they are using the products
• assessing whether the user also is a smoker
• advising the patient to quit.

It also is important to assess the patient’s knowledge and attitudes regarding ENDS use and provide education about the products. Some patients firmly believe that ENDS are the lesser of 2 evils, and they are decreasing the harms of smoking by using these devices. While the debate over a potential harm reduction strategy unfolds,⁴⁷ we think that because of the state of the evidence it is prudent to adopt a more precautionary stance and recommend that patients work toward abstinence from nicotine in any form.

For dual tobacco/ENDS users and for patients using ENDS who want to quit smoking, we recommend treatment with an approved pharmacotherapy (ie, NRTs, bupropion, and varenicline) combined with counseling. A 2013 Cochrane Review found that all pharamacotherapy options are more effective than placebo, and combination NRT and varenicline are superior to single NRT or bupropion (Box).^23,48

For a patient struggling with opioid addiction, opioid agonist therapy with methadone or buprenorphine can reduce craving and opioid use and may even save his or her life. But many clinicians are unfamiliar with this evidence-based treatment,^1,2 which is best started early in the course of addiction.³

See related editorial

This article outlines the pharmacology of these drugs, their clinical uses, and the challenges of using them to treat opioid addiction.

DIAGNOSTIC CRITERIA

Opioid addiction, formally known as opioid use disorder, is a pattern of opioid misuse leading to clinically significant impairment in multiple areas of life. The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, lists 11 diagnostic criteria, but only 2 need to be present within the past year to make the diagnosis⁴:

• Taking opioids longer or in higher doses than was intended
• A persistent desire or unsuccessful efforts to cut down or control opioid use
• Spending a great deal of time obtaining, using, or recovering from using opioids
• Craving opioids
• Repeatedly failing to fulfill obligations at work, school, or home due to opioid use
• Continuing to use opioids even though it causes or exacerbates social or interpersonal problems
• Giving up or curtailing important social, occupational, or recreational activities because of opioid use
• Repeatedly using opioids in situations in which it is physically hazardous
• Continuing to use opioids despite knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by the substance
• Tolerance
• Withdrawal.

Recent estimates indicate that 2.23 million people in the United States have opioid use disorder (426,000 with heroin and 1.8 million with prescription opioids).⁵

Progression from prescription opioids to heroin

We have observed that many patients with opioid use disorder start by misusing prescription opioids. Over time, tolerance can develop, which drives patients to use higher and higher doses.⁶

As the addiction progresses, a subset of prescription opioid users advances to using heroin, which is typically less expensive and easier to obtain.⁷ Most patients start with the intranasal route but eventually inject it intravenously.^6,7

For many addicts, heroin use has medical consequences such as hepatitis C virus (HCV) and human immunodeficiency virus (HIV) infection, psychiatric problems such as depression and anxiety, and illegal activities such as theft and sex work.⁸ People who use heroin appear to have more severe addiction and a lower socioeconomic status than prescription opioid users.^9–11 But recently, a growing number of middle class individuals are becoming addicted to heroin.¹²

METHADONE

Methadone is a long-acting synthetic opioid that functions as a full agonist on the mu-opioid receptor. The drug binds, occupies, and stimulates the receptor, preventing withdrawal symptoms and reducing opioid cravings for at least 24 hours.¹³

Adverse effects of methadone

The most common adverse effects include lightheadedness, dizziness, sedation, nausea, vomiting, and sweating.¹⁴ Other adverse effects:

Unintentional overdose. The risk is serious, as a single 30-mg dose can be fatal in people who are opioid-naïve.¹³

QTc prolongation, which can lead to torsade de pointes. This risk, which is dose-related, must be taken into consideration in patients who have any cardiac symptoms (eg, syncope, arrhythmia), pathology (familial QT prolongation), or other risk factors for QTc prolongation (eg, hypokalemia, QTc-prolonging medications).¹⁵

Respiratory depression, which can be fatal. This dose-related risk is heightened during the first 4 weeks of treatment if titration is too rapid or if methadone is used in combination with other drugs that cause central nervous system or respiratory depression.^13,14

Starting methadone

To prevent respiratory depression and death related to rapid induction, the general rule is to start methadone at a low daily dose (20–30 mg) depending on the patient’s withdrawal symptoms.¹⁴ During this period, patients need to be closely monitored and educated on the perils of concomitant use of central nervous system depressants.¹⁴

In most patients, the dose is titrated up until their withdrawal symptoms and cravings are eliminated, which generally requires 60 to 120 mg daily.¹⁴ Hepatic and renal impairment, pregnancy, and advanced age can alter methadone pharmacokinetics and may therefore necessitate dose adjustment.

BUPRENORPHINE

Buprenorphine is an alkaloid thebaine opioid derivative that acts as a partial mu-opioid agonist and a kappa antagonist.¹⁶ Like methadone, buprenorphine is used to manage cravings and withdrawal symptoms.¹⁶ Dosages of 4 to 16 mg (up to 32 mg) per day of buprenorphine are usually required to adequately control opioid cravings.¹⁶

Sublingual and subdermal products

Buprenorphine is currently available in the United States in sublingual and subdermal formulations.^16,17

Sublingual buprenorphine is usually combined with naloxone in a 4:1 ratio to deter intravenous use. Intravenous injection of the combination product can precipitate withdrawal due to the antagonist action of naloxone. (Taken orally or sublingually, naloxone is poorly absorbed and has little or no clinical effect.) Buprenorphine-naloxone is available in tablets, a sublingual film strip, and a buccal film strip. Buprenorphine is also available by itself in a sublingual formulation.

The US Food and Drug Administration has approved a buprenorphine subdermal implant, Probuphine. Four rods, about 1 inch long, are placed under the skin in the inner aspect of the upper arm and provide the equivalent of 8 mg of buprenorphine daily for 6 months.¹⁷ However, this method is formulated only for maintenance treatment and cannot be used for induction. Additionally, it is recommended that the implants be surgically removed at the end of 6 months, after which another set of implants can be inserted in the other arm or the patient can switch to sublingual therapy, depending on the clinical situation and patient preference.¹⁷

Generally safer than methadone

Buprenorphine works on the same receptor as methadone and therefore has a similar side effect profile. However, buprenorphine has a ceiling effect, which greatly reduces the risk of fatal respiratory depression.¹⁸ It also does not cause clinically significant QTc prolongation and is preferable in patients who have cardiac risk factors.¹⁸

Another advantage is that buprenorphine has fewer identified medication interactions than methadone.¹⁸ Further, induction of buprenorphine in patients with opioid use disorder has been shown to be safer than methadone.¹⁹

Although buprenorphine has been found to be 6 times safer than methadone with regard to overdose among the general population,²⁰ it can still cause fatal intoxication if used in combination with central nervous system depressants.²¹

Buprenorphine has been also associated with hepatotoxicity, though the risk of new-onset liver disease appears to be low.²²

Besides methadone and buprenorphine, the only other approved option for treating opioid use disorder is the opioid antagonist naltrexone.

Naltrexone has significantly less abuse potential, as it provides no euphoria, but patients do not like it. Even with the long-acting formulation (Vivitrol), naltrexone treatment is significantly less effective than methadone or buprenorphine.^23–25 Further, although naltrexone is not a controlled substance and so does not face the same scrutiny as the agonist therapies, there are other significant barriers. Additional information on naltrexone is presented in reviews by Modesto-Lowe and Van Kirk²⁴ and Woody.²⁵

OBSTACLES TO TREATMENT

People hold conflicting views about opioid agonist therapy. Some believe that “trading one drug for another” is not a legitimate therapeutic strategy, and they may feel ashamed of being on maintenance therapy.²⁶ Similarly, some argue that the answer to establishing stable abstinence does not lie simply in prescribing medications.

The contrary argument is that these medications, if used appropriately, confer many benefits such as reducing the medical and psychosocial sequelae of opioid addiction.¹⁸ In fact, properly treated patients no longer meet the diagnostic criteria of opioid use disorder, and both methadone and buprenorphine are on the World Health Organization’s (WHO) list of essential medicines.²⁷

Despite endorsement by the WHO, the stigma attached to the opioid agonists has been difficult to overcome. Patients with opioid use disorder may be viewed with distrust by healthcare providers and often do not feel welcome in healthcare settings or in self-help recovery groups.²⁸

Barriers to methadone therapy

Federal regulations on methadone prescribing and use were established to promote patient safety and decrease diversion, but they may also complicate access to care.²⁹ They stipulate that to qualify for methadone maintenance, patients need to demonstrate opioid addiction for 1 year, except for pregnant women and those who have been incarcerated in the past 6 months. Patients under the age of 18 must have 2 documented failed treatment episodes as well as approval by a guardian to receive treatment.

Inconvenience. Methadone can be prescribed for opioid dependence only by an accredited treatment program. Patients must therefore travel to the clinic and wait to be evaluated on a daily basis for a minimum of 90 days. Only after they demonstrate consistent responsible behavior and negative results on urine testing do they become eligible to take methadone home.²⁹ If a patient is to travel out of the area during the initial 90 days of treatment, he or she must make arrangements in advance to find a clinic that will provide a “guest dose.”

The inconvenience arising from the regulations may deter some patients from seeking methadone therapy. In spite of this, once patients are started on methadone, more of them continue treatment than with buprenorphine.¹⁸ A proposed reason is that methadone is a potent full opioid agonist and therefore relieves withdrawal symptoms and craving more effectively than buprenorphine, which is a partial agonist.³⁰ Another possible reason is the higher level of supervision afforded by methadone clinics, which require daily contact for at least 90 days. 

Safety concerns arise from methadone diversion, as illicit use may have lethal consequences. In the past decade, deaths from methadone overdose have risen significantly, most of them due to respiratory depression or torsade de pointes.¹³ However, most cases of diversion and overdose involve methadone that is prescribed for pain by individual practitioners and not from maintenance programs.¹³

Advantages of buprenorphine

Together, methadone’s lethality, stigma, and inconvenience may contribute to patients preferring buprenorphine.³¹

The regulations governing buprenorphine’s use are less restrictive than those with methadone. For example, patients must have a diagnosis of opioid addiction to be prescribed buprenorphine, but they are not required to carry the diagnosis for a year before treatment.³¹ Additionally, they do not need to travel to a federally approved opioid treatment center daily and can receive buprenorphine directly from a physician in an outpatient setting.

Under the Drug Abuse Treatment Act (DATA) of 2000, any physician can apply for a waiver to prescribe and dispense buprenorphine in his or her office. To qualify for an initial waiver, physicians must either obtain certification in the fields of addiction medicine or addiction psychiatry or complete an approved 8-hour training session.³² Each physician starts with a maximum of 30 patients, but can apply to treat up to 100 patients after 1 year and eventually up to 275 patients. Physicians must document every buprenorphine prescription they write and be able to refer patients for counseling.³¹

As of February 2017, nurse practitioners and physician assistants can also apply for a DATA 2000 waiver. All waivered providers are subject to unannounced visits from the Drug Enforcement Administration once every 5 years.³²

While there are no federal restrictions on the amount of buprenorphine that can be dispensed, some states and some insurance companies have placed restrictions on dose or length of treatment.³³ Buprenorphine patients can fill their prescriptions at any pharmacy and are permitted to bring their medication home, which improves access to care. However, office-based outpatient treatment is not without risk, and preventing buprenorphine diversion remains a challenge.³⁴

‘Lending’ buprenorphine is a felony

Addicts have illegally used buprenorphine to self-treat opioid withdrawal, craving, and dependence.³⁵ Its misuse has also been coupled with self-treatment of conditions that include depression and pain.³⁶

A survey found that 83.7% of patients deem buprenorphine diversion to be appropriate; further, most patients said they consider it unethical to withhold prescribed buprenorphine from individuals showing symptoms of withdrawal.³⁴ Physicians who prescribe buprenorphine must inform their patients that even “lending” or giving away their medication is a felony.

Prescribing physicians must also be diligent about monitoring for signs of diversion such as inconsistent urine toxicology screens, “lost” medication, and requests for early refills or escalating doses.³⁷

In addition to federal regulations, we propose a 4-step approach to evaluate eligibility for opioid replacement therapy based on existing guidelines.^37–39

Step 1: History and physical examination

The history should give particular attention to the patient’s cardiac, pulmonary, and hepatic status, with consideration of the risks of any medical comorbidities (eg, bacterial endocarditis, HIV and HCV infection) that might influence treatment.³⁷

It is also essential to evaluate for any contraindications or drug interactions before prescribing methadone or buprenorphine.³⁸

Contraindications to methadone maintenance include⁴⁰:

• Cor pulmonale
• Methadone hypersensitivity
• Pseudomembranous colitis
• Selegiline use (due to risk of serotonin syndrome)
• Ileum paralyticus.

Contraindications to buprenorphine use include:

• Hypersensitivity to naloxone or buprenorphine
• Impaired liver function (due to the risk of inadvertent overdose associated with slowed metabolism).

Concurrent use of alcohol or illicit benzodiazepines is a relative contraindication to both methadone and buprenorphine due to the risk of respiratory depression and overdose.³⁷ Likewise, avoid coprescribing opioid agonists and benzodiazepines whenever possible. Obtain a complete list of current medications and query a prescription-monitoring database to determine whether any controlled substances are currently prescribed.³⁷

During the physical examination, look for stigmata of intravenous drug use such as track marks or abscesses³⁷ and document any physical findings consistent with intoxication or withdrawal. Patients must be completely detoxed or in withdrawal before beginning buprenorphine induction; premature induction can precipitate withdrawal.³⁸

A discussion of pregnant patients with opioid use disorder is beyond the scope of this paper. However, it is incumbent on the prescriber to inquire whether the client is pregnant or intends to become pregnant and what birth control methods are in place.

Step 2: Assess psychiatric status

Assessment of the patient’s psychiatric status, including an assessment of alcohol and other drug use, will help determine his or her eligibility for opioid agonists.³⁷ To prepare for the need to manage patients with psychiatrically complex issues, it is helpful to develop relationships with addiction specialists and psychiatrists who are familiar with opioid replacement therapy in your area. This will make it easier to collaborate on patients’ care.

Ask all patients directly about suicidal or homicidal ideation. Any patient with active suicidal or homicidal ideation should be assessed for need of immediate hospitalization by a psychiatrist or another qualified mental health professional. Patients with a history of suicidal ideation should be monitored closely by a mental health professional throughout treatment.³⁷

Many if not most patients with opioid use disorder have concurrent psychiatric disorders, and the interplay between these disorders is complex.^40,41 Depression, for example, can precede and even precipitate drug use (an observation supporting the “self-medication theory”).⁴² If the underlying depressive disorder is not addressed, relapse is nearly inevitable.

It has also been shown that both chronic opioid use and withdrawal can exacerbate aversive emotional states. This escalation of symptoms may result from the pharmacologic effects of opioids or from psychosocial sequelae that can arise from chronic opioid use.⁴¹ In this situation, maintaining abstinence can lead to resolution of depressive symptoms. As depression and opioid use can occur together, successful treatment requires equal attention to both illnesses.

Other common comorbidities in patients with opioid use disorder include posttraumatic stress disorder, attention deficit hyperactivity disorder, antisocial personality disorder, and concurrent substance abuse disorders.⁴³ The confluence of antisocial personality disorder is particularly important, as patients with antisocial personality disorder display disruptive and maladaptive behaviors.

Identify any psychotropic medication that is prescribed and check carefully for drug interactions. This applies especially to methadone, as many psychiatric medications also prolong the QT interval. Moreover, patients may not be forthcoming about the use of psychiatric medication.

Find out whether the patient is using any other addictive substances, particularly those that affect the central nervous system, as those who use fentanyl, benzodiazepines, or alcohol are at the highest risk of overdose.³¹ Often the best option for those with concurrent substance use disorders is inpatient detoxification followed by residential rehabilitation care. Either buprenorphine or methadone can then be initiated upon return to an outpatient setting.

Step 3: Assess psychosocial status

To what extent do the patient’s home environment and support systems promote a drug-free lifestyle? Unfortunately, the psychosocial status of many of these patients is fragile, and they may live in areas where illicit drugs are readily available (which can be urban, suburban, or rural), making it difficult to stay substance-free.³⁸

Generally, lifestyle modifications are needed to transform maladaptive behaviors and promote an environment conducive to long-term recovery. Referrals to social services to address housing, vocational needs, and entitlements may be helpful.³⁹

Step 4: Assess readiness to change

According to one model, people go through 5 stages when changing a behavior: precontemplation, contemplation, preparation for action, action, and maintenance.⁴³ In general, the further along the stages a patient is, the more appropriate he or she is for office-based treatment with buprenorphine.³⁹

The level of change can be assessed with tools such as Stages of Change Readiness and Treatment Eagerness Scale (SOCRATES). Use of stage-specific strategies may enhance a patient’s readiness to cease opioid use.⁴³

Precontemplation. Those in the precontemplation stage are not ready to think about changing their behavior.⁴³ They may be unaware of or unwilling to consider the risks associated with their opioid use and resistant to the idea of quitting. Engagement with opioid agonists for individuals in this stage is low and dropout rates are likely high.

Thus, the proper approach for “precontemplators” is to help them develop some ambivalence about their opioid use. One tactic is to involve the patient in a discussion of the personal benefits and risks of opioid use.

Contemplation. Individuals in the contemplation stage have begun to weigh the costs and benefits of opioid use and express ambivalence about it.⁴⁴ Because the patient is willing to explore the risks of ongoing use and consider the benefits of treatment, the goal in this stage is to elicit a commitment from the individual to seek treatment.

Preparation. The person in this stage moves from thinking about treatment to planning what action to take.⁴⁵ As the individual prepares to enter treatment, indecision tends to resurface, as well as self-doubt about his or her ability to change. During this stage, it is important for the provider to spell out goals (abstinence) and strategies (eg, counseling, medication) and enhance a sense of self-efficacy.

Action and maintenance. Patients in these stages engage in treatment and employ new strategies to abstain from opioid use. Maintaining these behaviors can be a daily struggle. Expressing confidence in the patient’s ability to abstain from use will support his or her progress. Behavioral interventions such as strategic avoidance of triggers and engagement in alternative activities (eg, support groups, exercise, faith-based practices) will help to maintain abstinence.

A CHRONIC CONDITION

Opioid use disorder, like many chronic illnesses, requires long-term attention to attain successful patient outcomes. The opioid agonists methadone and buprenorphine are the mainstay of treatment for it, conferring benefits such as reducing opioid use and preventing relapse.

Candidates for opioid agonist therapy should undergo a multidisciplinary assessment, including an evaluation on the patient’s readiness to change his or her opioid use.

Patient education should include a discussion of the risks of methadone (eg, respiratory depression, fatal overdose, and QTc prolongation) and buprenorphine (eg hepatotoxicity) and their benefits (eg, controlling craving, decreasing the risk of relapse). Patients should also be educated about overdose and diversion.

Despite the difficulties inherent in treating patients with opioid use disorder, when used appropriately, opioid agonist therapy can be lifesaving for patients struggling with long-term opioid addiction.

Acknowledgment: We thank Katelyn Colosi, BS, and Drs. Susan Wolfe, Dennis Bouffard, and Sinha Shirshendu for their helpful comments.

For a patient struggling with opioid addiction, opioid agonist therapy with methadone or buprenorphine can reduce craving and opioid use and may even save his or her life. But many clinicians are unfamiliar with this evidence-based treatment,^1,2 which is best started early in the course of addiction.³

See related editorial

This article outlines the pharmacology of these drugs, their clinical uses, and the challenges of using them to treat opioid addiction.

DIAGNOSTIC CRITERIA

Opioid addiction, formally known as opioid use disorder, is a pattern of opioid misuse leading to clinically significant impairment in multiple areas of life. The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, lists 11 diagnostic criteria, but only 2 need to be present within the past year to make the diagnosis⁴:

• Taking opioids longer or in higher doses than was intended
• A persistent desire or unsuccessful efforts to cut down or control opioid use
• Spending a great deal of time obtaining, using, or recovering from using opioids
• Craving opioids
• Repeatedly failing to fulfill obligations at work, school, or home due to opioid use
• Continuing to use opioids even though it causes or exacerbates social or interpersonal problems
• Giving up or curtailing important social, occupational, or recreational activities because of opioid use
• Repeatedly using opioids in situations in which it is physically hazardous
• Continuing to use opioids despite knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by the substance
• Tolerance
• Withdrawal.

Recent estimates indicate that 2.23 million people in the United States have opioid use disorder (426,000 with heroin and 1.8 million with prescription opioids).⁵

Progression from prescription opioids to heroin

We have observed that many patients with opioid use disorder start by misusing prescription opioids. Over time, tolerance can develop, which drives patients to use higher and higher doses.⁶

As the addiction progresses, a subset of prescription opioid users advances to using heroin, which is typically less expensive and easier to obtain.⁷ Most patients start with the intranasal route but eventually inject it intravenously.^6,7

For many addicts, heroin use has medical consequences such as hepatitis C virus (HCV) and human immunodeficiency virus (HIV) infection, psychiatric problems such as depression and anxiety, and illegal activities such as theft and sex work.⁸ People who use heroin appear to have more severe addiction and a lower socioeconomic status than prescription opioid users.^9–11 But recently, a growing number of middle class individuals are becoming addicted to heroin.¹²

METHADONE

Methadone is a long-acting synthetic opioid that functions as a full agonist on the mu-opioid receptor. The drug binds, occupies, and stimulates the receptor, preventing withdrawal symptoms and reducing opioid cravings for at least 24 hours.¹³

Adverse effects of methadone

The most common adverse effects include lightheadedness, dizziness, sedation, nausea, vomiting, and sweating.¹⁴ Other adverse effects:

Unintentional overdose. The risk is serious, as a single 30-mg dose can be fatal in people who are opioid-naïve.¹³

QTc prolongation, which can lead to torsade de pointes. This risk, which is dose-related, must be taken into consideration in patients who have any cardiac symptoms (eg, syncope, arrhythmia), pathology (familial QT prolongation), or other risk factors for QTc prolongation (eg, hypokalemia, QTc-prolonging medications).¹⁵

Respiratory depression, which can be fatal. This dose-related risk is heightened during the first 4 weeks of treatment if titration is too rapid or if methadone is used in combination with other drugs that cause central nervous system or respiratory depression.^13,14

Starting methadone

To prevent respiratory depression and death related to rapid induction, the general rule is to start methadone at a low daily dose (20–30 mg) depending on the patient’s withdrawal symptoms.¹⁴ During this period, patients need to be closely monitored and educated on the perils of concomitant use of central nervous system depressants.¹⁴

In most patients, the dose is titrated up until their withdrawal symptoms and cravings are eliminated, which generally requires 60 to 120 mg daily.¹⁴ Hepatic and renal impairment, pregnancy, and advanced age can alter methadone pharmacokinetics and may therefore necessitate dose adjustment.

BUPRENORPHINE

Buprenorphine is an alkaloid thebaine opioid derivative that acts as a partial mu-opioid agonist and a kappa antagonist.¹⁶ Like methadone, buprenorphine is used to manage cravings and withdrawal symptoms.¹⁶ Dosages of 4 to 16 mg (up to 32 mg) per day of buprenorphine are usually required to adequately control opioid cravings.¹⁶

Sublingual and subdermal products

Buprenorphine is currently available in the United States in sublingual and subdermal formulations.^16,17

Sublingual buprenorphine is usually combined with naloxone in a 4:1 ratio to deter intravenous use. Intravenous injection of the combination product can precipitate withdrawal due to the antagonist action of naloxone. (Taken orally or sublingually, naloxone is poorly absorbed and has little or no clinical effect.) Buprenorphine-naloxone is available in tablets, a sublingual film strip, and a buccal film strip. Buprenorphine is also available by itself in a sublingual formulation.

The US Food and Drug Administration has approved a buprenorphine subdermal implant, Probuphine. Four rods, about 1 inch long, are placed under the skin in the inner aspect of the upper arm and provide the equivalent of 8 mg of buprenorphine daily for 6 months.¹⁷ However, this method is formulated only for maintenance treatment and cannot be used for induction. Additionally, it is recommended that the implants be surgically removed at the end of 6 months, after which another set of implants can be inserted in the other arm or the patient can switch to sublingual therapy, depending on the clinical situation and patient preference.¹⁷

Generally safer than methadone

Buprenorphine works on the same receptor as methadone and therefore has a similar side effect profile. However, buprenorphine has a ceiling effect, which greatly reduces the risk of fatal respiratory depression.¹⁸ It also does not cause clinically significant QTc prolongation and is preferable in patients who have cardiac risk factors.¹⁸

Another advantage is that buprenorphine has fewer identified medication interactions than methadone.¹⁸ Further, induction of buprenorphine in patients with opioid use disorder has been shown to be safer than methadone.¹⁹

Although buprenorphine has been found to be 6 times safer than methadone with regard to overdose among the general population,²⁰ it can still cause fatal intoxication if used in combination with central nervous system depressants.²¹

Buprenorphine has been also associated with hepatotoxicity, though the risk of new-onset liver disease appears to be low.²²

Besides methadone and buprenorphine, the only other approved option for treating opioid use disorder is the opioid antagonist naltrexone.

Naltrexone has significantly less abuse potential, as it provides no euphoria, but patients do not like it. Even with the long-acting formulation (Vivitrol), naltrexone treatment is significantly less effective than methadone or buprenorphine.^23–25 Further, although naltrexone is not a controlled substance and so does not face the same scrutiny as the agonist therapies, there are other significant barriers. Additional information on naltrexone is presented in reviews by Modesto-Lowe and Van Kirk²⁴ and Woody.²⁵

OBSTACLES TO TREATMENT

People hold conflicting views about opioid agonist therapy. Some believe that “trading one drug for another” is not a legitimate therapeutic strategy, and they may feel ashamed of being on maintenance therapy.²⁶ Similarly, some argue that the answer to establishing stable abstinence does not lie simply in prescribing medications.

The contrary argument is that these medications, if used appropriately, confer many benefits such as reducing the medical and psychosocial sequelae of opioid addiction.¹⁸ In fact, properly treated patients no longer meet the diagnostic criteria of opioid use disorder, and both methadone and buprenorphine are on the World Health Organization’s (WHO) list of essential medicines.²⁷

Despite endorsement by the WHO, the stigma attached to the opioid agonists has been difficult to overcome. Patients with opioid use disorder may be viewed with distrust by healthcare providers and often do not feel welcome in healthcare settings or in self-help recovery groups.²⁸

Barriers to methadone therapy

Federal regulations on methadone prescribing and use were established to promote patient safety and decrease diversion, but they may also complicate access to care.²⁹ They stipulate that to qualify for methadone maintenance, patients need to demonstrate opioid addiction for 1 year, except for pregnant women and those who have been incarcerated in the past 6 months. Patients under the age of 18 must have 2 documented failed treatment episodes as well as approval by a guardian to receive treatment.

Inconvenience. Methadone can be prescribed for opioid dependence only by an accredited treatment program. Patients must therefore travel to the clinic and wait to be evaluated on a daily basis for a minimum of 90 days. Only after they demonstrate consistent responsible behavior and negative results on urine testing do they become eligible to take methadone home.²⁹ If a patient is to travel out of the area during the initial 90 days of treatment, he or she must make arrangements in advance to find a clinic that will provide a “guest dose.”

The inconvenience arising from the regulations may deter some patients from seeking methadone therapy. In spite of this, once patients are started on methadone, more of them continue treatment than with buprenorphine.¹⁸ A proposed reason is that methadone is a potent full opioid agonist and therefore relieves withdrawal symptoms and craving more effectively than buprenorphine, which is a partial agonist.³⁰ Another possible reason is the higher level of supervision afforded by methadone clinics, which require daily contact for at least 90 days. 

Safety concerns arise from methadone diversion, as illicit use may have lethal consequences. In the past decade, deaths from methadone overdose have risen significantly, most of them due to respiratory depression or torsade de pointes.¹³ However, most cases of diversion and overdose involve methadone that is prescribed for pain by individual practitioners and not from maintenance programs.¹³

Advantages of buprenorphine

Together, methadone’s lethality, stigma, and inconvenience may contribute to patients preferring buprenorphine.³¹

The regulations governing buprenorphine’s use are less restrictive than those with methadone. For example, patients must have a diagnosis of opioid addiction to be prescribed buprenorphine, but they are not required to carry the diagnosis for a year before treatment.³¹ Additionally, they do not need to travel to a federally approved opioid treatment center daily and can receive buprenorphine directly from a physician in an outpatient setting.

Under the Drug Abuse Treatment Act (DATA) of 2000, any physician can apply for a waiver to prescribe and dispense buprenorphine in his or her office. To qualify for an initial waiver, physicians must either obtain certification in the fields of addiction medicine or addiction psychiatry or complete an approved 8-hour training session.³² Each physician starts with a maximum of 30 patients, but can apply to treat up to 100 patients after 1 year and eventually up to 275 patients. Physicians must document every buprenorphine prescription they write and be able to refer patients for counseling.³¹

As of February 2017, nurse practitioners and physician assistants can also apply for a DATA 2000 waiver. All waivered providers are subject to unannounced visits from the Drug Enforcement Administration once every 5 years.³²

While there are no federal restrictions on the amount of buprenorphine that can be dispensed, some states and some insurance companies have placed restrictions on dose or length of treatment.³³ Buprenorphine patients can fill their prescriptions at any pharmacy and are permitted to bring their medication home, which improves access to care. However, office-based outpatient treatment is not without risk, and preventing buprenorphine diversion remains a challenge.³⁴

‘Lending’ buprenorphine is a felony

Addicts have illegally used buprenorphine to self-treat opioid withdrawal, craving, and dependence.³⁵ Its misuse has also been coupled with self-treatment of conditions that include depression and pain.³⁶

A survey found that 83.7% of patients deem buprenorphine diversion to be appropriate; further, most patients said they consider it unethical to withhold prescribed buprenorphine from individuals showing symptoms of withdrawal.³⁴ Physicians who prescribe buprenorphine must inform their patients that even “lending” or giving away their medication is a felony.

Prescribing physicians must also be diligent about monitoring for signs of diversion such as inconsistent urine toxicology screens, “lost” medication, and requests for early refills or escalating doses.³⁷

In addition to federal regulations, we propose a 4-step approach to evaluate eligibility for opioid replacement therapy based on existing guidelines.^37–39

Step 1: History and physical examination

The history should give particular attention to the patient’s cardiac, pulmonary, and hepatic status, with consideration of the risks of any medical comorbidities (eg, bacterial endocarditis, HIV and HCV infection) that might influence treatment.³⁷

It is also essential to evaluate for any contraindications or drug interactions before prescribing methadone or buprenorphine.³⁸

Contraindications to methadone maintenance include⁴⁰:

• Cor pulmonale
• Methadone hypersensitivity
• Pseudomembranous colitis
• Selegiline use (due to risk of serotonin syndrome)
• Ileum paralyticus.

Contraindications to buprenorphine use include:

• Hypersensitivity to naloxone or buprenorphine
• Impaired liver function (due to the risk of inadvertent overdose associated with slowed metabolism).

Concurrent use of alcohol or illicit benzodiazepines is a relative contraindication to both methadone and buprenorphine due to the risk of respiratory depression and overdose.³⁷ Likewise, avoid coprescribing opioid agonists and benzodiazepines whenever possible. Obtain a complete list of current medications and query a prescription-monitoring database to determine whether any controlled substances are currently prescribed.³⁷

During the physical examination, look for stigmata of intravenous drug use such as track marks or abscesses³⁷ and document any physical findings consistent with intoxication or withdrawal. Patients must be completely detoxed or in withdrawal before beginning buprenorphine induction; premature induction can precipitate withdrawal.³⁸

A discussion of pregnant patients with opioid use disorder is beyond the scope of this paper. However, it is incumbent on the prescriber to inquire whether the client is pregnant or intends to become pregnant and what birth control methods are in place.

Step 2: Assess psychiatric status

Assessment of the patient’s psychiatric status, including an assessment of alcohol and other drug use, will help determine his or her eligibility for opioid agonists.³⁷ To prepare for the need to manage patients with psychiatrically complex issues, it is helpful to develop relationships with addiction specialists and psychiatrists who are familiar with opioid replacement therapy in your area. This will make it easier to collaborate on patients’ care.

Ask all patients directly about suicidal or homicidal ideation. Any patient with active suicidal or homicidal ideation should be assessed for need of immediate hospitalization by a psychiatrist or another qualified mental health professional. Patients with a history of suicidal ideation should be monitored closely by a mental health professional throughout treatment.³⁷

Many if not most patients with opioid use disorder have concurrent psychiatric disorders, and the interplay between these disorders is complex.^40,41 Depression, for example, can precede and even precipitate drug use (an observation supporting the “self-medication theory”).⁴² If the underlying depressive disorder is not addressed, relapse is nearly inevitable.

It has also been shown that both chronic opioid use and withdrawal can exacerbate aversive emotional states. This escalation of symptoms may result from the pharmacologic effects of opioids or from psychosocial sequelae that can arise from chronic opioid use.⁴¹ In this situation, maintaining abstinence can lead to resolution of depressive symptoms. As depression and opioid use can occur together, successful treatment requires equal attention to both illnesses.

Other common comorbidities in patients with opioid use disorder include posttraumatic stress disorder, attention deficit hyperactivity disorder, antisocial personality disorder, and concurrent substance abuse disorders.⁴³ The confluence of antisocial personality disorder is particularly important, as patients with antisocial personality disorder display disruptive and maladaptive behaviors.

Identify any psychotropic medication that is prescribed and check carefully for drug interactions. This applies especially to methadone, as many psychiatric medications also prolong the QT interval. Moreover, patients may not be forthcoming about the use of psychiatric medication.

Find out whether the patient is using any other addictive substances, particularly those that affect the central nervous system, as those who use fentanyl, benzodiazepines, or alcohol are at the highest risk of overdose.³¹ Often the best option for those with concurrent substance use disorders is inpatient detoxification followed by residential rehabilitation care. Either buprenorphine or methadone can then be initiated upon return to an outpatient setting.

Step 3: Assess psychosocial status

To what extent do the patient’s home environment and support systems promote a drug-free lifestyle? Unfortunately, the psychosocial status of many of these patients is fragile, and they may live in areas where illicit drugs are readily available (which can be urban, suburban, or rural), making it difficult to stay substance-free.³⁸

Generally, lifestyle modifications are needed to transform maladaptive behaviors and promote an environment conducive to long-term recovery. Referrals to social services to address housing, vocational needs, and entitlements may be helpful.³⁹

Step 4: Assess readiness to change

According to one model, people go through 5 stages when changing a behavior: precontemplation, contemplation, preparation for action, action, and maintenance.⁴³ In general, the further along the stages a patient is, the more appropriate he or she is for office-based treatment with buprenorphine.³⁹

The level of change can be assessed with tools such as Stages of Change Readiness and Treatment Eagerness Scale (SOCRATES). Use of stage-specific strategies may enhance a patient’s readiness to cease opioid use.⁴³

Precontemplation. Those in the precontemplation stage are not ready to think about changing their behavior.⁴³ They may be unaware of or unwilling to consider the risks associated with their opioid use and resistant to the idea of quitting. Engagement with opioid agonists for individuals in this stage is low and dropout rates are likely high.

Thus, the proper approach for “precontemplators” is to help them develop some ambivalence about their opioid use. One tactic is to involve the patient in a discussion of the personal benefits and risks of opioid use.

Contemplation. Individuals in the contemplation stage have begun to weigh the costs and benefits of opioid use and express ambivalence about it.⁴⁴ Because the patient is willing to explore the risks of ongoing use and consider the benefits of treatment, the goal in this stage is to elicit a commitment from the individual to seek treatment.

Preparation. The person in this stage moves from thinking about treatment to planning what action to take.⁴⁵ As the individual prepares to enter treatment, indecision tends to resurface, as well as self-doubt about his or her ability to change. During this stage, it is important for the provider to spell out goals (abstinence) and strategies (eg, counseling, medication) and enhance a sense of self-efficacy.

Action and maintenance. Patients in these stages engage in treatment and employ new strategies to abstain from opioid use. Maintaining these behaviors can be a daily struggle. Expressing confidence in the patient’s ability to abstain from use will support his or her progress. Behavioral interventions such as strategic avoidance of triggers and engagement in alternative activities (eg, support groups, exercise, faith-based practices) will help to maintain abstinence.

A CHRONIC CONDITION

Opioid use disorder, like many chronic illnesses, requires long-term attention to attain successful patient outcomes. The opioid agonists methadone and buprenorphine are the mainstay of treatment for it, conferring benefits such as reducing opioid use and preventing relapse.

Candidates for opioid agonist therapy should undergo a multidisciplinary assessment, including an evaluation on the patient’s readiness to change his or her opioid use.

Patient education should include a discussion of the risks of methadone (eg, respiratory depression, fatal overdose, and QTc prolongation) and buprenorphine (eg hepatotoxicity) and their benefits (eg, controlling craving, decreasing the risk of relapse). Patients should also be educated about overdose and diversion.

Despite the difficulties inherent in treating patients with opioid use disorder, when used appropriately, opioid agonist therapy can be lifesaving for patients struggling with long-term opioid addiction.

Acknowledgment: We thank Katelyn Colosi, BS, and Drs. Susan Wolfe, Dennis Bouffard, and Sinha Shirshendu for their helpful comments.

For a patient struggling with opioid addiction, opioid agonist therapy with methadone or buprenorphine can reduce craving and opioid use and may even save his or her life. But many clinicians are unfamiliar with this evidence-based treatment,^1,2 which is best started early in the course of addiction.³

See related editorial

This article outlines the pharmacology of these drugs, their clinical uses, and the challenges of using them to treat opioid addiction.

DIAGNOSTIC CRITERIA

Opioid addiction, formally known as opioid use disorder, is a pattern of opioid misuse leading to clinically significant impairment in multiple areas of life. The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, lists 11 diagnostic criteria, but only 2 need to be present within the past year to make the diagnosis⁴:

• Taking opioids longer or in higher doses than was intended
• A persistent desire or unsuccessful efforts to cut down or control opioid use
• Spending a great deal of time obtaining, using, or recovering from using opioids
• Craving opioids
• Repeatedly failing to fulfill obligations at work, school, or home due to opioid use
• Continuing to use opioids even though it causes or exacerbates social or interpersonal problems
• Giving up or curtailing important social, occupational, or recreational activities because of opioid use
• Repeatedly using opioids in situations in which it is physically hazardous
• Continuing to use opioids despite knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by the substance
• Tolerance
• Withdrawal.

Recent estimates indicate that 2.23 million people in the United States have opioid use disorder (426,000 with heroin and 1.8 million with prescription opioids).⁵

Progression from prescription opioids to heroin

We have observed that many patients with opioid use disorder start by misusing prescription opioids. Over time, tolerance can develop, which drives patients to use higher and higher doses.⁶

As the addiction progresses, a subset of prescription opioid users advances to using heroin, which is typically less expensive and easier to obtain.⁷ Most patients start with the intranasal route but eventually inject it intravenously.^6,7

For many addicts, heroin use has medical consequences such as hepatitis C virus (HCV) and human immunodeficiency virus (HIV) infection, psychiatric problems such as depression and anxiety, and illegal activities such as theft and sex work.⁸ People who use heroin appear to have more severe addiction and a lower socioeconomic status than prescription opioid users.^9–11 But recently, a growing number of middle class individuals are becoming addicted to heroin.¹²

METHADONE

Methadone is a long-acting synthetic opioid that functions as a full agonist on the mu-opioid receptor. The drug binds, occupies, and stimulates the receptor, preventing withdrawal symptoms and reducing opioid cravings for at least 24 hours.¹³

Adverse effects of methadone

The most common adverse effects include lightheadedness, dizziness, sedation, nausea, vomiting, and sweating.¹⁴ Other adverse effects:

Unintentional overdose. The risk is serious, as a single 30-mg dose can be fatal in people who are opioid-naïve.¹³

QTc prolongation, which can lead to torsade de pointes. This risk, which is dose-related, must be taken into consideration in patients who have any cardiac symptoms (eg, syncope, arrhythmia), pathology (familial QT prolongation), or other risk factors for QTc prolongation (eg, hypokalemia, QTc-prolonging medications).¹⁵

Respiratory depression, which can be fatal. This dose-related risk is heightened during the first 4 weeks of treatment if titration is too rapid or if methadone is used in combination with other drugs that cause central nervous system or respiratory depression.^13,14

Starting methadone

To prevent respiratory depression and death related to rapid induction, the general rule is to start methadone at a low daily dose (20–30 mg) depending on the patient’s withdrawal symptoms.¹⁴ During this period, patients need to be closely monitored and educated on the perils of concomitant use of central nervous system depressants.¹⁴

In most patients, the dose is titrated up until their withdrawal symptoms and cravings are eliminated, which generally requires 60 to 120 mg daily.¹⁴ Hepatic and renal impairment, pregnancy, and advanced age can alter methadone pharmacokinetics and may therefore necessitate dose adjustment.

BUPRENORPHINE

Buprenorphine is an alkaloid thebaine opioid derivative that acts as a partial mu-opioid agonist and a kappa antagonist.¹⁶ Like methadone, buprenorphine is used to manage cravings and withdrawal symptoms.¹⁶ Dosages of 4 to 16 mg (up to 32 mg) per day of buprenorphine are usually required to adequately control opioid cravings.¹⁶

Sublingual and subdermal products

Buprenorphine is currently available in the United States in sublingual and subdermal formulations.^16,17

Sublingual buprenorphine is usually combined with naloxone in a 4:1 ratio to deter intravenous use. Intravenous injection of the combination product can precipitate withdrawal due to the antagonist action of naloxone. (Taken orally or sublingually, naloxone is poorly absorbed and has little or no clinical effect.) Buprenorphine-naloxone is available in tablets, a sublingual film strip, and a buccal film strip. Buprenorphine is also available by itself in a sublingual formulation.

The US Food and Drug Administration has approved a buprenorphine subdermal implant, Probuphine. Four rods, about 1 inch long, are placed under the skin in the inner aspect of the upper arm and provide the equivalent of 8 mg of buprenorphine daily for 6 months.¹⁷ However, this method is formulated only for maintenance treatment and cannot be used for induction. Additionally, it is recommended that the implants be surgically removed at the end of 6 months, after which another set of implants can be inserted in the other arm or the patient can switch to sublingual therapy, depending on the clinical situation and patient preference.¹⁷

Generally safer than methadone

Buprenorphine works on the same receptor as methadone and therefore has a similar side effect profile. However, buprenorphine has a ceiling effect, which greatly reduces the risk of fatal respiratory depression.¹⁸ It also does not cause clinically significant QTc prolongation and is preferable in patients who have cardiac risk factors.¹⁸

Another advantage is that buprenorphine has fewer identified medication interactions than methadone.¹⁸ Further, induction of buprenorphine in patients with opioid use disorder has been shown to be safer than methadone.¹⁹

Although buprenorphine has been found to be 6 times safer than methadone with regard to overdose among the general population,²⁰ it can still cause fatal intoxication if used in combination with central nervous system depressants.²¹

Buprenorphine has been also associated with hepatotoxicity, though the risk of new-onset liver disease appears to be low.²²

Besides methadone and buprenorphine, the only other approved option for treating opioid use disorder is the opioid antagonist naltrexone.

Naltrexone has significantly less abuse potential, as it provides no euphoria, but patients do not like it. Even with the long-acting formulation (Vivitrol), naltrexone treatment is significantly less effective than methadone or buprenorphine.^23–25 Further, although naltrexone is not a controlled substance and so does not face the same scrutiny as the agonist therapies, there are other significant barriers. Additional information on naltrexone is presented in reviews by Modesto-Lowe and Van Kirk²⁴ and Woody.²⁵

OBSTACLES TO TREATMENT

People hold conflicting views about opioid agonist therapy. Some believe that “trading one drug for another” is not a legitimate therapeutic strategy, and they may feel ashamed of being on maintenance therapy.²⁶ Similarly, some argue that the answer to establishing stable abstinence does not lie simply in prescribing medications.

The contrary argument is that these medications, if used appropriately, confer many benefits such as reducing the medical and psychosocial sequelae of opioid addiction.¹⁸ In fact, properly treated patients no longer meet the diagnostic criteria of opioid use disorder, and both methadone and buprenorphine are on the World Health Organization’s (WHO) list of essential medicines.²⁷

Despite endorsement by the WHO, the stigma attached to the opioid agonists has been difficult to overcome. Patients with opioid use disorder may be viewed with distrust by healthcare providers and often do not feel welcome in healthcare settings or in self-help recovery groups.²⁸

Barriers to methadone therapy

Federal regulations on methadone prescribing and use were established to promote patient safety and decrease diversion, but they may also complicate access to care.²⁹ They stipulate that to qualify for methadone maintenance, patients need to demonstrate opioid addiction for 1 year, except for pregnant women and those who have been incarcerated in the past 6 months. Patients under the age of 18 must have 2 documented failed treatment episodes as well as approval by a guardian to receive treatment.

Inconvenience. Methadone can be prescribed for opioid dependence only by an accredited treatment program. Patients must therefore travel to the clinic and wait to be evaluated on a daily basis for a minimum of 90 days. Only after they demonstrate consistent responsible behavior and negative results on urine testing do they become eligible to take methadone home.²⁹ If a patient is to travel out of the area during the initial 90 days of treatment, he or she must make arrangements in advance to find a clinic that will provide a “guest dose.”

The inconvenience arising from the regulations may deter some patients from seeking methadone therapy. In spite of this, once patients are started on methadone, more of them continue treatment than with buprenorphine.¹⁸ A proposed reason is that methadone is a potent full opioid agonist and therefore relieves withdrawal symptoms and craving more effectively than buprenorphine, which is a partial agonist.³⁰ Another possible reason is the higher level of supervision afforded by methadone clinics, which require daily contact for at least 90 days. 

Safety concerns arise from methadone diversion, as illicit use may have lethal consequences. In the past decade, deaths from methadone overdose have risen significantly, most of them due to respiratory depression or torsade de pointes.¹³ However, most cases of diversion and overdose involve methadone that is prescribed for pain by individual practitioners and not from maintenance programs.¹³

Advantages of buprenorphine

Together, methadone’s lethality, stigma, and inconvenience may contribute to patients preferring buprenorphine.³¹

The regulations governing buprenorphine’s use are less restrictive than those with methadone. For example, patients must have a diagnosis of opioid addiction to be prescribed buprenorphine, but they are not required to carry the diagnosis for a year before treatment.³¹ Additionally, they do not need to travel to a federally approved opioid treatment center daily and can receive buprenorphine directly from a physician in an outpatient setting.

Under the Drug Abuse Treatment Act (DATA) of 2000, any physician can apply for a waiver to prescribe and dispense buprenorphine in his or her office. To qualify for an initial waiver, physicians must either obtain certification in the fields of addiction medicine or addiction psychiatry or complete an approved 8-hour training session.³² Each physician starts with a maximum of 30 patients, but can apply to treat up to 100 patients after 1 year and eventually up to 275 patients. Physicians must document every buprenorphine prescription they write and be able to refer patients for counseling.³¹

As of February 2017, nurse practitioners and physician assistants can also apply for a DATA 2000 waiver. All waivered providers are subject to unannounced visits from the Drug Enforcement Administration once every 5 years.³²

While there are no federal restrictions on the amount of buprenorphine that can be dispensed, some states and some insurance companies have placed restrictions on dose or length of treatment.³³ Buprenorphine patients can fill their prescriptions at any pharmacy and are permitted to bring their medication home, which improves access to care. However, office-based outpatient treatment is not without risk, and preventing buprenorphine diversion remains a challenge.³⁴

‘Lending’ buprenorphine is a felony

Addicts have illegally used buprenorphine to self-treat opioid withdrawal, craving, and dependence.³⁵ Its misuse has also been coupled with self-treatment of conditions that include depression and pain.³⁶

A survey found that 83.7% of patients deem buprenorphine diversion to be appropriate; further, most patients said they consider it unethical to withhold prescribed buprenorphine from individuals showing symptoms of withdrawal.³⁴ Physicians who prescribe buprenorphine must inform their patients that even “lending” or giving away their medication is a felony.

Prescribing physicians must also be diligent about monitoring for signs of diversion such as inconsistent urine toxicology screens, “lost” medication, and requests for early refills or escalating doses.³⁷

In addition to federal regulations, we propose a 4-step approach to evaluate eligibility for opioid replacement therapy based on existing guidelines.^37–39

Step 1: History and physical examination

The history should give particular attention to the patient’s cardiac, pulmonary, and hepatic status, with consideration of the risks of any medical comorbidities (eg, bacterial endocarditis, HIV and HCV infection) that might influence treatment.³⁷

It is also essential to evaluate for any contraindications or drug interactions before prescribing methadone or buprenorphine.³⁸

Contraindications to methadone maintenance include⁴⁰:

• Cor pulmonale
• Methadone hypersensitivity
• Pseudomembranous colitis
• Selegiline use (due to risk of serotonin syndrome)
• Ileum paralyticus.

Contraindications to buprenorphine use include:

• Hypersensitivity to naloxone or buprenorphine
• Impaired liver function (due to the risk of inadvertent overdose associated with slowed metabolism).

Concurrent use of alcohol or illicit benzodiazepines is a relative contraindication to both methadone and buprenorphine due to the risk of respiratory depression and overdose.³⁷ Likewise, avoid coprescribing opioid agonists and benzodiazepines whenever possible. Obtain a complete list of current medications and query a prescription-monitoring database to determine whether any controlled substances are currently prescribed.³⁷

During the physical examination, look for stigmata of intravenous drug use such as track marks or abscesses³⁷ and document any physical findings consistent with intoxication or withdrawal. Patients must be completely detoxed or in withdrawal before beginning buprenorphine induction; premature induction can precipitate withdrawal.³⁸

A discussion of pregnant patients with opioid use disorder is beyond the scope of this paper. However, it is incumbent on the prescriber to inquire whether the client is pregnant or intends to become pregnant and what birth control methods are in place.

Step 2: Assess psychiatric status

Assessment of the patient’s psychiatric status, including an assessment of alcohol and other drug use, will help determine his or her eligibility for opioid agonists.³⁷ To prepare for the need to manage patients with psychiatrically complex issues, it is helpful to develop relationships with addiction specialists and psychiatrists who are familiar with opioid replacement therapy in your area. This will make it easier to collaborate on patients’ care.

Ask all patients directly about suicidal or homicidal ideation. Any patient with active suicidal or homicidal ideation should be assessed for need of immediate hospitalization by a psychiatrist or another qualified mental health professional. Patients with a history of suicidal ideation should be monitored closely by a mental health professional throughout treatment.³⁷

Many if not most patients with opioid use disorder have concurrent psychiatric disorders, and the interplay between these disorders is complex.^40,41 Depression, for example, can precede and even precipitate drug use (an observation supporting the “self-medication theory”).⁴² If the underlying depressive disorder is not addressed, relapse is nearly inevitable.

It has also been shown that both chronic opioid use and withdrawal can exacerbate aversive emotional states. This escalation of symptoms may result from the pharmacologic effects of opioids or from psychosocial sequelae that can arise from chronic opioid use.⁴¹ In this situation, maintaining abstinence can lead to resolution of depressive symptoms. As depression and opioid use can occur together, successful treatment requires equal attention to both illnesses.

Other common comorbidities in patients with opioid use disorder include posttraumatic stress disorder, attention deficit hyperactivity disorder, antisocial personality disorder, and concurrent substance abuse disorders.⁴³ The confluence of antisocial personality disorder is particularly important, as patients with antisocial personality disorder display disruptive and maladaptive behaviors.

Identify any psychotropic medication that is prescribed and check carefully for drug interactions. This applies especially to methadone, as many psychiatric medications also prolong the QT interval. Moreover, patients may not be forthcoming about the use of psychiatric medication.

Find out whether the patient is using any other addictive substances, particularly those that affect the central nervous system, as those who use fentanyl, benzodiazepines, or alcohol are at the highest risk of overdose.³¹ Often the best option for those with concurrent substance use disorders is inpatient detoxification followed by residential rehabilitation care. Either buprenorphine or methadone can then be initiated upon return to an outpatient setting.

Step 3: Assess psychosocial status

To what extent do the patient’s home environment and support systems promote a drug-free lifestyle? Unfortunately, the psychosocial status of many of these patients is fragile, and they may live in areas where illicit drugs are readily available (which can be urban, suburban, or rural), making it difficult to stay substance-free.³⁸

Generally, lifestyle modifications are needed to transform maladaptive behaviors and promote an environment conducive to long-term recovery. Referrals to social services to address housing, vocational needs, and entitlements may be helpful.³⁹

Step 4: Assess readiness to change

According to one model, people go through 5 stages when changing a behavior: precontemplation, contemplation, preparation for action, action, and maintenance.⁴³ In general, the further along the stages a patient is, the more appropriate he or she is for office-based treatment with buprenorphine.³⁹

The level of change can be assessed with tools such as Stages of Change Readiness and Treatment Eagerness Scale (SOCRATES). Use of stage-specific strategies may enhance a patient’s readiness to cease opioid use.⁴³

Precontemplation. Those in the precontemplation stage are not ready to think about changing their behavior.⁴³ They may be unaware of or unwilling to consider the risks associated with their opioid use and resistant to the idea of quitting. Engagement with opioid agonists for individuals in this stage is low and dropout rates are likely high.

Thus, the proper approach for “precontemplators” is to help them develop some ambivalence about their opioid use. One tactic is to involve the patient in a discussion of the personal benefits and risks of opioid use.

Contemplation. Individuals in the contemplation stage have begun to weigh the costs and benefits of opioid use and express ambivalence about it.⁴⁴ Because the patient is willing to explore the risks of ongoing use and consider the benefits of treatment, the goal in this stage is to elicit a commitment from the individual to seek treatment.

Preparation. The person in this stage moves from thinking about treatment to planning what action to take.⁴⁵ As the individual prepares to enter treatment, indecision tends to resurface, as well as self-doubt about his or her ability to change. During this stage, it is important for the provider to spell out goals (abstinence) and strategies (eg, counseling, medication) and enhance a sense of self-efficacy.

Action and maintenance. Patients in these stages engage in treatment and employ new strategies to abstain from opioid use. Maintaining these behaviors can be a daily struggle. Expressing confidence in the patient’s ability to abstain from use will support his or her progress. Behavioral interventions such as strategic avoidance of triggers and engagement in alternative activities (eg, support groups, exercise, faith-based practices) will help to maintain abstinence.

A CHRONIC CONDITION

Opioid use disorder, like many chronic illnesses, requires long-term attention to attain successful patient outcomes. The opioid agonists methadone and buprenorphine are the mainstay of treatment for it, conferring benefits such as reducing opioid use and preventing relapse.

Candidates for opioid agonist therapy should undergo a multidisciplinary assessment, including an evaluation on the patient’s readiness to change his or her opioid use.

Patient education should include a discussion of the risks of methadone (eg, respiratory depression, fatal overdose, and QTc prolongation) and buprenorphine (eg hepatotoxicity) and their benefits (eg, controlling craving, decreasing the risk of relapse). Patients should also be educated about overdose and diversion.

Despite the difficulties inherent in treating patients with opioid use disorder, when used appropriately, opioid agonist therapy can be lifesaving for patients struggling with long-term opioid addiction.

Acknowledgment: We thank Katelyn Colosi, BS, and Drs. Susan Wolfe, Dennis Bouffard, and Sinha Shirshendu for their helpful comments.

Herpes zoster (HZ), or shingles, represents a reactivation of the varicella-zoster virus (VZV). Following primary infection, usually in childhood, the virus typically lies dormant in the dorsal root and sensory nerve ganglia for decades. The precise mechanism of reactivation is not well understood, but it is associated with a decline in cell-mediated immunity that occurs with advancing age, immune-compromising conditions such as HIV infection and cancer, or immunosuppressive therapies, including corticosteroids.¹ HZ is usually a self-limited disease characterized by unilateral dermatomal rash and pain, but can cause disseminated infection in immunocompromised individuals.²

Treatment with antiviral medications within 72 hours of rash onset can reduce acute HZ symptoms.¹ However, antiviral agents are only minimally effective in preventing postherpetic neuralgia, the most common complication of HZ.³ Therefore, efforts to reduce the burden of HZ morbidity have focused on prevention through vaccination.

Currently, the only shingles vaccine approved by the US Food and Drug Administration (FDA) is Zostavax (Merck), which contains the live-attenuated Oka strain of VZV at a concentration 14 times greater than that of the varicella vaccine (Varivax, Merck). The live-attenuated vaccine boosts VZV-specific cell-mediated immunity, preventing reactivation of the latent virus.

In this article, we describe the burden of disease and review recent developments in the literature on HZ vaccine, including duration of efficacy, uptake and barriers to vaccination, cost-effectiveness, and the outlook for future vaccines.

INCIDENCE INCREASES WITH AGE

The incidence of herpes zoster in the general population is between 3 and 5 per 1,000 person-years⁴ and increases with age, especially after age 60 when the incidence can approach 13 to 15 per 1,000 person-years.^5,6 An estimated 1 million new cases occur each year in the United States, and about 6% of patients experience a second episode of HZ within 8 years.^7,8 In immunocompromised patients, the incidence of HZ is 2 to 10 times higher than in the general population.⁹

The incidence of HZ has been increasing for reasons that are unclear. After varicella vaccine was introduced into the routine childhood immunization schedule in 1995, it was hypothesized that the resultant decrease in primary varicella infections would remove a natural source of immune boosting and cause an increase in HZ incidence for up to 20 years.¹⁰ However, recent studies demonstrate that the observed increase in HZ incidence actually predates the introduction of varicella vaccine,^11–13 and the widespread use of varicella vaccine has not resulted in an increase in the incidence of HZ.¹⁴

Other potential explanations for the rise in reported incidence include increasing awareness among patients, who might previously not have sought care and among physicians, who may be more likely to make the diagnosis. Advertisement of new treatments for HZ, including gabapentin and capsaicin, probably began to increase awareness in the 1990s, as did promotion of the HZ vaccine after its licensure in 2006.

HZ can occur in people who have been vaccinated against varicella due to reactivation of the vaccine-strain virus, but the risk is lower than after infection with wild-type varicella.¹⁵ Given that the varicella vaccine has been routinely used in children for only 20 years, the long-term effect of varicella vaccination on the incidence of HZ in elderly people is unknown.

Serious complications

HZ can cause rare but serious complications including encephalitis, herpes ophthalmicus, herpes oticus, myelitis, and retinitis.¹ These can lead to long-term disability including unilateral blindness and deafness.

The most common and debilitating complication is postherpetic neuralgia, a persistent pain lasting at least 3 months, with a mean duration of 3.3 years and sometimes as long as 10 years.¹⁶ Postherpetic neuralgia occurs in 8% to 32% of patients after acute HZ,⁴ and the incidence increases with age, being most common after age 70. The chronic pain of postherpetic neuralgia has a significant adverse impact on patients’ quality of life, including physical disability and emotional distress.¹⁷ Some pain is intense, and anecdotal reports of patients committing suicide were included in the Advisory Committee on Immunization Practices (ACIP) recommendations regarding herpes zoster vaccine.¹⁸

HZ and its complications also impose a substantial economic burden on society.¹⁹ In a population-based study, the mean direct medical costs of HZ ranged from $620 to $1,160 (2015 dollars) depending on age,²⁰ and the mean costs of postherpetic neuralgia were 2 to 5 times higher than that.^20–22 Immunocompromised patients had costs 2 to 3 times higher than those of immunocompetent adults.²³ In addition, for employed patients, HZ resulted in an average loss of 32 hours of work due to absenteeism and 84 hours due to presenteeism (ie, working while sick and therefore suboptimally).²⁴

Assuming there are 1 million cases of HZ each year, if 8% to 32% of patients go on to develop postherpetic neuralgia, that would translate into approximately $1 to $2 billion in direct medical costs. With 60% of adult patients working,²⁵ at an average wage of $23.23 per hour,²⁶ HZ illness could be responsible for another $1.6 billion in lost productivity.

EFFICACY AND SAFETY OF HZ VACCINE

In 2006, the FDA approved the live-attenuated Oka strain VZV vaccine for prevention of HZ and postherpetic neuralgia in adults age 60 and older based on findings from the Shingles Prevention Study (SPS).²⁷

The Shingles Prevention Study

This multicenter randomized placebo-controlled trial²⁷ enrolled 38,546 immunocompetent persons age 60 and older. Subjects in the intervention group received a single dose of live-attenuated vaccine, and all participants were followed for up to 4.9 years after vaccination.

HZ occurred in 315 (1.636%) of the 19,254 participants in the vaccine group and in 642 (3.336%) of the 19,247 participants in the placebo group, an absolute risk reduction of 1.7%, number needed to treat 59, relative risk reduction 51%, P < .001. Similarly, postherpetic neuralgia occurred in 27 (0.140%) of the 19,254 vaccine recipients and in 80 (0.416%) of the placebo recipients (an absolute risk reduction of 0.276%, number needed to treat 362, relative risk reduction 66%, P < .001). The investigators calculated that vaccination reduced the  overall burden of illness by 61% (Table 1).

The efficacy against HZ incidence decreased with age,²⁸ but the efficacy against postherpetic neuralgia did not. In addition, vaccine recipients who developed HZ generally had less severe manifestations.

The safety of the vaccine was assessed for all participants in the SPS. In addition, one-sixth of SPS participants were enrolled in a safety substudy. These participants completed a detailed report card regarding all medically important events within the first 42 days. Forty-eight percent of the vaccine group and 17% of the placebo group (P < .05) experienced adverse events, primarily at the injection site. Less than 1% of all local reactions were severe.²⁹ Serious adverse events were rare (< 2%), but occurred significantly more often in the vaccinated group.

Short-Term Persistence Substudy

Short-term efficacy of the live-attenuated vaccine (up to 7 years) was assessed in the Short-Term Persistence Substudy (STPS), which involved 14,270 of the initial participants and reported yearly and overall vaccine efficacy.³⁰ After 5 years, the yearly efficacy against postherpetic neuralgia incidence declined to 32% and was no longer statistically significant. Efficacy against HZ incidence and burden of illness displayed the same pattern. After the end of the STPS, all subjects in the placebo group received vaccination.

Long-Term Persistence Substudy

Those in the intervention group were followed for an additional 4 years in the Long-Term Persistence Substudy (LTPS).³¹ Due to the lack of concurrent controls in the LTPS, the authors used regression models based on historical controls to estimate contemporary population incidence of HZ and postherpetic neuralgia  for comparison.

Efficacy continued to decline over time, and by 10 years after vaccination there was no difference between vaccinated patients and historical controls in the rate of any end point (ie, efficacy declined to zero).

A trial of booster vaccination

Because many patients are vaccinated at age 60, waning immunity could leave them vulnerable to HZ and postherpetic neuralgia by age 70. A potential solution would be to give a booster dose after 10 years.

A recent phase 3 clinical trial of adults age 70 years and older found that a booster dose of live-attenuated vaccine was as safe and immunogenic as an initial dose.³² While antibody responses were similar in the boosted group and the newly vaccinated group, cell-mediated immunity was higher in the boosted group.

Because prevention of HZ is generally via cell-mediated immunity, the booster might be more effective than the initial vaccination, but clinical trials measuring actual cases prevented will be required to prove it. A booster dose is not currently recommended.

A trial of vaccination in adults 50 to 59

In 2011, the FDA extended its approval of HZ vaccine for use in adults ages 50 to 59.³³

In a randomized, double-blind, placebo-controlled trial in this age group,³³ the vaccine reduced HZ incidence by almost 70% (absolute risk reduction 0.614%, number needed to treat 156; Table 1), but the severity of HZ cases was not affected. There were too few cases of postherpetic neuralgia to assess the efficacy for this end point. The study followed patients for only 1.5 years after vaccination, so the duration of efficacy is unknown.

As in the older recipients, the vaccine was well tolerated; injection-site reactions and headache were the major adverse effects reported among vaccine recipients.³³

INDICATIONS AND CONTRAINDICATIONS

Although HZ vaccine is licensed for use in adults age 50 and older, the ACIP recommends it only for immunocompetent adults age 60 and older. At this time, the ACIP does not recommend HZ vaccine in those younger than 60 because of the low risk of HZ in this age group.³⁴

Any person age 60 or older should receive a single dose of the live-attenuated HZ vaccine subcutaneously, regardless of past history of HZ.

The vaccine is contraindicated in patients who have a history of allergic reaction to any vaccine component, immunosuppression or immunodeficiency conditions, and pregnancy. Specifically, people who will receive immunosuppressive therapies should have the vaccine at least 14 days before beginning treatment. Antiviral medications such as acyclovir, famciclovir, and valacyclovir should be discontinued at least 24 hours before vaccination and not resumed until 14 days later. Patients taking high-dose corticosteroids for more than 2 weeks should not be vaccinated until at least 1 month after therapy is completed.

In contrast, HZ vaccine is not contraindicated for leukemia patients who are in remission and who have not received chemotherapy or radiation for at least 3 months, or for patients receiving short-term, low-to-moderate dose, topical, intra-articular, bursal, or tendon injections of corticosteroids. Patients on low-dose methotrexate, azathioprine, or 6-mercaptopurine can also receive the vaccine.¹⁸

VACCINATION RATES ARE LOW

Although the vaccine has been recommended since 2008, uptake has been slow. Figure 1 shows the rate of HZ vaccination in adults age 60 and older surveyed in the National Health Interview Survey from 2007 to 2013.³⁵ Eight years after the vaccine was licensed, only 28% of eligible patients had been vaccinated. Assuming the current rate of increase remains constant, it will take 7 more years to reach a 60% coverage rate—the same as for pneumococcal vaccine³⁶—and 18 years to reach universal coverage.

Barriers to vaccination

Several barriers to HZ vaccination might account for the slow uptake.

For the first few years the vaccine was available, the requirement to store it frozen presented an obstacle for some physicians.³⁷ Physicians may also have been discouraged by the cumbersome Medicare reimbursement process because while the administration fee is covered through Medicare Part B, the live­-attenuated vaccine is reimbursed only through Medicare Part D, a benefit that varies by plans. Other barriers to physicians are supply shortages, high up-front costs, and uncertainties regarding the duration of vaccine protection, its safety, and side effects.^38–40

Patient barriers include lack of physician recommendation, lack of familiarity with the vaccine, high out-of-pocket costs, the perception that they are at low risk for HZ, underestimation of the pain associated with HZ and postherpetic neuralgia, and fear of vaccine adverse effects.^39,41,42

Interventions to increase vaccination rates

Certain interventions have been shown to increase vaccination adherence in general and HZ vaccination in particular. In randomized trials involving other vaccines, electronic medical record reminders supporting panel management or nurse-initiated protocols have been proven to increase vaccination rates, but these methods have not been tested for HZ vaccine specifically.^43,44

In an observational study, Chaudhry et al found that the number of HZ vaccinations administered at the Mayo Clinic increased 43% in one practice and 54% in another after the implementation of an electronic alert.⁴⁵ A randomized controlled trial showed that an informational package discussing HZ and the vaccine sent to patients via either their electronic personal health record or traditional mail increased HZ vaccination by almost 3 times.⁴⁶

Pharmacists can also influence vaccination rates. States that provide full immunization privileges to pharmacists have vaccination rates significantly higher than states with restricted or no authorization.⁴⁷

COST-EFFECTIVENESS CONSIDERATIONS

Unlike the Centers for Medicare and Medicaid Services, the ACIP does consider cost-effectiveness in their vaccine recommendations. Because of the morbidity associated with HZ and postherpetic neuralgia as well as the economic impact, vaccination is generally considered cost-effective for adults age 60 and older.^48,49

Analyses have demonstrated that cost-effectiveness hinges on 4 factors: initial vaccine efficacy, the duration of efficacy, the age-specific incidence of HZ, and the cost of the vaccine.

For patients ages 50 to 59, the incidence of HZ is low, and because the duration of vaccine efficacy is short even though initial vaccine efficacy is high, vaccination in this age group offers poor value.⁵⁰ At older ages, the incidence of HZ and postherpetic neuralgia rises, making vaccination more cost-effective. After age 60, the vaccine is cost-effective at all ages, although age 70 appears to offer the optimal trade-off between increasing incidence and declining vaccine efficacy.^48,49

For patients who plan to be vaccinated only once, waiting until age 70 would appear to offer the best value.⁵¹ For those who are willing to receive a booster dose, the optimal age for vaccination is unknown, but will likely depend on the effectiveness, cost, and duration of the booster.

A NEW HZ VACCINE

In 2015, GlaxoSmithKline tested a new HZ vaccine containing a single VZV glycoprotein in an AS01_B adjuvant system (HZ/su vaccine).⁵² In a phase 3 randomized trial involving 15,411 immunocompetent persons age 50  and older, a 2-dose schedule of HZ/su vaccine was 97% effective in preventing HZ (Table 1).⁵³ Importantly, the vaccine was equally effective in older patients.

This vaccine also had a high rate of adverse reactions, with 17% of vaccine recipients vs 3% of placebo recipients reporting events that prevented normal everyday activities for at least 1 day. However, the rate of serious adverse reactions was the same in both groups (9%). The company announced that they intended to submit a regulatory application for HZ/su vaccine in the second half of 2016.⁵⁴

Because of its high efficacy, HZ/su vaccine has the potential to change practice, but several issues must be resolved before it can supplant the current vaccine.

First, the AS01B adjuvant is not currently licensed in the United States, so it is unclear if the HZ/su vaccine can get FDA approval.^52,55

Second, there are several questions about the efficacy of the vaccine, including long-term efficacy, efficacy in the elderly, and efficacy in the case of a patient receiving only 1 of the 2 required doses.

Third, the impact of HZ/su vaccine on complications such as postherpetic neuralgia has not been established. The clinical trial (NCT01165229) examining vaccine efficacy against postherpetic neuralgia incidence and other complications in adults age 70 and older has recently been completed and data should be available soon. Given the extremely high efficacy against HZ, it is likely that it will be close to 100% effective against this complication.

Fourth, there is uncertainty as to how the HZ/su vaccine should be used in patients who have already received the live-attenuated vaccine, if it is determined that a booster is necessary.

Finally, the vaccine is not yet priced. Given its superior effectiveness, particularly in older individuals, competitive pricing could dramatically affect the market. How Medicare or other insurers cover the new vaccine will likely influence its acceptance.

HZ VACCINATION OF IMMUNOCOMPROMISED PATIENTS

Immunocompromised patients are at highest risk for developing HZ. Unfortunately, there are currently no HZ vaccines approved for use in this population. The current live-attenuated vaccine has been demonstrated to be safe, well tolerated, and immunogenic in patients age 60 and older who are receiving chronic or maintenance low to moderate doses of corticosteroids.⁵⁶

A clinical trial is being conducted to assess the immunogenicity, clinical effectiveness, and safety of the vaccine in rheumatoid arthritis patients receiving antitumor necrosis factor therapy (NCT01967316). Other trials are examining vaccine efficacy and safety in patients with solid organ tumors prior to chemotherapy (NCT02444936) and in patients who will be undergoing living donor kidney transplantation (NCT00940940). Researchers are also investigating the possibility of vaccinating allogeneic stem cell donors before donation in order to protect transplant recipients against HZ (NCT01573182).

ZVHT and HZ/su vaccination in immunocompromised patients

Heat-treated varicella-zoster vaccine (ZVHT) is a potential alternative for immunocompromised patients. A 4-dose regimen has been proven to reduce the risk of HZ in patients receiving autologous hematopoietic-cell transplants for non-Hodgkin or Hodgkin lymphoma.⁵⁷

In another trial, the 4-dose ZVHT was safe and elicited significant VZV-specific T-cell response through 28 days in immunosuppressed patients with solid tumor malignancy, hematologic malignancy, human immunodeficiency virus infection with CD4 counts of 200 cells/mm³ or less, and autologous hematopoietic-cell transplants. The T-cell response was poor in allogeneic hematopoietic-cell transplant recipients, however.⁵⁸

Because the HZ/su vaccine does not contain live virus, it seems particularly promising for immunocompromised patients. In phase 1 and 2 studies, a 3-dose regimen has been shown to be safe and immunogenic in hematopoietic-cell transplant recipients and HIV-infected adults with CD4 count higher than 200 cells/mm³.^59,60 A phase 3 trial assessing the efficacy of HZ/su vaccine in autologous hematopoietic-cell transplant recipients is under way (NCT01610414). Changes in recommendations for HZ vaccine in these most vulnerable populations await the results of these studies.

Herpes zoster (HZ), or shingles, represents a reactivation of the varicella-zoster virus (VZV). Following primary infection, usually in childhood, the virus typically lies dormant in the dorsal root and sensory nerve ganglia for decades. The precise mechanism of reactivation is not well understood, but it is associated with a decline in cell-mediated immunity that occurs with advancing age, immune-compromising conditions such as HIV infection and cancer, or immunosuppressive therapies, including corticosteroids.¹ HZ is usually a self-limited disease characterized by unilateral dermatomal rash and pain, but can cause disseminated infection in immunocompromised individuals.²

Treatment with antiviral medications within 72 hours of rash onset can reduce acute HZ symptoms.¹ However, antiviral agents are only minimally effective in preventing postherpetic neuralgia, the most common complication of HZ.³ Therefore, efforts to reduce the burden of HZ morbidity have focused on prevention through vaccination.

Currently, the only shingles vaccine approved by the US Food and Drug Administration (FDA) is Zostavax (Merck), which contains the live-attenuated Oka strain of VZV at a concentration 14 times greater than that of the varicella vaccine (Varivax, Merck). The live-attenuated vaccine boosts VZV-specific cell-mediated immunity, preventing reactivation of the latent virus.

In this article, we describe the burden of disease and review recent developments in the literature on HZ vaccine, including duration of efficacy, uptake and barriers to vaccination, cost-effectiveness, and the outlook for future vaccines.

INCIDENCE INCREASES WITH AGE

The incidence of herpes zoster in the general population is between 3 and 5 per 1,000 person-years⁴ and increases with age, especially after age 60 when the incidence can approach 13 to 15 per 1,000 person-years.^5,6 An estimated 1 million new cases occur each year in the United States, and about 6% of patients experience a second episode of HZ within 8 years.^7,8 In immunocompromised patients, the incidence of HZ is 2 to 10 times higher than in the general population.⁹

The incidence of HZ has been increasing for reasons that are unclear. After varicella vaccine was introduced into the routine childhood immunization schedule in 1995, it was hypothesized that the resultant decrease in primary varicella infections would remove a natural source of immune boosting and cause an increase in HZ incidence for up to 20 years.¹⁰ However, recent studies demonstrate that the observed increase in HZ incidence actually predates the introduction of varicella vaccine,^11–13 and the widespread use of varicella vaccine has not resulted in an increase in the incidence of HZ.¹⁴

Other potential explanations for the rise in reported incidence include increasing awareness among patients, who might previously not have sought care and among physicians, who may be more likely to make the diagnosis. Advertisement of new treatments for HZ, including gabapentin and capsaicin, probably began to increase awareness in the 1990s, as did promotion of the HZ vaccine after its licensure in 2006.

HZ can occur in people who have been vaccinated against varicella due to reactivation of the vaccine-strain virus, but the risk is lower than after infection with wild-type varicella.¹⁵ Given that the varicella vaccine has been routinely used in children for only 20 years, the long-term effect of varicella vaccination on the incidence of HZ in elderly people is unknown.

Serious complications

HZ can cause rare but serious complications including encephalitis, herpes ophthalmicus, herpes oticus, myelitis, and retinitis.¹ These can lead to long-term disability including unilateral blindness and deafness.

The most common and debilitating complication is postherpetic neuralgia, a persistent pain lasting at least 3 months, with a mean duration of 3.3 years and sometimes as long as 10 years.¹⁶ Postherpetic neuralgia occurs in 8% to 32% of patients after acute HZ,⁴ and the incidence increases with age, being most common after age 70. The chronic pain of postherpetic neuralgia has a significant adverse impact on patients’ quality of life, including physical disability and emotional distress.¹⁷ Some pain is intense, and anecdotal reports of patients committing suicide were included in the Advisory Committee on Immunization Practices (ACIP) recommendations regarding herpes zoster vaccine.¹⁸

HZ and its complications also impose a substantial economic burden on society.¹⁹ In a population-based study, the mean direct medical costs of HZ ranged from $620 to $1,160 (2015 dollars) depending on age,²⁰ and the mean costs of postherpetic neuralgia were 2 to 5 times higher than that.^20–22 Immunocompromised patients had costs 2 to 3 times higher than those of immunocompetent adults.²³ In addition, for employed patients, HZ resulted in an average loss of 32 hours of work due to absenteeism and 84 hours due to presenteeism (ie, working while sick and therefore suboptimally).²⁴

Assuming there are 1 million cases of HZ each year, if 8% to 32% of patients go on to develop postherpetic neuralgia, that would translate into approximately $1 to $2 billion in direct medical costs. With 60% of adult patients working,²⁵ at an average wage of $23.23 per hour,²⁶ HZ illness could be responsible for another $1.6 billion in lost productivity.

EFFICACY AND SAFETY OF HZ VACCINE

In 2006, the FDA approved the live-attenuated Oka strain VZV vaccine for prevention of HZ and postherpetic neuralgia in adults age 60 and older based on findings from the Shingles Prevention Study (SPS).²⁷

The Shingles Prevention Study

This multicenter randomized placebo-controlled trial²⁷ enrolled 38,546 immunocompetent persons age 60 and older. Subjects in the intervention group received a single dose of live-attenuated vaccine, and all participants were followed for up to 4.9 years after vaccination.

HZ occurred in 315 (1.636%) of the 19,254 participants in the vaccine group and in 642 (3.336%) of the 19,247 participants in the placebo group, an absolute risk reduction of 1.7%, number needed to treat 59, relative risk reduction 51%, P < .001. Similarly, postherpetic neuralgia occurred in 27 (0.140%) of the 19,254 vaccine recipients and in 80 (0.416%) of the placebo recipients (an absolute risk reduction of 0.276%, number needed to treat 362, relative risk reduction 66%, P < .001). The investigators calculated that vaccination reduced the  overall burden of illness by 61% (Table 1).

The efficacy against HZ incidence decreased with age,²⁸ but the efficacy against postherpetic neuralgia did not. In addition, vaccine recipients who developed HZ generally had less severe manifestations.

The safety of the vaccine was assessed for all participants in the SPS. In addition, one-sixth of SPS participants were enrolled in a safety substudy. These participants completed a detailed report card regarding all medically important events within the first 42 days. Forty-eight percent of the vaccine group and 17% of the placebo group (P < .05) experienced adverse events, primarily at the injection site. Less than 1% of all local reactions were severe.²⁹ Serious adverse events were rare (< 2%), but occurred significantly more often in the vaccinated group.

Short-Term Persistence Substudy

Short-term efficacy of the live-attenuated vaccine (up to 7 years) was assessed in the Short-Term Persistence Substudy (STPS), which involved 14,270 of the initial participants and reported yearly and overall vaccine efficacy.³⁰ After 5 years, the yearly efficacy against postherpetic neuralgia incidence declined to 32% and was no longer statistically significant. Efficacy against HZ incidence and burden of illness displayed the same pattern. After the end of the STPS, all subjects in the placebo group received vaccination.

Long-Term Persistence Substudy

Those in the intervention group were followed for an additional 4 years in the Long-Term Persistence Substudy (LTPS).³¹ Due to the lack of concurrent controls in the LTPS, the authors used regression models based on historical controls to estimate contemporary population incidence of HZ and postherpetic neuralgia  for comparison.

Efficacy continued to decline over time, and by 10 years after vaccination there was no difference between vaccinated patients and historical controls in the rate of any end point (ie, efficacy declined to zero).

A trial of booster vaccination

Because many patients are vaccinated at age 60, waning immunity could leave them vulnerable to HZ and postherpetic neuralgia by age 70. A potential solution would be to give a booster dose after 10 years.

A recent phase 3 clinical trial of adults age 70 years and older found that a booster dose of live-attenuated vaccine was as safe and immunogenic as an initial dose.³² While antibody responses were similar in the boosted group and the newly vaccinated group, cell-mediated immunity was higher in the boosted group.

Because prevention of HZ is generally via cell-mediated immunity, the booster might be more effective than the initial vaccination, but clinical trials measuring actual cases prevented will be required to prove it. A booster dose is not currently recommended.

A trial of vaccination in adults 50 to 59

In 2011, the FDA extended its approval of HZ vaccine for use in adults ages 50 to 59.³³

In a randomized, double-blind, placebo-controlled trial in this age group,³³ the vaccine reduced HZ incidence by almost 70% (absolute risk reduction 0.614%, number needed to treat 156; Table 1), but the severity of HZ cases was not affected. There were too few cases of postherpetic neuralgia to assess the efficacy for this end point. The study followed patients for only 1.5 years after vaccination, so the duration of efficacy is unknown.

As in the older recipients, the vaccine was well tolerated; injection-site reactions and headache were the major adverse effects reported among vaccine recipients.³³

INDICATIONS AND CONTRAINDICATIONS

Although HZ vaccine is licensed for use in adults age 50 and older, the ACIP recommends it only for immunocompetent adults age 60 and older. At this time, the ACIP does not recommend HZ vaccine in those younger than 60 because of the low risk of HZ in this age group.³⁴

Any person age 60 or older should receive a single dose of the live-attenuated HZ vaccine subcutaneously, regardless of past history of HZ.

The vaccine is contraindicated in patients who have a history of allergic reaction to any vaccine component, immunosuppression or immunodeficiency conditions, and pregnancy. Specifically, people who will receive immunosuppressive therapies should have the vaccine at least 14 days before beginning treatment. Antiviral medications such as acyclovir, famciclovir, and valacyclovir should be discontinued at least 24 hours before vaccination and not resumed until 14 days later. Patients taking high-dose corticosteroids for more than 2 weeks should not be vaccinated until at least 1 month after therapy is completed.

In contrast, HZ vaccine is not contraindicated for leukemia patients who are in remission and who have not received chemotherapy or radiation for at least 3 months, or for patients receiving short-term, low-to-moderate dose, topical, intra-articular, bursal, or tendon injections of corticosteroids. Patients on low-dose methotrexate, azathioprine, or 6-mercaptopurine can also receive the vaccine.¹⁸

VACCINATION RATES ARE LOW

Although the vaccine has been recommended since 2008, uptake has been slow. Figure 1 shows the rate of HZ vaccination in adults age 60 and older surveyed in the National Health Interview Survey from 2007 to 2013.³⁵ Eight years after the vaccine was licensed, only 28% of eligible patients had been vaccinated. Assuming the current rate of increase remains constant, it will take 7 more years to reach a 60% coverage rate—the same as for pneumococcal vaccine³⁶—and 18 years to reach universal coverage.

Barriers to vaccination

Several barriers to HZ vaccination might account for the slow uptake.

For the first few years the vaccine was available, the requirement to store it frozen presented an obstacle for some physicians.³⁷ Physicians may also have been discouraged by the cumbersome Medicare reimbursement process because while the administration fee is covered through Medicare Part B, the live­-attenuated vaccine is reimbursed only through Medicare Part D, a benefit that varies by plans. Other barriers to physicians are supply shortages, high up-front costs, and uncertainties regarding the duration of vaccine protection, its safety, and side effects.^38–40

Patient barriers include lack of physician recommendation, lack of familiarity with the vaccine, high out-of-pocket costs, the perception that they are at low risk for HZ, underestimation of the pain associated with HZ and postherpetic neuralgia, and fear of vaccine adverse effects.^39,41,42

Interventions to increase vaccination rates

Certain interventions have been shown to increase vaccination adherence in general and HZ vaccination in particular. In randomized trials involving other vaccines, electronic medical record reminders supporting panel management or nurse-initiated protocols have been proven to increase vaccination rates, but these methods have not been tested for HZ vaccine specifically.^43,44

In an observational study, Chaudhry et al found that the number of HZ vaccinations administered at the Mayo Clinic increased 43% in one practice and 54% in another after the implementation of an electronic alert.⁴⁵ A randomized controlled trial showed that an informational package discussing HZ and the vaccine sent to patients via either their electronic personal health record or traditional mail increased HZ vaccination by almost 3 times.⁴⁶

Pharmacists can also influence vaccination rates. States that provide full immunization privileges to pharmacists have vaccination rates significantly higher than states with restricted or no authorization.⁴⁷

COST-EFFECTIVENESS CONSIDERATIONS

Unlike the Centers for Medicare and Medicaid Services, the ACIP does consider cost-effectiveness in their vaccine recommendations. Because of the morbidity associated with HZ and postherpetic neuralgia as well as the economic impact, vaccination is generally considered cost-effective for adults age 60 and older.^48,49

Analyses have demonstrated that cost-effectiveness hinges on 4 factors: initial vaccine efficacy, the duration of efficacy, the age-specific incidence of HZ, and the cost of the vaccine.

For patients ages 50 to 59, the incidence of HZ is low, and because the duration of vaccine efficacy is short even though initial vaccine efficacy is high, vaccination in this age group offers poor value.⁵⁰ At older ages, the incidence of HZ and postherpetic neuralgia rises, making vaccination more cost-effective. After age 60, the vaccine is cost-effective at all ages, although age 70 appears to offer the optimal trade-off between increasing incidence and declining vaccine efficacy.^48,49

For patients who plan to be vaccinated only once, waiting until age 70 would appear to offer the best value.⁵¹ For those who are willing to receive a booster dose, the optimal age for vaccination is unknown, but will likely depend on the effectiveness, cost, and duration of the booster.

A NEW HZ VACCINE

In 2015, GlaxoSmithKline tested a new HZ vaccine containing a single VZV glycoprotein in an AS01_B adjuvant system (HZ/su vaccine).⁵² In a phase 3 randomized trial involving 15,411 immunocompetent persons age 50  and older, a 2-dose schedule of HZ/su vaccine was 97% effective in preventing HZ (Table 1).⁵³ Importantly, the vaccine was equally effective in older patients.

This vaccine also had a high rate of adverse reactions, with 17% of vaccine recipients vs 3% of placebo recipients reporting events that prevented normal everyday activities for at least 1 day. However, the rate of serious adverse reactions was the same in both groups (9%). The company announced that they intended to submit a regulatory application for HZ/su vaccine in the second half of 2016.⁵⁴

Because of its high efficacy, HZ/su vaccine has the potential to change practice, but several issues must be resolved before it can supplant the current vaccine.

First, the AS01B adjuvant is not currently licensed in the United States, so it is unclear if the HZ/su vaccine can get FDA approval.^52,55

Second, there are several questions about the efficacy of the vaccine, including long-term efficacy, efficacy in the elderly, and efficacy in the case of a patient receiving only 1 of the 2 required doses.

Third, the impact of HZ/su vaccine on complications such as postherpetic neuralgia has not been established. The clinical trial (NCT01165229) examining vaccine efficacy against postherpetic neuralgia incidence and other complications in adults age 70 and older has recently been completed and data should be available soon. Given the extremely high efficacy against HZ, it is likely that it will be close to 100% effective against this complication.

Fourth, there is uncertainty as to how the HZ/su vaccine should be used in patients who have already received the live-attenuated vaccine, if it is determined that a booster is necessary.

Finally, the vaccine is not yet priced. Given its superior effectiveness, particularly in older individuals, competitive pricing could dramatically affect the market. How Medicare or other insurers cover the new vaccine will likely influence its acceptance.

HZ VACCINATION OF IMMUNOCOMPROMISED PATIENTS

Immunocompromised patients are at highest risk for developing HZ. Unfortunately, there are currently no HZ vaccines approved for use in this population. The current live-attenuated vaccine has been demonstrated to be safe, well tolerated, and immunogenic in patients age 60 and older who are receiving chronic or maintenance low to moderate doses of corticosteroids.⁵⁶

A clinical trial is being conducted to assess the immunogenicity, clinical effectiveness, and safety of the vaccine in rheumatoid arthritis patients receiving antitumor necrosis factor therapy (NCT01967316). Other trials are examining vaccine efficacy and safety in patients with solid organ tumors prior to chemotherapy (NCT02444936) and in patients who will be undergoing living donor kidney transplantation (NCT00940940). Researchers are also investigating the possibility of vaccinating allogeneic stem cell donors before donation in order to protect transplant recipients against HZ (NCT01573182).

ZVHT and HZ/su vaccination in immunocompromised patients

Heat-treated varicella-zoster vaccine (ZVHT) is a potential alternative for immunocompromised patients. A 4-dose regimen has been proven to reduce the risk of HZ in patients receiving autologous hematopoietic-cell transplants for non-Hodgkin or Hodgkin lymphoma.⁵⁷

In another trial, the 4-dose ZVHT was safe and elicited significant VZV-specific T-cell response through 28 days in immunosuppressed patients with solid tumor malignancy, hematologic malignancy, human immunodeficiency virus infection with CD4 counts of 200 cells/mm³ or less, and autologous hematopoietic-cell transplants. The T-cell response was poor in allogeneic hematopoietic-cell transplant recipients, however.⁵⁸

Because the HZ/su vaccine does not contain live virus, it seems particularly promising for immunocompromised patients. In phase 1 and 2 studies, a 3-dose regimen has been shown to be safe and immunogenic in hematopoietic-cell transplant recipients and HIV-infected adults with CD4 count higher than 200 cells/mm³.^59,60 A phase 3 trial assessing the efficacy of HZ/su vaccine in autologous hematopoietic-cell transplant recipients is under way (NCT01610414). Changes in recommendations for HZ vaccine in these most vulnerable populations await the results of these studies.

Herpes zoster (HZ), or shingles, represents a reactivation of the varicella-zoster virus (VZV). Following primary infection, usually in childhood, the virus typically lies dormant in the dorsal root and sensory nerve ganglia for decades. The precise mechanism of reactivation is not well understood, but it is associated with a decline in cell-mediated immunity that occurs with advancing age, immune-compromising conditions such as HIV infection and cancer, or immunosuppressive therapies, including corticosteroids.¹ HZ is usually a self-limited disease characterized by unilateral dermatomal rash and pain, but can cause disseminated infection in immunocompromised individuals.²

Treatment with antiviral medications within 72 hours of rash onset can reduce acute HZ symptoms.¹ However, antiviral agents are only minimally effective in preventing postherpetic neuralgia, the most common complication of HZ.³ Therefore, efforts to reduce the burden of HZ morbidity have focused on prevention through vaccination.

Currently, the only shingles vaccine approved by the US Food and Drug Administration (FDA) is Zostavax (Merck), which contains the live-attenuated Oka strain of VZV at a concentration 14 times greater than that of the varicella vaccine (Varivax, Merck). The live-attenuated vaccine boosts VZV-specific cell-mediated immunity, preventing reactivation of the latent virus.

In this article, we describe the burden of disease and review recent developments in the literature on HZ vaccine, including duration of efficacy, uptake and barriers to vaccination, cost-effectiveness, and the outlook for future vaccines.

INCIDENCE INCREASES WITH AGE

The incidence of herpes zoster in the general population is between 3 and 5 per 1,000 person-years⁴ and increases with age, especially after age 60 when the incidence can approach 13 to 15 per 1,000 person-years.^5,6 An estimated 1 million new cases occur each year in the United States, and about 6% of patients experience a second episode of HZ within 8 years.^7,8 In immunocompromised patients, the incidence of HZ is 2 to 10 times higher than in the general population.⁹

The incidence of HZ has been increasing for reasons that are unclear. After varicella vaccine was introduced into the routine childhood immunization schedule in 1995, it was hypothesized that the resultant decrease in primary varicella infections would remove a natural source of immune boosting and cause an increase in HZ incidence for up to 20 years.¹⁰ However, recent studies demonstrate that the observed increase in HZ incidence actually predates the introduction of varicella vaccine,^11–13 and the widespread use of varicella vaccine has not resulted in an increase in the incidence of HZ.¹⁴

Other potential explanations for the rise in reported incidence include increasing awareness among patients, who might previously not have sought care and among physicians, who may be more likely to make the diagnosis. Advertisement of new treatments for HZ, including gabapentin and capsaicin, probably began to increase awareness in the 1990s, as did promotion of the HZ vaccine after its licensure in 2006.

HZ can occur in people who have been vaccinated against varicella due to reactivation of the vaccine-strain virus, but the risk is lower than after infection with wild-type varicella.¹⁵ Given that the varicella vaccine has been routinely used in children for only 20 years, the long-term effect of varicella vaccination on the incidence of HZ in elderly people is unknown.

Serious complications

HZ can cause rare but serious complications including encephalitis, herpes ophthalmicus, herpes oticus, myelitis, and retinitis.¹ These can lead to long-term disability including unilateral blindness and deafness.

The most common and debilitating complication is postherpetic neuralgia, a persistent pain lasting at least 3 months, with a mean duration of 3.3 years and sometimes as long as 10 years.¹⁶ Postherpetic neuralgia occurs in 8% to 32% of patients after acute HZ,⁴ and the incidence increases with age, being most common after age 70. The chronic pain of postherpetic neuralgia has a significant adverse impact on patients’ quality of life, including physical disability and emotional distress.¹⁷ Some pain is intense, and anecdotal reports of patients committing suicide were included in the Advisory Committee on Immunization Practices (ACIP) recommendations regarding herpes zoster vaccine.¹⁸

HZ and its complications also impose a substantial economic burden on society.¹⁹ In a population-based study, the mean direct medical costs of HZ ranged from $620 to $1,160 (2015 dollars) depending on age,²⁰ and the mean costs of postherpetic neuralgia were 2 to 5 times higher than that.^20–22 Immunocompromised patients had costs 2 to 3 times higher than those of immunocompetent adults.²³ In addition, for employed patients, HZ resulted in an average loss of 32 hours of work due to absenteeism and 84 hours due to presenteeism (ie, working while sick and therefore suboptimally).²⁴

Assuming there are 1 million cases of HZ each year, if 8% to 32% of patients go on to develop postherpetic neuralgia, that would translate into approximately $1 to $2 billion in direct medical costs. With 60% of adult patients working,²⁵ at an average wage of $23.23 per hour,²⁶ HZ illness could be responsible for another $1.6 billion in lost productivity.

EFFICACY AND SAFETY OF HZ VACCINE

In 2006, the FDA approved the live-attenuated Oka strain VZV vaccine for prevention of HZ and postherpetic neuralgia in adults age 60 and older based on findings from the Shingles Prevention Study (SPS).²⁷

The Shingles Prevention Study

This multicenter randomized placebo-controlled trial²⁷ enrolled 38,546 immunocompetent persons age 60 and older. Subjects in the intervention group received a single dose of live-attenuated vaccine, and all participants were followed for up to 4.9 years after vaccination.

HZ occurred in 315 (1.636%) of the 19,254 participants in the vaccine group and in 642 (3.336%) of the 19,247 participants in the placebo group, an absolute risk reduction of 1.7%, number needed to treat 59, relative risk reduction 51%, P < .001. Similarly, postherpetic neuralgia occurred in 27 (0.140%) of the 19,254 vaccine recipients and in 80 (0.416%) of the placebo recipients (an absolute risk reduction of 0.276%, number needed to treat 362, relative risk reduction 66%, P < .001). The investigators calculated that vaccination reduced the  overall burden of illness by 61% (Table 1).

The efficacy against HZ incidence decreased with age,²⁸ but the efficacy against postherpetic neuralgia did not. In addition, vaccine recipients who developed HZ generally had less severe manifestations.

The safety of the vaccine was assessed for all participants in the SPS. In addition, one-sixth of SPS participants were enrolled in a safety substudy. These participants completed a detailed report card regarding all medically important events within the first 42 days. Forty-eight percent of the vaccine group and 17% of the placebo group (P < .05) experienced adverse events, primarily at the injection site. Less than 1% of all local reactions were severe.²⁹ Serious adverse events were rare (< 2%), but occurred significantly more often in the vaccinated group.

Short-Term Persistence Substudy

Short-term efficacy of the live-attenuated vaccine (up to 7 years) was assessed in the Short-Term Persistence Substudy (STPS), which involved 14,270 of the initial participants and reported yearly and overall vaccine efficacy.³⁰ After 5 years, the yearly efficacy against postherpetic neuralgia incidence declined to 32% and was no longer statistically significant. Efficacy against HZ incidence and burden of illness displayed the same pattern. After the end of the STPS, all subjects in the placebo group received vaccination.

Long-Term Persistence Substudy

Those in the intervention group were followed for an additional 4 years in the Long-Term Persistence Substudy (LTPS).³¹ Due to the lack of concurrent controls in the LTPS, the authors used regression models based on historical controls to estimate contemporary population incidence of HZ and postherpetic neuralgia  for comparison.

Efficacy continued to decline over time, and by 10 years after vaccination there was no difference between vaccinated patients and historical controls in the rate of any end point (ie, efficacy declined to zero).

A trial of booster vaccination

Because many patients are vaccinated at age 60, waning immunity could leave them vulnerable to HZ and postherpetic neuralgia by age 70. A potential solution would be to give a booster dose after 10 years.

A recent phase 3 clinical trial of adults age 70 years and older found that a booster dose of live-attenuated vaccine was as safe and immunogenic as an initial dose.³² While antibody responses were similar in the boosted group and the newly vaccinated group, cell-mediated immunity was higher in the boosted group.

Because prevention of HZ is generally via cell-mediated immunity, the booster might be more effective than the initial vaccination, but clinical trials measuring actual cases prevented will be required to prove it. A booster dose is not currently recommended.

A trial of vaccination in adults 50 to 59

In 2011, the FDA extended its approval of HZ vaccine for use in adults ages 50 to 59.³³

In a randomized, double-blind, placebo-controlled trial in this age group,³³ the vaccine reduced HZ incidence by almost 70% (absolute risk reduction 0.614%, number needed to treat 156; Table 1), but the severity of HZ cases was not affected. There were too few cases of postherpetic neuralgia to assess the efficacy for this end point. The study followed patients for only 1.5 years after vaccination, so the duration of efficacy is unknown.

As in the older recipients, the vaccine was well tolerated; injection-site reactions and headache were the major adverse effects reported among vaccine recipients.³³

INDICATIONS AND CONTRAINDICATIONS

Although HZ vaccine is licensed for use in adults age 50 and older, the ACIP recommends it only for immunocompetent adults age 60 and older. At this time, the ACIP does not recommend HZ vaccine in those younger than 60 because of the low risk of HZ in this age group.³⁴

Any person age 60 or older should receive a single dose of the live-attenuated HZ vaccine subcutaneously, regardless of past history of HZ.

The vaccine is contraindicated in patients who have a history of allergic reaction to any vaccine component, immunosuppression or immunodeficiency conditions, and pregnancy. Specifically, people who will receive immunosuppressive therapies should have the vaccine at least 14 days before beginning treatment. Antiviral medications such as acyclovir, famciclovir, and valacyclovir should be discontinued at least 24 hours before vaccination and not resumed until 14 days later. Patients taking high-dose corticosteroids for more than 2 weeks should not be vaccinated until at least 1 month after therapy is completed.

In contrast, HZ vaccine is not contraindicated for leukemia patients who are in remission and who have not received chemotherapy or radiation for at least 3 months, or for patients receiving short-term, low-to-moderate dose, topical, intra-articular, bursal, or tendon injections of corticosteroids. Patients on low-dose methotrexate, azathioprine, or 6-mercaptopurine can also receive the vaccine.¹⁸

VACCINATION RATES ARE LOW

Although the vaccine has been recommended since 2008, uptake has been slow. Figure 1 shows the rate of HZ vaccination in adults age 60 and older surveyed in the National Health Interview Survey from 2007 to 2013.³⁵ Eight years after the vaccine was licensed, only 28% of eligible patients had been vaccinated. Assuming the current rate of increase remains constant, it will take 7 more years to reach a 60% coverage rate—the same as for pneumococcal vaccine³⁶—and 18 years to reach universal coverage.

Barriers to vaccination

Several barriers to HZ vaccination might account for the slow uptake.

For the first few years the vaccine was available, the requirement to store it frozen presented an obstacle for some physicians.³⁷ Physicians may also have been discouraged by the cumbersome Medicare reimbursement process because while the administration fee is covered through Medicare Part B, the live­-attenuated vaccine is reimbursed only through Medicare Part D, a benefit that varies by plans. Other barriers to physicians are supply shortages, high up-front costs, and uncertainties regarding the duration of vaccine protection, its safety, and side effects.^38–40

Patient barriers include lack of physician recommendation, lack of familiarity with the vaccine, high out-of-pocket costs, the perception that they are at low risk for HZ, underestimation of the pain associated with HZ and postherpetic neuralgia, and fear of vaccine adverse effects.^39,41,42

Interventions to increase vaccination rates

Certain interventions have been shown to increase vaccination adherence in general and HZ vaccination in particular. In randomized trials involving other vaccines, electronic medical record reminders supporting panel management or nurse-initiated protocols have been proven to increase vaccination rates, but these methods have not been tested for HZ vaccine specifically.^43,44

In an observational study, Chaudhry et al found that the number of HZ vaccinations administered at the Mayo Clinic increased 43% in one practice and 54% in another after the implementation of an electronic alert.⁴⁵ A randomized controlled trial showed that an informational package discussing HZ and the vaccine sent to patients via either their electronic personal health record or traditional mail increased HZ vaccination by almost 3 times.⁴⁶

Pharmacists can also influence vaccination rates. States that provide full immunization privileges to pharmacists have vaccination rates significantly higher than states with restricted or no authorization.⁴⁷

COST-EFFECTIVENESS CONSIDERATIONS

Unlike the Centers for Medicare and Medicaid Services, the ACIP does consider cost-effectiveness in their vaccine recommendations. Because of the morbidity associated with HZ and postherpetic neuralgia as well as the economic impact, vaccination is generally considered cost-effective for adults age 60 and older.^48,49

Analyses have demonstrated that cost-effectiveness hinges on 4 factors: initial vaccine efficacy, the duration of efficacy, the age-specific incidence of HZ, and the cost of the vaccine.

For patients ages 50 to 59, the incidence of HZ is low, and because the duration of vaccine efficacy is short even though initial vaccine efficacy is high, vaccination in this age group offers poor value.⁵⁰ At older ages, the incidence of HZ and postherpetic neuralgia rises, making vaccination more cost-effective. After age 60, the vaccine is cost-effective at all ages, although age 70 appears to offer the optimal trade-off between increasing incidence and declining vaccine efficacy.^48,49

For patients who plan to be vaccinated only once, waiting until age 70 would appear to offer the best value.⁵¹ For those who are willing to receive a booster dose, the optimal age for vaccination is unknown, but will likely depend on the effectiveness, cost, and duration of the booster.

A NEW HZ VACCINE

In 2015, GlaxoSmithKline tested a new HZ vaccine containing a single VZV glycoprotein in an AS01_B adjuvant system (HZ/su vaccine).⁵² In a phase 3 randomized trial involving 15,411 immunocompetent persons age 50  and older, a 2-dose schedule of HZ/su vaccine was 97% effective in preventing HZ (Table 1).⁵³ Importantly, the vaccine was equally effective in older patients.

This vaccine also had a high rate of adverse reactions, with 17% of vaccine recipients vs 3% of placebo recipients reporting events that prevented normal everyday activities for at least 1 day. However, the rate of serious adverse reactions was the same in both groups (9%). The company announced that they intended to submit a regulatory application for HZ/su vaccine in the second half of 2016.⁵⁴

Because of its high efficacy, HZ/su vaccine has the potential to change practice, but several issues must be resolved before it can supplant the current vaccine.

First, the AS01B adjuvant is not currently licensed in the United States, so it is unclear if the HZ/su vaccine can get FDA approval.^52,55

Second, there are several questions about the efficacy of the vaccine, including long-term efficacy, efficacy in the elderly, and efficacy in the case of a patient receiving only 1 of the 2 required doses.

Third, the impact of HZ/su vaccine on complications such as postherpetic neuralgia has not been established. The clinical trial (NCT01165229) examining vaccine efficacy against postherpetic neuralgia incidence and other complications in adults age 70 and older has recently been completed and data should be available soon. Given the extremely high efficacy against HZ, it is likely that it will be close to 100% effective against this complication.

Fourth, there is uncertainty as to how the HZ/su vaccine should be used in patients who have already received the live-attenuated vaccine, if it is determined that a booster is necessary.

Finally, the vaccine is not yet priced. Given its superior effectiveness, particularly in older individuals, competitive pricing could dramatically affect the market. How Medicare or other insurers cover the new vaccine will likely influence its acceptance.

HZ VACCINATION OF IMMUNOCOMPROMISED PATIENTS

Immunocompromised patients are at highest risk for developing HZ. Unfortunately, there are currently no HZ vaccines approved for use in this population. The current live-attenuated vaccine has been demonstrated to be safe, well tolerated, and immunogenic in patients age 60 and older who are receiving chronic or maintenance low to moderate doses of corticosteroids.⁵⁶

A clinical trial is being conducted to assess the immunogenicity, clinical effectiveness, and safety of the vaccine in rheumatoid arthritis patients receiving antitumor necrosis factor therapy (NCT01967316). Other trials are examining vaccine efficacy and safety in patients with solid organ tumors prior to chemotherapy (NCT02444936) and in patients who will be undergoing living donor kidney transplantation (NCT00940940). Researchers are also investigating the possibility of vaccinating allogeneic stem cell donors before donation in order to protect transplant recipients against HZ (NCT01573182).

ZVHT and HZ/su vaccination in immunocompromised patients

Heat-treated varicella-zoster vaccine (ZVHT) is a potential alternative for immunocompromised patients. A 4-dose regimen has been proven to reduce the risk of HZ in patients receiving autologous hematopoietic-cell transplants for non-Hodgkin or Hodgkin lymphoma.⁵⁷

In another trial, the 4-dose ZVHT was safe and elicited significant VZV-specific T-cell response through 28 days in immunosuppressed patients with solid tumor malignancy, hematologic malignancy, human immunodeficiency virus infection with CD4 counts of 200 cells/mm³ or less, and autologous hematopoietic-cell transplants. The T-cell response was poor in allogeneic hematopoietic-cell transplant recipients, however.⁵⁸

Because the HZ/su vaccine does not contain live virus, it seems particularly promising for immunocompromised patients. In phase 1 and 2 studies, a 3-dose regimen has been shown to be safe and immunogenic in hematopoietic-cell transplant recipients and HIV-infected adults with CD4 count higher than 200 cells/mm³.^59,60 A phase 3 trial assessing the efficacy of HZ/su vaccine in autologous hematopoietic-cell transplant recipients is under way (NCT01610414). Changes in recommendations for HZ vaccine in these most vulnerable populations await the results of these studies.

An estimated 50 million patients with diabetes worldwide practice daily fasting during Ramadan, the ninth month of the Islamic calendar, which lasts 29 or 30 days. In the United States, Ramadan begins this year at sundown on Friday, May 26, and ends at sundown on Sunday, June 25.

See related editorial

According to the Multi-Country Retrospective Observational Study of the Management and Outcomes of Patients With Diabetes During Ramadan, conducted in 13 countries, 94.2% of Muslim diabetic patients fasted at least 15 days, and 67.6% of these fasted every day.¹

The daily fasting period, which may extend from 14 to 18 hours, starts before sunrise and ends after sunset. The meal taken before sunrise is called Suhur, and the meal after sunset is called Iftar. The fast requires abstaining from eating, drinking, sexual activity, medications, and smoking. For diabetic patients, this poses medical challenges, increasing the risk of acute metabolic complications.

The goal of caring for diabetic patients during Ramadan fasting is to help them to fast without major complications and to empower them to modify their lifestyle in order to achieve this goal.

POSSIBLE METABOLIC COMPLICATIONS

Metabolic complications during Ramadan fasting include hypoglycemia, hyperglycemia, diabetic ketoacidosis, dehydration, and thrombosis.

Hypoglycemia

For patients with type 1 diabetes, fasting increases the risk of hypoglycemia 4.7 times, and the risk is 7.5 times higher for patients with type 2 diabetes.² However, this is often underreported, as mild to moderate hypoglycemia does not usually require medical assistance.

Precipitating factors include long fasting hours, missing the Suhur meal, and failure to modify drug dosage and timing.

Hyperglycemia

The risk of severe hyperglycemia during fasting is 3.2 times higher in patients with type 1 diabetes and 5 times higher in those with type 2 diabetes.² Precipitating factors include lack of diet control during the Iftar meal and excessive reduction in the dosage of diabetes medications due to fear of hypoglycemia.

Diabetic ketoacidosis

Ketoacidosis can be precipitated by a lack of diet control during the Iftar meal, excessive reduction in the dosage of insulin due to fear of hypoglycemia, acute stress, and illness or infection.

Dehydration and thrombosis

Patients can become dehydrated during long fasting hours in especially hot weather, by sweating during physical activity, and by osmotic diuresis in poorly controlled diabetes.

Diabetes is a procoagulant condition, and dehydration increases the risk of thrombosis.

OVERALL MANAGEMENT GOALS DURING RAMADAN FASTING

Important aspects of managing diabetes during Ramadan fasting are:

• The pre-Ramadan evaluation and risk stratification
• Promoting patient awareness with Ramadan-focused diabetes education
• Providing instruction on dietary modification
• Modification of the dosage and timing of diabetes medication
• Encouraging frequent monitoring of blood glucose levels
• Advising the patient when to break the fast
• Managing complications.

PRE-RAMADAN MEDICAL EVALUATION AND RISK STRATIFICATION

All diabetic patients who fast during Ramadan should undergo an evaluation 1 or 2 months before the start of Ramadan to determine their level of diabetes control and the presence of acute and chronic complications of diabetes and other comorbid conditions. Also important is to determine the patient’s social circumstances, ie, knowledge about diabetes, socioeconomic factors, religious beliefs, educational status, diabetes self-management skills, and family support in case of hypoglycemia or complications.

The evaluation helps to determine the patient’s risk of diabetes-related complications from Ramadan fasting, which is categorized as very high, high, or moderate/low according to the criteria of the International Diabetes Federation (Table 1).³ Patients should be advised as to the feasibility of fasting based on this risk categorization.

Even though the recommendation is to avoid fasting if the risk is very high or high, many patients fast. But patients should be advised about Islamic regulations exempting people from fasting (Table 2).⁴

RAMADAN-FOCUSED DIABETES EDUCATION

Improving the patient’s awareness of the risks of Ramadan fasting reduces the chance of complications. Education should include information on diet and exercise, changes in the timing and dosing of medications, signs and symptoms of hypoglycemia and hyperglycemia, the importance of monitoring blood glucose levels on fasting days, and the importance of breaking the fast in case of complications.⁵

All diabetic patients should be encouraged to remember to eat the predawn meal on fasting days. They should maintain a balanced diet, with complex carbohydrates with slow energy release for the predawn meal and simple carbohydrates for the sunset meal. Foods with a low glycemic index and high fiber content are recommended, and patients should be advised to avoid saturated fats and to drink plenty of fluids between sunset and sunrise to avoid dehydration.⁶

Diabetic patients can perform their usual physical activity, including moderate exercise, but should avoid excessive physical activity especially toward evening hours to prevent hypoglycemia.

Some patients may decide not to monitor their blood glucose as they believe that pricking the finger for blood sugar testing breaks the fast.⁷ Patients should be advised that this is a misconception.

ADJUSTING DIABETES MEDICATIONS

Oral diabetes drugs

Drugs such as metformin, alpha glucosidase inhibitors, thiazolidinediones, the short-acting insulin secretagogue nateglinide, dipeptidyl peptidase 4 inhibitors (eg, sitagliptin), and glucagon-like peptide 1 receptor agonists are associated with a lower risk of hypoglycemia and can be used during Ramadan fasting without significant changes in the daily dose (Table 3).⁸

Sulfonylureas carry a higher risk of hypoglycemia and should be used cautiously during fasting, with appropriate modification in dose and timing.^9,10

Sodium-glucose cotransporter 2 inhibitors, when not combined with insulin or sulfonylureas, carry a lower risk of hypoglycemia, but during Ramadan fasting there is an increased risk of dehydration, urinary tract infection, and postural hypotension since fluids cannot be taken during fasting hours.

Dipeptidyl peptidase 4 inhibitors carry a low risk of hypoglycemia and can be used during Ramadan without dosing modification. Glucagon-like peptide 1 agonists also can be used without adjusting the dosage.¹¹

Insulins

Insulin treatment is associated with a higher risk of hypoglycemia during Ramadan fasting.¹² During fasting, the risk of hypoglycemia from premixed insulin can be minimized by changing to a multiple-dose regimen involving a basal insulin and short-acting insulin before meals, with adjustment of the short- acting insulin dose based on the anticipated carbohydrate intake for each meal.¹³

Patients taking premixed insulin preparations consisting of 70% intermediate-acting or long-acting insulin and 30% short-acting insulin should change to a 50/50 preparation during Ramadan fasting to reduce hypoglycemic risk and improve glycemic control; taking more of the fast-acting component controls postprandial hyperglycemia, and taking less of the intermediate or long-acting component minimizes the risk of hypoglycemia during fasting hours.^14,15

Insulin analogues carry a lower risk of hypoglycemia than human insulin. Compared with a human insulin 70/30 preparation, an analogue premix containing 75% neutral protamine lispro and 25% insulin lispro resulted in better glycemic control during Ramadan fasting.¹⁶ This could be related to the pharmacodynamics of low-ratio premix analogues, as well as to the mealtime flexibility of analogue insulin, as the injections of the 75/25 mix were given immediately before the morning and evening meals. Insulin analogues are also less likely to cause postprandial hypoglycemia.¹⁶

A multiple-dose insulin regimen involving a long-acting basal insulin (eg, glargine, detemir, degludec) and a short-acting insulin (eg, glulisine, aspart, lispro) before meals is preferred in view of better glycemic control and lower risk of hypoglycemia.¹⁷

Use of an insulin pump during Ramadan is associated with a reduced risk of hypoglycemia.¹⁸ In patients with an insulin pump, the rate of basal insulin must be reduced during daytime, and the postprandial bolus of insulin must be increased after breaking the fast.

FREQUENT MONITORING OF BLOOD GLUCOSE DURING FASTING

Frequent monitoring reduces the risk of both hypoglycemia and hyperglycemia and helps control blood sugar levels during Ramadan fasting. As mentioned above, pricking the finger for blood sugar testing during fasting hours does not break the fast, and this should be emphasized during Ramadan-focused diabetes education.

The exact frequency of blood sugar testing is not defined. In patients with well-controlled diabetes without complications, testing once or twice a day is enough. Patients with poorly controlled diabetes and those with complications should test more often.

ADVICE REGARDING WHEN TO BREAK THE FAST

If signs or symptoms of hypoglycemia develop, the patient should break the fast in order to avoid serious complications. This is acceptable under Islamic law.^3,19–21

MANAGEMENT OF COMPLICATIONS

Management of diabetic complications in patients during Ramadan fasting is similar to that for other diabetic patients and includes management of hypo- and hyperglycemia, diabetic ketoacidosis, and dehydration.

An estimated 50 million patients with diabetes worldwide practice daily fasting during Ramadan, the ninth month of the Islamic calendar, which lasts 29 or 30 days. In the United States, Ramadan begins this year at sundown on Friday, May 26, and ends at sundown on Sunday, June 25.

See related editorial

According to the Multi-Country Retrospective Observational Study of the Management and Outcomes of Patients With Diabetes During Ramadan, conducted in 13 countries, 94.2% of Muslim diabetic patients fasted at least 15 days, and 67.6% of these fasted every day.¹

The daily fasting period, which may extend from 14 to 18 hours, starts before sunrise and ends after sunset. The meal taken before sunrise is called Suhur, and the meal after sunset is called Iftar. The fast requires abstaining from eating, drinking, sexual activity, medications, and smoking. For diabetic patients, this poses medical challenges, increasing the risk of acute metabolic complications.

The goal of caring for diabetic patients during Ramadan fasting is to help them to fast without major complications and to empower them to modify their lifestyle in order to achieve this goal.

POSSIBLE METABOLIC COMPLICATIONS

Metabolic complications during Ramadan fasting include hypoglycemia, hyperglycemia, diabetic ketoacidosis, dehydration, and thrombosis.

Hypoglycemia

For patients with type 1 diabetes, fasting increases the risk of hypoglycemia 4.7 times, and the risk is 7.5 times higher for patients with type 2 diabetes.² However, this is often underreported, as mild to moderate hypoglycemia does not usually require medical assistance.

Precipitating factors include long fasting hours, missing the Suhur meal, and failure to modify drug dosage and timing.

Hyperglycemia

The risk of severe hyperglycemia during fasting is 3.2 times higher in patients with type 1 diabetes and 5 times higher in those with type 2 diabetes.² Precipitating factors include lack of diet control during the Iftar meal and excessive reduction in the dosage of diabetes medications due to fear of hypoglycemia.

Diabetic ketoacidosis

Ketoacidosis can be precipitated by a lack of diet control during the Iftar meal, excessive reduction in the dosage of insulin due to fear of hypoglycemia, acute stress, and illness or infection.

Dehydration and thrombosis

Patients can become dehydrated during long fasting hours in especially hot weather, by sweating during physical activity, and by osmotic diuresis in poorly controlled diabetes.

Diabetes is a procoagulant condition, and dehydration increases the risk of thrombosis.

OVERALL MANAGEMENT GOALS DURING RAMADAN FASTING

Important aspects of managing diabetes during Ramadan fasting are:

• The pre-Ramadan evaluation and risk stratification
• Promoting patient awareness with Ramadan-focused diabetes education
• Providing instruction on dietary modification
• Modification of the dosage and timing of diabetes medication
• Encouraging frequent monitoring of blood glucose levels
• Advising the patient when to break the fast
• Managing complications.

PRE-RAMADAN MEDICAL EVALUATION AND RISK STRATIFICATION

All diabetic patients who fast during Ramadan should undergo an evaluation 1 or 2 months before the start of Ramadan to determine their level of diabetes control and the presence of acute and chronic complications of diabetes and other comorbid conditions. Also important is to determine the patient’s social circumstances, ie, knowledge about diabetes, socioeconomic factors, religious beliefs, educational status, diabetes self-management skills, and family support in case of hypoglycemia or complications.

The evaluation helps to determine the patient’s risk of diabetes-related complications from Ramadan fasting, which is categorized as very high, high, or moderate/low according to the criteria of the International Diabetes Federation (Table 1).³ Patients should be advised as to the feasibility of fasting based on this risk categorization.

Even though the recommendation is to avoid fasting if the risk is very high or high, many patients fast. But patients should be advised about Islamic regulations exempting people from fasting (Table 2).⁴

RAMADAN-FOCUSED DIABETES EDUCATION

Improving the patient’s awareness of the risks of Ramadan fasting reduces the chance of complications. Education should include information on diet and exercise, changes in the timing and dosing of medications, signs and symptoms of hypoglycemia and hyperglycemia, the importance of monitoring blood glucose levels on fasting days, and the importance of breaking the fast in case of complications.⁵

All diabetic patients should be encouraged to remember to eat the predawn meal on fasting days. They should maintain a balanced diet, with complex carbohydrates with slow energy release for the predawn meal and simple carbohydrates for the sunset meal. Foods with a low glycemic index and high fiber content are recommended, and patients should be advised to avoid saturated fats and to drink plenty of fluids between sunset and sunrise to avoid dehydration.⁶

Diabetic patients can perform their usual physical activity, including moderate exercise, but should avoid excessive physical activity especially toward evening hours to prevent hypoglycemia.

Some patients may decide not to monitor their blood glucose as they believe that pricking the finger for blood sugar testing breaks the fast.⁷ Patients should be advised that this is a misconception.

ADJUSTING DIABETES MEDICATIONS

Oral diabetes drugs

Drugs such as metformin, alpha glucosidase inhibitors, thiazolidinediones, the short-acting insulin secretagogue nateglinide, dipeptidyl peptidase 4 inhibitors (eg, sitagliptin), and glucagon-like peptide 1 receptor agonists are associated with a lower risk of hypoglycemia and can be used during Ramadan fasting without significant changes in the daily dose (Table 3).⁸

Sulfonylureas carry a higher risk of hypoglycemia and should be used cautiously during fasting, with appropriate modification in dose and timing.^9,10

Sodium-glucose cotransporter 2 inhibitors, when not combined with insulin or sulfonylureas, carry a lower risk of hypoglycemia, but during Ramadan fasting there is an increased risk of dehydration, urinary tract infection, and postural hypotension since fluids cannot be taken during fasting hours.

Dipeptidyl peptidase 4 inhibitors carry a low risk of hypoglycemia and can be used during Ramadan without dosing modification. Glucagon-like peptide 1 agonists also can be used without adjusting the dosage.¹¹

Insulins

Insulin treatment is associated with a higher risk of hypoglycemia during Ramadan fasting.¹² During fasting, the risk of hypoglycemia from premixed insulin can be minimized by changing to a multiple-dose regimen involving a basal insulin and short-acting insulin before meals, with adjustment of the short- acting insulin dose based on the anticipated carbohydrate intake for each meal.¹³

Patients taking premixed insulin preparations consisting of 70% intermediate-acting or long-acting insulin and 30% short-acting insulin should change to a 50/50 preparation during Ramadan fasting to reduce hypoglycemic risk and improve glycemic control; taking more of the fast-acting component controls postprandial hyperglycemia, and taking less of the intermediate or long-acting component minimizes the risk of hypoglycemia during fasting hours.^14,15

Insulin analogues carry a lower risk of hypoglycemia than human insulin. Compared with a human insulin 70/30 preparation, an analogue premix containing 75% neutral protamine lispro and 25% insulin lispro resulted in better glycemic control during Ramadan fasting.¹⁶ This could be related to the pharmacodynamics of low-ratio premix analogues, as well as to the mealtime flexibility of analogue insulin, as the injections of the 75/25 mix were given immediately before the morning and evening meals. Insulin analogues are also less likely to cause postprandial hypoglycemia.¹⁶

A multiple-dose insulin regimen involving a long-acting basal insulin (eg, glargine, detemir, degludec) and a short-acting insulin (eg, glulisine, aspart, lispro) before meals is preferred in view of better glycemic control and lower risk of hypoglycemia.¹⁷

Use of an insulin pump during Ramadan is associated with a reduced risk of hypoglycemia.¹⁸ In patients with an insulin pump, the rate of basal insulin must be reduced during daytime, and the postprandial bolus of insulin must be increased after breaking the fast.

FREQUENT MONITORING OF BLOOD GLUCOSE DURING FASTING

Frequent monitoring reduces the risk of both hypoglycemia and hyperglycemia and helps control blood sugar levels during Ramadan fasting. As mentioned above, pricking the finger for blood sugar testing during fasting hours does not break the fast, and this should be emphasized during Ramadan-focused diabetes education.

The exact frequency of blood sugar testing is not defined. In patients with well-controlled diabetes without complications, testing once or twice a day is enough. Patients with poorly controlled diabetes and those with complications should test more often.

ADVICE REGARDING WHEN TO BREAK THE FAST

If signs or symptoms of hypoglycemia develop, the patient should break the fast in order to avoid serious complications. This is acceptable under Islamic law.^3,19–21

MANAGEMENT OF COMPLICATIONS

Management of diabetic complications in patients during Ramadan fasting is similar to that for other diabetic patients and includes management of hypo- and hyperglycemia, diabetic ketoacidosis, and dehydration.

An estimated 50 million patients with diabetes worldwide practice daily fasting during Ramadan, the ninth month of the Islamic calendar, which lasts 29 or 30 days. In the United States, Ramadan begins this year at sundown on Friday, May 26, and ends at sundown on Sunday, June 25.

See related editorial

According to the Multi-Country Retrospective Observational Study of the Management and Outcomes of Patients With Diabetes During Ramadan, conducted in 13 countries, 94.2% of Muslim diabetic patients fasted at least 15 days, and 67.6% of these fasted every day.¹

The daily fasting period, which may extend from 14 to 18 hours, starts before sunrise and ends after sunset. The meal taken before sunrise is called Suhur, and the meal after sunset is called Iftar. The fast requires abstaining from eating, drinking, sexual activity, medications, and smoking. For diabetic patients, this poses medical challenges, increasing the risk of acute metabolic complications.

The goal of caring for diabetic patients during Ramadan fasting is to help them to fast without major complications and to empower them to modify their lifestyle in order to achieve this goal.

POSSIBLE METABOLIC COMPLICATIONS

Metabolic complications during Ramadan fasting include hypoglycemia, hyperglycemia, diabetic ketoacidosis, dehydration, and thrombosis.

Hypoglycemia

For patients with type 1 diabetes, fasting increases the risk of hypoglycemia 4.7 times, and the risk is 7.5 times higher for patients with type 2 diabetes.² However, this is often underreported, as mild to moderate hypoglycemia does not usually require medical assistance.

Precipitating factors include long fasting hours, missing the Suhur meal, and failure to modify drug dosage and timing.

Hyperglycemia

The risk of severe hyperglycemia during fasting is 3.2 times higher in patients with type 1 diabetes and 5 times higher in those with type 2 diabetes.² Precipitating factors include lack of diet control during the Iftar meal and excessive reduction in the dosage of diabetes medications due to fear of hypoglycemia.

Diabetic ketoacidosis

Ketoacidosis can be precipitated by a lack of diet control during the Iftar meal, excessive reduction in the dosage of insulin due to fear of hypoglycemia, acute stress, and illness or infection.

Dehydration and thrombosis

Patients can become dehydrated during long fasting hours in especially hot weather, by sweating during physical activity, and by osmotic diuresis in poorly controlled diabetes.

Diabetes is a procoagulant condition, and dehydration increases the risk of thrombosis.

OVERALL MANAGEMENT GOALS DURING RAMADAN FASTING

Important aspects of managing diabetes during Ramadan fasting are:

• The pre-Ramadan evaluation and risk stratification
• Promoting patient awareness with Ramadan-focused diabetes education
• Providing instruction on dietary modification
• Modification of the dosage and timing of diabetes medication
• Encouraging frequent monitoring of blood glucose levels
• Advising the patient when to break the fast
• Managing complications.

PRE-RAMADAN MEDICAL EVALUATION AND RISK STRATIFICATION

All diabetic patients who fast during Ramadan should undergo an evaluation 1 or 2 months before the start of Ramadan to determine their level of diabetes control and the presence of acute and chronic complications of diabetes and other comorbid conditions. Also important is to determine the patient’s social circumstances, ie, knowledge about diabetes, socioeconomic factors, religious beliefs, educational status, diabetes self-management skills, and family support in case of hypoglycemia or complications.

The evaluation helps to determine the patient’s risk of diabetes-related complications from Ramadan fasting, which is categorized as very high, high, or moderate/low according to the criteria of the International Diabetes Federation (Table 1).³ Patients should be advised as to the feasibility of fasting based on this risk categorization.

Even though the recommendation is to avoid fasting if the risk is very high or high, many patients fast. But patients should be advised about Islamic regulations exempting people from fasting (Table 2).⁴

RAMADAN-FOCUSED DIABETES EDUCATION

Improving the patient’s awareness of the risks of Ramadan fasting reduces the chance of complications. Education should include information on diet and exercise, changes in the timing and dosing of medications, signs and symptoms of hypoglycemia and hyperglycemia, the importance of monitoring blood glucose levels on fasting days, and the importance of breaking the fast in case of complications.⁵

All diabetic patients should be encouraged to remember to eat the predawn meal on fasting days. They should maintain a balanced diet, with complex carbohydrates with slow energy release for the predawn meal and simple carbohydrates for the sunset meal. Foods with a low glycemic index and high fiber content are recommended, and patients should be advised to avoid saturated fats and to drink plenty of fluids between sunset and sunrise to avoid dehydration.⁶

Diabetic patients can perform their usual physical activity, including moderate exercise, but should avoid excessive physical activity especially toward evening hours to prevent hypoglycemia.

Some patients may decide not to monitor their blood glucose as they believe that pricking the finger for blood sugar testing breaks the fast.⁷ Patients should be advised that this is a misconception.

ADJUSTING DIABETES MEDICATIONS

Oral diabetes drugs

Drugs such as metformin, alpha glucosidase inhibitors, thiazolidinediones, the short-acting insulin secretagogue nateglinide, dipeptidyl peptidase 4 inhibitors (eg, sitagliptin), and glucagon-like peptide 1 receptor agonists are associated with a lower risk of hypoglycemia and can be used during Ramadan fasting without significant changes in the daily dose (Table 3).⁸

Sulfonylureas carry a higher risk of hypoglycemia and should be used cautiously during fasting, with appropriate modification in dose and timing.^9,10

Sodium-glucose cotransporter 2 inhibitors, when not combined with insulin or sulfonylureas, carry a lower risk of hypoglycemia, but during Ramadan fasting there is an increased risk of dehydration, urinary tract infection, and postural hypotension since fluids cannot be taken during fasting hours.

Dipeptidyl peptidase 4 inhibitors carry a low risk of hypoglycemia and can be used during Ramadan without dosing modification. Glucagon-like peptide 1 agonists also can be used without adjusting the dosage.¹¹

Insulins

Insulin treatment is associated with a higher risk of hypoglycemia during Ramadan fasting.¹² During fasting, the risk of hypoglycemia from premixed insulin can be minimized by changing to a multiple-dose regimen involving a basal insulin and short-acting insulin before meals, with adjustment of the short- acting insulin dose based on the anticipated carbohydrate intake for each meal.¹³

Patients taking premixed insulin preparations consisting of 70% intermediate-acting or long-acting insulin and 30% short-acting insulin should change to a 50/50 preparation during Ramadan fasting to reduce hypoglycemic risk and improve glycemic control; taking more of the fast-acting component controls postprandial hyperglycemia, and taking less of the intermediate or long-acting component minimizes the risk of hypoglycemia during fasting hours.^14,15

Insulin analogues carry a lower risk of hypoglycemia than human insulin. Compared with a human insulin 70/30 preparation, an analogue premix containing 75% neutral protamine lispro and 25% insulin lispro resulted in better glycemic control during Ramadan fasting.¹⁶ This could be related to the pharmacodynamics of low-ratio premix analogues, as well as to the mealtime flexibility of analogue insulin, as the injections of the 75/25 mix were given immediately before the morning and evening meals. Insulin analogues are also less likely to cause postprandial hypoglycemia.¹⁶

A multiple-dose insulin regimen involving a long-acting basal insulin (eg, glargine, detemir, degludec) and a short-acting insulin (eg, glulisine, aspart, lispro) before meals is preferred in view of better glycemic control and lower risk of hypoglycemia.¹⁷

Use of an insulin pump during Ramadan is associated with a reduced risk of hypoglycemia.¹⁸ In patients with an insulin pump, the rate of basal insulin must be reduced during daytime, and the postprandial bolus of insulin must be increased after breaking the fast.

FREQUENT MONITORING OF BLOOD GLUCOSE DURING FASTING

Frequent monitoring reduces the risk of both hypoglycemia and hyperglycemia and helps control blood sugar levels during Ramadan fasting. As mentioned above, pricking the finger for blood sugar testing during fasting hours does not break the fast, and this should be emphasized during Ramadan-focused diabetes education.

The exact frequency of blood sugar testing is not defined. In patients with well-controlled diabetes without complications, testing once or twice a day is enough. Patients with poorly controlled diabetes and those with complications should test more often.

ADVICE REGARDING WHEN TO BREAK THE FAST

If signs or symptoms of hypoglycemia develop, the patient should break the fast in order to avoid serious complications. This is acceptable under Islamic law.^3,19–21

MANAGEMENT OF COMPLICATIONS

Management of diabetic complications in patients during Ramadan fasting is similar to that for other diabetic patients and includes management of hypo- and hyperglycemia, diabetic ketoacidosis, and dehydration.

Contrary to common belief, pregnancy does not confer protection against depression.^1,2 In fact, pregnant women are just as likely as nonpregnant women to become or remain depressed, and up to 12.7% of pregnant women meet criteria for depression.¹

In the postpartum period, women are particularly vulnerable to a major depressive episode, whether a first episode or a recurrence. The estimated prevalence of a depressive episode in the first 3 postpartum  months is 19.2%,² making postpartum depression the most common complication of childbearing.² At the same time, peripartum depression remains largely underrecognized and undertreated.³

As evidence mounts regarding the deleterious impact of untreated mental illness on the mother, the developing fetus, and the infant, early detection and intervention for peripartum depression are paramount.³

DEPRESSION DURING PREGNANCY: SIGNIFICANT CONSEQUENCES

Although the rates of depression in pregnant and nonpregnant women are similar, depression in pregnancy carries additional significant consequences. Further, many depressed pregnant women believe their depression will lift once their baby is born, though it is well documented that depression during pregnancy is the strongest predictor of postpartum depression and that if left untreated it can be devastating for mother, infant, and family.⁴

Compared with nondepressed pregnant women, depressed pregnant women have poorer overall health status,⁵ are more likely to engage in behaviors that pose risk to the developing fetus such as smoking,⁵ alcohol consumption, and substance use,⁶ and have poor nutrition and inadequate weight gain.^7,8

Pregnant women who are depressed and are also experiencing domestic violence are especially at risk for poor prenatal care as they tend to miss more prenatal appointments.⁹ Evidence also suggests that depressed pregnant women are less attached to the fetus and more likely to have elective terminations.^10,11

Depression in pregnancy is associated with higher rates of adverse pregnancy outcomes such as preterm birth, low birth weight, operative delivery, and longer predelivery hospital stay.^3,12 Depression and anxiety during pregnancy have been associated with prenatal hypertension,¹³ gestational diabetes,¹⁴ preeclampsia,¹⁵ and HELLP syndrome (ie, hemolysis, elevated liver enzymes, and low platelet count).¹⁵ Depression and anxiety during pregnancy are associated with subsequent poorer infant attachment^16,17 and an overall unfavorable impact on infant and child development.¹⁸

Risk factors for depression during pregnancy include past episodes of depression, current anxiety, poor social support, unintended pregnancy, life stress, being single, domestic violence, and being on Medicaid.¹⁹

Undoubtedly the most devastating consequence of severe depression during pregnancy is suicide. Rates of suicide are lower in peripartum women,²⁰ but when suicide does occur, pregnant women tend to use more violent means than nonpregnant women. Pregnant adolescents represent a particularly high-risk group.²¹

POSTPARTUM DEPRESSION

Postpartum depression is the most common complication of childbearing. Although the precise pathogenesis is undetermined, there is converging evidence of a subset of women particularly sensitive to dramatic fluctuations in levels of estradiol and progesterone that occur during childbirth.^22,23 There is also evidence that dysregulation of the hypothalamic-pituitary-adrenal axis contributes to the development of postpartum depression in certain women.²⁴ Further, women who have depression or anxiety during pregnancy are much more likely to experience postpartum depression than those who are not symptomatic during pregnancy.⁴ A history of peripartum depression or other lifetime depressive episodes, poverty, conflict with a primary partner, poor social support, stressful life events, and low self-esteem are strongly associated with postpartum depression.²⁵

When unrecognized and untreated, postpartum depression can have profound and persistent effects on the mother and the developing infant.^18,26 Mothers with postpartum depression are much more likely than mothers without depression to have impaired bonding,²⁷ to be less responsive to their infant’s needs,¹⁷ and to be more likely to miss well-baby checkups.²⁸

Postpartum depression’s effects on maternal-infant interactions can include maternal withdrawal, disengagement, intrusion, and hostility and can lead to long-term effects on child development, including poor cognitive functioning, emotional maladjustment, and behavioral inhibition.^29,30 Infants and children of mothers with untreated postpartum depression have been shown to exhibit a higher incidence of colic, excessive crying, sleep problems, and irritability.^31,32 Women with postpartum depression may be less likely to initiate or maintain breastfeeding, and depressive symptoms have been noted to precede the discontinuation of breastfeeding.^33–35

Risk factors for postpartum depression

Characteristics to look for in the prenatal care of pregnant women include the following:

• Depression during pregnancy
• History of postpartum or other depressive episode
• Poverty
• Conflict with primary partner
• Poor social support
• Low self-esteem
• Single status.

Primary care providers are often the first point of contact for depressed women. The diagnosis of major depression in pregnant and postpartum women is challenging because of changes in sleep, appetite, and energy brought on by pregnancy, complications of delivery, and demands of caring for a newborn.³⁶ Many pregnant and postpartum women are reluctant to disclose their symptoms due to a sense of shame and guilt for being depressed during a time in their life that society commonly regards as joyful, and this contributes to under-detection.

In the first few days postpartum, fatigue, emotionality, irritability, and worry over the infant’s well-being affect up to 75% of women. This period, typically referred to as the “baby blues” or “postpartum blues,” is not considered a disorder and responds well to support, reassurance, and adequate sleep, and it typically resolves within 2 weeks.^37,38 Table 1 lists features that help distinguish postpartum blues from major depression.

Signs of major depressive disorder

Major depressive disorder is a serious and disabling condition. To meet criteria for major depressive disorder, women must report depressed mood and loss of interest or pleasure in normally pleasurable activities for at least 2 weeks. Completing the symptom profile, at least 5 of the following must be present: sleep disturbance (insomnia or hypersomnia), lack of energy, feelings of worthlessness or low self-esteem, guilt, difficulty concentrating, indecisiveness, psychomotor retardation or agitation, and thoughts of suicide or death.

The Diagnostic and Statistical Manual of Mental Disorders (5th edition) recognizes that postpartum depression commonly begins during pregnancy, and now uses “peripartum onset” as the specifier for major depressive disorder that occurs during pregnancy, postpartum, or both.³⁹ Other hallmark symptoms with peripartum onset include a lack of interest in or attachment to the pregnancy or infant, and anxiety and worry often accompanied by intrusive, unwanted thoughts of harm befalling the infant.⁴⁰

Postpartum psychosis

Postpartum psychosis is a far less common presentation, occurring in 1 to 2 per 1,000 births, but it constitutes a psychiatric emergency requiring immediate referral to a psychiatric care setting. Women at highest risk are those with a personal or family history of bipolar disorder.

The clinical presentation is most commonly characterized by confusion, agitation, hallucinations, delusional beliefs, and disorientation. Suicide and infanticide, while rare, are more likely to occur in the context of a psychotic episode.⁴¹

SCREENING RECOMMENDATIONS

Screening for depression is routine in primary care settings and is no less important for peripartum women.

In 2016, the US Preventive Services Task Force issued a recommendation that all pregnant and postpartum women be screened for depression,⁴² highlighting the need for all medical providers to be alert to the potentially serious consequences of unrecognized and untreated maternal psychiatric illness.

The American College of Obstetricians and Gynecologists (ACOG) recommends screening for depression and anxiety at least once during the peripartum period,⁴³ and the American Academy of Pediatrics recommends screening mothers for depression at the 1-, 2-, and 4-month well-baby visits.⁴⁴

The peripartum period is associated with changes in sleep, appetite, and energy levels, but these are also typical of depression. Taking this into account, the Edinburgh Postnatal Depression Scale (EPDS) was developed to screen for depression specifically in this population.⁴⁵ The EPDS is a validated and widely used 10-item self-reporting questionnaire with a high degree of sensitivity and specificity; it is easily administered and quickly scored. A cutoff score of 13 (of a maximum of 30) is considered indicative of depressed mood and signals the need for further assessment.

Source: Kroenke K, Spitzer RL, Williams JB. The PHQ-9: Validity of a brief depression severity measure. J Gen In-tern Med 2001; 16:606–616. No permission required to reproduce, translate, display, or distribute.

ACOG, the American Academy of Pediatrics, and the US Preventive Services Task Force recommend a standardized validated tool and cite both the EPDS (https://psychology-tools.com/epds/) and the Patient Health Questionnaire-9 (PHQ-9) (Figure 1) as appropriate to screen for peripartum depression.^42–44 Primary care providers tend to be most familiar with the PHQ-9, a highly sensitive and specific 9-item depression screen that has been validated in primary care and obstetric clinic patients.⁴⁶ A score on the PHQ-9 ranging from 5 to 10 indicates mild depression, 10 to 14 moderate depression, 15 to 19 moderate to severe depression, and greater than 19 severe depression.

Many women prefer nondrug therapy

The gold standard treatment for moderate to severe major depressive disorder is psychotherapy plus pharmacotherapy. Yet many peripartum women voice concerns about exposure to pharmacologic treatment, and studies have shown that many women prefer nonpharmacologic intervention.⁴⁷

Evidence-based psychotherapies that have demonstrated efficacy in peripartum women include cognitive behavioral therapy⁴⁸ and interpersonal psychotherapy when administered by a psychotherapist trained in these treatments. Pregnant and breastfeeding women often express preference for psychotherapy and complementary and alternative treatments as a means of avoiding fetal and infant exposure to antidepressants.⁴⁷

For mild to moderate depression, complementary therapies such as exercise, yoga, bright light therapy, and acupuncture have shown efficacy and can be used alone or adjunctively.⁴⁹ Because a poor marital relationship is consistently associated with peripartum depression,²⁵ primary care physicians who routinely address social support and screen for family conflict are well positioned to detect this significant correlate and to recommend marital or family therapy as a primary or adjunctive treatment.

When to consider drug therapy

The decision to recommend drug therapy must be individualized and based on the severity of symptoms, functional impairment, number and frequency of depressive episodes, history of response to medications, and the preferences of the patient, with the recognition that no decision is risk-free and that antidepressants enter the amniotic fluid, so fetal exposure is unavoidable.

Table 2 lists common antidepressants. The antidepressants most commonly prescribed, especially in the primary care setting, are selective serotonin reuptake inhibitors (SSRIs), which are favored because of their effectiveness, low side-effect profile, and lack of overdose toxicity.

Serotonin syndrome is no more likely to occur in pregnant than in nonpregnant women. Close monitoring for this condition is warranted only when patients are taking very  high doses of SSRIs or SSRIs in combination with other serotonergic agonists.

Prescribing antidepressants for pregnant or breastfeeding women requires thoughtful consideration of the patient’s preferences, as well as weighing the risks and benefits of fetal and infant exposure to maternal depression vs exposure to medications. Additional considerations include monotherapy, avoiding medication changes, choosing drugs that have been effective in the past, and avoiding drugs with known drug-drug interactions or teratogenic effects.⁵⁰

There is increasing consensus that the short- and long-term consequences of undertreatment or nontreatment of maternal depression outweigh the risk of fetal exposure to SSRIs.^3,51,52 Cohen et al⁵³ have recommended that if a woman is on an antidepressant and learns she is pregnant, she should not discontinue it because of the likelihood of relapse; they found a 68% relapse rate in women who discontinued their antidepressant in the first trimester of pregnancy.⁵³

In a comprehensive review of studies published between 1996 and 2012 that examined antidepressant use during pregnancy, Byatt et al⁵⁴ found little or no evidence of increased teratogenic risk with antidepressants with the exception of paroxetine, which is associated with a small but significant increased risk of cardiac malformation during first-trimester exposure.⁵⁴

These conclusions were underscored in a large cohort study in the United Kingdom.⁵⁵ In addition, a joint task force of the American Psychiatric Association and ACOG reviewed studies looking at the association between depression, antidepressants, and birth outcomes including miscarriage, preterm birth, cardiac abnormalities (resulting from first trimester exposure), persistent pulmonary hypertension (related to second- and third-trimester exposure), and neonatal adaptation syndrome (associated with third-trimester exposure).⁸ They concluded that the available data neither support nor refute a link between the use of antidepressants and several of the above outcomes. No increase in risk of congenital malformations (including cardiac abnormalities) was found. An increased risk of persistent pulmonary hypertension was noted, although the absolute risk of this disorder remained low, at 3 to 6 per 1,000 infants exposed to SSRIs in utero.^8,56

Neonatal adaptation syndrome

Neonatal adaptation syndrome is characterized by jitteriness, irritability, decreased muscle tone, and feeding difficulty in the neonate. It can occur in 15% to 30% of infants exposed to SSRIs antenatally.^57,58 These symptoms, however, are transient and typically resolve within 7 to 10 days after birth. A more recent study suggested that neurobehavioral symptoms for some infants extend beyond 2 weeks and that concomitant exposure to benzodiazepines results in even higher rates of this syndrome.⁵⁹ There is no evidence that tapering or discontinuing antidepressants near term is necessary, safe, or effective in preventing transient neonatal complications. However, this approach would increase the risk of relapse for the mother.

Autism spectrum disorders

The possible association between antidepressants and autism spectrum disorders in pregnancy has captured much attention in recent years. One study based on healthcare claims⁶⁰ and one registry-based study⁶¹ associated in utero exposure to antidepressants with autism liability in children. However, a large-scale Danish registry-based study did not replicate this association.⁶² In addition, 2 recent cohort studies, identifying children with autism spectrum disorder or attention-deficit hyperactivity disorder from electronic health records, found that neither disorder was significantly associated with prenatal antidepressant exposure in crude or adjusted models. However, both studies found a significant association with the use of antidepressants before pregnancy, indicating that the risk of autism observed with prenatal antidepressant exposure is likely confounded by the severity of maternal illness.^63,64

Concerns about drug therapy during breastfeeding

For infants of breastfeeding women, exposure to antidepressants through breast milk is minimal. Amounts in breast milk depend on the timing of the antidepressant dose, timing of feeding, and genetically influenced metabolic activity in mother and infant. The current literature supports antidepressant use for breastfeeding mothers of healthy full-term infants.⁶⁵

The 2 most widely studied antidepressants in breastfed infants are paroxetine and sertraline. It has been shown that very little can be detected in the infant’s serum, with relative infant doses ranging from 0.4% to 2.8%.⁶⁵ While clinicians are cautioned against prescribing paroxetine for pregnant women, the drug remains a suitable alternative for breastfeeding women.

If an antidepressant is started postpartum, the recommendation is to start with a low dose and then slowly titrate upward while monitoring the infant for adverse effects.^65,66 Possible adverse effects in breastfeeding infants include irritability, sedation, poor weight gain, and a change in feeding patterns.⁶⁷ Adverse events are most likely to occur in newborns up to 8 weeks of age, and infants born prematurely or with medical problems may be particularly at risk.^65,68

Helping patients weigh risks and benefits of drug therapy

Women may hear about the risks of medications to the fetus and during breastfeeding and so may be reluctant to seek or accept intervention. Often, the information is not from a reliable, scientifically based source. Primary care physicians are well positioned to guide peripartum women in risk-benefit analysis of proper treatment of their depression vs no treatment or undertreatment. In addition, establishing referral sources—ideally with a peripartum mental health specialist—is advisable. Online resources that clinicians can refer patients to for help in managing peripartum depression include the following:

• www.postpartum.net
• www.womensmentalhealth.org
• www.mothertobaby.org (for pharmacologic guidance).

INCREASED AWARENESS IS KEY

Primary care physicians must remain alert to the high prevalence of depression in women of childbearing age and embrace routine screening for depression. (See the sidebar, “The primary care management of peripartum depression.”) Since half of pregnancies are unintended, awareness of the risks of undetected and untreated peripartum depression to the mother, developing fetus, and infant is essential. Untreated antepartum depression has been linked to poor pregnancy outcomes, nutritional deficits, and substance abuse. Untreated postpartum depression negatively affects mother-infant attachment, infant, and child development and maternal self care.

Not treating depression is hazardous

Drug treatment during pregnancy and breastfeeding poses challenges for the patient and physician due to the inevitability of fetal and infant exposure, but lack of treatment can be hazardous.

To date, the evidence on the use of antidepressants in pregnant and lactating women is reassuring. Specialized peripartum psychiatric partial hospital programs⁶⁹ and inpatient programs⁷⁰ exist for women who need a higher level of care. There is also substantial evidence that psychotherapy, especially cognitive behavioral therapy and interpersonal therapy, is highly effective, and emerging data on complementary and alternative treatments are promising. Coordinated care between primary care and behavioral healthcare providers with expertise in treating peripartum depression is most likely to yield optimal outcomes.

Contrary to common belief, pregnancy does not confer protection against depression.^1,2 In fact, pregnant women are just as likely as nonpregnant women to become or remain depressed, and up to 12.7% of pregnant women meet criteria for depression.¹

In the postpartum period, women are particularly vulnerable to a major depressive episode, whether a first episode or a recurrence. The estimated prevalence of a depressive episode in the first 3 postpartum  months is 19.2%,² making postpartum depression the most common complication of childbearing.² At the same time, peripartum depression remains largely underrecognized and undertreated.³

As evidence mounts regarding the deleterious impact of untreated mental illness on the mother, the developing fetus, and the infant, early detection and intervention for peripartum depression are paramount.³

DEPRESSION DURING PREGNANCY: SIGNIFICANT CONSEQUENCES

Although the rates of depression in pregnant and nonpregnant women are similar, depression in pregnancy carries additional significant consequences. Further, many depressed pregnant women believe their depression will lift once their baby is born, though it is well documented that depression during pregnancy is the strongest predictor of postpartum depression and that if left untreated it can be devastating for mother, infant, and family.⁴

Compared with nondepressed pregnant women, depressed pregnant women have poorer overall health status,⁵ are more likely to engage in behaviors that pose risk to the developing fetus such as smoking,⁵ alcohol consumption, and substance use,⁶ and have poor nutrition and inadequate weight gain.^7,8

Pregnant women who are depressed and are also experiencing domestic violence are especially at risk for poor prenatal care as they tend to miss more prenatal appointments.⁹ Evidence also suggests that depressed pregnant women are less attached to the fetus and more likely to have elective terminations.^10,11

Depression in pregnancy is associated with higher rates of adverse pregnancy outcomes such as preterm birth, low birth weight, operative delivery, and longer predelivery hospital stay.^3,12 Depression and anxiety during pregnancy have been associated with prenatal hypertension,¹³ gestational diabetes,¹⁴ preeclampsia,¹⁵ and HELLP syndrome (ie, hemolysis, elevated liver enzymes, and low platelet count).¹⁵ Depression and anxiety during pregnancy are associated with subsequent poorer infant attachment^16,17 and an overall unfavorable impact on infant and child development.¹⁸

Risk factors for depression during pregnancy include past episodes of depression, current anxiety, poor social support, unintended pregnancy, life stress, being single, domestic violence, and being on Medicaid.¹⁹

Undoubtedly the most devastating consequence of severe depression during pregnancy is suicide. Rates of suicide are lower in peripartum women,²⁰ but when suicide does occur, pregnant women tend to use more violent means than nonpregnant women. Pregnant adolescents represent a particularly high-risk group.²¹

POSTPARTUM DEPRESSION

Postpartum depression is the most common complication of childbearing. Although the precise pathogenesis is undetermined, there is converging evidence of a subset of women particularly sensitive to dramatic fluctuations in levels of estradiol and progesterone that occur during childbirth.^22,23 There is also evidence that dysregulation of the hypothalamic-pituitary-adrenal axis contributes to the development of postpartum depression in certain women.²⁴ Further, women who have depression or anxiety during pregnancy are much more likely to experience postpartum depression than those who are not symptomatic during pregnancy.⁴ A history of peripartum depression or other lifetime depressive episodes, poverty, conflict with a primary partner, poor social support, stressful life events, and low self-esteem are strongly associated with postpartum depression.²⁵

When unrecognized and untreated, postpartum depression can have profound and persistent effects on the mother and the developing infant.^18,26 Mothers with postpartum depression are much more likely than mothers without depression to have impaired bonding,²⁷ to be less responsive to their infant’s needs,¹⁷ and to be more likely to miss well-baby checkups.²⁸

Postpartum depression’s effects on maternal-infant interactions can include maternal withdrawal, disengagement, intrusion, and hostility and can lead to long-term effects on child development, including poor cognitive functioning, emotional maladjustment, and behavioral inhibition.^29,30 Infants and children of mothers with untreated postpartum depression have been shown to exhibit a higher incidence of colic, excessive crying, sleep problems, and irritability.^31,32 Women with postpartum depression may be less likely to initiate or maintain breastfeeding, and depressive symptoms have been noted to precede the discontinuation of breastfeeding.^33–35

Risk factors for postpartum depression

Characteristics to look for in the prenatal care of pregnant women include the following:

• Depression during pregnancy
• History of postpartum or other depressive episode
• Poverty
• Conflict with primary partner
• Poor social support
• Low self-esteem
• Single status.

Primary care providers are often the first point of contact for depressed women. The diagnosis of major depression in pregnant and postpartum women is challenging because of changes in sleep, appetite, and energy brought on by pregnancy, complications of delivery, and demands of caring for a newborn.³⁶ Many pregnant and postpartum women are reluctant to disclose their symptoms due to a sense of shame and guilt for being depressed during a time in their life that society commonly regards as joyful, and this contributes to under-detection.

In the first few days postpartum, fatigue, emotionality, irritability, and worry over the infant’s well-being affect up to 75% of women. This period, typically referred to as the “baby blues” or “postpartum blues,” is not considered a disorder and responds well to support, reassurance, and adequate sleep, and it typically resolves within 2 weeks.^37,38 Table 1 lists features that help distinguish postpartum blues from major depression.

Signs of major depressive disorder

Major depressive disorder is a serious and disabling condition. To meet criteria for major depressive disorder, women must report depressed mood and loss of interest or pleasure in normally pleasurable activities for at least 2 weeks. Completing the symptom profile, at least 5 of the following must be present: sleep disturbance (insomnia or hypersomnia), lack of energy, feelings of worthlessness or low self-esteem, guilt, difficulty concentrating, indecisiveness, psychomotor retardation or agitation, and thoughts of suicide or death.

The Diagnostic and Statistical Manual of Mental Disorders (5th edition) recognizes that postpartum depression commonly begins during pregnancy, and now uses “peripartum onset” as the specifier for major depressive disorder that occurs during pregnancy, postpartum, or both.³⁹ Other hallmark symptoms with peripartum onset include a lack of interest in or attachment to the pregnancy or infant, and anxiety and worry often accompanied by intrusive, unwanted thoughts of harm befalling the infant.⁴⁰

Postpartum psychosis

Postpartum psychosis is a far less common presentation, occurring in 1 to 2 per 1,000 births, but it constitutes a psychiatric emergency requiring immediate referral to a psychiatric care setting. Women at highest risk are those with a personal or family history of bipolar disorder.

The clinical presentation is most commonly characterized by confusion, agitation, hallucinations, delusional beliefs, and disorientation. Suicide and infanticide, while rare, are more likely to occur in the context of a psychotic episode.⁴¹

SCREENING RECOMMENDATIONS

Screening for depression is routine in primary care settings and is no less important for peripartum women.

In 2016, the US Preventive Services Task Force issued a recommendation that all pregnant and postpartum women be screened for depression,⁴² highlighting the need for all medical providers to be alert to the potentially serious consequences of unrecognized and untreated maternal psychiatric illness.

The American College of Obstetricians and Gynecologists (ACOG) recommends screening for depression and anxiety at least once during the peripartum period,⁴³ and the American Academy of Pediatrics recommends screening mothers for depression at the 1-, 2-, and 4-month well-baby visits.⁴⁴

The peripartum period is associated with changes in sleep, appetite, and energy levels, but these are also typical of depression. Taking this into account, the Edinburgh Postnatal Depression Scale (EPDS) was developed to screen for depression specifically in this population.⁴⁵ The EPDS is a validated and widely used 10-item self-reporting questionnaire with a high degree of sensitivity and specificity; it is easily administered and quickly scored. A cutoff score of 13 (of a maximum of 30) is considered indicative of depressed mood and signals the need for further assessment.

Source: Kroenke K, Spitzer RL, Williams JB. The PHQ-9: Validity of a brief depression severity measure. J Gen In-tern Med 2001; 16:606–616. No permission required to reproduce, translate, display, or distribute.

ACOG, the American Academy of Pediatrics, and the US Preventive Services Task Force recommend a standardized validated tool and cite both the EPDS (https://psychology-tools.com/epds/) and the Patient Health Questionnaire-9 (PHQ-9) (Figure 1) as appropriate to screen for peripartum depression.^42–44 Primary care providers tend to be most familiar with the PHQ-9, a highly sensitive and specific 9-item depression screen that has been validated in primary care and obstetric clinic patients.⁴⁶ A score on the PHQ-9 ranging from 5 to 10 indicates mild depression, 10 to 14 moderate depression, 15 to 19 moderate to severe depression, and greater than 19 severe depression.

Many women prefer nondrug therapy

The gold standard treatment for moderate to severe major depressive disorder is psychotherapy plus pharmacotherapy. Yet many peripartum women voice concerns about exposure to pharmacologic treatment, and studies have shown that many women prefer nonpharmacologic intervention.⁴⁷

Evidence-based psychotherapies that have demonstrated efficacy in peripartum women include cognitive behavioral therapy⁴⁸ and interpersonal psychotherapy when administered by a psychotherapist trained in these treatments. Pregnant and breastfeeding women often express preference for psychotherapy and complementary and alternative treatments as a means of avoiding fetal and infant exposure to antidepressants.⁴⁷

For mild to moderate depression, complementary therapies such as exercise, yoga, bright light therapy, and acupuncture have shown efficacy and can be used alone or adjunctively.⁴⁹ Because a poor marital relationship is consistently associated with peripartum depression,²⁵ primary care physicians who routinely address social support and screen for family conflict are well positioned to detect this significant correlate and to recommend marital or family therapy as a primary or adjunctive treatment.

When to consider drug therapy

The decision to recommend drug therapy must be individualized and based on the severity of symptoms, functional impairment, number and frequency of depressive episodes, history of response to medications, and the preferences of the patient, with the recognition that no decision is risk-free and that antidepressants enter the amniotic fluid, so fetal exposure is unavoidable.

Table 2 lists common antidepressants. The antidepressants most commonly prescribed, especially in the primary care setting, are selective serotonin reuptake inhibitors (SSRIs), which are favored because of their effectiveness, low side-effect profile, and lack of overdose toxicity.

Serotonin syndrome is no more likely to occur in pregnant than in nonpregnant women. Close monitoring for this condition is warranted only when patients are taking very  high doses of SSRIs or SSRIs in combination with other serotonergic agonists.

Prescribing antidepressants for pregnant or breastfeeding women requires thoughtful consideration of the patient’s preferences, as well as weighing the risks and benefits of fetal and infant exposure to maternal depression vs exposure to medications. Additional considerations include monotherapy, avoiding medication changes, choosing drugs that have been effective in the past, and avoiding drugs with known drug-drug interactions or teratogenic effects.⁵⁰

There is increasing consensus that the short- and long-term consequences of undertreatment or nontreatment of maternal depression outweigh the risk of fetal exposure to SSRIs.^3,51,52 Cohen et al⁵³ have recommended that if a woman is on an antidepressant and learns she is pregnant, she should not discontinue it because of the likelihood of relapse; they found a 68% relapse rate in women who discontinued their antidepressant in the first trimester of pregnancy.⁵³

In a comprehensive review of studies published between 1996 and 2012 that examined antidepressant use during pregnancy, Byatt et al⁵⁴ found little or no evidence of increased teratogenic risk with antidepressants with the exception of paroxetine, which is associated with a small but significant increased risk of cardiac malformation during first-trimester exposure.⁵⁴

These conclusions were underscored in a large cohort study in the United Kingdom.⁵⁵ In addition, a joint task force of the American Psychiatric Association and ACOG reviewed studies looking at the association between depression, antidepressants, and birth outcomes including miscarriage, preterm birth, cardiac abnormalities (resulting from first trimester exposure), persistent pulmonary hypertension (related to second- and third-trimester exposure), and neonatal adaptation syndrome (associated with third-trimester exposure).⁸ They concluded that the available data neither support nor refute a link between the use of antidepressants and several of the above outcomes. No increase in risk of congenital malformations (including cardiac abnormalities) was found. An increased risk of persistent pulmonary hypertension was noted, although the absolute risk of this disorder remained low, at 3 to 6 per 1,000 infants exposed to SSRIs in utero.^8,56

Neonatal adaptation syndrome

Neonatal adaptation syndrome is characterized by jitteriness, irritability, decreased muscle tone, and feeding difficulty in the neonate. It can occur in 15% to 30% of infants exposed to SSRIs antenatally.^57,58 These symptoms, however, are transient and typically resolve within 7 to 10 days after birth. A more recent study suggested that neurobehavioral symptoms for some infants extend beyond 2 weeks and that concomitant exposure to benzodiazepines results in even higher rates of this syndrome.⁵⁹ There is no evidence that tapering or discontinuing antidepressants near term is necessary, safe, or effective in preventing transient neonatal complications. However, this approach would increase the risk of relapse for the mother.

Autism spectrum disorders

The possible association between antidepressants and autism spectrum disorders in pregnancy has captured much attention in recent years. One study based on healthcare claims⁶⁰ and one registry-based study⁶¹ associated in utero exposure to antidepressants with autism liability in children. However, a large-scale Danish registry-based study did not replicate this association.⁶² In addition, 2 recent cohort studies, identifying children with autism spectrum disorder or attention-deficit hyperactivity disorder from electronic health records, found that neither disorder was significantly associated with prenatal antidepressant exposure in crude or adjusted models. However, both studies found a significant association with the use of antidepressants before pregnancy, indicating that the risk of autism observed with prenatal antidepressant exposure is likely confounded by the severity of maternal illness.^63,64

Concerns about drug therapy during breastfeeding

For infants of breastfeeding women, exposure to antidepressants through breast milk is minimal. Amounts in breast milk depend on the timing of the antidepressant dose, timing of feeding, and genetically influenced metabolic activity in mother and infant. The current literature supports antidepressant use for breastfeeding mothers of healthy full-term infants.⁶⁵

The 2 most widely studied antidepressants in breastfed infants are paroxetine and sertraline. It has been shown that very little can be detected in the infant’s serum, with relative infant doses ranging from 0.4% to 2.8%.⁶⁵ While clinicians are cautioned against prescribing paroxetine for pregnant women, the drug remains a suitable alternative for breastfeeding women.

If an antidepressant is started postpartum, the recommendation is to start with a low dose and then slowly titrate upward while monitoring the infant for adverse effects.^65,66 Possible adverse effects in breastfeeding infants include irritability, sedation, poor weight gain, and a change in feeding patterns.⁶⁷ Adverse events are most likely to occur in newborns up to 8 weeks of age, and infants born prematurely or with medical problems may be particularly at risk.^65,68

Helping patients weigh risks and benefits of drug therapy

Women may hear about the risks of medications to the fetus and during breastfeeding and so may be reluctant to seek or accept intervention. Often, the information is not from a reliable, scientifically based source. Primary care physicians are well positioned to guide peripartum women in risk-benefit analysis of proper treatment of their depression vs no treatment or undertreatment. In addition, establishing referral sources—ideally with a peripartum mental health specialist—is advisable. Online resources that clinicians can refer patients to for help in managing peripartum depression include the following:

• www.postpartum.net
• www.womensmentalhealth.org
• www.mothertobaby.org (for pharmacologic guidance).

INCREASED AWARENESS IS KEY

Primary care physicians must remain alert to the high prevalence of depression in women of childbearing age and embrace routine screening for depression. (See the sidebar, “The primary care management of peripartum depression.”) Since half of pregnancies are unintended, awareness of the risks of undetected and untreated peripartum depression to the mother, developing fetus, and infant is essential. Untreated antepartum depression has been linked to poor pregnancy outcomes, nutritional deficits, and substance abuse. Untreated postpartum depression negatively affects mother-infant attachment, infant, and child development and maternal self care.

Not treating depression is hazardous

Drug treatment during pregnancy and breastfeeding poses challenges for the patient and physician due to the inevitability of fetal and infant exposure, but lack of treatment can be hazardous.

To date, the evidence on the use of antidepressants in pregnant and lactating women is reassuring. Specialized peripartum psychiatric partial hospital programs⁶⁹ and inpatient programs⁷⁰ exist for women who need a higher level of care. There is also substantial evidence that psychotherapy, especially cognitive behavioral therapy and interpersonal therapy, is highly effective, and emerging data on complementary and alternative treatments are promising. Coordinated care between primary care and behavioral healthcare providers with expertise in treating peripartum depression is most likely to yield optimal outcomes.

Contrary to common belief, pregnancy does not confer protection against depression.^1,2 In fact, pregnant women are just as likely as nonpregnant women to become or remain depressed, and up to 12.7% of pregnant women meet criteria for depression.¹

In the postpartum period, women are particularly vulnerable to a major depressive episode, whether a first episode or a recurrence. The estimated prevalence of a depressive episode in the first 3 postpartum  months is 19.2%,² making postpartum depression the most common complication of childbearing.² At the same time, peripartum depression remains largely underrecognized and undertreated.³

As evidence mounts regarding the deleterious impact of untreated mental illness on the mother, the developing fetus, and the infant, early detection and intervention for peripartum depression are paramount.³

DEPRESSION DURING PREGNANCY: SIGNIFICANT CONSEQUENCES

Although the rates of depression in pregnant and nonpregnant women are similar, depression in pregnancy carries additional significant consequences. Further, many depressed pregnant women believe their depression will lift once their baby is born, though it is well documented that depression during pregnancy is the strongest predictor of postpartum depression and that if left untreated it can be devastating for mother, infant, and family.⁴

Compared with nondepressed pregnant women, depressed pregnant women have poorer overall health status,⁵ are more likely to engage in behaviors that pose risk to the developing fetus such as smoking,⁵ alcohol consumption, and substance use,⁶ and have poor nutrition and inadequate weight gain.^7,8

Pregnant women who are depressed and are also experiencing domestic violence are especially at risk for poor prenatal care as they tend to miss more prenatal appointments.⁹ Evidence also suggests that depressed pregnant women are less attached to the fetus and more likely to have elective terminations.^10,11

Depression in pregnancy is associated with higher rates of adverse pregnancy outcomes such as preterm birth, low birth weight, operative delivery, and longer predelivery hospital stay.^3,12 Depression and anxiety during pregnancy have been associated with prenatal hypertension,¹³ gestational diabetes,¹⁴ preeclampsia,¹⁵ and HELLP syndrome (ie, hemolysis, elevated liver enzymes, and low platelet count).¹⁵ Depression and anxiety during pregnancy are associated with subsequent poorer infant attachment^16,17 and an overall unfavorable impact on infant and child development.¹⁸

Risk factors for depression during pregnancy include past episodes of depression, current anxiety, poor social support, unintended pregnancy, life stress, being single, domestic violence, and being on Medicaid.¹⁹

Undoubtedly the most devastating consequence of severe depression during pregnancy is suicide. Rates of suicide are lower in peripartum women,²⁰ but when suicide does occur, pregnant women tend to use more violent means than nonpregnant women. Pregnant adolescents represent a particularly high-risk group.²¹

POSTPARTUM DEPRESSION

Postpartum depression is the most common complication of childbearing. Although the precise pathogenesis is undetermined, there is converging evidence of a subset of women particularly sensitive to dramatic fluctuations in levels of estradiol and progesterone that occur during childbirth.^22,23 There is also evidence that dysregulation of the hypothalamic-pituitary-adrenal axis contributes to the development of postpartum depression in certain women.²⁴ Further, women who have depression or anxiety during pregnancy are much more likely to experience postpartum depression than those who are not symptomatic during pregnancy.⁴ A history of peripartum depression or other lifetime depressive episodes, poverty, conflict with a primary partner, poor social support, stressful life events, and low self-esteem are strongly associated with postpartum depression.²⁵

When unrecognized and untreated, postpartum depression can have profound and persistent effects on the mother and the developing infant.^18,26 Mothers with postpartum depression are much more likely than mothers without depression to have impaired bonding,²⁷ to be less responsive to their infant’s needs,¹⁷ and to be more likely to miss well-baby checkups.²⁸

Postpartum depression’s effects on maternal-infant interactions can include maternal withdrawal, disengagement, intrusion, and hostility and can lead to long-term effects on child development, including poor cognitive functioning, emotional maladjustment, and behavioral inhibition.^29,30 Infants and children of mothers with untreated postpartum depression have been shown to exhibit a higher incidence of colic, excessive crying, sleep problems, and irritability.^31,32 Women with postpartum depression may be less likely to initiate or maintain breastfeeding, and depressive symptoms have been noted to precede the discontinuation of breastfeeding.^33–35

Risk factors for postpartum depression

Characteristics to look for in the prenatal care of pregnant women include the following:

• Depression during pregnancy
• History of postpartum or other depressive episode
• Poverty
• Conflict with primary partner
• Poor social support
• Low self-esteem
• Single status.

Primary care providers are often the first point of contact for depressed women. The diagnosis of major depression in pregnant and postpartum women is challenging because of changes in sleep, appetite, and energy brought on by pregnancy, complications of delivery, and demands of caring for a newborn.³⁶ Many pregnant and postpartum women are reluctant to disclose their symptoms due to a sense of shame and guilt for being depressed during a time in their life that society commonly regards as joyful, and this contributes to under-detection.

In the first few days postpartum, fatigue, emotionality, irritability, and worry over the infant’s well-being affect up to 75% of women. This period, typically referred to as the “baby blues” or “postpartum blues,” is not considered a disorder and responds well to support, reassurance, and adequate sleep, and it typically resolves within 2 weeks.^37,38 Table 1 lists features that help distinguish postpartum blues from major depression.

Signs of major depressive disorder

Major depressive disorder is a serious and disabling condition. To meet criteria for major depressive disorder, women must report depressed mood and loss of interest or pleasure in normally pleasurable activities for at least 2 weeks. Completing the symptom profile, at least 5 of the following must be present: sleep disturbance (insomnia or hypersomnia), lack of energy, feelings of worthlessness or low self-esteem, guilt, difficulty concentrating, indecisiveness, psychomotor retardation or agitation, and thoughts of suicide or death.

The Diagnostic and Statistical Manual of Mental Disorders (5th edition) recognizes that postpartum depression commonly begins during pregnancy, and now uses “peripartum onset” as the specifier for major depressive disorder that occurs during pregnancy, postpartum, or both.³⁹ Other hallmark symptoms with peripartum onset include a lack of interest in or attachment to the pregnancy or infant, and anxiety and worry often accompanied by intrusive, unwanted thoughts of harm befalling the infant.⁴⁰

Postpartum psychosis

Postpartum psychosis is a far less common presentation, occurring in 1 to 2 per 1,000 births, but it constitutes a psychiatric emergency requiring immediate referral to a psychiatric care setting. Women at highest risk are those with a personal or family history of bipolar disorder.

The clinical presentation is most commonly characterized by confusion, agitation, hallucinations, delusional beliefs, and disorientation. Suicide and infanticide, while rare, are more likely to occur in the context of a psychotic episode.⁴¹

SCREENING RECOMMENDATIONS

Screening for depression is routine in primary care settings and is no less important for peripartum women.

In 2016, the US Preventive Services Task Force issued a recommendation that all pregnant and postpartum women be screened for depression,⁴² highlighting the need for all medical providers to be alert to the potentially serious consequences of unrecognized and untreated maternal psychiatric illness.

The American College of Obstetricians and Gynecologists (ACOG) recommends screening for depression and anxiety at least once during the peripartum period,⁴³ and the American Academy of Pediatrics recommends screening mothers for depression at the 1-, 2-, and 4-month well-baby visits.⁴⁴

The peripartum period is associated with changes in sleep, appetite, and energy levels, but these are also typical of depression. Taking this into account, the Edinburgh Postnatal Depression Scale (EPDS) was developed to screen for depression specifically in this population.⁴⁵ The EPDS is a validated and widely used 10-item self-reporting questionnaire with a high degree of sensitivity and specificity; it is easily administered and quickly scored. A cutoff score of 13 (of a maximum of 30) is considered indicative of depressed mood and signals the need for further assessment.

Source: Kroenke K, Spitzer RL, Williams JB. The PHQ-9: Validity of a brief depression severity measure. J Gen In-tern Med 2001; 16:606–616. No permission required to reproduce, translate, display, or distribute.

ACOG, the American Academy of Pediatrics, and the US Preventive Services Task Force recommend a standardized validated tool and cite both the EPDS (https://psychology-tools.com/epds/) and the Patient Health Questionnaire-9 (PHQ-9) (Figure 1) as appropriate to screen for peripartum depression.^42–44 Primary care providers tend to be most familiar with the PHQ-9, a highly sensitive and specific 9-item depression screen that has been validated in primary care and obstetric clinic patients.⁴⁶ A score on the PHQ-9 ranging from 5 to 10 indicates mild depression, 10 to 14 moderate depression, 15 to 19 moderate to severe depression, and greater than 19 severe depression.

Many women prefer nondrug therapy

The gold standard treatment for moderate to severe major depressive disorder is psychotherapy plus pharmacotherapy. Yet many peripartum women voice concerns about exposure to pharmacologic treatment, and studies have shown that many women prefer nonpharmacologic intervention.⁴⁷

Evidence-based psychotherapies that have demonstrated efficacy in peripartum women include cognitive behavioral therapy⁴⁸ and interpersonal psychotherapy when administered by a psychotherapist trained in these treatments. Pregnant and breastfeeding women often express preference for psychotherapy and complementary and alternative treatments as a means of avoiding fetal and infant exposure to antidepressants.⁴⁷

For mild to moderate depression, complementary therapies such as exercise, yoga, bright light therapy, and acupuncture have shown efficacy and can be used alone or adjunctively.⁴⁹ Because a poor marital relationship is consistently associated with peripartum depression,²⁵ primary care physicians who routinely address social support and screen for family conflict are well positioned to detect this significant correlate and to recommend marital or family therapy as a primary or adjunctive treatment.

When to consider drug therapy

The decision to recommend drug therapy must be individualized and based on the severity of symptoms, functional impairment, number and frequency of depressive episodes, history of response to medications, and the preferences of the patient, with the recognition that no decision is risk-free and that antidepressants enter the amniotic fluid, so fetal exposure is unavoidable.

Table 2 lists common antidepressants. The antidepressants most commonly prescribed, especially in the primary care setting, are selective serotonin reuptake inhibitors (SSRIs), which are favored because of their effectiveness, low side-effect profile, and lack of overdose toxicity.

Serotonin syndrome is no more likely to occur in pregnant than in nonpregnant women. Close monitoring for this condition is warranted only when patients are taking very  high doses of SSRIs or SSRIs in combination with other serotonergic agonists.

Prescribing antidepressants for pregnant or breastfeeding women requires thoughtful consideration of the patient’s preferences, as well as weighing the risks and benefits of fetal and infant exposure to maternal depression vs exposure to medications. Additional considerations include monotherapy, avoiding medication changes, choosing drugs that have been effective in the past, and avoiding drugs with known drug-drug interactions or teratogenic effects.⁵⁰

There is increasing consensus that the short- and long-term consequences of undertreatment or nontreatment of maternal depression outweigh the risk of fetal exposure to SSRIs.^3,51,52 Cohen et al⁵³ have recommended that if a woman is on an antidepressant and learns she is pregnant, she should not discontinue it because of the likelihood of relapse; they found a 68% relapse rate in women who discontinued their antidepressant in the first trimester of pregnancy.⁵³

In a comprehensive review of studies published between 1996 and 2012 that examined antidepressant use during pregnancy, Byatt et al⁵⁴ found little or no evidence of increased teratogenic risk with antidepressants with the exception of paroxetine, which is associated with a small but significant increased risk of cardiac malformation during first-trimester exposure.⁵⁴

These conclusions were underscored in a large cohort study in the United Kingdom.⁵⁵ In addition, a joint task force of the American Psychiatric Association and ACOG reviewed studies looking at the association between depression, antidepressants, and birth outcomes including miscarriage, preterm birth, cardiac abnormalities (resulting from first trimester exposure), persistent pulmonary hypertension (related to second- and third-trimester exposure), and neonatal adaptation syndrome (associated with third-trimester exposure).⁸ They concluded that the available data neither support nor refute a link between the use of antidepressants and several of the above outcomes. No increase in risk of congenital malformations (including cardiac abnormalities) was found. An increased risk of persistent pulmonary hypertension was noted, although the absolute risk of this disorder remained low, at 3 to 6 per 1,000 infants exposed to SSRIs in utero.^8,56

Neonatal adaptation syndrome

Neonatal adaptation syndrome is characterized by jitteriness, irritability, decreased muscle tone, and feeding difficulty in the neonate. It can occur in 15% to 30% of infants exposed to SSRIs antenatally.^57,58 These symptoms, however, are transient and typically resolve within 7 to 10 days after birth. A more recent study suggested that neurobehavioral symptoms for some infants extend beyond 2 weeks and that concomitant exposure to benzodiazepines results in even higher rates of this syndrome.⁵⁹ There is no evidence that tapering or discontinuing antidepressants near term is necessary, safe, or effective in preventing transient neonatal complications. However, this approach would increase the risk of relapse for the mother.

Autism spectrum disorders

The possible association between antidepressants and autism spectrum disorders in pregnancy has captured much attention in recent years. One study based on healthcare claims⁶⁰ and one registry-based study⁶¹ associated in utero exposure to antidepressants with autism liability in children. However, a large-scale Danish registry-based study did not replicate this association.⁶² In addition, 2 recent cohort studies, identifying children with autism spectrum disorder or attention-deficit hyperactivity disorder from electronic health records, found that neither disorder was significantly associated with prenatal antidepressant exposure in crude or adjusted models. However, both studies found a significant association with the use of antidepressants before pregnancy, indicating that the risk of autism observed with prenatal antidepressant exposure is likely confounded by the severity of maternal illness.^63,64

Concerns about drug therapy during breastfeeding

For infants of breastfeeding women, exposure to antidepressants through breast milk is minimal. Amounts in breast milk depend on the timing of the antidepressant dose, timing of feeding, and genetically influenced metabolic activity in mother and infant. The current literature supports antidepressant use for breastfeeding mothers of healthy full-term infants.⁶⁵

The 2 most widely studied antidepressants in breastfed infants are paroxetine and sertraline. It has been shown that very little can be detected in the infant’s serum, with relative infant doses ranging from 0.4% to 2.8%.⁶⁵ While clinicians are cautioned against prescribing paroxetine for pregnant women, the drug remains a suitable alternative for breastfeeding women.

If an antidepressant is started postpartum, the recommendation is to start with a low dose and then slowly titrate upward while monitoring the infant for adverse effects.^65,66 Possible adverse effects in breastfeeding infants include irritability, sedation, poor weight gain, and a change in feeding patterns.⁶⁷ Adverse events are most likely to occur in newborns up to 8 weeks of age, and infants born prematurely or with medical problems may be particularly at risk.^65,68

Helping patients weigh risks and benefits of drug therapy

Women may hear about the risks of medications to the fetus and during breastfeeding and so may be reluctant to seek or accept intervention. Often, the information is not from a reliable, scientifically based source. Primary care physicians are well positioned to guide peripartum women in risk-benefit analysis of proper treatment of their depression vs no treatment or undertreatment. In addition, establishing referral sources—ideally with a peripartum mental health specialist—is advisable. Online resources that clinicians can refer patients to for help in managing peripartum depression include the following:

• www.postpartum.net
• www.womensmentalhealth.org
• www.mothertobaby.org (for pharmacologic guidance).

INCREASED AWARENESS IS KEY

Primary care physicians must remain alert to the high prevalence of depression in women of childbearing age and embrace routine screening for depression. (See the sidebar, “The primary care management of peripartum depression.”) Since half of pregnancies are unintended, awareness of the risks of undetected and untreated peripartum depression to the mother, developing fetus, and infant is essential. Untreated antepartum depression has been linked to poor pregnancy outcomes, nutritional deficits, and substance abuse. Untreated postpartum depression negatively affects mother-infant attachment, infant, and child development and maternal self care.

Not treating depression is hazardous

Drug treatment during pregnancy and breastfeeding poses challenges for the patient and physician due to the inevitability of fetal and infant exposure, but lack of treatment can be hazardous.

To date, the evidence on the use of antidepressants in pregnant and lactating women is reassuring. Specialized peripartum psychiatric partial hospital programs⁶⁹ and inpatient programs⁷⁰ exist for women who need a higher level of care. There is also substantial evidence that psychotherapy, especially cognitive behavioral therapy and interpersonal therapy, is highly effective, and emerging data on complementary and alternative treatments are promising. Coordinated care between primary care and behavioral healthcare providers with expertise in treating peripartum depression is most likely to yield optimal outcomes.