A 32-year-old man presents to the emergency department with excruciating abdominal pain associated with multiple episodes of vomiting for the past 2 days. He reports no fevers, headaches, diarrhea, constipation, hematochezia, melena, musculoskeletal symptoms, or weight loss. His abdominal pain is generalized and crampy. It does not radiate and has no precipitating factors. The pain is relieved only with intravenous narcotics.

See related editorial

He does not smoke, drink alcohol, or use illicit drugs. He has no known drug or food allergies. He says that his current condition causes him emotional stress that affects his performance at work.

About a year ago, after a complicated surgical procedure, he needed chronic high-dose narcotics. A few months later, he developed multiple bouts of abdominal pain and vomiting that required hospital visits. He now takes oral oxycodone 10–15 mg every 4–6 hours.

On admission, his vital signs are stable, but he is in excruciating pain. He is alert and oriented to person, place, and time. His sclera are anicteric, and the pupils are equal, round, and reactive to light. Lung and heart examinations are normal. The abdomen is soft and nondistended but tender in all four quadrants without guarding; the liver and spleen are not palpable, and no abdominal masses are detected. He has no skin rash, joint swelling or tenderness, or peripheral edema. The neurologic examination is normal. Computed tomography (CT) of the abdomen with contrast shows no signs of bowel obstruction, pancreatic calcifications or edema, cholecystitis, or hepatobiliary disease. Results of initial laboratory testing are shown in Table 1.

1. Based on the information available, which is the least likely cause of his symptoms?

• Acute pancreatitis
• Cyclic vomiting syndrome
• Acute intermittent porphyria
• Gastroparesis

Acute pancreatitis

Acute pancreatitis is the least likely cause of his symptoms. It is commonly caused by gallstones, alcohol, hypertriglyceridemia, and certain drugs.¹ The associated abdominal pain is usually epigastric, radiates to the back, and is accompanied by nausea or vomiting, or both. The onset of pain is sudden and rapidly increases in severity within 30 minutes. CT shows enlargement of the pancreas with diffuse edema, heterogeneity of pancreatic parenchyma, peripancreatic stranding, and peripancreatic fluid collections.¹ The diagnosis is based on two of the following three criteria: abdominal pain characteristic of acute pancreatitis; a serum amylase or lipase concentration three or more times the upper limit of normal; and characteristic findings of acute pancreatitis on CT.¹

Cyclic vomiting syndrome

Cyclic vomiting syndrome is thought to be caused by episodic dysautonomia, mitochondrial DNA mutations, and hypothalamic emetic response oversensitivity,^2–4 but the exact pathogenesis is unknown. The syndrome has been strongly linked to migraine and to the chronic excessive use of cannabinoids.^5–9 The Rome III diagnostic criteria¹⁰ are the following: the vomiting episodes are stereotypical, ie, they are acute and last for less than 1 week; the patient has had three or more episodes in the previous year; and the patient has no nausea or vomiting between episodes. The patient must meet all three criteria. A history of migraine or a family history of migraine further supports the diagnosis.

Acute intermittent porphyria

Acute intermittent porphyria is characterized by neurovisceral symptoms such as convulsions, paresis, autonomic dysfunction, constipation, and diarrhea that result from the overproduction of porphyrin precursors and deficiency of porphobilinogen deaminase.¹¹

Most patients have poorly localized, severe, steady abdominal pain that develops over hours to days and that may persist for days to weeks.¹¹ Since the pain is neuropathic, abdominal tenderness is usually minimal during an acute attack. Other clues include signs of ileus, such as constipation, nausea, abdominal distention, or decreased bowel sounds; bladder dysfunction, eg, urinary retention, incontinence, or dysuria; reddish-brown urine; and sensory neuropathy of the chest, back, and extremities.¹¹ Blistering skin lesions are usually not seen. The presence of porphobilinogen in the urine confirms the diagnosis.¹¹

Gastroparesis

Gastroparesis is a result of discoordination between the sympathetic and parasympathetic nervous systems, neurons, and smooth muscles within the stomach, causing a decrease in gastric motility. Common causes are diabetes,¹² scleroderma,¹³ and neurologic disorders.¹⁴ It can also be iatrogenic,¹⁵ resulting from visceral nerve injury and drug treatment with narcotics, calcium channel blockers, muscarinic cholinergic antagonists, or certain antidepressants. Symptoms are related to gastric stasis, ie, abdominal pain from gastric distention, bloating, vomiting, and early satiety.¹⁵ Abdominal pain may worsen after eating, and vomitus usually consists of recently ingested food. These patients may have abdominal distension or tenderness and succussion splash. After excluding possible mechanical obstruction, a gastric-emptying study may be necessary to make the diagnosis.¹⁵

CASE CONTINUED

A serum and urine drug screen in our patient is positive only for opioids. Urine measures of delta-aminolevulinic acid and porphobilinogen are normal. CT angiography of the abdomen shows no signs of mesenteric vascular occlusion. Esophagogastroduodenoscopy shows antral gastritis, but the esophagus and duodenum appear normal, and colonoscopy is normal as well. Histologic study of biopsy specimens obtained during endoscopy is unrevealing. A gastric-emptying study shows delayed emptying. The patient’s abdominal pain and vomiting persist with the initial dose of intravenous narcotic but resolve with escalating doses. When asked, the patient denies an excessive need for hot baths.

2. Which is the most likely diagnosis at this point?

• Narcotic bowel syndrome
• Opioid withdrawal
• Crohn disease
• Chronic pancreatitis
• Chronic mesenteric ischemia
• Cannabinoid hyperemesis

Narcotic bowel syndrome

Narcotic bowel syndrome is the most likely diagnosis. Grunkemeier et al¹⁶ described it as chronic or frequently recurring abdominal pain that is treated with narcotics, either chronically or acutely with high doses, and that includes all the following features¹⁶:

• The pain worsens or resolves incompletely with continued or increasing doses of narcotics
• The pain markedly worsens when the narcotic dose is decreased, and decreases when the drug is reinstituted (the “soarand-crash” effect)
• The frequency, duration, and intensity of the pain episodes gradually increase
• The nature of the pain and its intensity are not explained by a current or previous gastrointestinal diagnosis.¹⁶

This syndrome is common in patients who receive high doses of narcotics for postoperative pain or for other, nonmalignant causes of pain. Patients eventually become dependent on the drugs but are not aware that chronic use activates and facilitates areas in the brain that enhance the perception of pain.¹⁶ A study of a rat model of narcotic bowel syndrome¹⁷ showed that morphine-induced hyperalgesia depends on central sensitization involving the activation of spinal microglia. This eventually results in concomitant peripheral sensitization involving the colonic mucosal neuroimmune system, and also in central or peripheral activation of opioid kappa-receptors by dynorphin release.¹⁷

Patients tend to present with chronic or intermittent colicky abdominal pain that requires escalating doses of narcotics. Eventually, they develop tachyphylaxis and shortened pain-free periods and will require even higher doses of narcotics. This ultimately enhances the perception of pain and worsens opioid bowel symptoms, causing a vicious circle of pain and more narcotic use.¹⁶

Laboratory tests are usually normal, and imaging may show only ileus. Gastric emptying may be delayed in patients who have either narcotic bowel syndrome or gastroparesis, but since abdominal pain from narcotic bowel syndrome is a result of central and visceral hypersensitivity, these patients perceive more severe abdominal pain than patients with gastroparesis alone.

Opioid withdrawal

Symptoms of opioid withdrawal may appear as soon as 6 to 24 hours after cessation of the opioid in patients known to be dependent on opioids. These patients present with crampy abdominal pain with nausea.¹⁸ Other symptoms include agitation, rhinorrhea, lacrimation, excessive yawning, arthralgias, papillary dilation, and piloerection.¹⁸

Our patient did not have the typical signs of opioid withdrawal.

Crohn disease

Crohn disease is a multisystem disorder with specific clinical and pathologic features. It is characterized by focal, asymmetric, transmural, and occasionally granulomatous inflammation primarily affecting the gastrointestinal tract.¹⁹ Characteristic symptoms include abdominal pain, chronic diarrhea with or without rectal bleeding, and weight loss. Extraintestinal signs may include anemia and inflammatory changes in the eyes, skin, and joints. The diagnosis is based on endoscopic, radiographic, and pathologic findings.¹⁹

Our patient did not have diarrhea or signs of Crohn disease on CT, endoscopy, or histology.

Chronic pancreatitis

Chronic pancreatitis involves progressive inflammatory changes resulting in permanent structural damage to the pancreas and subsequent exocrine and endocrine dysfunction.²⁰ Patients have epigastric abdominal pain that often radiates to the back²⁰; it is associated with eating and is partly relieved with leaning forward. Symptoms of pancreatic insufficiency such as fat malabsorption (resulting in steatorrhea and fat-soluble vitamin deficiency) and diabetes are common. Calcifications within the pancreas on CT suggest chronic pancreatitis.²⁰ Serum lipase and amylase levels may be normal or slightly elevated.²⁰

Our patient’s abdominal pain was not typical of pancreatitis. He had no signs or symptoms of pancreatic insufficiency and no calcifications within the pancreas.

Chronic mesenteric ischemia

Chronic mesenteric ischemia (“intestinal angina”) is caused by a reduction in intestinal blood flow as a result of occlusion, vasospasm, or hypoperfusion of the mesenteric vasculature.²¹ It is commonly seen in patients who smoke or who have atherosclerotic vascular disease. These patients have chronic dull or crampy abdominal pain that usually occurs within 1 hour after eating.²¹ To avoid pain, patients avoid eating, resulting in weight loss.²¹ CT angiography with multi-detector CT is as effective as angiography (the gold standard) in depicting splanchnic arterial anatomy.²²

Our patient is young and has no known risk factors for atherosclerosis such as smoking. His abdominal pain is more intermittent than chronic and is not associated with eating.

Cannabinoid hyperemesis

Cannabinoid hyperemesis should be considered in patients with long-term cannabis use presenting with cyclic vomiting, abdominal pain, compulsive use of hot showers, and improvement of symptoms with cannabis cessation.²³ Although cannabinoids have been recognized for their antiemetic effects, long-term use may eventually cause autonomic instability and disturbances in the hypothalamic-pituitary-adrenal axis, resulting in cyclic vomiting and thermoregulatory impairment.²³

Although our patient presented with multiple episodes of vomiting and abdominal pain, he denied using marijuana, he tested negative for tetrahydrocannabinol, and he did not associate any relief of his symptoms with hot baths.

CASE CONTINUED

Our patient receives intravenous hydration, antiemetics, and a narcotic in tapering intravenous doses, and his symptoms gradually improve. He is discharged from the hospital. However, a few weeks later he is readmitted with the same symptoms of abdominal pain and nausea.

3. What is the cornerstone of treatment for narcotic bowel syndrome?

• Establishing a therapeutic relationship
• Detoxification
• Supportive management with intravenous fluids, antiemetics, and stool-softeners
• Medical management with a short-acting narcotic, clonidine, lorazepam, and desipramine

MANAGEMENT OF NARCOTIC BOWEL SYNDROME

An effective therapeutic relationship with the patient is the cornerstone of treatment and should be established before starting detoxification.¹⁷ The physician must first learn to accept that the patient’s condition is real and must show genuine empathy as well as provide information about the pathophysiologic basis of the condition, the rationale for withholding narcotics, and the detrimental role narcotics play in the vicious circle of pain.

Detoxification involves gradually withdrawing the narcotic and substituting a nonnarcotic such as an antidepressant for pain control, as well as prescribing a drug such as a benzodiazepine or clonidine to prevent withdrawal symptoms and a laxative to prevent constipation.^17,24 The physician must reassure the patient that he or she will not be abandoned in pain and that all medications will be continuously adjusted as needed to keep him or her comfortable throughout the detoxification process.^17,24 The physician must continuously gauge the patient’s willingness to continue with treatment and must also be readily available to address the patient’s concerns in a timely manner.^17,24 Involving family members and friends may provide additional support to the patient. Referral to a functional gastrointestinal motility program, a pain specialist, and a psychologist may also be considered.^17,24 Follow-up care is essential, even after the withdrawal program has ended.^17,24

BACK TO THE PATIENT

After successfully establishing a therapeutic relationship and discussing the treatment plan with our patient, we started him on the same dosage of narcotic that he had been receiving, calculated in intravenous morphine equivalents to achieve maximal comfort, and then decreased the dosage by 10% to 33% daily until he was completely off narcotics. An antidepressant and a benzodiazepine were given simultaneously with narcotic tapering. Oral clonidine (0.1–0.4 mg/day) was given after the narcotic dosage was reduced to about half, and polyethylene glycol was given as needed for constipation. The total duration of detoxification was 7 days.

The patient was referred to a psychologist for cognitive-behavioral and relaxation therapy, as well as for encouragement and support. At 6 months, he had had no recurrence of symptoms.

TAKE-HOME MESSAGE

In the United States, the number of patients taking a narcotic for nonmalignant pain is increasing, ²⁵ and physicians should be more aware of complications such as narcotic bowel syndrome.

Narcotic bowel syndrome should be suspected in any patient with prolonged narcotic use presenting with multiple recurrent episodes of abdominal pain after other causes are ruled out.

Establishing a good therapeutic relationship with the patient is the cornerstone of successful treatment. Patients who understand their condition and are willing to be treated tend to have better outcomes.

Supportive treatment, symptom relief, and emotional support during detoxification increase compliance.

A 32-year-old man presents to the emergency department with excruciating abdominal pain associated with multiple episodes of vomiting for the past 2 days. He reports no fevers, headaches, diarrhea, constipation, hematochezia, melena, musculoskeletal symptoms, or weight loss. His abdominal pain is generalized and crampy. It does not radiate and has no precipitating factors. The pain is relieved only with intravenous narcotics.

See related editorial

He does not smoke, drink alcohol, or use illicit drugs. He has no known drug or food allergies. He says that his current condition causes him emotional stress that affects his performance at work.

About a year ago, after a complicated surgical procedure, he needed chronic high-dose narcotics. A few months later, he developed multiple bouts of abdominal pain and vomiting that required hospital visits. He now takes oral oxycodone 10–15 mg every 4–6 hours.

On admission, his vital signs are stable, but he is in excruciating pain. He is alert and oriented to person, place, and time. His sclera are anicteric, and the pupils are equal, round, and reactive to light. Lung and heart examinations are normal. The abdomen is soft and nondistended but tender in all four quadrants without guarding; the liver and spleen are not palpable, and no abdominal masses are detected. He has no skin rash, joint swelling or tenderness, or peripheral edema. The neurologic examination is normal. Computed tomography (CT) of the abdomen with contrast shows no signs of bowel obstruction, pancreatic calcifications or edema, cholecystitis, or hepatobiliary disease. Results of initial laboratory testing are shown in Table 1.

1. Based on the information available, which is the least likely cause of his symptoms?

• Acute pancreatitis
• Cyclic vomiting syndrome
• Acute intermittent porphyria
• Gastroparesis

Acute pancreatitis

Acute pancreatitis is the least likely cause of his symptoms. It is commonly caused by gallstones, alcohol, hypertriglyceridemia, and certain drugs.¹ The associated abdominal pain is usually epigastric, radiates to the back, and is accompanied by nausea or vomiting, or both. The onset of pain is sudden and rapidly increases in severity within 30 minutes. CT shows enlargement of the pancreas with diffuse edema, heterogeneity of pancreatic parenchyma, peripancreatic stranding, and peripancreatic fluid collections.¹ The diagnosis is based on two of the following three criteria: abdominal pain characteristic of acute pancreatitis; a serum amylase or lipase concentration three or more times the upper limit of normal; and characteristic findings of acute pancreatitis on CT.¹

Cyclic vomiting syndrome

Cyclic vomiting syndrome is thought to be caused by episodic dysautonomia, mitochondrial DNA mutations, and hypothalamic emetic response oversensitivity,^2–4 but the exact pathogenesis is unknown. The syndrome has been strongly linked to migraine and to the chronic excessive use of cannabinoids.^5–9 The Rome III diagnostic criteria¹⁰ are the following: the vomiting episodes are stereotypical, ie, they are acute and last for less than 1 week; the patient has had three or more episodes in the previous year; and the patient has no nausea or vomiting between episodes. The patient must meet all three criteria. A history of migraine or a family history of migraine further supports the diagnosis.

Acute intermittent porphyria

Acute intermittent porphyria is characterized by neurovisceral symptoms such as convulsions, paresis, autonomic dysfunction, constipation, and diarrhea that result from the overproduction of porphyrin precursors and deficiency of porphobilinogen deaminase.¹¹

Most patients have poorly localized, severe, steady abdominal pain that develops over hours to days and that may persist for days to weeks.¹¹ Since the pain is neuropathic, abdominal tenderness is usually minimal during an acute attack. Other clues include signs of ileus, such as constipation, nausea, abdominal distention, or decreased bowel sounds; bladder dysfunction, eg, urinary retention, incontinence, or dysuria; reddish-brown urine; and sensory neuropathy of the chest, back, and extremities.¹¹ Blistering skin lesions are usually not seen. The presence of porphobilinogen in the urine confirms the diagnosis.¹¹

Gastroparesis

Gastroparesis is a result of discoordination between the sympathetic and parasympathetic nervous systems, neurons, and smooth muscles within the stomach, causing a decrease in gastric motility. Common causes are diabetes,¹² scleroderma,¹³ and neurologic disorders.¹⁴ It can also be iatrogenic,¹⁵ resulting from visceral nerve injury and drug treatment with narcotics, calcium channel blockers, muscarinic cholinergic antagonists, or certain antidepressants. Symptoms are related to gastric stasis, ie, abdominal pain from gastric distention, bloating, vomiting, and early satiety.¹⁵ Abdominal pain may worsen after eating, and vomitus usually consists of recently ingested food. These patients may have abdominal distension or tenderness and succussion splash. After excluding possible mechanical obstruction, a gastric-emptying study may be necessary to make the diagnosis.¹⁵

CASE CONTINUED

A serum and urine drug screen in our patient is positive only for opioids. Urine measures of delta-aminolevulinic acid and porphobilinogen are normal. CT angiography of the abdomen shows no signs of mesenteric vascular occlusion. Esophagogastroduodenoscopy shows antral gastritis, but the esophagus and duodenum appear normal, and colonoscopy is normal as well. Histologic study of biopsy specimens obtained during endoscopy is unrevealing. A gastric-emptying study shows delayed emptying. The patient’s abdominal pain and vomiting persist with the initial dose of intravenous narcotic but resolve with escalating doses. When asked, the patient denies an excessive need for hot baths.

2. Which is the most likely diagnosis at this point?

• Narcotic bowel syndrome
• Opioid withdrawal
• Crohn disease
• Chronic pancreatitis
• Chronic mesenteric ischemia
• Cannabinoid hyperemesis

Narcotic bowel syndrome

Narcotic bowel syndrome is the most likely diagnosis. Grunkemeier et al¹⁶ described it as chronic or frequently recurring abdominal pain that is treated with narcotics, either chronically or acutely with high doses, and that includes all the following features¹⁶:

• The pain worsens or resolves incompletely with continued or increasing doses of narcotics
• The pain markedly worsens when the narcotic dose is decreased, and decreases when the drug is reinstituted (the “soarand-crash” effect)
• The frequency, duration, and intensity of the pain episodes gradually increase
• The nature of the pain and its intensity are not explained by a current or previous gastrointestinal diagnosis.¹⁶

This syndrome is common in patients who receive high doses of narcotics for postoperative pain or for other, nonmalignant causes of pain. Patients eventually become dependent on the drugs but are not aware that chronic use activates and facilitates areas in the brain that enhance the perception of pain.¹⁶ A study of a rat model of narcotic bowel syndrome¹⁷ showed that morphine-induced hyperalgesia depends on central sensitization involving the activation of spinal microglia. This eventually results in concomitant peripheral sensitization involving the colonic mucosal neuroimmune system, and also in central or peripheral activation of opioid kappa-receptors by dynorphin release.¹⁷

Patients tend to present with chronic or intermittent colicky abdominal pain that requires escalating doses of narcotics. Eventually, they develop tachyphylaxis and shortened pain-free periods and will require even higher doses of narcotics. This ultimately enhances the perception of pain and worsens opioid bowel symptoms, causing a vicious circle of pain and more narcotic use.¹⁶

Laboratory tests are usually normal, and imaging may show only ileus. Gastric emptying may be delayed in patients who have either narcotic bowel syndrome or gastroparesis, but since abdominal pain from narcotic bowel syndrome is a result of central and visceral hypersensitivity, these patients perceive more severe abdominal pain than patients with gastroparesis alone.

Opioid withdrawal

Symptoms of opioid withdrawal may appear as soon as 6 to 24 hours after cessation of the opioid in patients known to be dependent on opioids. These patients present with crampy abdominal pain with nausea.¹⁸ Other symptoms include agitation, rhinorrhea, lacrimation, excessive yawning, arthralgias, papillary dilation, and piloerection.¹⁸

Our patient did not have the typical signs of opioid withdrawal.

Crohn disease

Crohn disease is a multisystem disorder with specific clinical and pathologic features. It is characterized by focal, asymmetric, transmural, and occasionally granulomatous inflammation primarily affecting the gastrointestinal tract.¹⁹ Characteristic symptoms include abdominal pain, chronic diarrhea with or without rectal bleeding, and weight loss. Extraintestinal signs may include anemia and inflammatory changes in the eyes, skin, and joints. The diagnosis is based on endoscopic, radiographic, and pathologic findings.¹⁹

Our patient did not have diarrhea or signs of Crohn disease on CT, endoscopy, or histology.

Chronic pancreatitis

Chronic pancreatitis involves progressive inflammatory changes resulting in permanent structural damage to the pancreas and subsequent exocrine and endocrine dysfunction.²⁰ Patients have epigastric abdominal pain that often radiates to the back²⁰; it is associated with eating and is partly relieved with leaning forward. Symptoms of pancreatic insufficiency such as fat malabsorption (resulting in steatorrhea and fat-soluble vitamin deficiency) and diabetes are common. Calcifications within the pancreas on CT suggest chronic pancreatitis.²⁰ Serum lipase and amylase levels may be normal or slightly elevated.²⁰

Our patient’s abdominal pain was not typical of pancreatitis. He had no signs or symptoms of pancreatic insufficiency and no calcifications within the pancreas.

Chronic mesenteric ischemia

Chronic mesenteric ischemia (“intestinal angina”) is caused by a reduction in intestinal blood flow as a result of occlusion, vasospasm, or hypoperfusion of the mesenteric vasculature.²¹ It is commonly seen in patients who smoke or who have atherosclerotic vascular disease. These patients have chronic dull or crampy abdominal pain that usually occurs within 1 hour after eating.²¹ To avoid pain, patients avoid eating, resulting in weight loss.²¹ CT angiography with multi-detector CT is as effective as angiography (the gold standard) in depicting splanchnic arterial anatomy.²²

Our patient is young and has no known risk factors for atherosclerosis such as smoking. His abdominal pain is more intermittent than chronic and is not associated with eating.

Cannabinoid hyperemesis

Cannabinoid hyperemesis should be considered in patients with long-term cannabis use presenting with cyclic vomiting, abdominal pain, compulsive use of hot showers, and improvement of symptoms with cannabis cessation.²³ Although cannabinoids have been recognized for their antiemetic effects, long-term use may eventually cause autonomic instability and disturbances in the hypothalamic-pituitary-adrenal axis, resulting in cyclic vomiting and thermoregulatory impairment.²³

Although our patient presented with multiple episodes of vomiting and abdominal pain, he denied using marijuana, he tested negative for tetrahydrocannabinol, and he did not associate any relief of his symptoms with hot baths.

CASE CONTINUED

Our patient receives intravenous hydration, antiemetics, and a narcotic in tapering intravenous doses, and his symptoms gradually improve. He is discharged from the hospital. However, a few weeks later he is readmitted with the same symptoms of abdominal pain and nausea.

3. What is the cornerstone of treatment for narcotic bowel syndrome?

• Establishing a therapeutic relationship
• Detoxification
• Supportive management with intravenous fluids, antiemetics, and stool-softeners
• Medical management with a short-acting narcotic, clonidine, lorazepam, and desipramine

MANAGEMENT OF NARCOTIC BOWEL SYNDROME

An effective therapeutic relationship with the patient is the cornerstone of treatment and should be established before starting detoxification.¹⁷ The physician must first learn to accept that the patient’s condition is real and must show genuine empathy as well as provide information about the pathophysiologic basis of the condition, the rationale for withholding narcotics, and the detrimental role narcotics play in the vicious circle of pain.

Detoxification involves gradually withdrawing the narcotic and substituting a nonnarcotic such as an antidepressant for pain control, as well as prescribing a drug such as a benzodiazepine or clonidine to prevent withdrawal symptoms and a laxative to prevent constipation.^17,24 The physician must reassure the patient that he or she will not be abandoned in pain and that all medications will be continuously adjusted as needed to keep him or her comfortable throughout the detoxification process.^17,24 The physician must continuously gauge the patient’s willingness to continue with treatment and must also be readily available to address the patient’s concerns in a timely manner.^17,24 Involving family members and friends may provide additional support to the patient. Referral to a functional gastrointestinal motility program, a pain specialist, and a psychologist may also be considered.^17,24 Follow-up care is essential, even after the withdrawal program has ended.^17,24

BACK TO THE PATIENT

After successfully establishing a therapeutic relationship and discussing the treatment plan with our patient, we started him on the same dosage of narcotic that he had been receiving, calculated in intravenous morphine equivalents to achieve maximal comfort, and then decreased the dosage by 10% to 33% daily until he was completely off narcotics. An antidepressant and a benzodiazepine were given simultaneously with narcotic tapering. Oral clonidine (0.1–0.4 mg/day) was given after the narcotic dosage was reduced to about half, and polyethylene glycol was given as needed for constipation. The total duration of detoxification was 7 days.

The patient was referred to a psychologist for cognitive-behavioral and relaxation therapy, as well as for encouragement and support. At 6 months, he had had no recurrence of symptoms.

TAKE-HOME MESSAGE

In the United States, the number of patients taking a narcotic for nonmalignant pain is increasing, ²⁵ and physicians should be more aware of complications such as narcotic bowel syndrome.

Narcotic bowel syndrome should be suspected in any patient with prolonged narcotic use presenting with multiple recurrent episodes of abdominal pain after other causes are ruled out.

Establishing a good therapeutic relationship with the patient is the cornerstone of successful treatment. Patients who understand their condition and are willing to be treated tend to have better outcomes.

Supportive treatment, symptom relief, and emotional support during detoxification increase compliance.

A 32-year-old man presents to the emergency department with excruciating abdominal pain associated with multiple episodes of vomiting for the past 2 days. He reports no fevers, headaches, diarrhea, constipation, hematochezia, melena, musculoskeletal symptoms, or weight loss. His abdominal pain is generalized and crampy. It does not radiate and has no precipitating factors. The pain is relieved only with intravenous narcotics.

See related editorial

He does not smoke, drink alcohol, or use illicit drugs. He has no known drug or food allergies. He says that his current condition causes him emotional stress that affects his performance at work.

About a year ago, after a complicated surgical procedure, he needed chronic high-dose narcotics. A few months later, he developed multiple bouts of abdominal pain and vomiting that required hospital visits. He now takes oral oxycodone 10–15 mg every 4–6 hours.

On admission, his vital signs are stable, but he is in excruciating pain. He is alert and oriented to person, place, and time. His sclera are anicteric, and the pupils are equal, round, and reactive to light. Lung and heart examinations are normal. The abdomen is soft and nondistended but tender in all four quadrants without guarding; the liver and spleen are not palpable, and no abdominal masses are detected. He has no skin rash, joint swelling or tenderness, or peripheral edema. The neurologic examination is normal. Computed tomography (CT) of the abdomen with contrast shows no signs of bowel obstruction, pancreatic calcifications or edema, cholecystitis, or hepatobiliary disease. Results of initial laboratory testing are shown in Table 1.

1. Based on the information available, which is the least likely cause of his symptoms?

• Acute pancreatitis
• Cyclic vomiting syndrome
• Acute intermittent porphyria
• Gastroparesis

Acute pancreatitis

Acute pancreatitis is the least likely cause of his symptoms. It is commonly caused by gallstones, alcohol, hypertriglyceridemia, and certain drugs.¹ The associated abdominal pain is usually epigastric, radiates to the back, and is accompanied by nausea or vomiting, or both. The onset of pain is sudden and rapidly increases in severity within 30 minutes. CT shows enlargement of the pancreas with diffuse edema, heterogeneity of pancreatic parenchyma, peripancreatic stranding, and peripancreatic fluid collections.¹ The diagnosis is based on two of the following three criteria: abdominal pain characteristic of acute pancreatitis; a serum amylase or lipase concentration three or more times the upper limit of normal; and characteristic findings of acute pancreatitis on CT.¹

Cyclic vomiting syndrome

Cyclic vomiting syndrome is thought to be caused by episodic dysautonomia, mitochondrial DNA mutations, and hypothalamic emetic response oversensitivity,^2–4 but the exact pathogenesis is unknown. The syndrome has been strongly linked to migraine and to the chronic excessive use of cannabinoids.^5–9 The Rome III diagnostic criteria¹⁰ are the following: the vomiting episodes are stereotypical, ie, they are acute and last for less than 1 week; the patient has had three or more episodes in the previous year; and the patient has no nausea or vomiting between episodes. The patient must meet all three criteria. A history of migraine or a family history of migraine further supports the diagnosis.

Acute intermittent porphyria

Acute intermittent porphyria is characterized by neurovisceral symptoms such as convulsions, paresis, autonomic dysfunction, constipation, and diarrhea that result from the overproduction of porphyrin precursors and deficiency of porphobilinogen deaminase.¹¹

Most patients have poorly localized, severe, steady abdominal pain that develops over hours to days and that may persist for days to weeks.¹¹ Since the pain is neuropathic, abdominal tenderness is usually minimal during an acute attack. Other clues include signs of ileus, such as constipation, nausea, abdominal distention, or decreased bowel sounds; bladder dysfunction, eg, urinary retention, incontinence, or dysuria; reddish-brown urine; and sensory neuropathy of the chest, back, and extremities.¹¹ Blistering skin lesions are usually not seen. The presence of porphobilinogen in the urine confirms the diagnosis.¹¹

Gastroparesis

Gastroparesis is a result of discoordination between the sympathetic and parasympathetic nervous systems, neurons, and smooth muscles within the stomach, causing a decrease in gastric motility. Common causes are diabetes,¹² scleroderma,¹³ and neurologic disorders.¹⁴ It can also be iatrogenic,¹⁵ resulting from visceral nerve injury and drug treatment with narcotics, calcium channel blockers, muscarinic cholinergic antagonists, or certain antidepressants. Symptoms are related to gastric stasis, ie, abdominal pain from gastric distention, bloating, vomiting, and early satiety.¹⁵ Abdominal pain may worsen after eating, and vomitus usually consists of recently ingested food. These patients may have abdominal distension or tenderness and succussion splash. After excluding possible mechanical obstruction, a gastric-emptying study may be necessary to make the diagnosis.¹⁵

CASE CONTINUED

A serum and urine drug screen in our patient is positive only for opioids. Urine measures of delta-aminolevulinic acid and porphobilinogen are normal. CT angiography of the abdomen shows no signs of mesenteric vascular occlusion. Esophagogastroduodenoscopy shows antral gastritis, but the esophagus and duodenum appear normal, and colonoscopy is normal as well. Histologic study of biopsy specimens obtained during endoscopy is unrevealing. A gastric-emptying study shows delayed emptying. The patient’s abdominal pain and vomiting persist with the initial dose of intravenous narcotic but resolve with escalating doses. When asked, the patient denies an excessive need for hot baths.

2. Which is the most likely diagnosis at this point?

• Narcotic bowel syndrome
• Opioid withdrawal
• Crohn disease
• Chronic pancreatitis
• Chronic mesenteric ischemia
• Cannabinoid hyperemesis

Narcotic bowel syndrome

Narcotic bowel syndrome is the most likely diagnosis. Grunkemeier et al¹⁶ described it as chronic or frequently recurring abdominal pain that is treated with narcotics, either chronically or acutely with high doses, and that includes all the following features¹⁶:

• The pain worsens or resolves incompletely with continued or increasing doses of narcotics
• The pain markedly worsens when the narcotic dose is decreased, and decreases when the drug is reinstituted (the “soarand-crash” effect)
• The frequency, duration, and intensity of the pain episodes gradually increase
• The nature of the pain and its intensity are not explained by a current or previous gastrointestinal diagnosis.¹⁶

This syndrome is common in patients who receive high doses of narcotics for postoperative pain or for other, nonmalignant causes of pain. Patients eventually become dependent on the drugs but are not aware that chronic use activates and facilitates areas in the brain that enhance the perception of pain.¹⁶ A study of a rat model of narcotic bowel syndrome¹⁷ showed that morphine-induced hyperalgesia depends on central sensitization involving the activation of spinal microglia. This eventually results in concomitant peripheral sensitization involving the colonic mucosal neuroimmune system, and also in central or peripheral activation of opioid kappa-receptors by dynorphin release.¹⁷

Patients tend to present with chronic or intermittent colicky abdominal pain that requires escalating doses of narcotics. Eventually, they develop tachyphylaxis and shortened pain-free periods and will require even higher doses of narcotics. This ultimately enhances the perception of pain and worsens opioid bowel symptoms, causing a vicious circle of pain and more narcotic use.¹⁶

Laboratory tests are usually normal, and imaging may show only ileus. Gastric emptying may be delayed in patients who have either narcotic bowel syndrome or gastroparesis, but since abdominal pain from narcotic bowel syndrome is a result of central and visceral hypersensitivity, these patients perceive more severe abdominal pain than patients with gastroparesis alone.

Opioid withdrawal

Symptoms of opioid withdrawal may appear as soon as 6 to 24 hours after cessation of the opioid in patients known to be dependent on opioids. These patients present with crampy abdominal pain with nausea.¹⁸ Other symptoms include agitation, rhinorrhea, lacrimation, excessive yawning, arthralgias, papillary dilation, and piloerection.¹⁸

Our patient did not have the typical signs of opioid withdrawal.

Crohn disease

Crohn disease is a multisystem disorder with specific clinical and pathologic features. It is characterized by focal, asymmetric, transmural, and occasionally granulomatous inflammation primarily affecting the gastrointestinal tract.¹⁹ Characteristic symptoms include abdominal pain, chronic diarrhea with or without rectal bleeding, and weight loss. Extraintestinal signs may include anemia and inflammatory changes in the eyes, skin, and joints. The diagnosis is based on endoscopic, radiographic, and pathologic findings.¹⁹

Our patient did not have diarrhea or signs of Crohn disease on CT, endoscopy, or histology.

Chronic pancreatitis

Chronic pancreatitis involves progressive inflammatory changes resulting in permanent structural damage to the pancreas and subsequent exocrine and endocrine dysfunction.²⁰ Patients have epigastric abdominal pain that often radiates to the back²⁰; it is associated with eating and is partly relieved with leaning forward. Symptoms of pancreatic insufficiency such as fat malabsorption (resulting in steatorrhea and fat-soluble vitamin deficiency) and diabetes are common. Calcifications within the pancreas on CT suggest chronic pancreatitis.²⁰ Serum lipase and amylase levels may be normal or slightly elevated.²⁰

Our patient’s abdominal pain was not typical of pancreatitis. He had no signs or symptoms of pancreatic insufficiency and no calcifications within the pancreas.

Chronic mesenteric ischemia

Chronic mesenteric ischemia (“intestinal angina”) is caused by a reduction in intestinal blood flow as a result of occlusion, vasospasm, or hypoperfusion of the mesenteric vasculature.²¹ It is commonly seen in patients who smoke or who have atherosclerotic vascular disease. These patients have chronic dull or crampy abdominal pain that usually occurs within 1 hour after eating.²¹ To avoid pain, patients avoid eating, resulting in weight loss.²¹ CT angiography with multi-detector CT is as effective as angiography (the gold standard) in depicting splanchnic arterial anatomy.²²

Our patient is young and has no known risk factors for atherosclerosis such as smoking. His abdominal pain is more intermittent than chronic and is not associated with eating.

Cannabinoid hyperemesis

Cannabinoid hyperemesis should be considered in patients with long-term cannabis use presenting with cyclic vomiting, abdominal pain, compulsive use of hot showers, and improvement of symptoms with cannabis cessation.²³ Although cannabinoids have been recognized for their antiemetic effects, long-term use may eventually cause autonomic instability and disturbances in the hypothalamic-pituitary-adrenal axis, resulting in cyclic vomiting and thermoregulatory impairment.²³

Although our patient presented with multiple episodes of vomiting and abdominal pain, he denied using marijuana, he tested negative for tetrahydrocannabinol, and he did not associate any relief of his symptoms with hot baths.

CASE CONTINUED

Our patient receives intravenous hydration, antiemetics, and a narcotic in tapering intravenous doses, and his symptoms gradually improve. He is discharged from the hospital. However, a few weeks later he is readmitted with the same symptoms of abdominal pain and nausea.

3. What is the cornerstone of treatment for narcotic bowel syndrome?

• Establishing a therapeutic relationship
• Detoxification
• Supportive management with intravenous fluids, antiemetics, and stool-softeners
• Medical management with a short-acting narcotic, clonidine, lorazepam, and desipramine

MANAGEMENT OF NARCOTIC BOWEL SYNDROME

An effective therapeutic relationship with the patient is the cornerstone of treatment and should be established before starting detoxification.¹⁷ The physician must first learn to accept that the patient’s condition is real and must show genuine empathy as well as provide information about the pathophysiologic basis of the condition, the rationale for withholding narcotics, and the detrimental role narcotics play in the vicious circle of pain.

Detoxification involves gradually withdrawing the narcotic and substituting a nonnarcotic such as an antidepressant for pain control, as well as prescribing a drug such as a benzodiazepine or clonidine to prevent withdrawal symptoms and a laxative to prevent constipation.^17,24 The physician must reassure the patient that he or she will not be abandoned in pain and that all medications will be continuously adjusted as needed to keep him or her comfortable throughout the detoxification process.^17,24 The physician must continuously gauge the patient’s willingness to continue with treatment and must also be readily available to address the patient’s concerns in a timely manner.^17,24 Involving family members and friends may provide additional support to the patient. Referral to a functional gastrointestinal motility program, a pain specialist, and a psychologist may also be considered.^17,24 Follow-up care is essential, even after the withdrawal program has ended.^17,24

BACK TO THE PATIENT

After successfully establishing a therapeutic relationship and discussing the treatment plan with our patient, we started him on the same dosage of narcotic that he had been receiving, calculated in intravenous morphine equivalents to achieve maximal comfort, and then decreased the dosage by 10% to 33% daily until he was completely off narcotics. An antidepressant and a benzodiazepine were given simultaneously with narcotic tapering. Oral clonidine (0.1–0.4 mg/day) was given after the narcotic dosage was reduced to about half, and polyethylene glycol was given as needed for constipation. The total duration of detoxification was 7 days.

The patient was referred to a psychologist for cognitive-behavioral and relaxation therapy, as well as for encouragement and support. At 6 months, he had had no recurrence of symptoms.

TAKE-HOME MESSAGE

In the United States, the number of patients taking a narcotic for nonmalignant pain is increasing, ²⁵ and physicians should be more aware of complications such as narcotic bowel syndrome.

Narcotic bowel syndrome should be suspected in any patient with prolonged narcotic use presenting with multiple recurrent episodes of abdominal pain after other causes are ruled out.

Establishing a good therapeutic relationship with the patient is the cornerstone of successful treatment. Patients who understand their condition and are willing to be treated tend to have better outcomes.

Supportive treatment, symptom relief, and emotional support during detoxification increase compliance.

One of the most common questions patients ask when they hear that they need surgery is, “How much pain will I have, and how will you manage it?”

Pain is a common human experience that provokes both fear and anxiety, which in some cases can last a lifetime. The medical community has been slow to meet the challenge of managing it. The US National Institutes of Health states that more than 80% of patients suffer postoperative pain, with fewer than 50% receiving adequate relief.¹ Patients have spoken out loudly through the Hospital Consumer Assessment of Healthcare Providers and Systems scores, demonstrating that the issue of inadequate postoperative pain management is real.

See related article

Clearly, as the push to tie reimbursement to patient satisfaction grows, clinicians have both a moral and a financial imperative to address postoperative pain.

The management of acute postoperative pain is evolving, and recognition of acute pain has progressed from considering it an afterthought or nuisance to realizing that improperly or inadequately treated postoperative pain can have a number of adverse effects, including debilitating chronic pain syndromes.² Inadequately treated pain is also contributing to the calamitous rise in addiction to illegal substances and prescription medications.³ The time has come to take responsibility and meet the expectations of our patients.

OPIOIDS HAVE MAJOR DRAWBACKS

Opioid derivatives are potent analgesics and have been the traditional first-line therapy for pain. “Judicious use of opium” for painful maladies has been a mainstay of Western medicine since the 16th century and was described in writings from Mesopotamia and China more than 2,000 years ago.

The ease of administration of these drugs coupled with their efficacy in managing a broad spectrum of pain syndromes has led to their frequent and widespread use, often, unfortunately, without consideration of the potential for negative short-term and long-term consequences. Headache, drowsiness, and pruritus are common adverse effects. Less common is a slowing of bowel motility, leading to constipation, bloating, or nausea. Additionally, in 5% to 10% of patients, narcotics may actually sensitize the nerves and make bowel-related pain worse. This narcotic bowel syndrome, as discussed by Agito and Rizk in this issue of the Journal, may make the patient uncomfortable and may lead to delays in recovery and hospital discharge.⁴

Opioid-related respiratory depression is especially devastating in the postoperative period, potentially causing respiratory arrest and death. The frequency of drug-induced respiratory depression and clinically significant adverse outcomes prompted the Anesthesia Patient Safety Foundation (APSF) to declare in 2011, “No patient shall be harmed by opioid-induced respiratory depression.”⁵ The APSF has recommended using new monitoring technology to enhance detection.

While many clinicians have been moving towards aggressive pain-management practice, hospital infrastructure has not kept pace. It is often ill-equipped to adequately monitor breathing patterns and to alert personnel to the need for rapid intervention. In the 21st century, we need to respond to this challenge with a combination of tools and technology, including improved clinical assessment and monitoring equipment that has proven to save lives in the perioperative setting.

A MULTIMODAL APPROACH IS BEST

Pain management professionals have also been moving from a predominantly opioid-based regimen to a more balanced, multimodal approach. The goal is to effectively treat acute postoperative pain while reducing the use of opioids and increasing the use of nonopioid drugs and alternative therapies for both pain management and convalescence.

Studies have shown the benefits of nonopioid drugs such as nonsteroidal anti-inflammatory drugs, paracetamol (intravenous acetaminophen), antidepressants, antiepileptics, and regional or local anesthetics combined with nontraditional treatments such as Reiki, massage therapy, and deep breathing.⁶

Each patient’s experience of pain is unique and responds to medications and alternative therapies in a distinctly different manner. We should not assume that one intervention is suitable for every patient. It is more beneficial to individualize treatment based on protocols that target different pain pathways. This may lead to better pain management and patient satisfaction while reducing the incidence of drug overdose and unwanted side effects.

WHAT WE NEED TO DO

Although many health care professionals have the authority to prescribe potent anesthetics and analgesics, we believe that there is a lack of adequate education, supervision, and experience, and this exposes patients to risks of prescription drug overdose.^7,8 All medical professionals who provide postoperative care need specific education and training to offer the best care to this vulnerable patient population. This includes specific and more extensive training in the appropriate use of controlled medications before receiving their controlled substance registration from the Drug Enforcement Agency. We must also extend education to patients and family members regarding the dangers of drug abuse and the safe use of prescription drugs.⁸

Finally, we need to engage and communicate more effectively with our patients, especially when they are in acute pain. How long should a patient expect to remain in pain while waiting for an assessment and intervention? The medical community must commit to rapid and consistent coverage throughout the day for all patients experiencing a new or changing pattern of pain not responding to current therapy. Problems do not end at 5 pm or at a shift change. We need to build a process of timely intervention, perhaps by using a model similar to that of the rapid response and resuscitation team, which has been effective in many institutions. When a patient is in pain, minutes spent waiting for relief seem like an eternity. The empathy we show patients by validating, not minimizing, their pain and by following a defined yet tailored therapeutic intervention may not only improve their physical discomfort, but improve their overall patient experience.

Margo McCaffery, RN, a pioneer in pain management nursing, defined pain as “whatever the experiencing person says it is, existing whenever the experiencing person says it does.”⁹ We have come a long way from the days when attending staff in the post-anesthesia care unit would routinely declare, “Pain never killed anyone.” As caregivers, we need to become engaged, empathetic, and effective as we meet the challenges of managing acute postoperative pain and improving our patients’ experience and outcomes.

One of the most common questions patients ask when they hear that they need surgery is, “How much pain will I have, and how will you manage it?”

Pain is a common human experience that provokes both fear and anxiety, which in some cases can last a lifetime. The medical community has been slow to meet the challenge of managing it. The US National Institutes of Health states that more than 80% of patients suffer postoperative pain, with fewer than 50% receiving adequate relief.¹ Patients have spoken out loudly through the Hospital Consumer Assessment of Healthcare Providers and Systems scores, demonstrating that the issue of inadequate postoperative pain management is real.

See related article

Clearly, as the push to tie reimbursement to patient satisfaction grows, clinicians have both a moral and a financial imperative to address postoperative pain.

The management of acute postoperative pain is evolving, and recognition of acute pain has progressed from considering it an afterthought or nuisance to realizing that improperly or inadequately treated postoperative pain can have a number of adverse effects, including debilitating chronic pain syndromes.² Inadequately treated pain is also contributing to the calamitous rise in addiction to illegal substances and prescription medications.³ The time has come to take responsibility and meet the expectations of our patients.

OPIOIDS HAVE MAJOR DRAWBACKS

Opioid derivatives are potent analgesics and have been the traditional first-line therapy for pain. “Judicious use of opium” for painful maladies has been a mainstay of Western medicine since the 16th century and was described in writings from Mesopotamia and China more than 2,000 years ago.

The ease of administration of these drugs coupled with their efficacy in managing a broad spectrum of pain syndromes has led to their frequent and widespread use, often, unfortunately, without consideration of the potential for negative short-term and long-term consequences. Headache, drowsiness, and pruritus are common adverse effects. Less common is a slowing of bowel motility, leading to constipation, bloating, or nausea. Additionally, in 5% to 10% of patients, narcotics may actually sensitize the nerves and make bowel-related pain worse. This narcotic bowel syndrome, as discussed by Agito and Rizk in this issue of the Journal, may make the patient uncomfortable and may lead to delays in recovery and hospital discharge.⁴

Opioid-related respiratory depression is especially devastating in the postoperative period, potentially causing respiratory arrest and death. The frequency of drug-induced respiratory depression and clinically significant adverse outcomes prompted the Anesthesia Patient Safety Foundation (APSF) to declare in 2011, “No patient shall be harmed by opioid-induced respiratory depression.”⁵ The APSF has recommended using new monitoring technology to enhance detection.

While many clinicians have been moving towards aggressive pain-management practice, hospital infrastructure has not kept pace. It is often ill-equipped to adequately monitor breathing patterns and to alert personnel to the need for rapid intervention. In the 21st century, we need to respond to this challenge with a combination of tools and technology, including improved clinical assessment and monitoring equipment that has proven to save lives in the perioperative setting.

A MULTIMODAL APPROACH IS BEST

Pain management professionals have also been moving from a predominantly opioid-based regimen to a more balanced, multimodal approach. The goal is to effectively treat acute postoperative pain while reducing the use of opioids and increasing the use of nonopioid drugs and alternative therapies for both pain management and convalescence.

Studies have shown the benefits of nonopioid drugs such as nonsteroidal anti-inflammatory drugs, paracetamol (intravenous acetaminophen), antidepressants, antiepileptics, and regional or local anesthetics combined with nontraditional treatments such as Reiki, massage therapy, and deep breathing.⁶

Each patient’s experience of pain is unique and responds to medications and alternative therapies in a distinctly different manner. We should not assume that one intervention is suitable for every patient. It is more beneficial to individualize treatment based on protocols that target different pain pathways. This may lead to better pain management and patient satisfaction while reducing the incidence of drug overdose and unwanted side effects.

WHAT WE NEED TO DO

Although many health care professionals have the authority to prescribe potent anesthetics and analgesics, we believe that there is a lack of adequate education, supervision, and experience, and this exposes patients to risks of prescription drug overdose.^7,8 All medical professionals who provide postoperative care need specific education and training to offer the best care to this vulnerable patient population. This includes specific and more extensive training in the appropriate use of controlled medications before receiving their controlled substance registration from the Drug Enforcement Agency. We must also extend education to patients and family members regarding the dangers of drug abuse and the safe use of prescription drugs.⁸

Finally, we need to engage and communicate more effectively with our patients, especially when they are in acute pain. How long should a patient expect to remain in pain while waiting for an assessment and intervention? The medical community must commit to rapid and consistent coverage throughout the day for all patients experiencing a new or changing pattern of pain not responding to current therapy. Problems do not end at 5 pm or at a shift change. We need to build a process of timely intervention, perhaps by using a model similar to that of the rapid response and resuscitation team, which has been effective in many institutions. When a patient is in pain, minutes spent waiting for relief seem like an eternity. The empathy we show patients by validating, not minimizing, their pain and by following a defined yet tailored therapeutic intervention may not only improve their physical discomfort, but improve their overall patient experience.

Margo McCaffery, RN, a pioneer in pain management nursing, defined pain as “whatever the experiencing person says it is, existing whenever the experiencing person says it does.”⁹ We have come a long way from the days when attending staff in the post-anesthesia care unit would routinely declare, “Pain never killed anyone.” As caregivers, we need to become engaged, empathetic, and effective as we meet the challenges of managing acute postoperative pain and improving our patients’ experience and outcomes.

One of the most common questions patients ask when they hear that they need surgery is, “How much pain will I have, and how will you manage it?”

Pain is a common human experience that provokes both fear and anxiety, which in some cases can last a lifetime. The medical community has been slow to meet the challenge of managing it. The US National Institutes of Health states that more than 80% of patients suffer postoperative pain, with fewer than 50% receiving adequate relief.¹ Patients have spoken out loudly through the Hospital Consumer Assessment of Healthcare Providers and Systems scores, demonstrating that the issue of inadequate postoperative pain management is real.

See related article

Clearly, as the push to tie reimbursement to patient satisfaction grows, clinicians have both a moral and a financial imperative to address postoperative pain.

The management of acute postoperative pain is evolving, and recognition of acute pain has progressed from considering it an afterthought or nuisance to realizing that improperly or inadequately treated postoperative pain can have a number of adverse effects, including debilitating chronic pain syndromes.² Inadequately treated pain is also contributing to the calamitous rise in addiction to illegal substances and prescription medications.³ The time has come to take responsibility and meet the expectations of our patients.

OPIOIDS HAVE MAJOR DRAWBACKS

Opioid derivatives are potent analgesics and have been the traditional first-line therapy for pain. “Judicious use of opium” for painful maladies has been a mainstay of Western medicine since the 16th century and was described in writings from Mesopotamia and China more than 2,000 years ago.

The ease of administration of these drugs coupled with their efficacy in managing a broad spectrum of pain syndromes has led to their frequent and widespread use, often, unfortunately, without consideration of the potential for negative short-term and long-term consequences. Headache, drowsiness, and pruritus are common adverse effects. Less common is a slowing of bowel motility, leading to constipation, bloating, or nausea. Additionally, in 5% to 10% of patients, narcotics may actually sensitize the nerves and make bowel-related pain worse. This narcotic bowel syndrome, as discussed by Agito and Rizk in this issue of the Journal, may make the patient uncomfortable and may lead to delays in recovery and hospital discharge.⁴

Opioid-related respiratory depression is especially devastating in the postoperative period, potentially causing respiratory arrest and death. The frequency of drug-induced respiratory depression and clinically significant adverse outcomes prompted the Anesthesia Patient Safety Foundation (APSF) to declare in 2011, “No patient shall be harmed by opioid-induced respiratory depression.”⁵ The APSF has recommended using new monitoring technology to enhance detection.

While many clinicians have been moving towards aggressive pain-management practice, hospital infrastructure has not kept pace. It is often ill-equipped to adequately monitor breathing patterns and to alert personnel to the need for rapid intervention. In the 21st century, we need to respond to this challenge with a combination of tools and technology, including improved clinical assessment and monitoring equipment that has proven to save lives in the perioperative setting.

A MULTIMODAL APPROACH IS BEST

Pain management professionals have also been moving from a predominantly opioid-based regimen to a more balanced, multimodal approach. The goal is to effectively treat acute postoperative pain while reducing the use of opioids and increasing the use of nonopioid drugs and alternative therapies for both pain management and convalescence.

Studies have shown the benefits of nonopioid drugs such as nonsteroidal anti-inflammatory drugs, paracetamol (intravenous acetaminophen), antidepressants, antiepileptics, and regional or local anesthetics combined with nontraditional treatments such as Reiki, massage therapy, and deep breathing.⁶

Each patient’s experience of pain is unique and responds to medications and alternative therapies in a distinctly different manner. We should not assume that one intervention is suitable for every patient. It is more beneficial to individualize treatment based on protocols that target different pain pathways. This may lead to better pain management and patient satisfaction while reducing the incidence of drug overdose and unwanted side effects.

WHAT WE NEED TO DO

Although many health care professionals have the authority to prescribe potent anesthetics and analgesics, we believe that there is a lack of adequate education, supervision, and experience, and this exposes patients to risks of prescription drug overdose.^7,8 All medical professionals who provide postoperative care need specific education and training to offer the best care to this vulnerable patient population. This includes specific and more extensive training in the appropriate use of controlled medications before receiving their controlled substance registration from the Drug Enforcement Agency. We must also extend education to patients and family members regarding the dangers of drug abuse and the safe use of prescription drugs.⁸

Finally, we need to engage and communicate more effectively with our patients, especially when they are in acute pain. How long should a patient expect to remain in pain while waiting for an assessment and intervention? The medical community must commit to rapid and consistent coverage throughout the day for all patients experiencing a new or changing pattern of pain not responding to current therapy. Problems do not end at 5 pm or at a shift change. We need to build a process of timely intervention, perhaps by using a model similar to that of the rapid response and resuscitation team, which has been effective in many institutions. When a patient is in pain, minutes spent waiting for relief seem like an eternity. The empathy we show patients by validating, not minimizing, their pain and by following a defined yet tailored therapeutic intervention may not only improve their physical discomfort, but improve their overall patient experience.

Margo McCaffery, RN, a pioneer in pain management nursing, defined pain as “whatever the experiencing person says it is, existing whenever the experiencing person says it does.”⁹ We have come a long way from the days when attending staff in the post-anesthesia care unit would routinely declare, “Pain never killed anyone.” As caregivers, we need to become engaged, empathetic, and effective as we meet the challenges of managing acute postoperative pain and improving our patients’ experience and outcomes.

A typographical error appeared in Figure 1 of: Park K, Bavry AA. Aspirin: its risks, benefits, and optimal use in preventing cardiovascular events (Cleve Clin J Med 2013; 80:318–326). The lower left side of the figure, discussing the use of aspirin for primary prevention in men, should read as follows:

Assess risk of myocardial infarction (http://hp2010.nhlbihin.net/atpiii/calculator.asp); give aspirin if:

• Age 45–59 and 10-year risk ≥ 4%
• Age 60–69 and 10-year risk ≥ 9%
• Age 70–79 and 10-year risk ≥ 12%

A typographical error appeared in Figure 1 of: Park K, Bavry AA. Aspirin: its risks, benefits, and optimal use in preventing cardiovascular events (Cleve Clin J Med 2013; 80:318–326). The lower left side of the figure, discussing the use of aspirin for primary prevention in men, should read as follows:

Assess risk of myocardial infarction (http://hp2010.nhlbihin.net/atpiii/calculator.asp); give aspirin if:

• Age 45–59 and 10-year risk ≥ 4%
• Age 60–69 and 10-year risk ≥ 9%
• Age 70–79 and 10-year risk ≥ 12%

A typographical error appeared in Figure 1 of: Park K, Bavry AA. Aspirin: its risks, benefits, and optimal use in preventing cardiovascular events (Cleve Clin J Med 2013; 80:318–326). The lower left side of the figure, discussing the use of aspirin for primary prevention in men, should read as follows:

Assess risk of myocardial infarction (http://hp2010.nhlbihin.net/atpiii/calculator.asp); give aspirin if:

• Age 45–59 and 10-year risk ≥ 4%
• Age 60–69 and 10-year risk ≥ 9%
• Age 70–79 and 10-year risk ≥ 12%

Surveys are common in medical research. Although survey research may be subject to inherent self-report bias, surveys have a great impact on policies and practices in medicine, often forming the basis for recommendations or new guidelines.^1,2 To interpret and use survey research results, clinicians should be familiar with key elements involved in the creation and validation of surveys.

The purpose of this article is to provide readers with a basic framework for evaluating surveys to allow them to be more informed as consumers of survey research.

IMPORTANT TOOLS IN MEDICAL RESEARCH

Surveys are important tools for answering questions on topics that are difficult to assess using other methods.³ They allow us to gather data systematically from subjects by asking questions, in order to make inferences about a larger population.^3,4 Clinicians use surveys to explore the opinions, beliefs, and perceptions of a group, or to investigate physician practice patterns and adherence to clinical guidelines. They may also use surveys to better understand why patients are not engaging in recommended behavioral or lifestyle changes.

Survey methods include interviews (in person, by phone) and questionnaires (paper-and-pencil, e-mailed, online).⁴

A well-constructed, validated survey can provide powerful data that may influence clinical practice, guide future research development, or drive the development and provision of needed programs and services. Surveys have the potential to transform the ways in which we think about and practice medicine.

READER BEWARE

While survey research in health care appears to have grown exponentially, the quality of reported survey research has not necessarily increased over time.

For consumers of survey research, the adage “reader beware” is apt. Although a considerable number of studies have examined the effects of survey methodology on the validity, reliability, and generalizability of the results,⁴ medical journals differ in their requirements for reporting survey methods.

In an analysis of 117 articles, Bennett et al³ found that more than 80% did not fully describe the survey development process or pretesting methods. They also found limited guidance and lack of consensus about the best way to report survey research. Of 95 surveys requiring scoring, 66% did not report scoring practices.

Duffett et al⁵ noted that of 127 critical care medicine surveys, only 36% had been pretested or pilot-tested, and half of all surveys reviewed did not include participant demographics or included only minimal information.

Because journal reporting practices differ, physicians may be unaware of the steps involved in survey construction and validation. Knowledge of these steps is helpful not only in constructing surveys but also in assessing published articles that used survey research.

LIMITATIONS OF SURVEY RESEARCH

Indirect measures of attitudes and behaviors

Surveys that rely on participants’ self-reports of behaviors, attitudes, beliefs, or actions are indirect measures and are susceptible to self-report and social-desirability biases. Participants may overestimate their own expertise or knowledge in self-report surveys. They may wish to reduce embarrassment⁶ or answer in ways that would make them “look better,”⁷ resulting in social-desirability bias. These issues need to be mentioned in the limitations section in papers reporting survey research.

Questions and response choices

The data derived from surveys are only as good as the questions that are asked.⁸ Stone⁹ noted that questions should be intelligible, unambiguous, and unbiased. If respondents do not comprehend questions as researchers intended, if questionnaire response choices are inadequate, or if questions trigger unintended emotional responses,^10–14 researchers may unwittingly introduce error, which will affect the validity of results. Even seemingly objective questions, such as those related to clinical algorithm use, practice patterns, or equipment available to hospital staff, may be interpreted differently by different respondents.

In their eagerness to launch a survey, clinician researchers may not realize that it must be carefully constructed. A focus on question development and validation is critical, as the questions determine the quality of the data derived from the survey.⁸ Even the position of the question or answer in the survey can affect how participants respond,¹⁵ as they may be guided to a response choice by preceding questions.¹⁶

WHAT DO YOU NEED TO KNOW ABOUT ASSESSING SURVEY RESEARCH?

What follows are questions and a basic framework that can be used to evaluate published survey research. Recommendations are based on the work of survey scientists,^{4,7,10,14,15,17,18} survey researchers in medicine and the social sciences, and national standards for test and questionnaire construction and validation (Table 1).^4,19,20

Who created the survey? How did they do it?

How the survey was created should be sufficiently described to allow readers to judge the adequacy of instrument development.^3–5 It is generally recommended that feedback from multiple sources be solicited during survey creation. Both questionnaire-design experts and subject-matter experts are considered critical in the process.⁴

What question was the survey designed to answer?

Is the objective of the study articulated in the paper? ^3,20 To judge survey research, readers need to know if the survey appears to adequately address the research question or questions and the objectives of the study in terms of methods used.⁴

Instrument pretesting and field testing are considered best practices by the American Association for Public Opinion Research, a professional organization for US survey scientists.⁴

Pretesting can include cognitive interviewing, the use of questionnaire appraisal tools, and hybrid methods, all of which are aimed at addressing validity issues.²¹ Pretesting with a group of participants similar to the target population allows for assessment of item ambiguity, instrument ease of use, adequacy of response categories (response choices), and time to completion.^4,12

Cognitive interviewing is designed to explore respondents’ comprehension of questions, response processes, and decision processes governing how they answer questions.^4,7,10,11 In cognitive interviewing, respondents are generally interviewed one on one. Techniques vary, but typically include “think alouds” (in which a respondent is asked to verbalize thoughts while responding to questions) and “verbal probing” (in which the respondent answers a question, then is asked follow-up questions as the interviewer probes for information related to the response choice or question itself).⁷ These techniques can provide evidence that researchers are actually measuring what they set out to measure and not an unrelated construct.^4,19

Field testing of a survey under realistic conditions can help to uncover problems in administration, such as issues in standardization of key procedures, and to ensure that the survey was administered as the researchers intended.^21,22 Field testing is vital before phone or in-person interviews to ensure standardization of any critical procedures. Pilot testing in a sample similar to the intended population allows for further refinement, with deletion of problem items, before the survey is launched.¹⁵

Because even “objective” questions can be somewhat subjective, all research surveys should go through some type of pretesting.^4,21 Based on the results of pretesting and field testing, surveys should then be revised before launch.^4,21 If an article on a self-report survey makes no mention of survey validation steps, readers may well question the validity of the results.

Are the survey questions and response choices understandable?

Is the meaning of each question unambiguous? Is the reading level appropriate for the sample population (a critical consideration in patient surveys)? Do any of the items actually ask two different questions?¹³ An example would be: “Was the representative courteous and prompt?” as it is possible to be courteous, but not prompt, and vice versa. If so, respondents may be confused or frustrated in attempting to answer it. If a rating scale is used throughout the questionnaire, are the anchors appropriate? For example, a question may be written in such a way that respondents want to answer “yes/no” or “agree/disagree,” but the scale used may include response options such as “poor,” “marginal,” “good,” and “excellent.” Items with Likert-response formats are commonly used in self-report surveys and allow participants to respond to a statement by choosing from a range of responses (eg, strongly disagree to strongly agree), often spaced horizontally under a line.

It is recommended that surveys also include options for answers beyond the response choices provided,²⁰ such as comment boxes or fill-in-the-blank items. Surveys with a closed-response format may constrain the quality of data collected because investigators may not foresee all possible answers. Surveys need to be available for review either within the article itself, in an appendix, or as supplementary material that is available elsewhere.

Does the sample appear to be appropriate?

Articles that report the results of surveys should describe the target population, the sample design, and, in a demographic table, respondents and nonrespondents. To judge appropriateness, several questions can be asked regarding sampling:

Target population. Is the population of interest (ie, the target population) described, including regional demographics, if applicable? The relationship between the sample and the target population is important, as a nonrepresentative sample may result in misleading conclusions about the population of interest.

Sampling frame. Who had an opportunity to participate in the survey? At its simplest, the sampling frame establishes who (or what, in the case of institutions) should be included within the sample. This is typically a list of elements (Groves et al⁴) that acts to “frame” or define the sample to be selected. Where the target population may be all academic internal medicine physicians in the United States, the sampling frame may be all male and female US physicians who are members of particular internal medicine professional organizations, identified by their directory email addresses.

Sample design. How was the sample actually selected?⁴ For example, did investigators use a convenience sample of colleagues at other institutions or use a stratified random sample, ensuring adequate representation of respondents with certain characteristics?

Description of respondents. How is the sample of respondents described? Are demographic features reported, including statistics on regional or national representativeness?⁵ Does the sample of survey respondents appear to be representative of the researcher’s population of interest (ie, the target population)?^3,23 If not, is this adequately described in the limitations section? Although outcomes will not be available on nonrespondents, demographic and baseline data often are available and should be reported. Are there systematic differences between respondents and nonrespondents?

Was the response rate adequate?

Was the response rate adequate, given the number of participants initially recruited? If the response rate was not adequate, did the researchers discuss this limitation?

Maximum response rate, defined as the total number of surveys returned divided by the total number of surveys sent,¹⁸ may be difficult to calculate with electronic or Web-based survey platforms. When the maximum response rate cannot be calculated, this issue needs to be addressed in the article’s limitations section.

The number of surveys has increased across fields over the past few decades, but survey response rates in general have decreased.^17,21,24,25 In fields outside of clinical medicine, response rates in the 40% range are common.¹⁷ In the 1990s, the mean response rate for surveys published in medical journals (mailed surveys) was approximately 60%.²⁶ A 2001 review of physician questionnaire studies found a similar average response rate (61%), with a 52% response rate for large-sample surveys.²⁷ In 2002, Field et al²⁸ examined the impact of incentives in physician survey studies and found response rates ranging from 8.5% to 80%.

Importantly, electronically delivered surveys (e-mail, Web-based) often have lower response rates than mailed surveys.^24,29 Nominal financial incentives have been associated with enhanced response rates.²⁸

A relatively low response rate does not necessarily mean you cannot trust the data. Survey scientists note that the representativeness of the sample may be more critical than response rate alone.¹⁷ Studies with small sample sizes may be more representative—and findings more valid—than those with large samples, if large samples are nonrepresentative when considering the target population.¹⁷

Do the conclusions go beyond the data?

Are the inferences overreaching, in view of the survey design? In studies with low response rates and nonrepresentative samples, researchers must be careful in interpreting the results. If the results cannot be generalized beyond the research sample, is this clear from the limitations, discussion, and conclusion sections?

In this review, we have summarized the findings of three published surveys^1,2,30 and commented on how they appear to meet—or don’t quite meet—recommendations for survey development, validation, and use. The papers chosen were deemed strong examples in particular categories, such as description of survey authorship,¹ instrument validation,³⁰ sampling methodology,² and response rate.¹

It should be noted that even when surveys are conducted with the utmost rigor, survey reporting may leave out critical details. Survey methodology may not be adequately described for a variety of reasons, including researchers’ training in survey design and methodology; a lack of universally accepted journal-reporting guidelines³; and even journals’ space limitations. At times, journals may excise descriptions of survey development and validation, deeming these sections superfluous. Limitations sections can be critical to interpreting the results of survey research and evaluating the scope of conclusions.

Surveys are common in medical research. Although survey research may be subject to inherent self-report bias, surveys have a great impact on policies and practices in medicine, often forming the basis for recommendations or new guidelines.^1,2 To interpret and use survey research results, clinicians should be familiar with key elements involved in the creation and validation of surveys.

The purpose of this article is to provide readers with a basic framework for evaluating surveys to allow them to be more informed as consumers of survey research.

IMPORTANT TOOLS IN MEDICAL RESEARCH

Surveys are important tools for answering questions on topics that are difficult to assess using other methods.³ They allow us to gather data systematically from subjects by asking questions, in order to make inferences about a larger population.^3,4 Clinicians use surveys to explore the opinions, beliefs, and perceptions of a group, or to investigate physician practice patterns and adherence to clinical guidelines. They may also use surveys to better understand why patients are not engaging in recommended behavioral or lifestyle changes.

Survey methods include interviews (in person, by phone) and questionnaires (paper-and-pencil, e-mailed, online).⁴

A well-constructed, validated survey can provide powerful data that may influence clinical practice, guide future research development, or drive the development and provision of needed programs and services. Surveys have the potential to transform the ways in which we think about and practice medicine.

READER BEWARE

While survey research in health care appears to have grown exponentially, the quality of reported survey research has not necessarily increased over time.

For consumers of survey research, the adage “reader beware” is apt. Although a considerable number of studies have examined the effects of survey methodology on the validity, reliability, and generalizability of the results,⁴ medical journals differ in their requirements for reporting survey methods.

In an analysis of 117 articles, Bennett et al³ found that more than 80% did not fully describe the survey development process or pretesting methods. They also found limited guidance and lack of consensus about the best way to report survey research. Of 95 surveys requiring scoring, 66% did not report scoring practices.

Duffett et al⁵ noted that of 127 critical care medicine surveys, only 36% had been pretested or pilot-tested, and half of all surveys reviewed did not include participant demographics or included only minimal information.

Because journal reporting practices differ, physicians may be unaware of the steps involved in survey construction and validation. Knowledge of these steps is helpful not only in constructing surveys but also in assessing published articles that used survey research.

LIMITATIONS OF SURVEY RESEARCH

Indirect measures of attitudes and behaviors

Surveys that rely on participants’ self-reports of behaviors, attitudes, beliefs, or actions are indirect measures and are susceptible to self-report and social-desirability biases. Participants may overestimate their own expertise or knowledge in self-report surveys. They may wish to reduce embarrassment⁶ or answer in ways that would make them “look better,”⁷ resulting in social-desirability bias. These issues need to be mentioned in the limitations section in papers reporting survey research.

Questions and response choices

The data derived from surveys are only as good as the questions that are asked.⁸ Stone⁹ noted that questions should be intelligible, unambiguous, and unbiased. If respondents do not comprehend questions as researchers intended, if questionnaire response choices are inadequate, or if questions trigger unintended emotional responses,^10–14 researchers may unwittingly introduce error, which will affect the validity of results. Even seemingly objective questions, such as those related to clinical algorithm use, practice patterns, or equipment available to hospital staff, may be interpreted differently by different respondents.

In their eagerness to launch a survey, clinician researchers may not realize that it must be carefully constructed. A focus on question development and validation is critical, as the questions determine the quality of the data derived from the survey.⁸ Even the position of the question or answer in the survey can affect how participants respond,¹⁵ as they may be guided to a response choice by preceding questions.¹⁶

WHAT DO YOU NEED TO KNOW ABOUT ASSESSING SURVEY RESEARCH?

What follows are questions and a basic framework that can be used to evaluate published survey research. Recommendations are based on the work of survey scientists,^{4,7,10,14,15,17,18} survey researchers in medicine and the social sciences, and national standards for test and questionnaire construction and validation (Table 1).^4,19,20

Who created the survey? How did they do it?

How the survey was created should be sufficiently described to allow readers to judge the adequacy of instrument development.^3–5 It is generally recommended that feedback from multiple sources be solicited during survey creation. Both questionnaire-design experts and subject-matter experts are considered critical in the process.⁴

What question was the survey designed to answer?

Is the objective of the study articulated in the paper? ^3,20 To judge survey research, readers need to know if the survey appears to adequately address the research question or questions and the objectives of the study in terms of methods used.⁴

Instrument pretesting and field testing are considered best practices by the American Association for Public Opinion Research, a professional organization for US survey scientists.⁴

Pretesting can include cognitive interviewing, the use of questionnaire appraisal tools, and hybrid methods, all of which are aimed at addressing validity issues.²¹ Pretesting with a group of participants similar to the target population allows for assessment of item ambiguity, instrument ease of use, adequacy of response categories (response choices), and time to completion.^4,12

Cognitive interviewing is designed to explore respondents’ comprehension of questions, response processes, and decision processes governing how they answer questions.^4,7,10,11 In cognitive interviewing, respondents are generally interviewed one on one. Techniques vary, but typically include “think alouds” (in which a respondent is asked to verbalize thoughts while responding to questions) and “verbal probing” (in which the respondent answers a question, then is asked follow-up questions as the interviewer probes for information related to the response choice or question itself).⁷ These techniques can provide evidence that researchers are actually measuring what they set out to measure and not an unrelated construct.^4,19

Field testing of a survey under realistic conditions can help to uncover problems in administration, such as issues in standardization of key procedures, and to ensure that the survey was administered as the researchers intended.^21,22 Field testing is vital before phone or in-person interviews to ensure standardization of any critical procedures. Pilot testing in a sample similar to the intended population allows for further refinement, with deletion of problem items, before the survey is launched.¹⁵

Because even “objective” questions can be somewhat subjective, all research surveys should go through some type of pretesting.^4,21 Based on the results of pretesting and field testing, surveys should then be revised before launch.^4,21 If an article on a self-report survey makes no mention of survey validation steps, readers may well question the validity of the results.

Are the survey questions and response choices understandable?

Is the meaning of each question unambiguous? Is the reading level appropriate for the sample population (a critical consideration in patient surveys)? Do any of the items actually ask two different questions?¹³ An example would be: “Was the representative courteous and prompt?” as it is possible to be courteous, but not prompt, and vice versa. If so, respondents may be confused or frustrated in attempting to answer it. If a rating scale is used throughout the questionnaire, are the anchors appropriate? For example, a question may be written in such a way that respondents want to answer “yes/no” or “agree/disagree,” but the scale used may include response options such as “poor,” “marginal,” “good,” and “excellent.” Items with Likert-response formats are commonly used in self-report surveys and allow participants to respond to a statement by choosing from a range of responses (eg, strongly disagree to strongly agree), often spaced horizontally under a line.

It is recommended that surveys also include options for answers beyond the response choices provided,²⁰ such as comment boxes or fill-in-the-blank items. Surveys with a closed-response format may constrain the quality of data collected because investigators may not foresee all possible answers. Surveys need to be available for review either within the article itself, in an appendix, or as supplementary material that is available elsewhere.

Does the sample appear to be appropriate?

Articles that report the results of surveys should describe the target population, the sample design, and, in a demographic table, respondents and nonrespondents. To judge appropriateness, several questions can be asked regarding sampling:

Target population. Is the population of interest (ie, the target population) described, including regional demographics, if applicable? The relationship between the sample and the target population is important, as a nonrepresentative sample may result in misleading conclusions about the population of interest.

Sampling frame. Who had an opportunity to participate in the survey? At its simplest, the sampling frame establishes who (or what, in the case of institutions) should be included within the sample. This is typically a list of elements (Groves et al⁴) that acts to “frame” or define the sample to be selected. Where the target population may be all academic internal medicine physicians in the United States, the sampling frame may be all male and female US physicians who are members of particular internal medicine professional organizations, identified by their directory email addresses.

Sample design. How was the sample actually selected?⁴ For example, did investigators use a convenience sample of colleagues at other institutions or use a stratified random sample, ensuring adequate representation of respondents with certain characteristics?

Description of respondents. How is the sample of respondents described? Are demographic features reported, including statistics on regional or national representativeness?⁵ Does the sample of survey respondents appear to be representative of the researcher’s population of interest (ie, the target population)?^3,23 If not, is this adequately described in the limitations section? Although outcomes will not be available on nonrespondents, demographic and baseline data often are available and should be reported. Are there systematic differences between respondents and nonrespondents?

Was the response rate adequate?

Was the response rate adequate, given the number of participants initially recruited? If the response rate was not adequate, did the researchers discuss this limitation?

Maximum response rate, defined as the total number of surveys returned divided by the total number of surveys sent,¹⁸ may be difficult to calculate with electronic or Web-based survey platforms. When the maximum response rate cannot be calculated, this issue needs to be addressed in the article’s limitations section.

The number of surveys has increased across fields over the past few decades, but survey response rates in general have decreased.^17,21,24,25 In fields outside of clinical medicine, response rates in the 40% range are common.¹⁷ In the 1990s, the mean response rate for surveys published in medical journals (mailed surveys) was approximately 60%.²⁶ A 2001 review of physician questionnaire studies found a similar average response rate (61%), with a 52% response rate for large-sample surveys.²⁷ In 2002, Field et al²⁸ examined the impact of incentives in physician survey studies and found response rates ranging from 8.5% to 80%.

Importantly, electronically delivered surveys (e-mail, Web-based) often have lower response rates than mailed surveys.^24,29 Nominal financial incentives have been associated with enhanced response rates.²⁸

A relatively low response rate does not necessarily mean you cannot trust the data. Survey scientists note that the representativeness of the sample may be more critical than response rate alone.¹⁷ Studies with small sample sizes may be more representative—and findings more valid—than those with large samples, if large samples are nonrepresentative when considering the target population.¹⁷

Do the conclusions go beyond the data?

Are the inferences overreaching, in view of the survey design? In studies with low response rates and nonrepresentative samples, researchers must be careful in interpreting the results. If the results cannot be generalized beyond the research sample, is this clear from the limitations, discussion, and conclusion sections?

In this review, we have summarized the findings of three published surveys^1,2,30 and commented on how they appear to meet—or don’t quite meet—recommendations for survey development, validation, and use. The papers chosen were deemed strong examples in particular categories, such as description of survey authorship,¹ instrument validation,³⁰ sampling methodology,² and response rate.¹

It should be noted that even when surveys are conducted with the utmost rigor, survey reporting may leave out critical details. Survey methodology may not be adequately described for a variety of reasons, including researchers’ training in survey design and methodology; a lack of universally accepted journal-reporting guidelines³; and even journals’ space limitations. At times, journals may excise descriptions of survey development and validation, deeming these sections superfluous. Limitations sections can be critical to interpreting the results of survey research and evaluating the scope of conclusions.

Surveys are common in medical research. Although survey research may be subject to inherent self-report bias, surveys have a great impact on policies and practices in medicine, often forming the basis for recommendations or new guidelines.^1,2 To interpret and use survey research results, clinicians should be familiar with key elements involved in the creation and validation of surveys.

The purpose of this article is to provide readers with a basic framework for evaluating surveys to allow them to be more informed as consumers of survey research.

IMPORTANT TOOLS IN MEDICAL RESEARCH

Surveys are important tools for answering questions on topics that are difficult to assess using other methods.³ They allow us to gather data systematically from subjects by asking questions, in order to make inferences about a larger population.^3,4 Clinicians use surveys to explore the opinions, beliefs, and perceptions of a group, or to investigate physician practice patterns and adherence to clinical guidelines. They may also use surveys to better understand why patients are not engaging in recommended behavioral or lifestyle changes.

Survey methods include interviews (in person, by phone) and questionnaires (paper-and-pencil, e-mailed, online).⁴

A well-constructed, validated survey can provide powerful data that may influence clinical practice, guide future research development, or drive the development and provision of needed programs and services. Surveys have the potential to transform the ways in which we think about and practice medicine.

READER BEWARE

While survey research in health care appears to have grown exponentially, the quality of reported survey research has not necessarily increased over time.

For consumers of survey research, the adage “reader beware” is apt. Although a considerable number of studies have examined the effects of survey methodology on the validity, reliability, and generalizability of the results,⁴ medical journals differ in their requirements for reporting survey methods.

In an analysis of 117 articles, Bennett et al³ found that more than 80% did not fully describe the survey development process or pretesting methods. They also found limited guidance and lack of consensus about the best way to report survey research. Of 95 surveys requiring scoring, 66% did not report scoring practices.

Duffett et al⁵ noted that of 127 critical care medicine surveys, only 36% had been pretested or pilot-tested, and half of all surveys reviewed did not include participant demographics or included only minimal information.

Because journal reporting practices differ, physicians may be unaware of the steps involved in survey construction and validation. Knowledge of these steps is helpful not only in constructing surveys but also in assessing published articles that used survey research.

LIMITATIONS OF SURVEY RESEARCH

Indirect measures of attitudes and behaviors

Surveys that rely on participants’ self-reports of behaviors, attitudes, beliefs, or actions are indirect measures and are susceptible to self-report and social-desirability biases. Participants may overestimate their own expertise or knowledge in self-report surveys. They may wish to reduce embarrassment⁶ or answer in ways that would make them “look better,”⁷ resulting in social-desirability bias. These issues need to be mentioned in the limitations section in papers reporting survey research.

Questions and response choices

The data derived from surveys are only as good as the questions that are asked.⁸ Stone⁹ noted that questions should be intelligible, unambiguous, and unbiased. If respondents do not comprehend questions as researchers intended, if questionnaire response choices are inadequate, or if questions trigger unintended emotional responses,^10–14 researchers may unwittingly introduce error, which will affect the validity of results. Even seemingly objective questions, such as those related to clinical algorithm use, practice patterns, or equipment available to hospital staff, may be interpreted differently by different respondents.

In their eagerness to launch a survey, clinician researchers may not realize that it must be carefully constructed. A focus on question development and validation is critical, as the questions determine the quality of the data derived from the survey.⁸ Even the position of the question or answer in the survey can affect how participants respond,¹⁵ as they may be guided to a response choice by preceding questions.¹⁶

WHAT DO YOU NEED TO KNOW ABOUT ASSESSING SURVEY RESEARCH?

What follows are questions and a basic framework that can be used to evaluate published survey research. Recommendations are based on the work of survey scientists,^{4,7,10,14,15,17,18} survey researchers in medicine and the social sciences, and national standards for test and questionnaire construction and validation (Table 1).^4,19,20

Who created the survey? How did they do it?

How the survey was created should be sufficiently described to allow readers to judge the adequacy of instrument development.^3–5 It is generally recommended that feedback from multiple sources be solicited during survey creation. Both questionnaire-design experts and subject-matter experts are considered critical in the process.⁴

What question was the survey designed to answer?

Is the objective of the study articulated in the paper? ^3,20 To judge survey research, readers need to know if the survey appears to adequately address the research question or questions and the objectives of the study in terms of methods used.⁴

Instrument pretesting and field testing are considered best practices by the American Association for Public Opinion Research, a professional organization for US survey scientists.⁴

Pretesting can include cognitive interviewing, the use of questionnaire appraisal tools, and hybrid methods, all of which are aimed at addressing validity issues.²¹ Pretesting with a group of participants similar to the target population allows for assessment of item ambiguity, instrument ease of use, adequacy of response categories (response choices), and time to completion.^4,12

Cognitive interviewing is designed to explore respondents’ comprehension of questions, response processes, and decision processes governing how they answer questions.^4,7,10,11 In cognitive interviewing, respondents are generally interviewed one on one. Techniques vary, but typically include “think alouds” (in which a respondent is asked to verbalize thoughts while responding to questions) and “verbal probing” (in which the respondent answers a question, then is asked follow-up questions as the interviewer probes for information related to the response choice or question itself).⁷ These techniques can provide evidence that researchers are actually measuring what they set out to measure and not an unrelated construct.^4,19

Field testing of a survey under realistic conditions can help to uncover problems in administration, such as issues in standardization of key procedures, and to ensure that the survey was administered as the researchers intended.^21,22 Field testing is vital before phone or in-person interviews to ensure standardization of any critical procedures. Pilot testing in a sample similar to the intended population allows for further refinement, with deletion of problem items, before the survey is launched.¹⁵

Because even “objective” questions can be somewhat subjective, all research surveys should go through some type of pretesting.^4,21 Based on the results of pretesting and field testing, surveys should then be revised before launch.^4,21 If an article on a self-report survey makes no mention of survey validation steps, readers may well question the validity of the results.

Are the survey questions and response choices understandable?

Is the meaning of each question unambiguous? Is the reading level appropriate for the sample population (a critical consideration in patient surveys)? Do any of the items actually ask two different questions?¹³ An example would be: “Was the representative courteous and prompt?” as it is possible to be courteous, but not prompt, and vice versa. If so, respondents may be confused or frustrated in attempting to answer it. If a rating scale is used throughout the questionnaire, are the anchors appropriate? For example, a question may be written in such a way that respondents want to answer “yes/no” or “agree/disagree,” but the scale used may include response options such as “poor,” “marginal,” “good,” and “excellent.” Items with Likert-response formats are commonly used in self-report surveys and allow participants to respond to a statement by choosing from a range of responses (eg, strongly disagree to strongly agree), often spaced horizontally under a line.

It is recommended that surveys also include options for answers beyond the response choices provided,²⁰ such as comment boxes or fill-in-the-blank items. Surveys with a closed-response format may constrain the quality of data collected because investigators may not foresee all possible answers. Surveys need to be available for review either within the article itself, in an appendix, or as supplementary material that is available elsewhere.

Does the sample appear to be appropriate?

Articles that report the results of surveys should describe the target population, the sample design, and, in a demographic table, respondents and nonrespondents. To judge appropriateness, several questions can be asked regarding sampling:

Target population. Is the population of interest (ie, the target population) described, including regional demographics, if applicable? The relationship between the sample and the target population is important, as a nonrepresentative sample may result in misleading conclusions about the population of interest.

Sampling frame. Who had an opportunity to participate in the survey? At its simplest, the sampling frame establishes who (or what, in the case of institutions) should be included within the sample. This is typically a list of elements (Groves et al⁴) that acts to “frame” or define the sample to be selected. Where the target population may be all academic internal medicine physicians in the United States, the sampling frame may be all male and female US physicians who are members of particular internal medicine professional organizations, identified by their directory email addresses.

Sample design. How was the sample actually selected?⁴ For example, did investigators use a convenience sample of colleagues at other institutions or use a stratified random sample, ensuring adequate representation of respondents with certain characteristics?

Description of respondents. How is the sample of respondents described? Are demographic features reported, including statistics on regional or national representativeness?⁵ Does the sample of survey respondents appear to be representative of the researcher’s population of interest (ie, the target population)?^3,23 If not, is this adequately described in the limitations section? Although outcomes will not be available on nonrespondents, demographic and baseline data often are available and should be reported. Are there systematic differences between respondents and nonrespondents?

Was the response rate adequate?

Was the response rate adequate, given the number of participants initially recruited? If the response rate was not adequate, did the researchers discuss this limitation?

Maximum response rate, defined as the total number of surveys returned divided by the total number of surveys sent,¹⁸ may be difficult to calculate with electronic or Web-based survey platforms. When the maximum response rate cannot be calculated, this issue needs to be addressed in the article’s limitations section.

The number of surveys has increased across fields over the past few decades, but survey response rates in general have decreased.^17,21,24,25 In fields outside of clinical medicine, response rates in the 40% range are common.¹⁷ In the 1990s, the mean response rate for surveys published in medical journals (mailed surveys) was approximately 60%.²⁶ A 2001 review of physician questionnaire studies found a similar average response rate (61%), with a 52% response rate for large-sample surveys.²⁷ In 2002, Field et al²⁸ examined the impact of incentives in physician survey studies and found response rates ranging from 8.5% to 80%.

Importantly, electronically delivered surveys (e-mail, Web-based) often have lower response rates than mailed surveys.^24,29 Nominal financial incentives have been associated with enhanced response rates.²⁸

A relatively low response rate does not necessarily mean you cannot trust the data. Survey scientists note that the representativeness of the sample may be more critical than response rate alone.¹⁷ Studies with small sample sizes may be more representative—and findings more valid—than those with large samples, if large samples are nonrepresentative when considering the target population.¹⁷

Do the conclusions go beyond the data?

Are the inferences overreaching, in view of the survey design? In studies with low response rates and nonrepresentative samples, researchers must be careful in interpreting the results. If the results cannot be generalized beyond the research sample, is this clear from the limitations, discussion, and conclusion sections?

In this review, we have summarized the findings of three published surveys^1,2,30 and commented on how they appear to meet—or don’t quite meet—recommendations for survey development, validation, and use. The papers chosen were deemed strong examples in particular categories, such as description of survey authorship,¹ instrument validation,³⁰ sampling methodology,² and response rate.¹

It should be noted that even when surveys are conducted with the utmost rigor, survey reporting may leave out critical details. Survey methodology may not be adequately described for a variety of reasons, including researchers’ training in survey design and methodology; a lack of universally accepted journal-reporting guidelines³; and even journals’ space limitations. At times, journals may excise descriptions of survey development and validation, deeming these sections superfluous. Limitations sections can be critical to interpreting the results of survey research and evaluating the scope of conclusions.

A 60-year-old woman presented with sudden swelling and pain in her right arm. She reported progressive lower-extremity edema and abdominal girth over the past month, associated with shortness of breath and orthopnea. She had a remote history of two spontaneous abortions.

Duplex ultrasonography revealed massive venous thrombosis extending from the antecubital fossa to the right atrium. Transthoracic echocardiography revealed severe left ventricular (LV) dysfunction and multiple echo-dense masses in the LV apex, the right ventricle, and the left atrium, as well as at the base of the tricuspid valve (Figure 1). There was no evidence of a structural heart defect, eg, patent foramen ovale, atrial septal defect, or ventricular septal defect. Cardiovascular magnetic resonance imaging (MRI) confirmed the densities as thrombi (Figure 2). Her ejection fraction was 35%.

Blood testing on admission showed a prolonged partial thromboplastin time of 55.0 sec (reference range 22.7–35.6) and a prothrombin time of 13.4 sec (reference range 11.3–14.5). Tissue thromboplastin inhibition at a dilution of 1:50 was elevated at 1.5 sec (reference range 0.7–1.3), as was the tissue thromboplastin inhibition at a dilution of 1:500—ie, 1.6 sec (0.7–1.3). Dilute Russell viper venom testing and anticardiolipin antibody immunoglobulin G and M testing were negative. The lupus antiphospholipid antibody test and the hexagonal lipid neutralization test were positive.

The patient’s clinical presentation of extensive unprovoked venous thrombosis and her laboratory profile together suggested the antiphospholipid antibody syndrome.

SURGICAL TREATMENT NOT AN OPTION

Given her extensive clot burden, surgical thrombectomy was not an option. Instead, warfarin therapy was started and resulted in a progressive diminution of the thrombi. At 4-month follow-up, the thrombi had nearly resolved (Figure 3), and her LV ejection fraction had increased to 45% to 50%. Eighteen months later, she was diagnosed with cholangiocarcinoma. In retrospect, we believe the cancer predisposed the patient to the hypercoagulable state and, subsequently, to thrombosis.

DIAGNOSING AND TREATING LEFT VENTRICULAR THROMBOSIS

Ventricular thrombosis is a serious problem, most commonly associated with extensive myocardial infarction. It is a relatively common complication of myocardial infarction and of ischemic and nonischemic cardiomy-opathies.¹ In this population, the incidence of LV thrombosis is reported to be in the range of 10% to 25%, and it increases with increasing LV end-diastolic diameter, lower ejection fraction, and anterior-wall-motion akinesia, and with the presence of apical aneurysms.² It is an important cause of morbidity and death, whether the thrombus is sessile or mobile.

How diagnostic imaging tests compare

The diagnosis of LV thrombosis requires a certain level of suspicion and has traditionally relied on echocardiography. However, several studies have raised doubt about the sensitivity of echocardiography for the detection of left or right ventricular thrombi.³ In a 2006 report, the sensitivity of transthoracic echocardiography in detecting LV thrombi was 23% and the sensitivity of transesophageal echocardiography was 40%.⁴ In contrast, delayed-enhancement cardiovascular MRI had a sensitivity near 90%. Similarly, in another study,⁵ contrast-enhanced echocardiography had a low but higher sensitivity of nearly 60%.⁵ Therefore, cardiovascular MRI is emerging as the new gold standard test for the detection of this important complication of ventricular dysfunction and myocardial infarction.

Treatment and screening

The optimal management of intraventricular thrombi is poorly defined. It has been suggested from case series that large, mobile, or protruding LV thrombi have more potential for embolization and, therefore, that patients with these findings may benefit from surgical thrombectomy.⁶ Oral anticoagulation has been reported to dissolve intraventricular thrombi, with success rates from 13% to 59%.⁷ A prospective study of enoxaparin in 26 patients with LV thrombi reported resolution rates close to 73% at 3-week follow-up.⁸

There are no guidelines at present on which to base recommendations for screening patients for intracavitary thrombi or for starting empiric anticoagulation in those at risk.

A 60-year-old woman presented with sudden swelling and pain in her right arm. She reported progressive lower-extremity edema and abdominal girth over the past month, associated with shortness of breath and orthopnea. She had a remote history of two spontaneous abortions.

Duplex ultrasonography revealed massive venous thrombosis extending from the antecubital fossa to the right atrium. Transthoracic echocardiography revealed severe left ventricular (LV) dysfunction and multiple echo-dense masses in the LV apex, the right ventricle, and the left atrium, as well as at the base of the tricuspid valve (Figure 1). There was no evidence of a structural heart defect, eg, patent foramen ovale, atrial septal defect, or ventricular septal defect. Cardiovascular magnetic resonance imaging (MRI) confirmed the densities as thrombi (Figure 2). Her ejection fraction was 35%.

Blood testing on admission showed a prolonged partial thromboplastin time of 55.0 sec (reference range 22.7–35.6) and a prothrombin time of 13.4 sec (reference range 11.3–14.5). Tissue thromboplastin inhibition at a dilution of 1:50 was elevated at 1.5 sec (reference range 0.7–1.3), as was the tissue thromboplastin inhibition at a dilution of 1:500—ie, 1.6 sec (0.7–1.3). Dilute Russell viper venom testing and anticardiolipin antibody immunoglobulin G and M testing were negative. The lupus antiphospholipid antibody test and the hexagonal lipid neutralization test were positive.

The patient’s clinical presentation of extensive unprovoked venous thrombosis and her laboratory profile together suggested the antiphospholipid antibody syndrome.

SURGICAL TREATMENT NOT AN OPTION

Given her extensive clot burden, surgical thrombectomy was not an option. Instead, warfarin therapy was started and resulted in a progressive diminution of the thrombi. At 4-month follow-up, the thrombi had nearly resolved (Figure 3), and her LV ejection fraction had increased to 45% to 50%. Eighteen months later, she was diagnosed with cholangiocarcinoma. In retrospect, we believe the cancer predisposed the patient to the hypercoagulable state and, subsequently, to thrombosis.

DIAGNOSING AND TREATING LEFT VENTRICULAR THROMBOSIS

Ventricular thrombosis is a serious problem, most commonly associated with extensive myocardial infarction. It is a relatively common complication of myocardial infarction and of ischemic and nonischemic cardiomy-opathies.¹ In this population, the incidence of LV thrombosis is reported to be in the range of 10% to 25%, and it increases with increasing LV end-diastolic diameter, lower ejection fraction, and anterior-wall-motion akinesia, and with the presence of apical aneurysms.² It is an important cause of morbidity and death, whether the thrombus is sessile or mobile.

How diagnostic imaging tests compare

The diagnosis of LV thrombosis requires a certain level of suspicion and has traditionally relied on echocardiography. However, several studies have raised doubt about the sensitivity of echocardiography for the detection of left or right ventricular thrombi.³ In a 2006 report, the sensitivity of transthoracic echocardiography in detecting LV thrombi was 23% and the sensitivity of transesophageal echocardiography was 40%.⁴ In contrast, delayed-enhancement cardiovascular MRI had a sensitivity near 90%. Similarly, in another study,⁵ contrast-enhanced echocardiography had a low but higher sensitivity of nearly 60%.⁵ Therefore, cardiovascular MRI is emerging as the new gold standard test for the detection of this important complication of ventricular dysfunction and myocardial infarction.

Treatment and screening

The optimal management of intraventricular thrombi is poorly defined. It has been suggested from case series that large, mobile, or protruding LV thrombi have more potential for embolization and, therefore, that patients with these findings may benefit from surgical thrombectomy.⁶ Oral anticoagulation has been reported to dissolve intraventricular thrombi, with success rates from 13% to 59%.⁷ A prospective study of enoxaparin in 26 patients with LV thrombi reported resolution rates close to 73% at 3-week follow-up.⁸

There are no guidelines at present on which to base recommendations for screening patients for intracavitary thrombi or for starting empiric anticoagulation in those at risk.

A 60-year-old woman presented with sudden swelling and pain in her right arm. She reported progressive lower-extremity edema and abdominal girth over the past month, associated with shortness of breath and orthopnea. She had a remote history of two spontaneous abortions.

Duplex ultrasonography revealed massive venous thrombosis extending from the antecubital fossa to the right atrium. Transthoracic echocardiography revealed severe left ventricular (LV) dysfunction and multiple echo-dense masses in the LV apex, the right ventricle, and the left atrium, as well as at the base of the tricuspid valve (Figure 1). There was no evidence of a structural heart defect, eg, patent foramen ovale, atrial septal defect, or ventricular septal defect. Cardiovascular magnetic resonance imaging (MRI) confirmed the densities as thrombi (Figure 2). Her ejection fraction was 35%.

Blood testing on admission showed a prolonged partial thromboplastin time of 55.0 sec (reference range 22.7–35.6) and a prothrombin time of 13.4 sec (reference range 11.3–14.5). Tissue thromboplastin inhibition at a dilution of 1:50 was elevated at 1.5 sec (reference range 0.7–1.3), as was the tissue thromboplastin inhibition at a dilution of 1:500—ie, 1.6 sec (0.7–1.3). Dilute Russell viper venom testing and anticardiolipin antibody immunoglobulin G and M testing were negative. The lupus antiphospholipid antibody test and the hexagonal lipid neutralization test were positive.

The patient’s clinical presentation of extensive unprovoked venous thrombosis and her laboratory profile together suggested the antiphospholipid antibody syndrome.

SURGICAL TREATMENT NOT AN OPTION

Given her extensive clot burden, surgical thrombectomy was not an option. Instead, warfarin therapy was started and resulted in a progressive diminution of the thrombi. At 4-month follow-up, the thrombi had nearly resolved (Figure 3), and her LV ejection fraction had increased to 45% to 50%. Eighteen months later, she was diagnosed with cholangiocarcinoma. In retrospect, we believe the cancer predisposed the patient to the hypercoagulable state and, subsequently, to thrombosis.

DIAGNOSING AND TREATING LEFT VENTRICULAR THROMBOSIS

Ventricular thrombosis is a serious problem, most commonly associated with extensive myocardial infarction. It is a relatively common complication of myocardial infarction and of ischemic and nonischemic cardiomy-opathies.¹ In this population, the incidence of LV thrombosis is reported to be in the range of 10% to 25%, and it increases with increasing LV end-diastolic diameter, lower ejection fraction, and anterior-wall-motion akinesia, and with the presence of apical aneurysms.² It is an important cause of morbidity and death, whether the thrombus is sessile or mobile.

How diagnostic imaging tests compare

The diagnosis of LV thrombosis requires a certain level of suspicion and has traditionally relied on echocardiography. However, several studies have raised doubt about the sensitivity of echocardiography for the detection of left or right ventricular thrombi.³ In a 2006 report, the sensitivity of transthoracic echocardiography in detecting LV thrombi was 23% and the sensitivity of transesophageal echocardiography was 40%.⁴ In contrast, delayed-enhancement cardiovascular MRI had a sensitivity near 90%. Similarly, in another study,⁵ contrast-enhanced echocardiography had a low but higher sensitivity of nearly 60%.⁵ Therefore, cardiovascular MRI is emerging as the new gold standard test for the detection of this important complication of ventricular dysfunction and myocardial infarction.

Treatment and screening

The optimal management of intraventricular thrombi is poorly defined. It has been suggested from case series that large, mobile, or protruding LV thrombi have more potential for embolization and, therefore, that patients with these findings may benefit from surgical thrombectomy.⁶ Oral anticoagulation has been reported to dissolve intraventricular thrombi, with success rates from 13% to 59%.⁷ A prospective study of enoxaparin in 26 patients with LV thrombi reported resolution rates close to 73% at 3-week follow-up.⁸

There are no guidelines at present on which to base recommendations for screening patients for intracavitary thrombi or for starting empiric anticoagulation in those at risk.

In this edition of the Cleveland Clinic Journal of Medicine, Dr. Jamie Stoller raises the issue of “electronic silos,” an unintended consequence of using an electronic health record (EHR) system. Dr. Stoller observes that ever since we began using EHRs, clinicians have been talking to each other less.

See related article

As a hospitalist, I would agree. I only need to go to the nursing station on any given morning to confirm this. Working in the hospital, a clinician has two hubs of activity, the patient and the chart. With the advent of the EHR, the chart is now virtual and I no longer need to be physically present in the nursing station.

Our environment has changed, and the EHR provides us a new world in which we must interact as providers. Understanding these challenges will begin to shift our approach to this new world. In addition to this, and to Dr. Stoller’s observations, I would add that we also need to expect more from our EHR. We need an EHR that works for us, one that extends our abilities and improves the care we give. I believe the best is yet to come.

WE GOT WHAT WE ASKED FOR

Clinical communication is the cornerstone of patient safety. In a seminal report, the Institutes of Medicine estimated that 98,000 people die in any given year from medical errors, and most of the errors are from poor communication.¹ Findings such as this gave momentum to the movement to convert from a paper-based health delivery system to an electronic one.²

However, a requirement in designing these systems was to mimic paper-based tasks. We asked for the EHR to look like paper, and we got it, and that has truly affected the way we practice, interact, and use electronic health information. Although Dr. Stoller and others want to improve communication and workflow through the EHR, there has been little research into the cognitive requirements or workflow paths needed to make this a reality. A National Research Council report states that current EHRs are not designed on the basis of human-computer interaction, human factors, or ergonomic design principles, and these design failures contribute to their inefficient use and to the potential propagation of error.³

‘HUMAN FACTORS ENGINEERING’ COULD IMPROVE EHR DESIGN

In industries other than health care, the effect of technology on the workplace has been studied in a discipline called human factors engineering. Studies show significant lags between the adoption of workplace automation and the redesign of the workplace to accommodate the new technology and workforce needs.⁴

In health care, even computerized physician order entry, one of the central drivers of EHR adoption to promote patient safety, is fallible as a result of poor human factors engineering. Poor design can introduce new errors into the care delivery system if the technology and the environment in which it is deployed are not well understood.⁵

We must mitigate this risk of poor design and error by applying the principles of human factors engineering to health care. Three areas need to be taken into account to prevent failure: the user, the device, and the environment in which the device is used. For example, a glucometer with a small display would be difficult to use for patients with impaired vision from diabetic retinopathy—the user needs to be taken into account. We have all had experience with devices that are too complicated to use, with an unfriendly user interface or too much irrelevant material in the display. And in the noisy environment of an operating room full of beeping machines, yet another beep may not be a good way to alert the user. The outcomes of these domains together yield either a safe and effective experience or an ineffective experience that promotes error and puts patient safety at risk.

We can start to achieve good design in health care by first applying the techniques of human factors engineering that have been well honed outside of medicine. Information about the patient should be displayed on a “dashboard” in a way that is intuitive and easy to understand, making for more efficient use of the clinician’s brain cells. Visionaries such as Edward Tuft are investigating how to compile discrete data into a cohesive visual experience.⁶ Application of analytics and predicative modeling can pull together information in a way that tells the provider not only about what has happened, but also about what might happen.

Second, the EHR should include tools for effectively sharing information. I agree with Dr. Stoller about the idea of embedding virtual care teams in the record. I can see when my friends are online with social networking tools—why not extend this feature to the record? Beyond enabling simple physician-to-physician exchanges, the EHR affords new powerful care opportunities that paper never could: the wisdom of the cohort. Virtual care of a population is a promising way to manage patients who share attributes. Beyond improved clinical outcomes, digital collaborative care has the additional benefit of allowing input from nonclinical teams. Combining clinical, operational, and financial data can help make sure we achieve the best quality of care, at the best cost, with the best outcome. That is the value proposition of health care reform.

FINDING THE NEEDLE, NOT STORING MORE HAY

Beyond poor design, another problem with current EHR systems is that they overload us with information, so that our time is spent sifting through data rather than synthesizing it. We are seeing an unprecedented proliferation of both clinical data in the EHR and supporting research data. This combination has not helped the physician find the “needle.” Rather, it has managed to just store more hay.

All health care providers need to know how to read a chart quickly and efficiently to ascertain the story. In medical school, we teach new doctors about what makes for a good consult: synthesize the data and ask for an opinion. While a first-year medical school student would say, “I need a GI consult: the hemoglobin is 6, platelets are low, and there is blood in the stool,” a resident would say, “I need a GI consult for upper endoscopy, as I suspect this patient has alcoholic cirrhosis and likely portal hypertension: I am worried about variceal bleeding.” We should expect the same from our EHR.

Our relationship with health technology needs to shift. We need not view the EHR merely as a record, as something to physically hold data, but rather as a system that digests data to produce knowledge. The EHR needs to be viewed as a mentor and a colleague, a place that not only records data, but that also ascertains data incongruities, displays information that is relevant, and gives providers rapid, at-a-glance knowledge of the patient’s condition. The silo Dr. Stoller describes is not just the physical separation of providers, it is also the separation of providers and knowledge. We are still hunters and gatherers of information. Let the EHR work for the clinician. Tell me that I have not addressed my patient’s hyperkalemia. Tell me that my gastroenterology consultant is online and has just completed a consult note. Tell me that my patient is having uncontrolled pain now, rather than my having to discover this 9 hours later. We should expect our EHR to deliver the right information to the right person at the right time in the right format. The electronic health colleague might be a more apt term.

MAKING THE EHR WORK FOR US

So, has the EHR destroyed clinician collaboration? Certainly not. It has just changed the environment and the way we interact with the medical system. In fact, I argue that it could actually make it better, if we shift our expectations of our EHR systems. The future state of collaboration may not be in the traditional form of speaking to a colleague next to you, but rather in having a system that supports real-time access and sharing of digested knowledge about the patient. This knowledge can then be shared with other providers, finance systems, national health exchanges, predictive models, and even the patient, breaking the silos.

Someday the EHR might give back time to the provider, and we might say, “I just finished my patient panel early—let’s go get a cup of coffee and catch up.”

In this edition of the Cleveland Clinic Journal of Medicine, Dr. Jamie Stoller raises the issue of “electronic silos,” an unintended consequence of using an electronic health record (EHR) system. Dr. Stoller observes that ever since we began using EHRs, clinicians have been talking to each other less.

See related article

As a hospitalist, I would agree. I only need to go to the nursing station on any given morning to confirm this. Working in the hospital, a clinician has two hubs of activity, the patient and the chart. With the advent of the EHR, the chart is now virtual and I no longer need to be physically present in the nursing station.

Our environment has changed, and the EHR provides us a new world in which we must interact as providers. Understanding these challenges will begin to shift our approach to this new world. In addition to this, and to Dr. Stoller’s observations, I would add that we also need to expect more from our EHR. We need an EHR that works for us, one that extends our abilities and improves the care we give. I believe the best is yet to come.

WE GOT WHAT WE ASKED FOR

Clinical communication is the cornerstone of patient safety. In a seminal report, the Institutes of Medicine estimated that 98,000 people die in any given year from medical errors, and most of the errors are from poor communication.¹ Findings such as this gave momentum to the movement to convert from a paper-based health delivery system to an electronic one.²

However, a requirement in designing these systems was to mimic paper-based tasks. We asked for the EHR to look like paper, and we got it, and that has truly affected the way we practice, interact, and use electronic health information. Although Dr. Stoller and others want to improve communication and workflow through the EHR, there has been little research into the cognitive requirements or workflow paths needed to make this a reality. A National Research Council report states that current EHRs are not designed on the basis of human-computer interaction, human factors, or ergonomic design principles, and these design failures contribute to their inefficient use and to the potential propagation of error.³

‘HUMAN FACTORS ENGINEERING’ COULD IMPROVE EHR DESIGN

In industries other than health care, the effect of technology on the workplace has been studied in a discipline called human factors engineering. Studies show significant lags between the adoption of workplace automation and the redesign of the workplace to accommodate the new technology and workforce needs.⁴

In health care, even computerized physician order entry, one of the central drivers of EHR adoption to promote patient safety, is fallible as a result of poor human factors engineering. Poor design can introduce new errors into the care delivery system if the technology and the environment in which it is deployed are not well understood.⁵

We must mitigate this risk of poor design and error by applying the principles of human factors engineering to health care. Three areas need to be taken into account to prevent failure: the user, the device, and the environment in which the device is used. For example, a glucometer with a small display would be difficult to use for patients with impaired vision from diabetic retinopathy—the user needs to be taken into account. We have all had experience with devices that are too complicated to use, with an unfriendly user interface or too much irrelevant material in the display. And in the noisy environment of an operating room full of beeping machines, yet another beep may not be a good way to alert the user. The outcomes of these domains together yield either a safe and effective experience or an ineffective experience that promotes error and puts patient safety at risk.

We can start to achieve good design in health care by first applying the techniques of human factors engineering that have been well honed outside of medicine. Information about the patient should be displayed on a “dashboard” in a way that is intuitive and easy to understand, making for more efficient use of the clinician’s brain cells. Visionaries such as Edward Tuft are investigating how to compile discrete data into a cohesive visual experience.⁶ Application of analytics and predicative modeling can pull together information in a way that tells the provider not only about what has happened, but also about what might happen.

Second, the EHR should include tools for effectively sharing information. I agree with Dr. Stoller about the idea of embedding virtual care teams in the record. I can see when my friends are online with social networking tools—why not extend this feature to the record? Beyond enabling simple physician-to-physician exchanges, the EHR affords new powerful care opportunities that paper never could: the wisdom of the cohort. Virtual care of a population is a promising way to manage patients who share attributes. Beyond improved clinical outcomes, digital collaborative care has the additional benefit of allowing input from nonclinical teams. Combining clinical, operational, and financial data can help make sure we achieve the best quality of care, at the best cost, with the best outcome. That is the value proposition of health care reform.

FINDING THE NEEDLE, NOT STORING MORE HAY

Beyond poor design, another problem with current EHR systems is that they overload us with information, so that our time is spent sifting through data rather than synthesizing it. We are seeing an unprecedented proliferation of both clinical data in the EHR and supporting research data. This combination has not helped the physician find the “needle.” Rather, it has managed to just store more hay.

All health care providers need to know how to read a chart quickly and efficiently to ascertain the story. In medical school, we teach new doctors about what makes for a good consult: synthesize the data and ask for an opinion. While a first-year medical school student would say, “I need a GI consult: the hemoglobin is 6, platelets are low, and there is blood in the stool,” a resident would say, “I need a GI consult for upper endoscopy, as I suspect this patient has alcoholic cirrhosis and likely portal hypertension: I am worried about variceal bleeding.” We should expect the same from our EHR.

Our relationship with health technology needs to shift. We need not view the EHR merely as a record, as something to physically hold data, but rather as a system that digests data to produce knowledge. The EHR needs to be viewed as a mentor and a colleague, a place that not only records data, but that also ascertains data incongruities, displays information that is relevant, and gives providers rapid, at-a-glance knowledge of the patient’s condition. The silo Dr. Stoller describes is not just the physical separation of providers, it is also the separation of providers and knowledge. We are still hunters and gatherers of information. Let the EHR work for the clinician. Tell me that I have not addressed my patient’s hyperkalemia. Tell me that my gastroenterology consultant is online and has just completed a consult note. Tell me that my patient is having uncontrolled pain now, rather than my having to discover this 9 hours later. We should expect our EHR to deliver the right information to the right person at the right time in the right format. The electronic health colleague might be a more apt term.

MAKING THE EHR WORK FOR US

So, has the EHR destroyed clinician collaboration? Certainly not. It has just changed the environment and the way we interact with the medical system. In fact, I argue that it could actually make it better, if we shift our expectations of our EHR systems. The future state of collaboration may not be in the traditional form of speaking to a colleague next to you, but rather in having a system that supports real-time access and sharing of digested knowledge about the patient. This knowledge can then be shared with other providers, finance systems, national health exchanges, predictive models, and even the patient, breaking the silos.

Someday the EHR might give back time to the provider, and we might say, “I just finished my patient panel early—let’s go get a cup of coffee and catch up.”

In this edition of the Cleveland Clinic Journal of Medicine, Dr. Jamie Stoller raises the issue of “electronic silos,” an unintended consequence of using an electronic health record (EHR) system. Dr. Stoller observes that ever since we began using EHRs, clinicians have been talking to each other less.

See related article

As a hospitalist, I would agree. I only need to go to the nursing station on any given morning to confirm this. Working in the hospital, a clinician has two hubs of activity, the patient and the chart. With the advent of the EHR, the chart is now virtual and I no longer need to be physically present in the nursing station.

Our environment has changed, and the EHR provides us a new world in which we must interact as providers. Understanding these challenges will begin to shift our approach to this new world. In addition to this, and to Dr. Stoller’s observations, I would add that we also need to expect more from our EHR. We need an EHR that works for us, one that extends our abilities and improves the care we give. I believe the best is yet to come.

WE GOT WHAT WE ASKED FOR

Clinical communication is the cornerstone of patient safety. In a seminal report, the Institutes of Medicine estimated that 98,000 people die in any given year from medical errors, and most of the errors are from poor communication.¹ Findings such as this gave momentum to the movement to convert from a paper-based health delivery system to an electronic one.²

However, a requirement in designing these systems was to mimic paper-based tasks. We asked for the EHR to look like paper, and we got it, and that has truly affected the way we practice, interact, and use electronic health information. Although Dr. Stoller and others want to improve communication and workflow through the EHR, there has been little research into the cognitive requirements or workflow paths needed to make this a reality. A National Research Council report states that current EHRs are not designed on the basis of human-computer interaction, human factors, or ergonomic design principles, and these design failures contribute to their inefficient use and to the potential propagation of error.³

‘HUMAN FACTORS ENGINEERING’ COULD IMPROVE EHR DESIGN

In industries other than health care, the effect of technology on the workplace has been studied in a discipline called human factors engineering. Studies show significant lags between the adoption of workplace automation and the redesign of the workplace to accommodate the new technology and workforce needs.⁴

In health care, even computerized physician order entry, one of the central drivers of EHR adoption to promote patient safety, is fallible as a result of poor human factors engineering. Poor design can introduce new errors into the care delivery system if the technology and the environment in which it is deployed are not well understood.⁵

We must mitigate this risk of poor design and error by applying the principles of human factors engineering to health care. Three areas need to be taken into account to prevent failure: the user, the device, and the environment in which the device is used. For example, a glucometer with a small display would be difficult to use for patients with impaired vision from diabetic retinopathy—the user needs to be taken into account. We have all had experience with devices that are too complicated to use, with an unfriendly user interface or too much irrelevant material in the display. And in the noisy environment of an operating room full of beeping machines, yet another beep may not be a good way to alert the user. The outcomes of these domains together yield either a safe and effective experience or an ineffective experience that promotes error and puts patient safety at risk.

We can start to achieve good design in health care by first applying the techniques of human factors engineering that have been well honed outside of medicine. Information about the patient should be displayed on a “dashboard” in a way that is intuitive and easy to understand, making for more efficient use of the clinician’s brain cells. Visionaries such as Edward Tuft are investigating how to compile discrete data into a cohesive visual experience.⁶ Application of analytics and predicative modeling can pull together information in a way that tells the provider not only about what has happened, but also about what might happen.

Second, the EHR should include tools for effectively sharing information. I agree with Dr. Stoller about the idea of embedding virtual care teams in the record. I can see when my friends are online with social networking tools—why not extend this feature to the record? Beyond enabling simple physician-to-physician exchanges, the EHR affords new powerful care opportunities that paper never could: the wisdom of the cohort. Virtual care of a population is a promising way to manage patients who share attributes. Beyond improved clinical outcomes, digital collaborative care has the additional benefit of allowing input from nonclinical teams. Combining clinical, operational, and financial data can help make sure we achieve the best quality of care, at the best cost, with the best outcome. That is the value proposition of health care reform.

FINDING THE NEEDLE, NOT STORING MORE HAY

Beyond poor design, another problem with current EHR systems is that they overload us with information, so that our time is spent sifting through data rather than synthesizing it. We are seeing an unprecedented proliferation of both clinical data in the EHR and supporting research data. This combination has not helped the physician find the “needle.” Rather, it has managed to just store more hay.

All health care providers need to know how to read a chart quickly and efficiently to ascertain the story. In medical school, we teach new doctors about what makes for a good consult: synthesize the data and ask for an opinion. While a first-year medical school student would say, “I need a GI consult: the hemoglobin is 6, platelets are low, and there is blood in the stool,” a resident would say, “I need a GI consult for upper endoscopy, as I suspect this patient has alcoholic cirrhosis and likely portal hypertension: I am worried about variceal bleeding.” We should expect the same from our EHR.

Our relationship with health technology needs to shift. We need not view the EHR merely as a record, as something to physically hold data, but rather as a system that digests data to produce knowledge. The EHR needs to be viewed as a mentor and a colleague, a place that not only records data, but that also ascertains data incongruities, displays information that is relevant, and gives providers rapid, at-a-glance knowledge of the patient’s condition. The silo Dr. Stoller describes is not just the physical separation of providers, it is also the separation of providers and knowledge. We are still hunters and gatherers of information. Let the EHR work for the clinician. Tell me that I have not addressed my patient’s hyperkalemia. Tell me that my gastroenterology consultant is online and has just completed a consult note. Tell me that my patient is having uncontrolled pain now, rather than my having to discover this 9 hours later. We should expect our EHR to deliver the right information to the right person at the right time in the right format. The electronic health colleague might be a more apt term.

MAKING THE EHR WORK FOR US

So, has the EHR destroyed clinician collaboration? Certainly not. It has just changed the environment and the way we interact with the medical system. In fact, I argue that it could actually make it better, if we shift our expectations of our EHR systems. The future state of collaboration may not be in the traditional form of speaking to a colleague next to you, but rather in having a system that supports real-time access and sharing of digested knowledge about the patient. This knowledge can then be shared with other providers, finance systems, national health exchanges, predictive models, and even the patient, breaking the silos.

Someday the EHR might give back time to the provider, and we might say, “I just finished my patient panel early—let’s go get a cup of coffee and catch up.”

For all the purported benefits of the electronic health record (EHR), an unintended adverse effect is “electronic siloing.”

I define electronic siloing as the isolating effect of the EHR on clinical workflow that drives caregivers to work in silos, ie, alone at their workstations, thereby discouraging spontaneous interaction. To the extent that increasing evidence supports the importance of interaction among clinical colleagues and of teamwork to optimize clinical outcomes, electronic siloing threatens optimal practice and quality.

See related editorial

Mindfulness that the EHR can foster siloing will help mitigate the risk, as can novel solutions such as using “viewbox watering holes”¹ and embedding secure social messaging functions within the EHR, thereby allowing clinicians to reach out to colleagues with clinical challenges in the moment.

THE EHR BRINGS CHANGES, GOOD AND BAD

The EHR represents a major change in health care, with reported benefits that include standardized ordering, reduced medical errors, embedded protocols for guideline-based care, data access to analyze clinical practice patterns and outcomes, and enhanced communication among colleagues who are geographically separated (eg, virtual consults²). On the basis of these benefits and the federal Medicare and Medicaid financial incentives associated with “meaningful use,” the EHR is being increasingly adopted.^3–5

Yet for all these benefits and the promise that technology can enhance interaction among health care providers, unintended risks of the EHR paradoxically threaten optimal clinical care.⁶ Recognized risks include the threat to care should the EHR fail,⁶ the time and inefficiency costs of typing and multiple log-ons, and the perpetuation of errors in the medical record caused by the cutting and pasting of clinical notes.

Indeed, a substantial body of literature on sociotechnical interactions—how technology affects human patterns of practice—informs analyses of the impact of changing from a paper medical chart to an EHR.^6,8–12 For example, in a review of the impact of computerized physician order entry on inpatient clinical workflow, Niazkhani et al¹¹ noted that computerized ordering can change communication channels and collaboration mechanisms. More specifically, they point out that these systems can “replace interpersonal contacts that may result in fewer opportunities for team-wide negotiations.”¹¹

Similarly, Ash et al⁸ cited the unintended consequences of patient care information systems, especially increased overreliance on the system to communicate, which can undermine direct communication between healthcare providers.

Finally, Dykstra¹⁰ described the “reciprocal impact” of computerized physician order entry systems on communication between physicians and nurses. One observer stated, “[You] start doing physician order entry and direct entry of notes and you move that away from the ward into a room and now you eliminate the sense of team, and the kind of human communication that really was essential… You create physician separation.”¹⁰ Taken together, these observations suggest that the EHR and computerized order entry in particular can disrupt interaction between physicians and other health care providers, such as nurses and pharmacists.

BENEFITS OF TEAMWORK

A growing body of evidence indicates that teamwork and collaboration among health care providers—which involve frequent, critical face-to-face interaction—has clinical benefit. Demonstrated benefits of teamwork in health care¹¹ include lower surgical and intensive care unit mortality rates, fewer errors in emergency room management, better neonatal resuscitation, and enhanced diagnostic accuracy in interpreting images and biopsies.^12,13

As a specific example of the benefits of face-to-face conversation for interpreting chest images, O’Donovan et al¹⁴ showed that the diagnostic accuracy of a pulmonologist and thoracic radiologist in assessing rounded atelectasis was better when they reviewed chest CT scans together than when they interpreted the images solo.

Similarly, Flaherty et al¹⁵ showed that the level of agreement among pulmonologists, chest radiologists, and lung pathologists progressively increased as interaction and conversation increased when assessing the etiology of patients’ interstitial lung diseases.

As yet another demonstrable benefit of teamwork that should command interest in the current reimbursement-attentive era, analyses by Press Ganey¹⁶ and by Gallup have shown that the single best correlate of high patient satisfaction scores regarding hospitalization (including Hospital Consumer Assessment of Healthcare Providers and Systems ratings) is patients’ perception that their caregivers functioned as a team serving their needs.

The current perspective extends this observation about the unintended adverse effects of the EHR by suggesting that the EHR can inadvertently lessen spontaneous interaction between physicians as they care for outpatients. I have proposed the term electronic siloing to reflect the isolating impact of the EHR on clinical workflow that drives caregivers to work alone at their workstations, thereby discouraging spontaneous interaction between colleagues (eg, between primary care physicians and subspecialists, and between subspecialists in different disciplines). Because spontaneous face-to-face encounters and conversations among clinicians can encourage clinical insights that benefit patient care, electronic siloing can undermine optimal care. My thesis here is that the EHR predisposes to electronic siloing and that the solution is to first recognize and then to design care to prevent this effect.

DECLINE OF THE ‘CURBSIDE’ CONSULT

How does the subtle but sinister effect of electronic siloing really manifest itself at the bedside? I’ll offer an example from my personal clinical experience and then review similar examples from other clinical settings.

First, consider the following real change in clinical workflow that was caused by implementing the EHR in a pulmonary outpatient clinic and its impact on clinical hallway discussions among pulmonologists caring for their outpatients (Figure 1).

The pre-EHR scene was a straight corridor of examination rooms with a long desk outside the rooms and a bank of x-ray viewboxes where clinicians would review films, gather their thoughts, and write notes before re-entering the patient’s room to discuss recommendations. This scene was undoubtedly common in outpatient clinics of all types around the world.

In the bygone era of paper charting and printed x-ray films, the pulmonologists seeing their patients in examination rooms along this corridor and seated next to one another while they wrote their notes would frequently turn to a colleague seated next to them and request a “curbside” consult, ie, an opinion on the films and the case. Typically, a brief, spontaneous conversation would follow, either confirming the requester’s impressions or raising some new, unconsidered approaches. The effect of these brief, spontaneous conversations was either a new diagnostic or treatment consideration or enhanced clinician confidence in the current plan of care. Each outcome has great merit.

Now consider the same scenario in the EHR era. Printed films and viewboxes are gone (which has the benefits of lower production cost and better film retrieval), and images are now reviewed digitally on computer workstations. Workstations are characteristically spread out along the corridor at distances or may be mounted on mobile platforms. Often, physicians now retreat to their nearby offices to write notes, allowing easier access to workstations or to use voice transcription software to record notes. The net effect of this physical separation and of the subtle but powerful change in workflow is that spontaneous curbside consults over a chest film are less likely to occur and, to the extent that such interactions enhance diagnostic accuracy, beneficial face-to-face clinical discussions are less likely. This is the risk of electronic siloing realized.

Defenders of the EHR will point out that the EHR does not preclude such face-to-face encounters. While technically this is correct, it is also equally true that such encounters are less likely because they no longer flow naturally from the workflow of writing a note side-by-side with colleagues with the films displayed nearby. Pressured for time, clinicians learn efficiency of motion and are simply less likely to leave their workstations to seek another colleague who, in turn, may be tethered to a workstation and absorbed in keyboarding and monitor-watching. The net effect is that such spontaneous face-to-face encounters are clearly less common in the EHR era.

Electronic siloing undoubtedly occurs in many other outpatient and inpatient settings in other specialties. For example, consults between orthopedic surgeons seeing outpatients must be similarly affected, as might be discussions between pathologists reviewing tissue slides on a multiheaded microscope vs individually at their own microscopes or work stations. Indeed, observations that computerized order entry isolates physicians from nurses and that the EHR undermines communication between inpatient health care providers^6,8–11 represent other manifestations of electronic siloing.

Another variant of siloing occurs when there are not enough computers to go around. When clinicians seek but cannot find available workstations on the hospital ward, they move from the ward to their offices or other locations, separating them from the nurses and other physicians caring for those patients and, thereby, creating isolation and another form of siloing. A related theme is the importance of architecture in driving desirable interactions in the workplace in general and in hospitals in particular,^17,18 where interchanges between health care providers are critical to enhancing quality of care.

OUT OF THE SILO, INTO THE FIELD

So, given the many clear benefits of the EHR and its current wave of adoption in health care, how can we maximize the benefits of the EHR while minimizing the adverse effects of electronic siloing?

The key point is that we must realize, appreciate, and prioritize the value of face-toface interaction among providers as we try to offer optimal care to patients with ever more complex clinical problems.

In doing so, clinical workspaces and the number and placement of workstations must be designed with an explicit intent and priority to encourage interchange between providers and to avoid electronic siloing. As an example related to reviewing images, imaging suites and clinics should be designed with the concept of a viewbox watering hole¹ in which clinicians arrayed in a common space could review images on their individual computers but could easily prompt colleagues and send an image to a large, centrally visible monitor for the group’s review and comment. Furthermore, the EHR workflows themselves should drive caregivers to the patient rather than requiring their attention to the keyboard and the monitor. One could also imagine embedding secure social messaging within the EHR to encourage interactions among clinicians about pressing clinical challenges they are facing in the moment.

Overall, only through mindfulness of electronic siloing and of its subtle but adverse effects will we break out of the silos and emerge onto the fields of optimal health care.

For all the purported benefits of the electronic health record (EHR), an unintended adverse effect is “electronic siloing.”

I define electronic siloing as the isolating effect of the EHR on clinical workflow that drives caregivers to work in silos, ie, alone at their workstations, thereby discouraging spontaneous interaction. To the extent that increasing evidence supports the importance of interaction among clinical colleagues and of teamwork to optimize clinical outcomes, electronic siloing threatens optimal practice and quality.

See related editorial

Mindfulness that the EHR can foster siloing will help mitigate the risk, as can novel solutions such as using “viewbox watering holes”¹ and embedding secure social messaging functions within the EHR, thereby allowing clinicians to reach out to colleagues with clinical challenges in the moment.

THE EHR BRINGS CHANGES, GOOD AND BAD

The EHR represents a major change in health care, with reported benefits that include standardized ordering, reduced medical errors, embedded protocols for guideline-based care, data access to analyze clinical practice patterns and outcomes, and enhanced communication among colleagues who are geographically separated (eg, virtual consults²). On the basis of these benefits and the federal Medicare and Medicaid financial incentives associated with “meaningful use,” the EHR is being increasingly adopted.^3–5

Yet for all these benefits and the promise that technology can enhance interaction among health care providers, unintended risks of the EHR paradoxically threaten optimal clinical care.⁶ Recognized risks include the threat to care should the EHR fail,⁶ the time and inefficiency costs of typing and multiple log-ons, and the perpetuation of errors in the medical record caused by the cutting and pasting of clinical notes.

Indeed, a substantial body of literature on sociotechnical interactions—how technology affects human patterns of practice—informs analyses of the impact of changing from a paper medical chart to an EHR.^6,8–12 For example, in a review of the impact of computerized physician order entry on inpatient clinical workflow, Niazkhani et al¹¹ noted that computerized ordering can change communication channels and collaboration mechanisms. More specifically, they point out that these systems can “replace interpersonal contacts that may result in fewer opportunities for team-wide negotiations.”¹¹

Similarly, Ash et al⁸ cited the unintended consequences of patient care information systems, especially increased overreliance on the system to communicate, which can undermine direct communication between healthcare providers.

Finally, Dykstra¹⁰ described the “reciprocal impact” of computerized physician order entry systems on communication between physicians and nurses. One observer stated, “[You] start doing physician order entry and direct entry of notes and you move that away from the ward into a room and now you eliminate the sense of team, and the kind of human communication that really was essential… You create physician separation.”¹⁰ Taken together, these observations suggest that the EHR and computerized order entry in particular can disrupt interaction between physicians and other health care providers, such as nurses and pharmacists.

BENEFITS OF TEAMWORK

A growing body of evidence indicates that teamwork and collaboration among health care providers—which involve frequent, critical face-to-face interaction—has clinical benefit. Demonstrated benefits of teamwork in health care¹¹ include lower surgical and intensive care unit mortality rates, fewer errors in emergency room management, better neonatal resuscitation, and enhanced diagnostic accuracy in interpreting images and biopsies.^12,13

As a specific example of the benefits of face-to-face conversation for interpreting chest images, O’Donovan et al¹⁴ showed that the diagnostic accuracy of a pulmonologist and thoracic radiologist in assessing rounded atelectasis was better when they reviewed chest CT scans together than when they interpreted the images solo.

Similarly, Flaherty et al¹⁵ showed that the level of agreement among pulmonologists, chest radiologists, and lung pathologists progressively increased as interaction and conversation increased when assessing the etiology of patients’ interstitial lung diseases.

As yet another demonstrable benefit of teamwork that should command interest in the current reimbursement-attentive era, analyses by Press Ganey¹⁶ and by Gallup have shown that the single best correlate of high patient satisfaction scores regarding hospitalization (including Hospital Consumer Assessment of Healthcare Providers and Systems ratings) is patients’ perception that their caregivers functioned as a team serving their needs.

The current perspective extends this observation about the unintended adverse effects of the EHR by suggesting that the EHR can inadvertently lessen spontaneous interaction between physicians as they care for outpatients. I have proposed the term electronic siloing to reflect the isolating impact of the EHR on clinical workflow that drives caregivers to work alone at their workstations, thereby discouraging spontaneous interaction between colleagues (eg, between primary care physicians and subspecialists, and between subspecialists in different disciplines). Because spontaneous face-to-face encounters and conversations among clinicians can encourage clinical insights that benefit patient care, electronic siloing can undermine optimal care. My thesis here is that the EHR predisposes to electronic siloing and that the solution is to first recognize and then to design care to prevent this effect.

DECLINE OF THE ‘CURBSIDE’ CONSULT

How does the subtle but sinister effect of electronic siloing really manifest itself at the bedside? I’ll offer an example from my personal clinical experience and then review similar examples from other clinical settings.

First, consider the following real change in clinical workflow that was caused by implementing the EHR in a pulmonary outpatient clinic and its impact on clinical hallway discussions among pulmonologists caring for their outpatients (Figure 1).

The pre-EHR scene was a straight corridor of examination rooms with a long desk outside the rooms and a bank of x-ray viewboxes where clinicians would review films, gather their thoughts, and write notes before re-entering the patient’s room to discuss recommendations. This scene was undoubtedly common in outpatient clinics of all types around the world.

In the bygone era of paper charting and printed x-ray films, the pulmonologists seeing their patients in examination rooms along this corridor and seated next to one another while they wrote their notes would frequently turn to a colleague seated next to them and request a “curbside” consult, ie, an opinion on the films and the case. Typically, a brief, spontaneous conversation would follow, either confirming the requester’s impressions or raising some new, unconsidered approaches. The effect of these brief, spontaneous conversations was either a new diagnostic or treatment consideration or enhanced clinician confidence in the current plan of care. Each outcome has great merit.

Now consider the same scenario in the EHR era. Printed films and viewboxes are gone (which has the benefits of lower production cost and better film retrieval), and images are now reviewed digitally on computer workstations. Workstations are characteristically spread out along the corridor at distances or may be mounted on mobile platforms. Often, physicians now retreat to their nearby offices to write notes, allowing easier access to workstations or to use voice transcription software to record notes. The net effect of this physical separation and of the subtle but powerful change in workflow is that spontaneous curbside consults over a chest film are less likely to occur and, to the extent that such interactions enhance diagnostic accuracy, beneficial face-to-face clinical discussions are less likely. This is the risk of electronic siloing realized.

Defenders of the EHR will point out that the EHR does not preclude such face-to-face encounters. While technically this is correct, it is also equally true that such encounters are less likely because they no longer flow naturally from the workflow of writing a note side-by-side with colleagues with the films displayed nearby. Pressured for time, clinicians learn efficiency of motion and are simply less likely to leave their workstations to seek another colleague who, in turn, may be tethered to a workstation and absorbed in keyboarding and monitor-watching. The net effect is that such spontaneous face-to-face encounters are clearly less common in the EHR era.

Electronic siloing undoubtedly occurs in many other outpatient and inpatient settings in other specialties. For example, consults between orthopedic surgeons seeing outpatients must be similarly affected, as might be discussions between pathologists reviewing tissue slides on a multiheaded microscope vs individually at their own microscopes or work stations. Indeed, observations that computerized order entry isolates physicians from nurses and that the EHR undermines communication between inpatient health care providers^6,8–11 represent other manifestations of electronic siloing.

Another variant of siloing occurs when there are not enough computers to go around. When clinicians seek but cannot find available workstations on the hospital ward, they move from the ward to their offices or other locations, separating them from the nurses and other physicians caring for those patients and, thereby, creating isolation and another form of siloing. A related theme is the importance of architecture in driving desirable interactions in the workplace in general and in hospitals in particular,^17,18 where interchanges between health care providers are critical to enhancing quality of care.

OUT OF THE SILO, INTO THE FIELD

So, given the many clear benefits of the EHR and its current wave of adoption in health care, how can we maximize the benefits of the EHR while minimizing the adverse effects of electronic siloing?

The key point is that we must realize, appreciate, and prioritize the value of face-toface interaction among providers as we try to offer optimal care to patients with ever more complex clinical problems.

In doing so, clinical workspaces and the number and placement of workstations must be designed with an explicit intent and priority to encourage interchange between providers and to avoid electronic siloing. As an example related to reviewing images, imaging suites and clinics should be designed with the concept of a viewbox watering hole¹ in which clinicians arrayed in a common space could review images on their individual computers but could easily prompt colleagues and send an image to a large, centrally visible monitor for the group’s review and comment. Furthermore, the EHR workflows themselves should drive caregivers to the patient rather than requiring their attention to the keyboard and the monitor. One could also imagine embedding secure social messaging within the EHR to encourage interactions among clinicians about pressing clinical challenges they are facing in the moment.

Overall, only through mindfulness of electronic siloing and of its subtle but adverse effects will we break out of the silos and emerge onto the fields of optimal health care.

For all the purported benefits of the electronic health record (EHR), an unintended adverse effect is “electronic siloing.”

I define electronic siloing as the isolating effect of the EHR on clinical workflow that drives caregivers to work in silos, ie, alone at their workstations, thereby discouraging spontaneous interaction. To the extent that increasing evidence supports the importance of interaction among clinical colleagues and of teamwork to optimize clinical outcomes, electronic siloing threatens optimal practice and quality.

See related editorial

Mindfulness that the EHR can foster siloing will help mitigate the risk, as can novel solutions such as using “viewbox watering holes”¹ and embedding secure social messaging functions within the EHR, thereby allowing clinicians to reach out to colleagues with clinical challenges in the moment.

THE EHR BRINGS CHANGES, GOOD AND BAD

The EHR represents a major change in health care, with reported benefits that include standardized ordering, reduced medical errors, embedded protocols for guideline-based care, data access to analyze clinical practice patterns and outcomes, and enhanced communication among colleagues who are geographically separated (eg, virtual consults²). On the basis of these benefits and the federal Medicare and Medicaid financial incentives associated with “meaningful use,” the EHR is being increasingly adopted.^3–5

Yet for all these benefits and the promise that technology can enhance interaction among health care providers, unintended risks of the EHR paradoxically threaten optimal clinical care.⁶ Recognized risks include the threat to care should the EHR fail,⁶ the time and inefficiency costs of typing and multiple log-ons, and the perpetuation of errors in the medical record caused by the cutting and pasting of clinical notes.

Indeed, a substantial body of literature on sociotechnical interactions—how technology affects human patterns of practice—informs analyses of the impact of changing from a paper medical chart to an EHR.^6,8–12 For example, in a review of the impact of computerized physician order entry on inpatient clinical workflow, Niazkhani et al¹¹ noted that computerized ordering can change communication channels and collaboration mechanisms. More specifically, they point out that these systems can “replace interpersonal contacts that may result in fewer opportunities for team-wide negotiations.”¹¹

Similarly, Ash et al⁸ cited the unintended consequences of patient care information systems, especially increased overreliance on the system to communicate, which can undermine direct communication between healthcare providers.

Finally, Dykstra¹⁰ described the “reciprocal impact” of computerized physician order entry systems on communication between physicians and nurses. One observer stated, “[You] start doing physician order entry and direct entry of notes and you move that away from the ward into a room and now you eliminate the sense of team, and the kind of human communication that really was essential… You create physician separation.”¹⁰ Taken together, these observations suggest that the EHR and computerized order entry in particular can disrupt interaction between physicians and other health care providers, such as nurses and pharmacists.

BENEFITS OF TEAMWORK

A growing body of evidence indicates that teamwork and collaboration among health care providers—which involve frequent, critical face-to-face interaction—has clinical benefit. Demonstrated benefits of teamwork in health care¹¹ include lower surgical and intensive care unit mortality rates, fewer errors in emergency room management, better neonatal resuscitation, and enhanced diagnostic accuracy in interpreting images and biopsies.^12,13

As a specific example of the benefits of face-to-face conversation for interpreting chest images, O’Donovan et al¹⁴ showed that the diagnostic accuracy of a pulmonologist and thoracic radiologist in assessing rounded atelectasis was better when they reviewed chest CT scans together than when they interpreted the images solo.

Similarly, Flaherty et al¹⁵ showed that the level of agreement among pulmonologists, chest radiologists, and lung pathologists progressively increased as interaction and conversation increased when assessing the etiology of patients’ interstitial lung diseases.

As yet another demonstrable benefit of teamwork that should command interest in the current reimbursement-attentive era, analyses by Press Ganey¹⁶ and by Gallup have shown that the single best correlate of high patient satisfaction scores regarding hospitalization (including Hospital Consumer Assessment of Healthcare Providers and Systems ratings) is patients’ perception that their caregivers functioned as a team serving their needs.

The current perspective extends this observation about the unintended adverse effects of the EHR by suggesting that the EHR can inadvertently lessen spontaneous interaction between physicians as they care for outpatients. I have proposed the term electronic siloing to reflect the isolating impact of the EHR on clinical workflow that drives caregivers to work alone at their workstations, thereby discouraging spontaneous interaction between colleagues (eg, between primary care physicians and subspecialists, and between subspecialists in different disciplines). Because spontaneous face-to-face encounters and conversations among clinicians can encourage clinical insights that benefit patient care, electronic siloing can undermine optimal care. My thesis here is that the EHR predisposes to electronic siloing and that the solution is to first recognize and then to design care to prevent this effect.

DECLINE OF THE ‘CURBSIDE’ CONSULT

How does the subtle but sinister effect of electronic siloing really manifest itself at the bedside? I’ll offer an example from my personal clinical experience and then review similar examples from other clinical settings.

First, consider the following real change in clinical workflow that was caused by implementing the EHR in a pulmonary outpatient clinic and its impact on clinical hallway discussions among pulmonologists caring for their outpatients (Figure 1).

The pre-EHR scene was a straight corridor of examination rooms with a long desk outside the rooms and a bank of x-ray viewboxes where clinicians would review films, gather their thoughts, and write notes before re-entering the patient’s room to discuss recommendations. This scene was undoubtedly common in outpatient clinics of all types around the world.

In the bygone era of paper charting and printed x-ray films, the pulmonologists seeing their patients in examination rooms along this corridor and seated next to one another while they wrote their notes would frequently turn to a colleague seated next to them and request a “curbside” consult, ie, an opinion on the films and the case. Typically, a brief, spontaneous conversation would follow, either confirming the requester’s impressions or raising some new, unconsidered approaches. The effect of these brief, spontaneous conversations was either a new diagnostic or treatment consideration or enhanced clinician confidence in the current plan of care. Each outcome has great merit.

Now consider the same scenario in the EHR era. Printed films and viewboxes are gone (which has the benefits of lower production cost and better film retrieval), and images are now reviewed digitally on computer workstations. Workstations are characteristically spread out along the corridor at distances or may be mounted on mobile platforms. Often, physicians now retreat to their nearby offices to write notes, allowing easier access to workstations or to use voice transcription software to record notes. The net effect of this physical separation and of the subtle but powerful change in workflow is that spontaneous curbside consults over a chest film are less likely to occur and, to the extent that such interactions enhance diagnostic accuracy, beneficial face-to-face clinical discussions are less likely. This is the risk of electronic siloing realized.

Defenders of the EHR will point out that the EHR does not preclude such face-to-face encounters. While technically this is correct, it is also equally true that such encounters are less likely because they no longer flow naturally from the workflow of writing a note side-by-side with colleagues with the films displayed nearby. Pressured for time, clinicians learn efficiency of motion and are simply less likely to leave their workstations to seek another colleague who, in turn, may be tethered to a workstation and absorbed in keyboarding and monitor-watching. The net effect is that such spontaneous face-to-face encounters are clearly less common in the EHR era.

Electronic siloing undoubtedly occurs in many other outpatient and inpatient settings in other specialties. For example, consults between orthopedic surgeons seeing outpatients must be similarly affected, as might be discussions between pathologists reviewing tissue slides on a multiheaded microscope vs individually at their own microscopes or work stations. Indeed, observations that computerized order entry isolates physicians from nurses and that the EHR undermines communication between inpatient health care providers^6,8–11 represent other manifestations of electronic siloing.

Another variant of siloing occurs when there are not enough computers to go around. When clinicians seek but cannot find available workstations on the hospital ward, they move from the ward to their offices or other locations, separating them from the nurses and other physicians caring for those patients and, thereby, creating isolation and another form of siloing. A related theme is the importance of architecture in driving desirable interactions in the workplace in general and in hospitals in particular,^17,18 where interchanges between health care providers are critical to enhancing quality of care.

OUT OF THE SILO, INTO THE FIELD

So, given the many clear benefits of the EHR and its current wave of adoption in health care, how can we maximize the benefits of the EHR while minimizing the adverse effects of electronic siloing?

The key point is that we must realize, appreciate, and prioritize the value of face-toface interaction among providers as we try to offer optimal care to patients with ever more complex clinical problems.

In doing so, clinical workspaces and the number and placement of workstations must be designed with an explicit intent and priority to encourage interchange between providers and to avoid electronic siloing. As an example related to reviewing images, imaging suites and clinics should be designed with the concept of a viewbox watering hole¹ in which clinicians arrayed in a common space could review images on their individual computers but could easily prompt colleagues and send an image to a large, centrally visible monitor for the group’s review and comment. Furthermore, the EHR workflows themselves should drive caregivers to the patient rather than requiring their attention to the keyboard and the monitor. One could also imagine embedding secure social messaging within the EHR to encourage interactions among clinicians about pressing clinical challenges they are facing in the moment.

Overall, only through mindfulness of electronic siloing and of its subtle but adverse effects will we break out of the silos and emerge onto the fields of optimal health care.

The promise of the electronic health record (EHR) has not yet been realized. I find it extremely beneficial to have access to shared, accurate information during each patient encounter, but my expectations are still far ahead of reality. We should demand more-flexible software with more clinician-tailored utilities—more bang for the click. However, we users also need to improve.

Benefits and challenges of computers in the examination room

With the EHR, the monitor and keyboard have been interposed between the physician and patient. Physicians now must type or dictate their office notes, enter electronic orders and prescriptions, and remember to use specific phrases to fulfill compliance regulations. Many physicians have to see more patients in less time while incorporating the EHR into each visit. Under these new pressures, some have chosen to retire early or to drastically change the scope of their practice.

I too experience these challenges. I have more electronic tasks to do during each visit and wonder if this is really the best use of my time. I run even further behind than I used to, and I almost uniformly have to apologize to my patients for being late. I am not the world’s best typist. Patients note my clerical challenges, and some of them offer to type in their information for me—a bonding experience I could do without.

Lest the computer become the primary object of my attention, I push back from the keyboard intermittently, with my hands in my lap, or make physical contact with my (human) patient. I try to make eye contact as we converse, and patients leave with a legible—albeit possibly misspelled—summary. During visits, I can share graphs of my patient’s lab tests or vital signs over time, and I hope that more sophisticated EHRs will correlate this information with medication changes and other events. I have less work to do at the end of the day than I used to, since during my clinic time, multitasking as I go, I send prescriptions to pharmacies, review test results, and send letters to my patients and their referring physicians about their test results and my suggestions. I encourage patients to e-mail me directly with their questions or problems as they arise—an opportunity that many have used and none have abused. Technology is not all bad.

How the EHR needs to improve

The EHR is still evolving, and it needs to be better honed to the needs of the user. My EHR still does not give me reminders for routine screening and monitoring. It is not yet tailored to the specific problems shared by many of my patients. It does not yet provide snapshots or specifics about tailored measures of quality of my practice.

As nicely summarized by Dr. William Morris in this issue, we need to get the EHR to work for us, not mainly for those responsible for billing and regulatory compliance. But all groups can be served equally; “alerts” can be activated as screen pop-ups to drive physician behavior towards best practice—with the caveat that alerts must be meaningful, triggered intelligently, and individualized to avoid pop-up fatigue.

In addition, as Dr. James Stoller discusses in this issue, the solitary work involved in using the EHR has also affected the natural collegial interchange that took place around the chart rack in the past. He, Dr. Morris, and I agree that direct physician-physician communication has diminished in our medical centers. But I believe that this is the result of many pressures, not simply the renewed emphasis¹ on the physician’s role as scribe and more-cloistered physician keyboarding. We all extol the value of the phone call and face-to-face conversation between consultants and primary care providers, and at times this is necessary to reach decisions of care. But physicians are more strapped for time than ever. In this era of the “flash mob” and instant texting and tweeting, we should be able to promote effective digital dialogue between physicians. We should embrace and facilitate digital communication.

How physicians need to improve

I see many copy-and-paste reiterations of semi-irrelevant (and I suspect, usually not independently confirmed) details of social history and physical examinations from visits gone by. I read completed templates with information that clearly was not collected at the time of the encounter. The potential for misuse and misrepresentation (even without any malevolent intent) with the use of templates and copy-and-paste functions is apparent. These bad practices must stop.

Another problem: some of my colleagues do not read their messages regarding forwarded charts or patient questions within our EHR—“It is just too many e-mails to check.” This reluctance to fully connect in cyberspace is perhaps a case of failing to teach old dogs new tricks, and we do have too much e-mail. But I think it is also partly a result of paranoia over maintaining confidentiality of patient-related communication, at the expense of the efficiency of digital communication. The forwarding of EHR messages to our office e-mail system and phones is blocked by a firewall to ensure privacy—but this makes necessary medical communication more difficult. Is this the right trade-off? If the EHR is to become the hub for tracking patient-centered care, we need to use it to our advantage and to ease access to all aspects of the EHR from multiple venues.

Even when read, our notes leave much to be desired. Beyond the problem with copying and pasting of earlier notes, paragraphs of unfiltered, often irrelevant or untimely lab and imaging reports are repeatedly inserted into multiple notes, while a clearly expressed impression and plan are often nowhere to be found. Some of my colleagues dictate their notes with a delay before uploading, without any concise placeholder summary in the EHR, or they have an assistant or trainee enter a summary, without the nuanced explanation that I need to fully understand the consultant’s reasoning. These behaviors negate the potential power of the EHR.

Bemoaning the new technology and developing work-arounds is not the answer. We need to refine the clinician-computer interface,² and we need to do much better with our documentation.

The basic principles of physician communication are as important now as they were 50 years ago, when notes were illegibly written with pen and paper and discussed by docs seated around the chart rack in the nursing station. We need to take ownership of the EHR and to insist with other stakeholders that all aspects work better for us and for our patients. This includes the software and, maybe more important, the user.

The promise of the electronic health record (EHR) has not yet been realized. I find it extremely beneficial to have access to shared, accurate information during each patient encounter, but my expectations are still far ahead of reality. We should demand more-flexible software with more clinician-tailored utilities—more bang for the click. However, we users also need to improve.

Benefits and challenges of computers in the examination room

With the EHR, the monitor and keyboard have been interposed between the physician and patient. Physicians now must type or dictate their office notes, enter electronic orders and prescriptions, and remember to use specific phrases to fulfill compliance regulations. Many physicians have to see more patients in less time while incorporating the EHR into each visit. Under these new pressures, some have chosen to retire early or to drastically change the scope of their practice.

I too experience these challenges. I have more electronic tasks to do during each visit and wonder if this is really the best use of my time. I run even further behind than I used to, and I almost uniformly have to apologize to my patients for being late. I am not the world’s best typist. Patients note my clerical challenges, and some of them offer to type in their information for me—a bonding experience I could do without.

Lest the computer become the primary object of my attention, I push back from the keyboard intermittently, with my hands in my lap, or make physical contact with my (human) patient. I try to make eye contact as we converse, and patients leave with a legible—albeit possibly misspelled—summary. During visits, I can share graphs of my patient’s lab tests or vital signs over time, and I hope that more sophisticated EHRs will correlate this information with medication changes and other events. I have less work to do at the end of the day than I used to, since during my clinic time, multitasking as I go, I send prescriptions to pharmacies, review test results, and send letters to my patients and their referring physicians about their test results and my suggestions. I encourage patients to e-mail me directly with their questions or problems as they arise—an opportunity that many have used and none have abused. Technology is not all bad.

How the EHR needs to improve

The EHR is still evolving, and it needs to be better honed to the needs of the user. My EHR still does not give me reminders for routine screening and monitoring. It is not yet tailored to the specific problems shared by many of my patients. It does not yet provide snapshots or specifics about tailored measures of quality of my practice.

As nicely summarized by Dr. William Morris in this issue, we need to get the EHR to work for us, not mainly for those responsible for billing and regulatory compliance. But all groups can be served equally; “alerts” can be activated as screen pop-ups to drive physician behavior towards best practice—with the caveat that alerts must be meaningful, triggered intelligently, and individualized to avoid pop-up fatigue.

In addition, as Dr. James Stoller discusses in this issue, the solitary work involved in using the EHR has also affected the natural collegial interchange that took place around the chart rack in the past. He, Dr. Morris, and I agree that direct physician-physician communication has diminished in our medical centers. But I believe that this is the result of many pressures, not simply the renewed emphasis¹ on the physician’s role as scribe and more-cloistered physician keyboarding. We all extol the value of the phone call and face-to-face conversation between consultants and primary care providers, and at times this is necessary to reach decisions of care. But physicians are more strapped for time than ever. In this era of the “flash mob” and instant texting and tweeting, we should be able to promote effective digital dialogue between physicians. We should embrace and facilitate digital communication.

How physicians need to improve

I see many copy-and-paste reiterations of semi-irrelevant (and I suspect, usually not independently confirmed) details of social history and physical examinations from visits gone by. I read completed templates with information that clearly was not collected at the time of the encounter. The potential for misuse and misrepresentation (even without any malevolent intent) with the use of templates and copy-and-paste functions is apparent. These bad practices must stop.

Another problem: some of my colleagues do not read their messages regarding forwarded charts or patient questions within our EHR—“It is just too many e-mails to check.” This reluctance to fully connect in cyberspace is perhaps a case of failing to teach old dogs new tricks, and we do have too much e-mail. But I think it is also partly a result of paranoia over maintaining confidentiality of patient-related communication, at the expense of the efficiency of digital communication. The forwarding of EHR messages to our office e-mail system and phones is blocked by a firewall to ensure privacy—but this makes necessary medical communication more difficult. Is this the right trade-off? If the EHR is to become the hub for tracking patient-centered care, we need to use it to our advantage and to ease access to all aspects of the EHR from multiple venues.

Even when read, our notes leave much to be desired. Beyond the problem with copying and pasting of earlier notes, paragraphs of unfiltered, often irrelevant or untimely lab and imaging reports are repeatedly inserted into multiple notes, while a clearly expressed impression and plan are often nowhere to be found. Some of my colleagues dictate their notes with a delay before uploading, without any concise placeholder summary in the EHR, or they have an assistant or trainee enter a summary, without the nuanced explanation that I need to fully understand the consultant’s reasoning. These behaviors negate the potential power of the EHR.

Bemoaning the new technology and developing work-arounds is not the answer. We need to refine the clinician-computer interface,² and we need to do much better with our documentation.

The basic principles of physician communication are as important now as they were 50 years ago, when notes were illegibly written with pen and paper and discussed by docs seated around the chart rack in the nursing station. We need to take ownership of the EHR and to insist with other stakeholders that all aspects work better for us and for our patients. This includes the software and, maybe more important, the user.

The promise of the electronic health record (EHR) has not yet been realized. I find it extremely beneficial to have access to shared, accurate information during each patient encounter, but my expectations are still far ahead of reality. We should demand more-flexible software with more clinician-tailored utilities—more bang for the click. However, we users also need to improve.

Benefits and challenges of computers in the examination room

With the EHR, the monitor and keyboard have been interposed between the physician and patient. Physicians now must type or dictate their office notes, enter electronic orders and prescriptions, and remember to use specific phrases to fulfill compliance regulations. Many physicians have to see more patients in less time while incorporating the EHR into each visit. Under these new pressures, some have chosen to retire early or to drastically change the scope of their practice.

I too experience these challenges. I have more electronic tasks to do during each visit and wonder if this is really the best use of my time. I run even further behind than I used to, and I almost uniformly have to apologize to my patients for being late. I am not the world’s best typist. Patients note my clerical challenges, and some of them offer to type in their information for me—a bonding experience I could do without.

Lest the computer become the primary object of my attention, I push back from the keyboard intermittently, with my hands in my lap, or make physical contact with my (human) patient. I try to make eye contact as we converse, and patients leave with a legible—albeit possibly misspelled—summary. During visits, I can share graphs of my patient’s lab tests or vital signs over time, and I hope that more sophisticated EHRs will correlate this information with medication changes and other events. I have less work to do at the end of the day than I used to, since during my clinic time, multitasking as I go, I send prescriptions to pharmacies, review test results, and send letters to my patients and their referring physicians about their test results and my suggestions. I encourage patients to e-mail me directly with their questions or problems as they arise—an opportunity that many have used and none have abused. Technology is not all bad.

How the EHR needs to improve

The EHR is still evolving, and it needs to be better honed to the needs of the user. My EHR still does not give me reminders for routine screening and monitoring. It is not yet tailored to the specific problems shared by many of my patients. It does not yet provide snapshots or specifics about tailored measures of quality of my practice.

As nicely summarized by Dr. William Morris in this issue, we need to get the EHR to work for us, not mainly for those responsible for billing and regulatory compliance. But all groups can be served equally; “alerts” can be activated as screen pop-ups to drive physician behavior towards best practice—with the caveat that alerts must be meaningful, triggered intelligently, and individualized to avoid pop-up fatigue.

In addition, as Dr. James Stoller discusses in this issue, the solitary work involved in using the EHR has also affected the natural collegial interchange that took place around the chart rack in the past. He, Dr. Morris, and I agree that direct physician-physician communication has diminished in our medical centers. But I believe that this is the result of many pressures, not simply the renewed emphasis¹ on the physician’s role as scribe and more-cloistered physician keyboarding. We all extol the value of the phone call and face-to-face conversation between consultants and primary care providers, and at times this is necessary to reach decisions of care. But physicians are more strapped for time than ever. In this era of the “flash mob” and instant texting and tweeting, we should be able to promote effective digital dialogue between physicians. We should embrace and facilitate digital communication.

How physicians need to improve

I see many copy-and-paste reiterations of semi-irrelevant (and I suspect, usually not independently confirmed) details of social history and physical examinations from visits gone by. I read completed templates with information that clearly was not collected at the time of the encounter. The potential for misuse and misrepresentation (even without any malevolent intent) with the use of templates and copy-and-paste functions is apparent. These bad practices must stop.

Another problem: some of my colleagues do not read their messages regarding forwarded charts or patient questions within our EHR—“It is just too many e-mails to check.” This reluctance to fully connect in cyberspace is perhaps a case of failing to teach old dogs new tricks, and we do have too much e-mail. But I think it is also partly a result of paranoia over maintaining confidentiality of patient-related communication, at the expense of the efficiency of digital communication. The forwarding of EHR messages to our office e-mail system and phones is blocked by a firewall to ensure privacy—but this makes necessary medical communication more difficult. Is this the right trade-off? If the EHR is to become the hub for tracking patient-centered care, we need to use it to our advantage and to ease access to all aspects of the EHR from multiple venues.

Even when read, our notes leave much to be desired. Beyond the problem with copying and pasting of earlier notes, paragraphs of unfiltered, often irrelevant or untimely lab and imaging reports are repeatedly inserted into multiple notes, while a clearly expressed impression and plan are often nowhere to be found. Some of my colleagues dictate their notes with a delay before uploading, without any concise placeholder summary in the EHR, or they have an assistant or trainee enter a summary, without the nuanced explanation that I need to fully understand the consultant’s reasoning. These behaviors negate the potential power of the EHR.

Bemoaning the new technology and developing work-arounds is not the answer. We need to refine the clinician-computer interface,² and we need to do much better with our documentation.

The basic principles of physician communication are as important now as they were 50 years ago, when notes were illegibly written with pen and paper and discussed by docs seated around the chart rack in the nursing station. We need to take ownership of the EHR and to insist with other stakeholders that all aspects work better for us and for our patients. This includes the software and, maybe more important, the user.

Paget disease of bone is a focal disorder of the aging skeleton that can be asymptomatic or can present with pain, bowing deformities, fractures, or nonspecific rheumatic complaints. Physicians often discover it in asymptomatic patients when serum alkaline phosphatase levels are elevated or as an incidental finding on radiography. Despite evidence of germline mutations and polymorphisms that predispose to Paget disease, the environmental determinants that permit disease expression in older people remain unknown.

A STRIKING GEOGRAPHIC DISTRIBUTION

Researchers have been studying the determinants and distribution of Paget disease ever since Sir James Paget first described it in 1877.¹

Paget disease has a predilection for the axial skeleton, particularly the lumbosacral spine and pelvis, as well as the skull, femur, and tibia.² Knowing this, investigators have used screening plain films of the abdomen (kidney-ureter-bladder views) to estimate its prevalence in different populations, as these images capture the lumbosacral spine, pelvis, and proximal femurs. Other means of assessing prevalence have included autopsy series, questionnaires, and screens for biochemical markers of bone turnover, such as elevated serum alkaline phosphatase from bone.^3–6

Using these methods, Paget disease has been estimated to occur in 1% to 3% of people over age 55, and in as many as 8% of people over age 80 in certain countries.⁷

This disease has a striking geographic distribution, being frequent in Europe, Canada, the United States, Australia, New Zealand, and cities of South America, but rare in Scandinavia and Japan. It seems to be equally rare in other countries of the Far East and in India, Russia, and Africa, although its prevalence in these areas has not been thoroughly investigated.⁸

That it is an ancient disease has been corroborated by excavations in churchyards in Great Britain.^9,10 It may be familial or sporadic, but its expression is delayed until late middle age in most persons, and it does not occur in children. For reasons unclear, the prevalence seems to be decreasing in many countries.^11–13

GENETICS IS NOT THE WHOLE STORY

The variable prevalence of Paget disease in different geographic regions and its sometimes-familial expression suggest a genetic predisposition, environmental factor, or both.

Mutations in SQSTM1

In 2002, scientists investigating a cohort of French Canadian families found a mutation in the SQSTM1 gene that was present in almost 50% of people with familial Paget disease and in 16% of those with sporadic Paget disease.¹⁴ Hocking and his colleagues in the United Kingdom subsequently found the same mutation in 19% of cases of familial Paget disease and in 9% of sporadic cases.¹⁵

Further, investigators noted that the mutation was often present on a conserved haplotype, consistent with a stable genetic change occurring in the affected population.¹⁶ This observation of a “founder effect” dovetailed with the epidemiology of Paget disease,¹⁷ but only with this SQSTM1 mutation.

Throughout Europe, Australia, and the United States, comparable rates of the SQSTM1 mutation were reported in or around the ubiquitin-associated domain. Several specific mutations exist, the most common one being P392L, ie, a prolineto-leucine substitution at amino acid 392. Scientists have tried to correlate severity of disease with genotype, but the findings have been inconsistent.^18–21

Investigations into the mechanism of disease have pointed to the role of p62, the product of SQSTM1, in signaling osteoclast activation via nuclear factor kappa B. Since this initial discovery, polymorphisms in the genes affecting osteoclast maturation, activation, and fusion pathways have been shown to predispose to Paget disease. Examples:

• TNFRSF11A, which codes for receptor activator of nuclear factor kappa B, or RANK
• TNFRSF11B, which codes for osteoprotegerin, or OPG
• CSF1, which codes for macrophage colony-stimulating factor 1, and
• OPTN, which codes for optineurin, a member of the nuclear factor kappa B-modulating protein family.

Clinicians interested in these details can read an excellent review of the pathogenesis of Paget disease.²²

Other possible factors

Although there is good evidence that measles and canine distemper virus can infect osteoclasts and modify their phenotype, there is no good evidence that these infections by themselves cause Paget disease.^23–25 It is, however, tempting to think of these RNA paramyxoviruses as precipitating factors; conceivably, an infectious agent might seed the ends of long bones, accounting for the fixed distribution of Paget disease and its late expression.

Epidemiologic studies from around the world have failed to identify conclusively any environmental exposure that predisposes to Paget disease, although a rural setting, trauma, infection, and milk ingestion have all been proposed.^26–28 It is also possible that as bone ages and the marrow becomes less cellular and more fatty, these changes may permit the disease to develop.

The greatest risk factor for Paget disease is perhaps aging, followed by ancestry and a known family history of it. That genetics is not the whole story is evident by reports of people with SQSTM1 mutations who show no clinical evidence of Paget disease in their old age, and patients with Paget disease who have no SQSTM1 mutation.^20,29

CLINICAL PRESENTATION

Most patients with Paget disease have no symptoms and come to medical attention because of an elevated serum alkaline phosphatase level or characteristic findings on radiographs ordered for other indications.¹¹ Paget disease is the second most common disorder of aging bone after osteoporosis. Yet unlike osteoporosis, which presents as a systemic fragility of bone, the clinical manifestations of Paget disease depend on which bones are affected and how enlarged or misshapen they have become.

Common complications

As a consequence of this abnormal bone remodeling and overgrowth, many patients present with bone pain. Bone deformity, headache, and hearing loss may also occur (Figure 1), as well as fractures and nerve compression syndromes (eg, spinal stenosis, sciatica, cauda equina syndrome).

It is important to remember that “pagetic” bone may not be the source of pain, and that functional impairment caused by degenerative changes at affected sites is common (Figure  2).^30,31

In a study from the New England Registry for Paget’s Disease,³² most patients knew fairly well which bones were affected and what complications resulted from this when deformity, fracture, or total joint replacement had occurred.³² Although Paget disease did affect their quality of life as measured by physical functioning on the Short Form-12 assessment, these impairments did not seem to affect their outlook, which was as good as or better than that in other people their age.

Metabolic complications

Metabolic complications of Paget disease are rare today but can occur in an elderly patient who has active, polyostotic (multibone) disease.³³ The accelerated rate of bone remodeling and the increased vascularity of pagetic bone have been reported to lead to high-output heart failure. In theory, treatment should ease this by diminishing blood flow to pagetic bone and restoring bone turnover to more normal levels.³⁴

Hypercalcemia can occur when patients with Paget disease are immobilized for any reason, and there is probably a higher incidence of renal stones in patients with Paget disease.^35,36

Malignant complications

Osteosarcoma rarely arises in pagetic bone. Yet Paget disease may account for a significant number of cases of this cancer in the elderly.³⁷ In these cases, osteosarcoma is presumed to be driven by a second genetic mutation, has a genetic signature distinct from that in osteosarcomas occurring in youth, and is quite resistant to treatment.³⁸ In Scandinavia and Japan, where Paget disease is rare, the second peak of osteosarcoma that occurs with aging seems muted as well.^39,40 These cancers present with pain, soft-tissue swelling, and variable elevations in serum alkaline phosphatase. Investigations to date suggest that pagetic lesions and osteosarcomas arising in pagetic bone are probably both driven to some extent by stromal cells overexpressing RANK ligand and may not represent defects intrinsic to the osteoclast.⁴¹

Giant-cell tumors of bone are also rare but can arise in pagetic bone. A cluster of cases was reported in Avellino and other towns of southern Italy.⁴² Again, the lesions occur in older individuals and in different sites than those seen in the benign giant-cell tumors recorded in patients without Paget disease.

Metastases from lymphomas, prostate cancer, and breast cancer certainly occur in bone, but rarely in pagetic sites.⁴³ A recent case study noted that patients with prostate cancer who also had Paget disease had a later onset of metastasis to bone than patients without coincident Paget disease.⁴⁴

A THOUGHTFUL ASSESSMENT

Evaluating a patient with Paget disease requires a thoughtful assessment of its musculoskeletal consequences in an aging skeleton. Pain in Paget disease is often multifactorial. In the elderly, end-stage degenerative disease of the spine, hip, and knees, mechanical instability, compression fractures of the spine, and neuropathies may compound the clinical picture. Therefore, a thorough evaluation is required to plan effective therapy.

Alkaline phosphatase and other markers

A screening serum alkaline phosphatase level is usually sufficient to measure bone turnover. Produced by osteoblasts, alkaline phosphatase is a marker of bone formation, but an imperfect one. Often it is elevated in active Paget disease—but not always.⁴⁵ Many patients have normal serum alkaline phosphatase levels, particularly if they have monostotic (single-bone) disease. It is unclear why, in a disorder marked by accelerated bone remodeling, the biochemical markers are inconsistent measures of bone turnover.

Research into biochemical markers of Paget disease has had two aims: to identify the single best marker for baseline assessment of pagetic bone activity and to find out whether this measurement responds to therapy.^46,47 Measures of bone formation such as bone-specific alkaline phosphatase, osteocalcin, and the procollagen type I peptides, and measures of bone resorption including the pyridinolines, hydroxyproline, and cross-linked collagens, have been analyzed as markers of bone remodeling and show no real advantage over the serum alkaline phosphatase level as reflections of bone turnover. As alkaline phosphatase measurement is inexpensive, available, and reliable, it should be used preferentially, with gamma-glutamyl transpeptidate or 5′ nucleotidase confirming the source as either liver or bone. Readers are directed to a recent review in which the utility of these markers is explored in more detail.⁴⁸

Imaging studies

Bone scans can give us an idea of the extent, location, and general activity of the disease (Figure 3). Uptake is avid in affected bones, beginning in the subchondral region and spreading throughout the bone. Bone scans can be particularly useful in defining sites of active disease when the serum alkaline phosphatase level is normal.

Plain radiography of the affected bones outlines the anatomy of the problem and gives some insight into the cause of pain (Figure 3).

Computed tomography or magnetic resonance imaging may prove useful in cases of spinal stenosis, cauda equina syndrome, compression fractures, or suspected malignancy (Figure  4), but these studies are expensive and generally are not needed.

Radiographic features. Paget disease is presumed to be a disease of the osteoclast, and the earliest lesion is described as lytic. In my own experience, it is unusual to see a purely lytic lesion, although sometimes the disease presents in the skull in this way—osteoporosis circumscripta—or in the femur or tibia with an advancing edge of pure osteolysis.

More often, one sees evidence of both resorption by osteoclasts and formation by osteoblasts, reflecting the coupling of these two processes in this disease. Radiographic findings on plain films are usually definitive, showing enlargement of the affected bone, deformity, coarsened trabeculae, and thickened cortices with tunneling (Figure 5).⁴⁹ In weightbearing bones, pseudofractures may stud the convex surface. These incongruities of bone may persist for years, heralding fracture only when there is focal pain (Figure 6).⁵⁰

Biopsy is infrequently needed

If these diagnostic findings are not present, then biopsy is indicated. In the United Sates and Canada, where Paget disease is fairly common, biopsy is infrequently needed and is usually reserved for situations in which the differential diagnosis includes cancer, as when the cortex cannot be clearly visualized, the lesions are atypical in pattern or location, or there is a single sclerotic vertebral body on imaging.⁵¹

The other indication for biopsy is a “new” pagetic lesion. For reasons unknown, the pattern of skeletal involvement in Paget disease tends to be stable throughout the patient’s lifetime. This is another reason why a baseline bone scan is useful.

TREATMENT WITH BISPHOSPHONATES

Treatment of Paget disease today relies for the most part on the new generation of nitrogen-containing bisphosphonates. As a class, these are antiresorptive agents that inhibit osteoclasts; in this way they slow bone remodeling and enhance the deposition of normal lamellar bone. Their clinical efficacy in Paget disease, coupled with the observation that the earliest lesion in Paget disease is lytic, underscores the principle that Paget disease is a disorder of the osteoclast.

Oral bisphosphonates

Etidronate, approved in 1977, was the first bisphosphonate licensed to treat Paget disease, and it remains available for this indication in the United States. Used in 6-month regimens, it lowers the serum alkaline phosphatase level in some patients, but it has a narrow therapeutic margin. Drug-induced osteomalacia and worsening lytic lesions and fractures in weight-bearing bones are some of the complications.⁵² When the nitrogen-containing bisphosphonates were developed, they proved to be more potent antiresorptive agents that pose less risk of mineralization defects at prescribed doses.

Alendronate, approved in 1995, is an oral nitrogen-containing bisphosphonate that is effective in treating Paget disease.⁵³ Alendronate is now available in the United States only through special programs (eg, the CVS ProCare Program); the paperwork required to secure this drug is onerous, so the drug is used infrequently. Studies in Paget disease showed that it normalizes the serum alkaline phosphatase level, improves the radiographic appearance, and eases pain in many patients.⁵⁴ The dosage is 40 mg daily for 6 months.

Risedronate, approved in 1998, is another oral nitrogen-containing bisphosphonate and is comparable to alendronate in efficacy.⁵⁵ The dosage is 30 mg daily for 2 months.

Tiludronate is another oral bisphosphonate with a different mechanism of action from the nitrogen-containing bisphosphonates.⁵⁶ It is safe, often effective, but less potent than the newer agents.

The oral bisphosphonates are well tolerated, with few side effects other than gastrointestinal distress. As a class, they are poorly absorbed and so must be taken fasting with a full glass of water on rising, after which the patient should remain upright without food or drink for 30 to 60 minutes. This is a nuisance for elderly patients already on multiple medications and thus makes intravenous agents appealing.

Intravenous bisphosphonates

Pamidronate was approved in 1994. It is quite effective in many patients with Paget disease. There is no consensus around the world on dosing, with regimens ranging from 30 mg to 90 mg or more intravenously in divided doses given over 2 to 4 hours from once a day to once a week. In the United States, 30 mg is given over 4 hours on 3 consecutive days. Resistance to pamidronate has been described; the mechanism is unknown.

Zoledronic acid is a nitrogen-containing bisphosphonate. It is given as a single infusion over 15 minutes, and re-treatment may not be necessary for years. A randomized clinical trial in 2005 demonstrated the efficacy of zoledronic acid 5 mg by infusion compared with oral risedronate in the treatment of Paget disease.⁵⁷ In observational extension studies lasting as long as 6.5 years, zoledronic acid has been shown to be superior to risedronate in terms of the proportion of patients experiencing a sustained clinical remission.⁵⁸

While there are many bisphosphonates on the market, an infusion of 5 mg of zoledronic acid seems optimal in most patients who do not have a contraindication or an aversion to intravenous therapy. It tends to normalize the serum alkaline phosphatase level quickly and to leave more patients in sustained biochemical remission than do older bisphosphonates, as noted above. It also tends to be more effective in normalizing the serum alkaline phosphatase level when a patient has used other bisphosphonates in the past or has become resistant to them.

Bisphosphonates reduce bone turnover but do not correct deformities

In randomized clinical trials, bisphosphonates have been shown to restore bone remodeling to more normal levels, to ease pain from pagetic bone, to lower the serum alkaline phosphatase level, and to heal radiographic lesions, but these drugs have not been proven to prevent progression of deformity or to restore the structural integrity of bone (Figure 6).

The Paget’s Disease: Randomized Trial of Intensive Versus Symptomatic Management (PRISM), in 1,324 people with Paget disease in the United Kingdom, showed no difference in the incidence of fracture, orthopedic surgery, quality of life, or hearing thresholds over 2 to 5 years in patients treated with bisphosphonates vs those treated symptomatically, despite a significant difference in serum alkaline phosphatase in the two groups (P < .001).⁵⁹

In the observational extension study of zoledronic acid described above,⁵⁸ three of four fractures occurred in the group treated with zoledronic acid, echoing the findings of the PRISM study.

Adverse effects of bisphosphonates

The more potent the bisphosphonate is as an antiresorptive agent, the more it suppresses normal bone remodeling, which can lead to osteonecrosis of the jaw and to atypical femoral fractures.^60,61 These complications are unusual in patients with Paget disease because the treatment is intermittent. Sometimes a single dose of zoledronic acid or one course of risedronate or alendronate will last for years.

All the nitrogen-containing bisphosphonates, particularly zoledronic acid, may provoke flulike symptoms of fever, arthralgias, and bone pain. This effect is self-limited, resolves in days, and does not tend to recur. Bone pain may be more sustained, but this also passes, and within weeks the antiresorptive process has abated and pagetic bone pain will ease. Atrial fibrillation is not an anticipated complication of treatment with a bisphosphonate.⁶² The risk of esophageal cancer is not confirmed at this time.⁶³ Other rare complications of the bisphosphonates include iritis, acute renal failure, and allergy.

Bisphosphonates are not approved for use in patients with creatinine clearance less than 30 mL/min, or in pregnancy.

Other treatments

Calcitonin, an older agent, can still be useful in easing the pain of Paget disease, healing bone lesions, and reducing the metabolic activity of pagetic bone in patients who cannot receive bisphosphonates. It is given by injection in doses of 50 to 100 IU daily or every other day. Although unlikely to effect a sustained clinical remission, calcitonin remains a safe, well-tolerated, and well-studied medication in Paget disease and is approved for this indication.^64,65

Denosumab has not been formally studied in Paget disease, but a recent case report indicated it was effective.⁶⁶

A conservative strategy

Guidelines for treating Paget disease have been written at various times in many countries, including Italy (2007),⁶⁷ the United Kingdom (2004),⁶⁸ Japan (2006),⁶⁹ and Canada (2007).⁷⁰ Recommendations differ, in part because it is hard to ascertain whether long-term outcomes are improved by treatment, and in part because the prevalence of Paget disease is decreasing and its severity is lessening.^11,12 Some guidelines are outdated, since they do not include the newer bisphosphonates.

If the natural history of untreated Paget disease involves the gradual evolution over more than 20 years of bowing deformities in the lower limbs, rigidity and overgrowth of the spine, and softening and enlargement of the skull, as described by Sir James Paget, then treatment should be initiated in hopes that it will modify the outcome. We have no lens to better focus this question on the effect of treatment on the natural history of the disease. We have the PRISM study, designed before zoledronic acid was approved and only 2 to 5 years in duration. And we have the epidemiologic data demonstrating that most patients have no symptoms during their lifetime.

We see the crippling bone disease described by Sir James Paget so infrequently today in the United States that we forget the profound morbidity that may attend the skeletal changes of Paget disease that were common in the early 20th century. Once the bones of the skull are overgrown, the limbs are bowed, and the degenerative joint disease is present, no medication can reverse these changes. Then, the integrity of the bone is lost, and the vulnerability to fracture, early osteoarthritis, nerve compression syndromes, and hearing loss persist. Understanding these consequences prompts the recommendation of early treatment in patients with Paget disease, in hopes of mitigating disease progression.

Patients with active Paget disease, documented either by an elevated serum alkaline phosphatase or by a bone scan, should be treated with a bisphosphonate if the disease is found in sites where remodeling of bone may lead to complications. Such sites include the skull, spine, and long bones of the lower extremity. Paget disease of bone in the pelvis tends to give little trouble (Figure 2) unless it is proximal to a joint, when pain and early arthritis may result. Treatment is safe and, I think, prudent to undertake in any person over age 55 with active disease. To prevent hypocalcemia during treatment, all patients should be repleted with vitamin D and maintained on calcium 1,200 mg daily through diet or supplements with meals.

Throughout the evaluation and treatment, it is important to remember that pain may not emanate from pagetic bone. If medication for Paget disease proves ineffective in the first few months, analgesics, bracing, walking aids, and operative management⁷¹ are adjunctive therapies to improve the functional status of these patients.

It is a remarkable clinical observation that treatment of Paget disease may rapidly reverse neurologic syndromes, resolve the erythema or warmth overlying active pagetic bone, and diminish the risk of bleeding with surgery. This response to therapy suggests that there is prompt inhibition and apoptosis of the osteoclasts, accompanied by diminished vascularity of bone. Whatever the mechanism, it is worth treating patients who have spinal stenosis, arthritis, and nerve compression syndromes with calcitonin or bisphosphonates before surgical intervention, whenever possible.^34,72

Paget disease of bone is a focal disorder of the aging skeleton that can be asymptomatic or can present with pain, bowing deformities, fractures, or nonspecific rheumatic complaints. Physicians often discover it in asymptomatic patients when serum alkaline phosphatase levels are elevated or as an incidental finding on radiography. Despite evidence of germline mutations and polymorphisms that predispose to Paget disease, the environmental determinants that permit disease expression in older people remain unknown.

A STRIKING GEOGRAPHIC DISTRIBUTION

Researchers have been studying the determinants and distribution of Paget disease ever since Sir James Paget first described it in 1877.¹

Paget disease has a predilection for the axial skeleton, particularly the lumbosacral spine and pelvis, as well as the skull, femur, and tibia.² Knowing this, investigators have used screening plain films of the abdomen (kidney-ureter-bladder views) to estimate its prevalence in different populations, as these images capture the lumbosacral spine, pelvis, and proximal femurs. Other means of assessing prevalence have included autopsy series, questionnaires, and screens for biochemical markers of bone turnover, such as elevated serum alkaline phosphatase from bone.^3–6

Using these methods, Paget disease has been estimated to occur in 1% to 3% of people over age 55, and in as many as 8% of people over age 80 in certain countries.⁷

This disease has a striking geographic distribution, being frequent in Europe, Canada, the United States, Australia, New Zealand, and cities of South America, but rare in Scandinavia and Japan. It seems to be equally rare in other countries of the Far East and in India, Russia, and Africa, although its prevalence in these areas has not been thoroughly investigated.⁸

That it is an ancient disease has been corroborated by excavations in churchyards in Great Britain.^9,10 It may be familial or sporadic, but its expression is delayed until late middle age in most persons, and it does not occur in children. For reasons unclear, the prevalence seems to be decreasing in many countries.^11–13

GENETICS IS NOT THE WHOLE STORY

The variable prevalence of Paget disease in different geographic regions and its sometimes-familial expression suggest a genetic predisposition, environmental factor, or both.

Mutations in SQSTM1

In 2002, scientists investigating a cohort of French Canadian families found a mutation in the SQSTM1 gene that was present in almost 50% of people with familial Paget disease and in 16% of those with sporadic Paget disease.¹⁴ Hocking and his colleagues in the United Kingdom subsequently found the same mutation in 19% of cases of familial Paget disease and in 9% of sporadic cases.¹⁵

Further, investigators noted that the mutation was often present on a conserved haplotype, consistent with a stable genetic change occurring in the affected population.¹⁶ This observation of a “founder effect” dovetailed with the epidemiology of Paget disease,¹⁷ but only with this SQSTM1 mutation.

Throughout Europe, Australia, and the United States, comparable rates of the SQSTM1 mutation were reported in or around the ubiquitin-associated domain. Several specific mutations exist, the most common one being P392L, ie, a prolineto-leucine substitution at amino acid 392. Scientists have tried to correlate severity of disease with genotype, but the findings have been inconsistent.^18–21

Investigations into the mechanism of disease have pointed to the role of p62, the product of SQSTM1, in signaling osteoclast activation via nuclear factor kappa B. Since this initial discovery, polymorphisms in the genes affecting osteoclast maturation, activation, and fusion pathways have been shown to predispose to Paget disease. Examples:

• TNFRSF11A, which codes for receptor activator of nuclear factor kappa B, or RANK
• TNFRSF11B, which codes for osteoprotegerin, or OPG
• CSF1, which codes for macrophage colony-stimulating factor 1, and
• OPTN, which codes for optineurin, a member of the nuclear factor kappa B-modulating protein family.

Clinicians interested in these details can read an excellent review of the pathogenesis of Paget disease.²²

Other possible factors

Although there is good evidence that measles and canine distemper virus can infect osteoclasts and modify their phenotype, there is no good evidence that these infections by themselves cause Paget disease.^23–25 It is, however, tempting to think of these RNA paramyxoviruses as precipitating factors; conceivably, an infectious agent might seed the ends of long bones, accounting for the fixed distribution of Paget disease and its late expression.

Epidemiologic studies from around the world have failed to identify conclusively any environmental exposure that predisposes to Paget disease, although a rural setting, trauma, infection, and milk ingestion have all been proposed.^26–28 It is also possible that as bone ages and the marrow becomes less cellular and more fatty, these changes may permit the disease to develop.

The greatest risk factor for Paget disease is perhaps aging, followed by ancestry and a known family history of it. That genetics is not the whole story is evident by reports of people with SQSTM1 mutations who show no clinical evidence of Paget disease in their old age, and patients with Paget disease who have no SQSTM1 mutation.^20,29

CLINICAL PRESENTATION

Most patients with Paget disease have no symptoms and come to medical attention because of an elevated serum alkaline phosphatase level or characteristic findings on radiographs ordered for other indications.¹¹ Paget disease is the second most common disorder of aging bone after osteoporosis. Yet unlike osteoporosis, which presents as a systemic fragility of bone, the clinical manifestations of Paget disease depend on which bones are affected and how enlarged or misshapen they have become.

Common complications

As a consequence of this abnormal bone remodeling and overgrowth, many patients present with bone pain. Bone deformity, headache, and hearing loss may also occur (Figure 1), as well as fractures and nerve compression syndromes (eg, spinal stenosis, sciatica, cauda equina syndrome).

It is important to remember that “pagetic” bone may not be the source of pain, and that functional impairment caused by degenerative changes at affected sites is common (Figure  2).^30,31

In a study from the New England Registry for Paget’s Disease,³² most patients knew fairly well which bones were affected and what complications resulted from this when deformity, fracture, or total joint replacement had occurred.³² Although Paget disease did affect their quality of life as measured by physical functioning on the Short Form-12 assessment, these impairments did not seem to affect their outlook, which was as good as or better than that in other people their age.

Metabolic complications

Metabolic complications of Paget disease are rare today but can occur in an elderly patient who has active, polyostotic (multibone) disease.³³ The accelerated rate of bone remodeling and the increased vascularity of pagetic bone have been reported to lead to high-output heart failure. In theory, treatment should ease this by diminishing blood flow to pagetic bone and restoring bone turnover to more normal levels.³⁴

Hypercalcemia can occur when patients with Paget disease are immobilized for any reason, and there is probably a higher incidence of renal stones in patients with Paget disease.^35,36

Malignant complications

Osteosarcoma rarely arises in pagetic bone. Yet Paget disease may account for a significant number of cases of this cancer in the elderly.³⁷ In these cases, osteosarcoma is presumed to be driven by a second genetic mutation, has a genetic signature distinct from that in osteosarcomas occurring in youth, and is quite resistant to treatment.³⁸ In Scandinavia and Japan, where Paget disease is rare, the second peak of osteosarcoma that occurs with aging seems muted as well.^39,40 These cancers present with pain, soft-tissue swelling, and variable elevations in serum alkaline phosphatase. Investigations to date suggest that pagetic lesions and osteosarcomas arising in pagetic bone are probably both driven to some extent by stromal cells overexpressing RANK ligand and may not represent defects intrinsic to the osteoclast.⁴¹

Giant-cell tumors of bone are also rare but can arise in pagetic bone. A cluster of cases was reported in Avellino and other towns of southern Italy.⁴² Again, the lesions occur in older individuals and in different sites than those seen in the benign giant-cell tumors recorded in patients without Paget disease.

Metastases from lymphomas, prostate cancer, and breast cancer certainly occur in bone, but rarely in pagetic sites.⁴³ A recent case study noted that patients with prostate cancer who also had Paget disease had a later onset of metastasis to bone than patients without coincident Paget disease.⁴⁴

A THOUGHTFUL ASSESSMENT

Evaluating a patient with Paget disease requires a thoughtful assessment of its musculoskeletal consequences in an aging skeleton. Pain in Paget disease is often multifactorial. In the elderly, end-stage degenerative disease of the spine, hip, and knees, mechanical instability, compression fractures of the spine, and neuropathies may compound the clinical picture. Therefore, a thorough evaluation is required to plan effective therapy.

Alkaline phosphatase and other markers

A screening serum alkaline phosphatase level is usually sufficient to measure bone turnover. Produced by osteoblasts, alkaline phosphatase is a marker of bone formation, but an imperfect one. Often it is elevated in active Paget disease—but not always.⁴⁵ Many patients have normal serum alkaline phosphatase levels, particularly if they have monostotic (single-bone) disease. It is unclear why, in a disorder marked by accelerated bone remodeling, the biochemical markers are inconsistent measures of bone turnover.

Research into biochemical markers of Paget disease has had two aims: to identify the single best marker for baseline assessment of pagetic bone activity and to find out whether this measurement responds to therapy.^46,47 Measures of bone formation such as bone-specific alkaline phosphatase, osteocalcin, and the procollagen type I peptides, and measures of bone resorption including the pyridinolines, hydroxyproline, and cross-linked collagens, have been analyzed as markers of bone remodeling and show no real advantage over the serum alkaline phosphatase level as reflections of bone turnover. As alkaline phosphatase measurement is inexpensive, available, and reliable, it should be used preferentially, with gamma-glutamyl transpeptidate or 5′ nucleotidase confirming the source as either liver or bone. Readers are directed to a recent review in which the utility of these markers is explored in more detail.⁴⁸

Imaging studies

Bone scans can give us an idea of the extent, location, and general activity of the disease (Figure 3). Uptake is avid in affected bones, beginning in the subchondral region and spreading throughout the bone. Bone scans can be particularly useful in defining sites of active disease when the serum alkaline phosphatase level is normal.

Plain radiography of the affected bones outlines the anatomy of the problem and gives some insight into the cause of pain (Figure 3).

Computed tomography or magnetic resonance imaging may prove useful in cases of spinal stenosis, cauda equina syndrome, compression fractures, or suspected malignancy (Figure  4), but these studies are expensive and generally are not needed.

Radiographic features. Paget disease is presumed to be a disease of the osteoclast, and the earliest lesion is described as lytic. In my own experience, it is unusual to see a purely lytic lesion, although sometimes the disease presents in the skull in this way—osteoporosis circumscripta—or in the femur or tibia with an advancing edge of pure osteolysis.

More often, one sees evidence of both resorption by osteoclasts and formation by osteoblasts, reflecting the coupling of these two processes in this disease. Radiographic findings on plain films are usually definitive, showing enlargement of the affected bone, deformity, coarsened trabeculae, and thickened cortices with tunneling (Figure 5).⁴⁹ In weightbearing bones, pseudofractures may stud the convex surface. These incongruities of bone may persist for years, heralding fracture only when there is focal pain (Figure 6).⁵⁰

Biopsy is infrequently needed

If these diagnostic findings are not present, then biopsy is indicated. In the United Sates and Canada, where Paget disease is fairly common, biopsy is infrequently needed and is usually reserved for situations in which the differential diagnosis includes cancer, as when the cortex cannot be clearly visualized, the lesions are atypical in pattern or location, or there is a single sclerotic vertebral body on imaging.⁵¹

The other indication for biopsy is a “new” pagetic lesion. For reasons unknown, the pattern of skeletal involvement in Paget disease tends to be stable throughout the patient’s lifetime. This is another reason why a baseline bone scan is useful.

TREATMENT WITH BISPHOSPHONATES

Treatment of Paget disease today relies for the most part on the new generation of nitrogen-containing bisphosphonates. As a class, these are antiresorptive agents that inhibit osteoclasts; in this way they slow bone remodeling and enhance the deposition of normal lamellar bone. Their clinical efficacy in Paget disease, coupled with the observation that the earliest lesion in Paget disease is lytic, underscores the principle that Paget disease is a disorder of the osteoclast.

Oral bisphosphonates

Etidronate, approved in 1977, was the first bisphosphonate licensed to treat Paget disease, and it remains available for this indication in the United States. Used in 6-month regimens, it lowers the serum alkaline phosphatase level in some patients, but it has a narrow therapeutic margin. Drug-induced osteomalacia and worsening lytic lesions and fractures in weight-bearing bones are some of the complications.⁵² When the nitrogen-containing bisphosphonates were developed, they proved to be more potent antiresorptive agents that pose less risk of mineralization defects at prescribed doses.

Alendronate, approved in 1995, is an oral nitrogen-containing bisphosphonate that is effective in treating Paget disease.⁵³ Alendronate is now available in the United States only through special programs (eg, the CVS ProCare Program); the paperwork required to secure this drug is onerous, so the drug is used infrequently. Studies in Paget disease showed that it normalizes the serum alkaline phosphatase level, improves the radiographic appearance, and eases pain in many patients.⁵⁴ The dosage is 40 mg daily for 6 months.

Risedronate, approved in 1998, is another oral nitrogen-containing bisphosphonate and is comparable to alendronate in efficacy.⁵⁵ The dosage is 30 mg daily for 2 months.

Tiludronate is another oral bisphosphonate with a different mechanism of action from the nitrogen-containing bisphosphonates.⁵⁶ It is safe, often effective, but less potent than the newer agents.

The oral bisphosphonates are well tolerated, with few side effects other than gastrointestinal distress. As a class, they are poorly absorbed and so must be taken fasting with a full glass of water on rising, after which the patient should remain upright without food or drink for 30 to 60 minutes. This is a nuisance for elderly patients already on multiple medications and thus makes intravenous agents appealing.

Intravenous bisphosphonates

Pamidronate was approved in 1994. It is quite effective in many patients with Paget disease. There is no consensus around the world on dosing, with regimens ranging from 30 mg to 90 mg or more intravenously in divided doses given over 2 to 4 hours from once a day to once a week. In the United States, 30 mg is given over 4 hours on 3 consecutive days. Resistance to pamidronate has been described; the mechanism is unknown.

Zoledronic acid is a nitrogen-containing bisphosphonate. It is given as a single infusion over 15 minutes, and re-treatment may not be necessary for years. A randomized clinical trial in 2005 demonstrated the efficacy of zoledronic acid 5 mg by infusion compared with oral risedronate in the treatment of Paget disease.⁵⁷ In observational extension studies lasting as long as 6.5 years, zoledronic acid has been shown to be superior to risedronate in terms of the proportion of patients experiencing a sustained clinical remission.⁵⁸

While there are many bisphosphonates on the market, an infusion of 5 mg of zoledronic acid seems optimal in most patients who do not have a contraindication or an aversion to intravenous therapy. It tends to normalize the serum alkaline phosphatase level quickly and to leave more patients in sustained biochemical remission than do older bisphosphonates, as noted above. It also tends to be more effective in normalizing the serum alkaline phosphatase level when a patient has used other bisphosphonates in the past or has become resistant to them.

Bisphosphonates reduce bone turnover but do not correct deformities

In randomized clinical trials, bisphosphonates have been shown to restore bone remodeling to more normal levels, to ease pain from pagetic bone, to lower the serum alkaline phosphatase level, and to heal radiographic lesions, but these drugs have not been proven to prevent progression of deformity or to restore the structural integrity of bone (Figure 6).

The Paget’s Disease: Randomized Trial of Intensive Versus Symptomatic Management (PRISM), in 1,324 people with Paget disease in the United Kingdom, showed no difference in the incidence of fracture, orthopedic surgery, quality of life, or hearing thresholds over 2 to 5 years in patients treated with bisphosphonates vs those treated symptomatically, despite a significant difference in serum alkaline phosphatase in the two groups (P < .001).⁵⁹

In the observational extension study of zoledronic acid described above,⁵⁸ three of four fractures occurred in the group treated with zoledronic acid, echoing the findings of the PRISM study.

Adverse effects of bisphosphonates

The more potent the bisphosphonate is as an antiresorptive agent, the more it suppresses normal bone remodeling, which can lead to osteonecrosis of the jaw and to atypical femoral fractures.^60,61 These complications are unusual in patients with Paget disease because the treatment is intermittent. Sometimes a single dose of zoledronic acid or one course of risedronate or alendronate will last for years.

All the nitrogen-containing bisphosphonates, particularly zoledronic acid, may provoke flulike symptoms of fever, arthralgias, and bone pain. This effect is self-limited, resolves in days, and does not tend to recur. Bone pain may be more sustained, but this also passes, and within weeks the antiresorptive process has abated and pagetic bone pain will ease. Atrial fibrillation is not an anticipated complication of treatment with a bisphosphonate.⁶² The risk of esophageal cancer is not confirmed at this time.⁶³ Other rare complications of the bisphosphonates include iritis, acute renal failure, and allergy.

Bisphosphonates are not approved for use in patients with creatinine clearance less than 30 mL/min, or in pregnancy.

Other treatments

Calcitonin, an older agent, can still be useful in easing the pain of Paget disease, healing bone lesions, and reducing the metabolic activity of pagetic bone in patients who cannot receive bisphosphonates. It is given by injection in doses of 50 to 100 IU daily or every other day. Although unlikely to effect a sustained clinical remission, calcitonin remains a safe, well-tolerated, and well-studied medication in Paget disease and is approved for this indication.^64,65

Denosumab has not been formally studied in Paget disease, but a recent case report indicated it was effective.⁶⁶

A conservative strategy

Guidelines for treating Paget disease have been written at various times in many countries, including Italy (2007),⁶⁷ the United Kingdom (2004),⁶⁸ Japan (2006),⁶⁹ and Canada (2007).⁷⁰ Recommendations differ, in part because it is hard to ascertain whether long-term outcomes are improved by treatment, and in part because the prevalence of Paget disease is decreasing and its severity is lessening.^11,12 Some guidelines are outdated, since they do not include the newer bisphosphonates.

If the natural history of untreated Paget disease involves the gradual evolution over more than 20 years of bowing deformities in the lower limbs, rigidity and overgrowth of the spine, and softening and enlargement of the skull, as described by Sir James Paget, then treatment should be initiated in hopes that it will modify the outcome. We have no lens to better focus this question on the effect of treatment on the natural history of the disease. We have the PRISM study, designed before zoledronic acid was approved and only 2 to 5 years in duration. And we have the epidemiologic data demonstrating that most patients have no symptoms during their lifetime.

We see the crippling bone disease described by Sir James Paget so infrequently today in the United States that we forget the profound morbidity that may attend the skeletal changes of Paget disease that were common in the early 20th century. Once the bones of the skull are overgrown, the limbs are bowed, and the degenerative joint disease is present, no medication can reverse these changes. Then, the integrity of the bone is lost, and the vulnerability to fracture, early osteoarthritis, nerve compression syndromes, and hearing loss persist. Understanding these consequences prompts the recommendation of early treatment in patients with Paget disease, in hopes of mitigating disease progression.

Patients with active Paget disease, documented either by an elevated serum alkaline phosphatase or by a bone scan, should be treated with a bisphosphonate if the disease is found in sites where remodeling of bone may lead to complications. Such sites include the skull, spine, and long bones of the lower extremity. Paget disease of bone in the pelvis tends to give little trouble (Figure 2) unless it is proximal to a joint, when pain and early arthritis may result. Treatment is safe and, I think, prudent to undertake in any person over age 55 with active disease. To prevent hypocalcemia during treatment, all patients should be repleted with vitamin D and maintained on calcium 1,200 mg daily through diet or supplements with meals.

Throughout the evaluation and treatment, it is important to remember that pain may not emanate from pagetic bone. If medication for Paget disease proves ineffective in the first few months, analgesics, bracing, walking aids, and operative management⁷¹ are adjunctive therapies to improve the functional status of these patients.

It is a remarkable clinical observation that treatment of Paget disease may rapidly reverse neurologic syndromes, resolve the erythema or warmth overlying active pagetic bone, and diminish the risk of bleeding with surgery. This response to therapy suggests that there is prompt inhibition and apoptosis of the osteoclasts, accompanied by diminished vascularity of bone. Whatever the mechanism, it is worth treating patients who have spinal stenosis, arthritis, and nerve compression syndromes with calcitonin or bisphosphonates before surgical intervention, whenever possible.^34,72

Paget disease of bone is a focal disorder of the aging skeleton that can be asymptomatic or can present with pain, bowing deformities, fractures, or nonspecific rheumatic complaints. Physicians often discover it in asymptomatic patients when serum alkaline phosphatase levels are elevated or as an incidental finding on radiography. Despite evidence of germline mutations and polymorphisms that predispose to Paget disease, the environmental determinants that permit disease expression in older people remain unknown.

A STRIKING GEOGRAPHIC DISTRIBUTION

Researchers have been studying the determinants and distribution of Paget disease ever since Sir James Paget first described it in 1877.¹

Paget disease has a predilection for the axial skeleton, particularly the lumbosacral spine and pelvis, as well as the skull, femur, and tibia.² Knowing this, investigators have used screening plain films of the abdomen (kidney-ureter-bladder views) to estimate its prevalence in different populations, as these images capture the lumbosacral spine, pelvis, and proximal femurs. Other means of assessing prevalence have included autopsy series, questionnaires, and screens for biochemical markers of bone turnover, such as elevated serum alkaline phosphatase from bone.^3–6

Using these methods, Paget disease has been estimated to occur in 1% to 3% of people over age 55, and in as many as 8% of people over age 80 in certain countries.⁷

This disease has a striking geographic distribution, being frequent in Europe, Canada, the United States, Australia, New Zealand, and cities of South America, but rare in Scandinavia and Japan. It seems to be equally rare in other countries of the Far East and in India, Russia, and Africa, although its prevalence in these areas has not been thoroughly investigated.⁸

That it is an ancient disease has been corroborated by excavations in churchyards in Great Britain.^9,10 It may be familial or sporadic, but its expression is delayed until late middle age in most persons, and it does not occur in children. For reasons unclear, the prevalence seems to be decreasing in many countries.^11–13

GENETICS IS NOT THE WHOLE STORY

The variable prevalence of Paget disease in different geographic regions and its sometimes-familial expression suggest a genetic predisposition, environmental factor, or both.

Mutations in SQSTM1

In 2002, scientists investigating a cohort of French Canadian families found a mutation in the SQSTM1 gene that was present in almost 50% of people with familial Paget disease and in 16% of those with sporadic Paget disease.¹⁴ Hocking and his colleagues in the United Kingdom subsequently found the same mutation in 19% of cases of familial Paget disease and in 9% of sporadic cases.¹⁵

Further, investigators noted that the mutation was often present on a conserved haplotype, consistent with a stable genetic change occurring in the affected population.¹⁶ This observation of a “founder effect” dovetailed with the epidemiology of Paget disease,¹⁷ but only with this SQSTM1 mutation.

Throughout Europe, Australia, and the United States, comparable rates of the SQSTM1 mutation were reported in or around the ubiquitin-associated domain. Several specific mutations exist, the most common one being P392L, ie, a prolineto-leucine substitution at amino acid 392. Scientists have tried to correlate severity of disease with genotype, but the findings have been inconsistent.^18–21

Investigations into the mechanism of disease have pointed to the role of p62, the product of SQSTM1, in signaling osteoclast activation via nuclear factor kappa B. Since this initial discovery, polymorphisms in the genes affecting osteoclast maturation, activation, and fusion pathways have been shown to predispose to Paget disease. Examples:

• TNFRSF11A, which codes for receptor activator of nuclear factor kappa B, or RANK
• TNFRSF11B, which codes for osteoprotegerin, or OPG
• CSF1, which codes for macrophage colony-stimulating factor 1, and
• OPTN, which codes for optineurin, a member of the nuclear factor kappa B-modulating protein family.

Clinicians interested in these details can read an excellent review of the pathogenesis of Paget disease.²²

Other possible factors

Although there is good evidence that measles and canine distemper virus can infect osteoclasts and modify their phenotype, there is no good evidence that these infections by themselves cause Paget disease.^23–25 It is, however, tempting to think of these RNA paramyxoviruses as precipitating factors; conceivably, an infectious agent might seed the ends of long bones, accounting for the fixed distribution of Paget disease and its late expression.

Epidemiologic studies from around the world have failed to identify conclusively any environmental exposure that predisposes to Paget disease, although a rural setting, trauma, infection, and milk ingestion have all been proposed.^26–28 It is also possible that as bone ages and the marrow becomes less cellular and more fatty, these changes may permit the disease to develop.

The greatest risk factor for Paget disease is perhaps aging, followed by ancestry and a known family history of it. That genetics is not the whole story is evident by reports of people with SQSTM1 mutations who show no clinical evidence of Paget disease in their old age, and patients with Paget disease who have no SQSTM1 mutation.^20,29

CLINICAL PRESENTATION

Most patients with Paget disease have no symptoms and come to medical attention because of an elevated serum alkaline phosphatase level or characteristic findings on radiographs ordered for other indications.¹¹ Paget disease is the second most common disorder of aging bone after osteoporosis. Yet unlike osteoporosis, which presents as a systemic fragility of bone, the clinical manifestations of Paget disease depend on which bones are affected and how enlarged or misshapen they have become.

Common complications

As a consequence of this abnormal bone remodeling and overgrowth, many patients present with bone pain. Bone deformity, headache, and hearing loss may also occur (Figure 1), as well as fractures and nerve compression syndromes (eg, spinal stenosis, sciatica, cauda equina syndrome).

It is important to remember that “pagetic” bone may not be the source of pain, and that functional impairment caused by degenerative changes at affected sites is common (Figure  2).^30,31

In a study from the New England Registry for Paget’s Disease,³² most patients knew fairly well which bones were affected and what complications resulted from this when deformity, fracture, or total joint replacement had occurred.³² Although Paget disease did affect their quality of life as measured by physical functioning on the Short Form-12 assessment, these impairments did not seem to affect their outlook, which was as good as or better than that in other people their age.

Metabolic complications

Metabolic complications of Paget disease are rare today but can occur in an elderly patient who has active, polyostotic (multibone) disease.³³ The accelerated rate of bone remodeling and the increased vascularity of pagetic bone have been reported to lead to high-output heart failure. In theory, treatment should ease this by diminishing blood flow to pagetic bone and restoring bone turnover to more normal levels.³⁴

Hypercalcemia can occur when patients with Paget disease are immobilized for any reason, and there is probably a higher incidence of renal stones in patients with Paget disease.^35,36

Malignant complications

Osteosarcoma rarely arises in pagetic bone. Yet Paget disease may account for a significant number of cases of this cancer in the elderly.³⁷ In these cases, osteosarcoma is presumed to be driven by a second genetic mutation, has a genetic signature distinct from that in osteosarcomas occurring in youth, and is quite resistant to treatment.³⁸ In Scandinavia and Japan, where Paget disease is rare, the second peak of osteosarcoma that occurs with aging seems muted as well.^39,40 These cancers present with pain, soft-tissue swelling, and variable elevations in serum alkaline phosphatase. Investigations to date suggest that pagetic lesions and osteosarcomas arising in pagetic bone are probably both driven to some extent by stromal cells overexpressing RANK ligand and may not represent defects intrinsic to the osteoclast.⁴¹

Giant-cell tumors of bone are also rare but can arise in pagetic bone. A cluster of cases was reported in Avellino and other towns of southern Italy.⁴² Again, the lesions occur in older individuals and in different sites than those seen in the benign giant-cell tumors recorded in patients without Paget disease.

Metastases from lymphomas, prostate cancer, and breast cancer certainly occur in bone, but rarely in pagetic sites.⁴³ A recent case study noted that patients with prostate cancer who also had Paget disease had a later onset of metastasis to bone than patients without coincident Paget disease.⁴⁴

A THOUGHTFUL ASSESSMENT

Evaluating a patient with Paget disease requires a thoughtful assessment of its musculoskeletal consequences in an aging skeleton. Pain in Paget disease is often multifactorial. In the elderly, end-stage degenerative disease of the spine, hip, and knees, mechanical instability, compression fractures of the spine, and neuropathies may compound the clinical picture. Therefore, a thorough evaluation is required to plan effective therapy.

Alkaline phosphatase and other markers

A screening serum alkaline phosphatase level is usually sufficient to measure bone turnover. Produced by osteoblasts, alkaline phosphatase is a marker of bone formation, but an imperfect one. Often it is elevated in active Paget disease—but not always.⁴⁵ Many patients have normal serum alkaline phosphatase levels, particularly if they have monostotic (single-bone) disease. It is unclear why, in a disorder marked by accelerated bone remodeling, the biochemical markers are inconsistent measures of bone turnover.

Research into biochemical markers of Paget disease has had two aims: to identify the single best marker for baseline assessment of pagetic bone activity and to find out whether this measurement responds to therapy.^46,47 Measures of bone formation such as bone-specific alkaline phosphatase, osteocalcin, and the procollagen type I peptides, and measures of bone resorption including the pyridinolines, hydroxyproline, and cross-linked collagens, have been analyzed as markers of bone remodeling and show no real advantage over the serum alkaline phosphatase level as reflections of bone turnover. As alkaline phosphatase measurement is inexpensive, available, and reliable, it should be used preferentially, with gamma-glutamyl transpeptidate or 5′ nucleotidase confirming the source as either liver or bone. Readers are directed to a recent review in which the utility of these markers is explored in more detail.⁴⁸

Imaging studies

Bone scans can give us an idea of the extent, location, and general activity of the disease (Figure 3). Uptake is avid in affected bones, beginning in the subchondral region and spreading throughout the bone. Bone scans can be particularly useful in defining sites of active disease when the serum alkaline phosphatase level is normal.

Plain radiography of the affected bones outlines the anatomy of the problem and gives some insight into the cause of pain (Figure 3).

Computed tomography or magnetic resonance imaging may prove useful in cases of spinal stenosis, cauda equina syndrome, compression fractures, or suspected malignancy (Figure  4), but these studies are expensive and generally are not needed.

Radiographic features. Paget disease is presumed to be a disease of the osteoclast, and the earliest lesion is described as lytic. In my own experience, it is unusual to see a purely lytic lesion, although sometimes the disease presents in the skull in this way—osteoporosis circumscripta—or in the femur or tibia with an advancing edge of pure osteolysis.

More often, one sees evidence of both resorption by osteoclasts and formation by osteoblasts, reflecting the coupling of these two processes in this disease. Radiographic findings on plain films are usually definitive, showing enlargement of the affected bone, deformity, coarsened trabeculae, and thickened cortices with tunneling (Figure 5).⁴⁹ In weightbearing bones, pseudofractures may stud the convex surface. These incongruities of bone may persist for years, heralding fracture only when there is focal pain (Figure 6).⁵⁰

Biopsy is infrequently needed

If these diagnostic findings are not present, then biopsy is indicated. In the United Sates and Canada, where Paget disease is fairly common, biopsy is infrequently needed and is usually reserved for situations in which the differential diagnosis includes cancer, as when the cortex cannot be clearly visualized, the lesions are atypical in pattern or location, or there is a single sclerotic vertebral body on imaging.⁵¹

The other indication for biopsy is a “new” pagetic lesion. For reasons unknown, the pattern of skeletal involvement in Paget disease tends to be stable throughout the patient’s lifetime. This is another reason why a baseline bone scan is useful.

TREATMENT WITH BISPHOSPHONATES

Treatment of Paget disease today relies for the most part on the new generation of nitrogen-containing bisphosphonates. As a class, these are antiresorptive agents that inhibit osteoclasts; in this way they slow bone remodeling and enhance the deposition of normal lamellar bone. Their clinical efficacy in Paget disease, coupled with the observation that the earliest lesion in Paget disease is lytic, underscores the principle that Paget disease is a disorder of the osteoclast.

Oral bisphosphonates

Etidronate, approved in 1977, was the first bisphosphonate licensed to treat Paget disease, and it remains available for this indication in the United States. Used in 6-month regimens, it lowers the serum alkaline phosphatase level in some patients, but it has a narrow therapeutic margin. Drug-induced osteomalacia and worsening lytic lesions and fractures in weight-bearing bones are some of the complications.⁵² When the nitrogen-containing bisphosphonates were developed, they proved to be more potent antiresorptive agents that pose less risk of mineralization defects at prescribed doses.

Alendronate, approved in 1995, is an oral nitrogen-containing bisphosphonate that is effective in treating Paget disease.⁵³ Alendronate is now available in the United States only through special programs (eg, the CVS ProCare Program); the paperwork required to secure this drug is onerous, so the drug is used infrequently. Studies in Paget disease showed that it normalizes the serum alkaline phosphatase level, improves the radiographic appearance, and eases pain in many patients.⁵⁴ The dosage is 40 mg daily for 6 months.

Risedronate, approved in 1998, is another oral nitrogen-containing bisphosphonate and is comparable to alendronate in efficacy.⁵⁵ The dosage is 30 mg daily for 2 months.

Tiludronate is another oral bisphosphonate with a different mechanism of action from the nitrogen-containing bisphosphonates.⁵⁶ It is safe, often effective, but less potent than the newer agents.

The oral bisphosphonates are well tolerated, with few side effects other than gastrointestinal distress. As a class, they are poorly absorbed and so must be taken fasting with a full glass of water on rising, after which the patient should remain upright without food or drink for 30 to 60 minutes. This is a nuisance for elderly patients already on multiple medications and thus makes intravenous agents appealing.

Intravenous bisphosphonates

Pamidronate was approved in 1994. It is quite effective in many patients with Paget disease. There is no consensus around the world on dosing, with regimens ranging from 30 mg to 90 mg or more intravenously in divided doses given over 2 to 4 hours from once a day to once a week. In the United States, 30 mg is given over 4 hours on 3 consecutive days. Resistance to pamidronate has been described; the mechanism is unknown.

Zoledronic acid is a nitrogen-containing bisphosphonate. It is given as a single infusion over 15 minutes, and re-treatment may not be necessary for years. A randomized clinical trial in 2005 demonstrated the efficacy of zoledronic acid 5 mg by infusion compared with oral risedronate in the treatment of Paget disease.⁵⁷ In observational extension studies lasting as long as 6.5 years, zoledronic acid has been shown to be superior to risedronate in terms of the proportion of patients experiencing a sustained clinical remission.⁵⁸

While there are many bisphosphonates on the market, an infusion of 5 mg of zoledronic acid seems optimal in most patients who do not have a contraindication or an aversion to intravenous therapy. It tends to normalize the serum alkaline phosphatase level quickly and to leave more patients in sustained biochemical remission than do older bisphosphonates, as noted above. It also tends to be more effective in normalizing the serum alkaline phosphatase level when a patient has used other bisphosphonates in the past or has become resistant to them.

Bisphosphonates reduce bone turnover but do not correct deformities

In randomized clinical trials, bisphosphonates have been shown to restore bone remodeling to more normal levels, to ease pain from pagetic bone, to lower the serum alkaline phosphatase level, and to heal radiographic lesions, but these drugs have not been proven to prevent progression of deformity or to restore the structural integrity of bone (Figure 6).

The Paget’s Disease: Randomized Trial of Intensive Versus Symptomatic Management (PRISM), in 1,324 people with Paget disease in the United Kingdom, showed no difference in the incidence of fracture, orthopedic surgery, quality of life, or hearing thresholds over 2 to 5 years in patients treated with bisphosphonates vs those treated symptomatically, despite a significant difference in serum alkaline phosphatase in the two groups (P < .001).⁵⁹

In the observational extension study of zoledronic acid described above,⁵⁸ three of four fractures occurred in the group treated with zoledronic acid, echoing the findings of the PRISM study.

Adverse effects of bisphosphonates

The more potent the bisphosphonate is as an antiresorptive agent, the more it suppresses normal bone remodeling, which can lead to osteonecrosis of the jaw and to atypical femoral fractures.^60,61 These complications are unusual in patients with Paget disease because the treatment is intermittent. Sometimes a single dose of zoledronic acid or one course of risedronate or alendronate will last for years.

All the nitrogen-containing bisphosphonates, particularly zoledronic acid, may provoke flulike symptoms of fever, arthralgias, and bone pain. This effect is self-limited, resolves in days, and does not tend to recur. Bone pain may be more sustained, but this also passes, and within weeks the antiresorptive process has abated and pagetic bone pain will ease. Atrial fibrillation is not an anticipated complication of treatment with a bisphosphonate.⁶² The risk of esophageal cancer is not confirmed at this time.⁶³ Other rare complications of the bisphosphonates include iritis, acute renal failure, and allergy.

Bisphosphonates are not approved for use in patients with creatinine clearance less than 30 mL/min, or in pregnancy.

Other treatments

Calcitonin, an older agent, can still be useful in easing the pain of Paget disease, healing bone lesions, and reducing the metabolic activity of pagetic bone in patients who cannot receive bisphosphonates. It is given by injection in doses of 50 to 100 IU daily or every other day. Although unlikely to effect a sustained clinical remission, calcitonin remains a safe, well-tolerated, and well-studied medication in Paget disease and is approved for this indication.^64,65

Denosumab has not been formally studied in Paget disease, but a recent case report indicated it was effective.⁶⁶

A conservative strategy

Guidelines for treating Paget disease have been written at various times in many countries, including Italy (2007),⁶⁷ the United Kingdom (2004),⁶⁸ Japan (2006),⁶⁹ and Canada (2007).⁷⁰ Recommendations differ, in part because it is hard to ascertain whether long-term outcomes are improved by treatment, and in part because the prevalence of Paget disease is decreasing and its severity is lessening.^11,12 Some guidelines are outdated, since they do not include the newer bisphosphonates.

If the natural history of untreated Paget disease involves the gradual evolution over more than 20 years of bowing deformities in the lower limbs, rigidity and overgrowth of the spine, and softening and enlargement of the skull, as described by Sir James Paget, then treatment should be initiated in hopes that it will modify the outcome. We have no lens to better focus this question on the effect of treatment on the natural history of the disease. We have the PRISM study, designed before zoledronic acid was approved and only 2 to 5 years in duration. And we have the epidemiologic data demonstrating that most patients have no symptoms during their lifetime.

We see the crippling bone disease described by Sir James Paget so infrequently today in the United States that we forget the profound morbidity that may attend the skeletal changes of Paget disease that were common in the early 20th century. Once the bones of the skull are overgrown, the limbs are bowed, and the degenerative joint disease is present, no medication can reverse these changes. Then, the integrity of the bone is lost, and the vulnerability to fracture, early osteoarthritis, nerve compression syndromes, and hearing loss persist. Understanding these consequences prompts the recommendation of early treatment in patients with Paget disease, in hopes of mitigating disease progression.

Patients with active Paget disease, documented either by an elevated serum alkaline phosphatase or by a bone scan, should be treated with a bisphosphonate if the disease is found in sites where remodeling of bone may lead to complications. Such sites include the skull, spine, and long bones of the lower extremity. Paget disease of bone in the pelvis tends to give little trouble (Figure 2) unless it is proximal to a joint, when pain and early arthritis may result. Treatment is safe and, I think, prudent to undertake in any person over age 55 with active disease. To prevent hypocalcemia during treatment, all patients should be repleted with vitamin D and maintained on calcium 1,200 mg daily through diet or supplements with meals.

Throughout the evaluation and treatment, it is important to remember that pain may not emanate from pagetic bone. If medication for Paget disease proves ineffective in the first few months, analgesics, bracing, walking aids, and operative management⁷¹ are adjunctive therapies to improve the functional status of these patients.

It is a remarkable clinical observation that treatment of Paget disease may rapidly reverse neurologic syndromes, resolve the erythema or warmth overlying active pagetic bone, and diminish the risk of bleeding with surgery. This response to therapy suggests that there is prompt inhibition and apoptosis of the osteoclasts, accompanied by diminished vascularity of bone. Whatever the mechanism, it is worth treating patients who have spinal stenosis, arthritis, and nerve compression syndromes with calcitonin or bisphosphonates before surgical intervention, whenever possible.^34,72