CASE Sam M, age 48, is in your office for the first time in more than 2 years. He has gained a considerable amount of weight and appears a bit sluggish, and you wonder whether he’s depressed. While taking a history, Sam reminds you that he was laid off 16 months ago and had been caring for his wife, who sustained a debilitating back injury. When you saw her recently, she told you she’s back to work and pain-free. So you’re taken aback when Sam asks you to refill his wife’s oxycodone prescription for lingering pain that often keeps her up at night.
If Sam were your patient, would you suspect opioid dependence?

Dependence on opioid analgesics and the adverse consequences associated with it have steadily increased during the past decade. Consider the following:

• Between 2004 and 2008, the number of emergency department visits related to nonmedical prescription opioid use more than doubled, rising by 111%.¹
• The increasing prevalence of opioid abuse has led to a recent spike in unintentional deaths,² with the number of lives lost to opioid analgesic overdose now exceeding that of heroin or cocaine.³
• More than 75% of opioids used for nonmedical purposes were prescribed for someone else.⁴

The course of opioid use is highly variable. Some people start with a legitimate medical prescription for an opioid analgesic, then continue taking it after the pain subsides. Others experiment briefly with nonmedical prescription opioids or use them intermittently without adverse effect. Some progress from prescription opioids to heroin, despite its dangers.⁵ Still others have a catastrophic outcome, such as an overdose or severe accident, the first time they use opioids.⁶ Rapid progression from misuse of opioids to dependence is most likely in vulnerable populations, such as those with concurrent mental illness, other substance use disorders, or increased sensitivity to pain.⁷

Understanding the terms. Before we continue, a word about terminology is in order. “Misuse” generally refers to the use of a medication in a manner (ie, purpose, dose, or frequency) other than its intended use, while “drug addiction” is the repeated use of a drug despite resulting harm. Here we will use “opioid dependence” to mean a pattern of increasing use characterized by significant impairment and distress and an inability to stop, and “opioid withdrawal” to reflect a constellation of symptoms, such as insomnia, nausea, diarrhea, and muscle aches, that can follow physiological dependence (though not necessarily opioid dependence). Our definitions of these terms are consistent with those of the American Psychiatric Association (APA).⁸ Worth noting, however, is the fact that as the APA prepares for the publication of the 5th edition of its Diagnostic and Statistical Manual of Mental Disorders, its Substance Disorder Work Group has proposed replacing the term “opioid dependence” with “opioid use disorder” to reduce the confusion associated with these definitions.⁹

Assessing illicit opioid use: Start with a targeted question

Most patients who are opioid dependent do not seek treatment for it,¹⁰ and are typically free of medical sequelae associated with drug addiction when they see family practitioners. The absence of self-reporting and obvious physical signs and symptoms, coupled with the increase in illicit use of prescription opioids, underscores the need for family physicians to identify patients who are abusing opioids and ensure that they get the help they need.

Screening tools. There are a number of screening tools you can use for this purpose—eg, CAGE-Adapted to Include Drugs (CAGE-AID) and Drug Abuse Screening Test (DAST)^11,12—but they have not been found to be significantly better than a careful substance abuse history.¹³

Straightforward questions. You can start by asking, “Do you take any medications for pain?” If the answer is Yes, get the name of the drug and inquire about the frequency of use and the route, the amount typically taken, and the duration of the current use pattern. Ask specifically about opioids when taking a substance abuse history. After a question about alcohol use, you can say, “Do you use any other drugs in a serious way? Marijuana? Opioids like Percocet, Vicodin, or Oxycontin?” Although it can be very difficult to detect opioid dependence if the patient is not forthcoming, other likely indicators of drug-seeking behavior should trigger additional questions. (See “Opioid dependence: Red flags to keep in mind”.^14-16)

“Brief” protocols. Recent studies of Screening, Brief Intervention, and Referral to Treatment (SBIRT) programs have found that the simple, time-limited interventions they offer (visit http://www.samhsa.gov/prevention/sbirt/SBIRTwhitepaper.pdf to learn more) lead to a reduction in self-reported illicit opioid use.^17,18 Family physicians can readily incorporate SBIRT protocols into routine practice, as an evidence-based and often reimbursable approach to substance abuse.¹⁷

Additional steps before initiating treatment
After screening and diagnostic evaluation provide evidence that a patient is opioid dependent, you can take several steps to guide him or her to the appropriate treatment.

A thorough biopsychosocial assessment covering co-occurring psychiatric illnesses, pain, psychosocial stressors contributing to opioid use, and infectious disease screening is required to gain a clear picture of the patient’s situation. In every case, acute emergencies such as suicidal ideation require immediate intervention, which may involve hospitalization.¹⁹

Assess the patient’s desire for help. After the initial assessment, it is often helpful to categorize the patient’s “stage of change” (precontemplation, contemplation, preparation, action, or maintenance),²⁰ and to tailor your next step accordingly. A patient who denies that opioid use is a problem or is clearly ambivalent about seeking treatment may require a conversation that uses principles of motivational interviewing—a collaborative approach that aims to evoke and strengthen personal motivation for change.²¹ Consider a question that encourages him or her to express reasons for change, such as: “How would you like your current situation to be different?” As almost everyone abusing opioids has thoughts about stopping, such a question may help the patient focus on specific changes.

CASE When you question Sam about his interest in oxycodone, he breaks down. He’s been unable to find work or to lose the excess weight he gained during the many months he cared for his wife. He tells you that soon after his wife stopped taking the pain pills, he started taking them. At first, he took one occasionally. Then he started taking the opioids every day, and finally, whenever he awakened at night. Now, Sam says, he has no more pills, and he’s nauseous, depressed, and unable to sleep—and looking to you for help.

Sam fits the criteria for opioid withdrawal as a result of physiological dependence; further questioning reveals that he also suffers from opioid dependence, and that he is receptive to treatment.

Recommending treatment and following up

Several options are available for patients who, like Sam, have signs and symptoms of opioid withdrawal as a result of physiological dependence. You can provide a referral to a physician specializing in addiction, recommend detoxification and/or treatment in an inpatient facility, or initiate pharmacological treatment and provide a referral to a behavioral therapist. Whatever the initial approach, most patients will ultimately be treated as outpatients, with a combination of pharmacotherapy and behavioral therapy—often, with monitoring and oversight by a primary care physician. Which approach to pursue should be guided by evidence-based recommendations (TABLE)^17,22-27 and jointly decided by physician and patient.

TABLE
Treating opioid dependence: Key clinical recommendations

Medication plays a key role in recovery
Recommend medication-assisted treatment, either with an agonist (buprenorphine or methadone) or an antagonist (naltrexone), for every patient with physiological opioid dependence. The goals of pharmacotherapy are to prevent or reduce withdrawal symptoms and craving, avoid relapse, and restore to a normal state any physiological functions (eg, sleep, bowel movements) that have been disrupted by opioid use.²⁸ When continued for ≥3 months, medication has been shown to improve outcomes.^23,24,29 In one recent study, 49% of opioid-dependent participants who were still taking buprenorphine-naloxone at 12 weeks had successful outcomes (minimal or no opioid use), vs 7% of those undergoing a brief buprenorphine-naloxone taper.²⁴

There are risks associated with medication-assisted therapy, however. The ones of greatest concern are a potential increase in drug-drug interactions, the risk of diversion (a concern with both buprenorphine and methadone), and the potential for accidental overdose.^2,30

Buprenorphine, a partial mu-opioid receptor agonist, is a Schedule III controlled substance and can be dispensed by a pharmacy, making inpatient opioid detoxification unnecessary for many opioid-dependent patients. Physicians who wish to prescribe buprenorphine for the treatment of opioid dependence must complete an 8-hour course, offered by the American Medical Association and the APA, among other medical groups, and obtain a Drug Enforcement Administration code (“X”) license. ³¹

Buprenorphine has a high affinity for, and a slow dissociation from, mu-opioid receptors, resulting in the displacement of other opioids from the mu receptor and less severe withdrawal.³² As a partial agonist, buprenorphine attenuates opioid withdrawal symptoms with a ceiling, or near maximal, effect at 16 mg, thereby lowering the risk for overdose.³³ A sublingual formulation that combines buprenorphine with naloxone, an opioid antagonist that exerts its full effect when injected but is minimally absorbed sublingually, reduces the potential for abuse of buprenorphine without interfering with its effectiveness.³⁴

Compared with methadone, buprenorphine is less likely to interact with antiretroviral medications or to cause QTc prolongation, erectile dysfunction, or cognitive or psychomotor impairment.^31,35-37 Limitations include the ceiling effect, which can be a problem for cases in which more agonist is needed; cost (approximately $12/d), and the lack of approval by the US Food and Drug Administration (FDA) for use during pregnancy.

Buprenorphine maintenance involves 3 phases: induction, stabilization, and maintenance.³⁸ Induction takes place in a clinician’s office at the time the patient experiences opioid withdrawal symptoms, typically 6 to 48 hours after taking the last opioid. Extended treatment improves clinical outcomes,^23,24 and longer-term maintenance (of indefinite duration) is frequently required.

Naltrexone is a mu-receptor antagonist, and therefore does not cause physical dependence or have agonist effects such as euphoria and sedation. As a result, it has no diversion value and may appeal to those who view opioid-agonist pharmacotherapy as simply trading one drug for another.³⁹ Naltrexone is not a controlled substance and is not subject to the regulatory requirements that buprenorphine and methadone face.

Although agonists can be started in the first day or 2 after a patient decides to stop using opioids, patients must be opioid-free for ≥7 days before starting naltrexone. That’s because its antagonist properties will precipitate withdrawal if another opioid is present on the opioid receptors. During the 7-day “washout” period, you can treat opioid withdrawal symptoms with medications such as clonidine and dicyclomine, but such symptoms make patients especially vulnerable to relapse while waiting to start naltrexone.

Oral naltrexone’s effectiveness as a treatment for opioid dependence has been limited by poor adherence. But a long-acting intramuscular form of the drug, approved by the FDA in 2010 and requiring once-a-month injection, mitigates this concern.^40,41

Methadone is a full mu-opioid agonist, administered daily at specialized clinics, as a maintenance therapy for opioid dependence. Although office-based physicians can prescribe methadone for pain, the drug can only be used for opioid dependence under the auspices of state- and federally regulated opioid treatment programs (http://findtreatment.samhsa.gov/TreatmentLocator/faces/quickSearch.jspx; a mobile phone application is also available at http://www.samhsa.gov/mobile/treatmentlocator.aspx).

Methadone, a Schedule III controlled substance with a half-life averaging 24 to 36 hours, requires daily dosing.⁴² Its slow metabolism and long half-life increase the risk for overdose.

Methadone is best for patients who are highly dependent on opioids and likely to benefit from a structured treatment environment with daily supervision (although patients who are doing well may earn take-home privileges so they don’t have to come to the clinic every day).⁴³ New patients should receive an initial dose of 30 mg or less, and a maximum first-day dose of 40 mg.⁴⁴

Methadone remains the standard of care for pregnant women being treated for opioid dependence, while studies of the effects of buprenorphine and naltrexone on a developing fetus continue. Although methadone’s efficacy, particularly in lower doses, is similar to that of buprenorphine,⁴⁵ its adverse effect profile is worse. Adverse effects include drug-drug interactions, the potential for respiratory depression (especially when combined with alcohol or sedatives), QTc prolongation (which requires monitoring by electrocardiogram), sedation, and weight gain, and should be considered before selecting methadone as a maintenance pharmacotherapy.^30,37,46 And, because relapse rates within 12 months of tapering off methadone have been reported to exceed 80%,⁴⁷ both the clinician and the patient need to consider the likelihood of long-term, even lifelong, maintenance before initiating treatment.

Behavioral interventions are a vital part of the picture
Studies evaluating the extent to which various types and amounts of counseling improve outcomes compared with pharmacotherapy alone have had conflicting results.^24,48 Nonetheless, most clinicians consider counseling to be a critical component of treatment for opioid dependence and recommend, at a minimum, either individual or group counseling (various modalities have been shown to be effective) and regular attendance at a self-help group like Narcotics Anonymous. Contingency management, a type of therapy that uses prizes as incentives for desired behaviors; and family therapy, individual counseling, and community-based programs have all been found to improve outcomes.^6,49

CASE You refer Sam to an addiction psychiatrist, who stabilizes him on 16 mg buprenorphine/naloxone daily as part of an outpatient treatment program. Sam is enrolled in a weekly buprenorphine stabilization group, where he gives a urine sample each week. He also begins seeing a social worker weekly for counseling and attends Narcotics Anonymous meetings 2 to 3 times a week. At a follow-up appointment with you 6 months later, he reports that he has been abstinent from oxycodone for 6 months, his sleep is improved, and he feels better about his chances of finding another job.

Your role in safeguarding the patient

With the rising prevalence of opioid overdose, patient education aimed at crisis prevention is crucial, as well. Warn patients of the risk of accidental overdose, often associated with relapse, stressing the importance of continuing treatment and taking their maintenance medication exactly as prescribed.

There are other steps you can take to safeguard patients—eg, providing naloxone rescue kits to patients and their families when appropriate. You can also institute diversion and overdose prevention measures for patients taking buprenorphine or methadone—providing a lock box for take-home medication, implementing treatment contracts, and using a designated pharmacy to dispense buprenorphine, for example.^26,27,50

Regular monitoring, urine drug screens (see TABLE W1), and random pill counts, in which patients are typically given 24 hours to bring in their prescribed medication so it can be counted, can also help keep patients on track. Treatment for concurrent psychiatric disorders—depression, anxiety, and personality disorders are common among patients with opioid dependence—is likely to improve the outcome of treatment, as well.

TABLE W1
Pharmacokinetics of common opioids: Time detectable in urine*

CORRESPONDENCE Kevin P. Hill, MD, MHS, McLean Hospital, 115 Mill Street, Belmont, MA 02478; [email protected]

CASE Sam M, age 48, is in your office for the first time in more than 2 years. He has gained a considerable amount of weight and appears a bit sluggish, and you wonder whether he’s depressed. While taking a history, Sam reminds you that he was laid off 16 months ago and had been caring for his wife, who sustained a debilitating back injury. When you saw her recently, she told you she’s back to work and pain-free. So you’re taken aback when Sam asks you to refill his wife’s oxycodone prescription for lingering pain that often keeps her up at night.
If Sam were your patient, would you suspect opioid dependence?

Dependence on opioid analgesics and the adverse consequences associated with it have steadily increased during the past decade. Consider the following:

• Between 2004 and 2008, the number of emergency department visits related to nonmedical prescription opioid use more than doubled, rising by 111%.¹
• The increasing prevalence of opioid abuse has led to a recent spike in unintentional deaths,² with the number of lives lost to opioid analgesic overdose now exceeding that of heroin or cocaine.³
• More than 75% of opioids used for nonmedical purposes were prescribed for someone else.⁴

The course of opioid use is highly variable. Some people start with a legitimate medical prescription for an opioid analgesic, then continue taking it after the pain subsides. Others experiment briefly with nonmedical prescription opioids or use them intermittently without adverse effect. Some progress from prescription opioids to heroin, despite its dangers.⁵ Still others have a catastrophic outcome, such as an overdose or severe accident, the first time they use opioids.⁶ Rapid progression from misuse of opioids to dependence is most likely in vulnerable populations, such as those with concurrent mental illness, other substance use disorders, or increased sensitivity to pain.⁷

Understanding the terms. Before we continue, a word about terminology is in order. “Misuse” generally refers to the use of a medication in a manner (ie, purpose, dose, or frequency) other than its intended use, while “drug addiction” is the repeated use of a drug despite resulting harm. Here we will use “opioid dependence” to mean a pattern of increasing use characterized by significant impairment and distress and an inability to stop, and “opioid withdrawal” to reflect a constellation of symptoms, such as insomnia, nausea, diarrhea, and muscle aches, that can follow physiological dependence (though not necessarily opioid dependence). Our definitions of these terms are consistent with those of the American Psychiatric Association (APA).⁸ Worth noting, however, is the fact that as the APA prepares for the publication of the 5th edition of its Diagnostic and Statistical Manual of Mental Disorders, its Substance Disorder Work Group has proposed replacing the term “opioid dependence” with “opioid use disorder” to reduce the confusion associated with these definitions.⁹

Assessing illicit opioid use: Start with a targeted question

Most patients who are opioid dependent do not seek treatment for it,¹⁰ and are typically free of medical sequelae associated with drug addiction when they see family practitioners. The absence of self-reporting and obvious physical signs and symptoms, coupled with the increase in illicit use of prescription opioids, underscores the need for family physicians to identify patients who are abusing opioids and ensure that they get the help they need.

Screening tools. There are a number of screening tools you can use for this purpose—eg, CAGE-Adapted to Include Drugs (CAGE-AID) and Drug Abuse Screening Test (DAST)^11,12—but they have not been found to be significantly better than a careful substance abuse history.¹³

Straightforward questions. You can start by asking, “Do you take any medications for pain?” If the answer is Yes, get the name of the drug and inquire about the frequency of use and the route, the amount typically taken, and the duration of the current use pattern. Ask specifically about opioids when taking a substance abuse history. After a question about alcohol use, you can say, “Do you use any other drugs in a serious way? Marijuana? Opioids like Percocet, Vicodin, or Oxycontin?” Although it can be very difficult to detect opioid dependence if the patient is not forthcoming, other likely indicators of drug-seeking behavior should trigger additional questions. (See “Opioid dependence: Red flags to keep in mind”.^14-16)

“Brief” protocols. Recent studies of Screening, Brief Intervention, and Referral to Treatment (SBIRT) programs have found that the simple, time-limited interventions they offer (visit http://www.samhsa.gov/prevention/sbirt/SBIRTwhitepaper.pdf to learn more) lead to a reduction in self-reported illicit opioid use.^17,18 Family physicians can readily incorporate SBIRT protocols into routine practice, as an evidence-based and often reimbursable approach to substance abuse.¹⁷

Additional steps before initiating treatment
After screening and diagnostic evaluation provide evidence that a patient is opioid dependent, you can take several steps to guide him or her to the appropriate treatment.

A thorough biopsychosocial assessment covering co-occurring psychiatric illnesses, pain, psychosocial stressors contributing to opioid use, and infectious disease screening is required to gain a clear picture of the patient’s situation. In every case, acute emergencies such as suicidal ideation require immediate intervention, which may involve hospitalization.¹⁹

Assess the patient’s desire for help. After the initial assessment, it is often helpful to categorize the patient’s “stage of change” (precontemplation, contemplation, preparation, action, or maintenance),²⁰ and to tailor your next step accordingly. A patient who denies that opioid use is a problem or is clearly ambivalent about seeking treatment may require a conversation that uses principles of motivational interviewing—a collaborative approach that aims to evoke and strengthen personal motivation for change.²¹ Consider a question that encourages him or her to express reasons for change, such as: “How would you like your current situation to be different?” As almost everyone abusing opioids has thoughts about stopping, such a question may help the patient focus on specific changes.

CASE When you question Sam about his interest in oxycodone, he breaks down. He’s been unable to find work or to lose the excess weight he gained during the many months he cared for his wife. He tells you that soon after his wife stopped taking the pain pills, he started taking them. At first, he took one occasionally. Then he started taking the opioids every day, and finally, whenever he awakened at night. Now, Sam says, he has no more pills, and he’s nauseous, depressed, and unable to sleep—and looking to you for help.

Sam fits the criteria for opioid withdrawal as a result of physiological dependence; further questioning reveals that he also suffers from opioid dependence, and that he is receptive to treatment.

Recommending treatment and following up

Several options are available for patients who, like Sam, have signs and symptoms of opioid withdrawal as a result of physiological dependence. You can provide a referral to a physician specializing in addiction, recommend detoxification and/or treatment in an inpatient facility, or initiate pharmacological treatment and provide a referral to a behavioral therapist. Whatever the initial approach, most patients will ultimately be treated as outpatients, with a combination of pharmacotherapy and behavioral therapy—often, with monitoring and oversight by a primary care physician. Which approach to pursue should be guided by evidence-based recommendations (TABLE)^17,22-27 and jointly decided by physician and patient.

TABLE
Treating opioid dependence: Key clinical recommendations

Medication plays a key role in recovery
Recommend medication-assisted treatment, either with an agonist (buprenorphine or methadone) or an antagonist (naltrexone), for every patient with physiological opioid dependence. The goals of pharmacotherapy are to prevent or reduce withdrawal symptoms and craving, avoid relapse, and restore to a normal state any physiological functions (eg, sleep, bowel movements) that have been disrupted by opioid use.²⁸ When continued for ≥3 months, medication has been shown to improve outcomes.^23,24,29 In one recent study, 49% of opioid-dependent participants who were still taking buprenorphine-naloxone at 12 weeks had successful outcomes (minimal or no opioid use), vs 7% of those undergoing a brief buprenorphine-naloxone taper.²⁴

There are risks associated with medication-assisted therapy, however. The ones of greatest concern are a potential increase in drug-drug interactions, the risk of diversion (a concern with both buprenorphine and methadone), and the potential for accidental overdose.^2,30

Buprenorphine, a partial mu-opioid receptor agonist, is a Schedule III controlled substance and can be dispensed by a pharmacy, making inpatient opioid detoxification unnecessary for many opioid-dependent patients. Physicians who wish to prescribe buprenorphine for the treatment of opioid dependence must complete an 8-hour course, offered by the American Medical Association and the APA, among other medical groups, and obtain a Drug Enforcement Administration code (“X”) license. ³¹

Buprenorphine has a high affinity for, and a slow dissociation from, mu-opioid receptors, resulting in the displacement of other opioids from the mu receptor and less severe withdrawal.³² As a partial agonist, buprenorphine attenuates opioid withdrawal symptoms with a ceiling, or near maximal, effect at 16 mg, thereby lowering the risk for overdose.³³ A sublingual formulation that combines buprenorphine with naloxone, an opioid antagonist that exerts its full effect when injected but is minimally absorbed sublingually, reduces the potential for abuse of buprenorphine without interfering with its effectiveness.³⁴

Compared with methadone, buprenorphine is less likely to interact with antiretroviral medications or to cause QTc prolongation, erectile dysfunction, or cognitive or psychomotor impairment.^31,35-37 Limitations include the ceiling effect, which can be a problem for cases in which more agonist is needed; cost (approximately $12/d), and the lack of approval by the US Food and Drug Administration (FDA) for use during pregnancy.

Buprenorphine maintenance involves 3 phases: induction, stabilization, and maintenance.³⁸ Induction takes place in a clinician’s office at the time the patient experiences opioid withdrawal symptoms, typically 6 to 48 hours after taking the last opioid. Extended treatment improves clinical outcomes,^23,24 and longer-term maintenance (of indefinite duration) is frequently required.

Naltrexone is a mu-receptor antagonist, and therefore does not cause physical dependence or have agonist effects such as euphoria and sedation. As a result, it has no diversion value and may appeal to those who view opioid-agonist pharmacotherapy as simply trading one drug for another.³⁹ Naltrexone is not a controlled substance and is not subject to the regulatory requirements that buprenorphine and methadone face.

Although agonists can be started in the first day or 2 after a patient decides to stop using opioids, patients must be opioid-free for ≥7 days before starting naltrexone. That’s because its antagonist properties will precipitate withdrawal if another opioid is present on the opioid receptors. During the 7-day “washout” period, you can treat opioid withdrawal symptoms with medications such as clonidine and dicyclomine, but such symptoms make patients especially vulnerable to relapse while waiting to start naltrexone.

Oral naltrexone’s effectiveness as a treatment for opioid dependence has been limited by poor adherence. But a long-acting intramuscular form of the drug, approved by the FDA in 2010 and requiring once-a-month injection, mitigates this concern.^40,41

Methadone is a full mu-opioid agonist, administered daily at specialized clinics, as a maintenance therapy for opioid dependence. Although office-based physicians can prescribe methadone for pain, the drug can only be used for opioid dependence under the auspices of state- and federally regulated opioid treatment programs (http://findtreatment.samhsa.gov/TreatmentLocator/faces/quickSearch.jspx; a mobile phone application is also available at http://www.samhsa.gov/mobile/treatmentlocator.aspx).

Methadone, a Schedule III controlled substance with a half-life averaging 24 to 36 hours, requires daily dosing.⁴² Its slow metabolism and long half-life increase the risk for overdose.

Methadone is best for patients who are highly dependent on opioids and likely to benefit from a structured treatment environment with daily supervision (although patients who are doing well may earn take-home privileges so they don’t have to come to the clinic every day).⁴³ New patients should receive an initial dose of 30 mg or less, and a maximum first-day dose of 40 mg.⁴⁴

Methadone remains the standard of care for pregnant women being treated for opioid dependence, while studies of the effects of buprenorphine and naltrexone on a developing fetus continue. Although methadone’s efficacy, particularly in lower doses, is similar to that of buprenorphine,⁴⁵ its adverse effect profile is worse. Adverse effects include drug-drug interactions, the potential for respiratory depression (especially when combined with alcohol or sedatives), QTc prolongation (which requires monitoring by electrocardiogram), sedation, and weight gain, and should be considered before selecting methadone as a maintenance pharmacotherapy.^30,37,46 And, because relapse rates within 12 months of tapering off methadone have been reported to exceed 80%,⁴⁷ both the clinician and the patient need to consider the likelihood of long-term, even lifelong, maintenance before initiating treatment.

Behavioral interventions are a vital part of the picture
Studies evaluating the extent to which various types and amounts of counseling improve outcomes compared with pharmacotherapy alone have had conflicting results.^24,48 Nonetheless, most clinicians consider counseling to be a critical component of treatment for opioid dependence and recommend, at a minimum, either individual or group counseling (various modalities have been shown to be effective) and regular attendance at a self-help group like Narcotics Anonymous. Contingency management, a type of therapy that uses prizes as incentives for desired behaviors; and family therapy, individual counseling, and community-based programs have all been found to improve outcomes.^6,49

CASE You refer Sam to an addiction psychiatrist, who stabilizes him on 16 mg buprenorphine/naloxone daily as part of an outpatient treatment program. Sam is enrolled in a weekly buprenorphine stabilization group, where he gives a urine sample each week. He also begins seeing a social worker weekly for counseling and attends Narcotics Anonymous meetings 2 to 3 times a week. At a follow-up appointment with you 6 months later, he reports that he has been abstinent from oxycodone for 6 months, his sleep is improved, and he feels better about his chances of finding another job.

Your role in safeguarding the patient

With the rising prevalence of opioid overdose, patient education aimed at crisis prevention is crucial, as well. Warn patients of the risk of accidental overdose, often associated with relapse, stressing the importance of continuing treatment and taking their maintenance medication exactly as prescribed.

There are other steps you can take to safeguard patients—eg, providing naloxone rescue kits to patients and their families when appropriate. You can also institute diversion and overdose prevention measures for patients taking buprenorphine or methadone—providing a lock box for take-home medication, implementing treatment contracts, and using a designated pharmacy to dispense buprenorphine, for example.^26,27,50

Regular monitoring, urine drug screens (see TABLE W1), and random pill counts, in which patients are typically given 24 hours to bring in their prescribed medication so it can be counted, can also help keep patients on track. Treatment for concurrent psychiatric disorders—depression, anxiety, and personality disorders are common among patients with opioid dependence—is likely to improve the outcome of treatment, as well.

TABLE W1
Pharmacokinetics of common opioids: Time detectable in urine*

CORRESPONDENCE Kevin P. Hill, MD, MHS, McLean Hospital, 115 Mill Street, Belmont, MA 02478; [email protected]

CASE Sam M, age 48, is in your office for the first time in more than 2 years. He has gained a considerable amount of weight and appears a bit sluggish, and you wonder whether he’s depressed. While taking a history, Sam reminds you that he was laid off 16 months ago and had been caring for his wife, who sustained a debilitating back injury. When you saw her recently, she told you she’s back to work and pain-free. So you’re taken aback when Sam asks you to refill his wife’s oxycodone prescription for lingering pain that often keeps her up at night.
If Sam were your patient, would you suspect opioid dependence?

Dependence on opioid analgesics and the adverse consequences associated with it have steadily increased during the past decade. Consider the following:

• Between 2004 and 2008, the number of emergency department visits related to nonmedical prescription opioid use more than doubled, rising by 111%.¹
• The increasing prevalence of opioid abuse has led to a recent spike in unintentional deaths,² with the number of lives lost to opioid analgesic overdose now exceeding that of heroin or cocaine.³
• More than 75% of opioids used for nonmedical purposes were prescribed for someone else.⁴

The course of opioid use is highly variable. Some people start with a legitimate medical prescription for an opioid analgesic, then continue taking it after the pain subsides. Others experiment briefly with nonmedical prescription opioids or use them intermittently without adverse effect. Some progress from prescription opioids to heroin, despite its dangers.⁵ Still others have a catastrophic outcome, such as an overdose or severe accident, the first time they use opioids.⁶ Rapid progression from misuse of opioids to dependence is most likely in vulnerable populations, such as those with concurrent mental illness, other substance use disorders, or increased sensitivity to pain.⁷

Understanding the terms. Before we continue, a word about terminology is in order. “Misuse” generally refers to the use of a medication in a manner (ie, purpose, dose, or frequency) other than its intended use, while “drug addiction” is the repeated use of a drug despite resulting harm. Here we will use “opioid dependence” to mean a pattern of increasing use characterized by significant impairment and distress and an inability to stop, and “opioid withdrawal” to reflect a constellation of symptoms, such as insomnia, nausea, diarrhea, and muscle aches, that can follow physiological dependence (though not necessarily opioid dependence). Our definitions of these terms are consistent with those of the American Psychiatric Association (APA).⁸ Worth noting, however, is the fact that as the APA prepares for the publication of the 5th edition of its Diagnostic and Statistical Manual of Mental Disorders, its Substance Disorder Work Group has proposed replacing the term “opioid dependence” with “opioid use disorder” to reduce the confusion associated with these definitions.⁹

Assessing illicit opioid use: Start with a targeted question

Most patients who are opioid dependent do not seek treatment for it,¹⁰ and are typically free of medical sequelae associated with drug addiction when they see family practitioners. The absence of self-reporting and obvious physical signs and symptoms, coupled with the increase in illicit use of prescription opioids, underscores the need for family physicians to identify patients who are abusing opioids and ensure that they get the help they need.

Screening tools. There are a number of screening tools you can use for this purpose—eg, CAGE-Adapted to Include Drugs (CAGE-AID) and Drug Abuse Screening Test (DAST)^11,12—but they have not been found to be significantly better than a careful substance abuse history.¹³

Straightforward questions. You can start by asking, “Do you take any medications for pain?” If the answer is Yes, get the name of the drug and inquire about the frequency of use and the route, the amount typically taken, and the duration of the current use pattern. Ask specifically about opioids when taking a substance abuse history. After a question about alcohol use, you can say, “Do you use any other drugs in a serious way? Marijuana? Opioids like Percocet, Vicodin, or Oxycontin?” Although it can be very difficult to detect opioid dependence if the patient is not forthcoming, other likely indicators of drug-seeking behavior should trigger additional questions. (See “Opioid dependence: Red flags to keep in mind”.^14-16)

“Brief” protocols. Recent studies of Screening, Brief Intervention, and Referral to Treatment (SBIRT) programs have found that the simple, time-limited interventions they offer (visit http://www.samhsa.gov/prevention/sbirt/SBIRTwhitepaper.pdf to learn more) lead to a reduction in self-reported illicit opioid use.^17,18 Family physicians can readily incorporate SBIRT protocols into routine practice, as an evidence-based and often reimbursable approach to substance abuse.¹⁷

Additional steps before initiating treatment
After screening and diagnostic evaluation provide evidence that a patient is opioid dependent, you can take several steps to guide him or her to the appropriate treatment.

A thorough biopsychosocial assessment covering co-occurring psychiatric illnesses, pain, psychosocial stressors contributing to opioid use, and infectious disease screening is required to gain a clear picture of the patient’s situation. In every case, acute emergencies such as suicidal ideation require immediate intervention, which may involve hospitalization.¹⁹

Assess the patient’s desire for help. After the initial assessment, it is often helpful to categorize the patient’s “stage of change” (precontemplation, contemplation, preparation, action, or maintenance),²⁰ and to tailor your next step accordingly. A patient who denies that opioid use is a problem or is clearly ambivalent about seeking treatment may require a conversation that uses principles of motivational interviewing—a collaborative approach that aims to evoke and strengthen personal motivation for change.²¹ Consider a question that encourages him or her to express reasons for change, such as: “How would you like your current situation to be different?” As almost everyone abusing opioids has thoughts about stopping, such a question may help the patient focus on specific changes.

CASE When you question Sam about his interest in oxycodone, he breaks down. He’s been unable to find work or to lose the excess weight he gained during the many months he cared for his wife. He tells you that soon after his wife stopped taking the pain pills, he started taking them. At first, he took one occasionally. Then he started taking the opioids every day, and finally, whenever he awakened at night. Now, Sam says, he has no more pills, and he’s nauseous, depressed, and unable to sleep—and looking to you for help.

Sam fits the criteria for opioid withdrawal as a result of physiological dependence; further questioning reveals that he also suffers from opioid dependence, and that he is receptive to treatment.

Recommending treatment and following up

Several options are available for patients who, like Sam, have signs and symptoms of opioid withdrawal as a result of physiological dependence. You can provide a referral to a physician specializing in addiction, recommend detoxification and/or treatment in an inpatient facility, or initiate pharmacological treatment and provide a referral to a behavioral therapist. Whatever the initial approach, most patients will ultimately be treated as outpatients, with a combination of pharmacotherapy and behavioral therapy—often, with monitoring and oversight by a primary care physician. Which approach to pursue should be guided by evidence-based recommendations (TABLE)^17,22-27 and jointly decided by physician and patient.

TABLE
Treating opioid dependence: Key clinical recommendations

Medication plays a key role in recovery
Recommend medication-assisted treatment, either with an agonist (buprenorphine or methadone) or an antagonist (naltrexone), for every patient with physiological opioid dependence. The goals of pharmacotherapy are to prevent or reduce withdrawal symptoms and craving, avoid relapse, and restore to a normal state any physiological functions (eg, sleep, bowel movements) that have been disrupted by opioid use.²⁸ When continued for ≥3 months, medication has been shown to improve outcomes.^23,24,29 In one recent study, 49% of opioid-dependent participants who were still taking buprenorphine-naloxone at 12 weeks had successful outcomes (minimal or no opioid use), vs 7% of those undergoing a brief buprenorphine-naloxone taper.²⁴

There are risks associated with medication-assisted therapy, however. The ones of greatest concern are a potential increase in drug-drug interactions, the risk of diversion (a concern with both buprenorphine and methadone), and the potential for accidental overdose.^2,30

Buprenorphine, a partial mu-opioid receptor agonist, is a Schedule III controlled substance and can be dispensed by a pharmacy, making inpatient opioid detoxification unnecessary for many opioid-dependent patients. Physicians who wish to prescribe buprenorphine for the treatment of opioid dependence must complete an 8-hour course, offered by the American Medical Association and the APA, among other medical groups, and obtain a Drug Enforcement Administration code (“X”) license. ³¹

Buprenorphine has a high affinity for, and a slow dissociation from, mu-opioid receptors, resulting in the displacement of other opioids from the mu receptor and less severe withdrawal.³² As a partial agonist, buprenorphine attenuates opioid withdrawal symptoms with a ceiling, or near maximal, effect at 16 mg, thereby lowering the risk for overdose.³³ A sublingual formulation that combines buprenorphine with naloxone, an opioid antagonist that exerts its full effect when injected but is minimally absorbed sublingually, reduces the potential for abuse of buprenorphine without interfering with its effectiveness.³⁴

Compared with methadone, buprenorphine is less likely to interact with antiretroviral medications or to cause QTc prolongation, erectile dysfunction, or cognitive or psychomotor impairment.^31,35-37 Limitations include the ceiling effect, which can be a problem for cases in which more agonist is needed; cost (approximately $12/d), and the lack of approval by the US Food and Drug Administration (FDA) for use during pregnancy.

Buprenorphine maintenance involves 3 phases: induction, stabilization, and maintenance.³⁸ Induction takes place in a clinician’s office at the time the patient experiences opioid withdrawal symptoms, typically 6 to 48 hours after taking the last opioid. Extended treatment improves clinical outcomes,^23,24 and longer-term maintenance (of indefinite duration) is frequently required.

Naltrexone is a mu-receptor antagonist, and therefore does not cause physical dependence or have agonist effects such as euphoria and sedation. As a result, it has no diversion value and may appeal to those who view opioid-agonist pharmacotherapy as simply trading one drug for another.³⁹ Naltrexone is not a controlled substance and is not subject to the regulatory requirements that buprenorphine and methadone face.

Although agonists can be started in the first day or 2 after a patient decides to stop using opioids, patients must be opioid-free for ≥7 days before starting naltrexone. That’s because its antagonist properties will precipitate withdrawal if another opioid is present on the opioid receptors. During the 7-day “washout” period, you can treat opioid withdrawal symptoms with medications such as clonidine and dicyclomine, but such symptoms make patients especially vulnerable to relapse while waiting to start naltrexone.

Oral naltrexone’s effectiveness as a treatment for opioid dependence has been limited by poor adherence. But a long-acting intramuscular form of the drug, approved by the FDA in 2010 and requiring once-a-month injection, mitigates this concern.^40,41

Methadone is a full mu-opioid agonist, administered daily at specialized clinics, as a maintenance therapy for opioid dependence. Although office-based physicians can prescribe methadone for pain, the drug can only be used for opioid dependence under the auspices of state- and federally regulated opioid treatment programs (http://findtreatment.samhsa.gov/TreatmentLocator/faces/quickSearch.jspx; a mobile phone application is also available at http://www.samhsa.gov/mobile/treatmentlocator.aspx).

Methadone, a Schedule III controlled substance with a half-life averaging 24 to 36 hours, requires daily dosing.⁴² Its slow metabolism and long half-life increase the risk for overdose.

Methadone is best for patients who are highly dependent on opioids and likely to benefit from a structured treatment environment with daily supervision (although patients who are doing well may earn take-home privileges so they don’t have to come to the clinic every day).⁴³ New patients should receive an initial dose of 30 mg or less, and a maximum first-day dose of 40 mg.⁴⁴

Methadone remains the standard of care for pregnant women being treated for opioid dependence, while studies of the effects of buprenorphine and naltrexone on a developing fetus continue. Although methadone’s efficacy, particularly in lower doses, is similar to that of buprenorphine,⁴⁵ its adverse effect profile is worse. Adverse effects include drug-drug interactions, the potential for respiratory depression (especially when combined with alcohol or sedatives), QTc prolongation (which requires monitoring by electrocardiogram), sedation, and weight gain, and should be considered before selecting methadone as a maintenance pharmacotherapy.^30,37,46 And, because relapse rates within 12 months of tapering off methadone have been reported to exceed 80%,⁴⁷ both the clinician and the patient need to consider the likelihood of long-term, even lifelong, maintenance before initiating treatment.

Behavioral interventions are a vital part of the picture
Studies evaluating the extent to which various types and amounts of counseling improve outcomes compared with pharmacotherapy alone have had conflicting results.^24,48 Nonetheless, most clinicians consider counseling to be a critical component of treatment for opioid dependence and recommend, at a minimum, either individual or group counseling (various modalities have been shown to be effective) and regular attendance at a self-help group like Narcotics Anonymous. Contingency management, a type of therapy that uses prizes as incentives for desired behaviors; and family therapy, individual counseling, and community-based programs have all been found to improve outcomes.^6,49

CASE You refer Sam to an addiction psychiatrist, who stabilizes him on 16 mg buprenorphine/naloxone daily as part of an outpatient treatment program. Sam is enrolled in a weekly buprenorphine stabilization group, where he gives a urine sample each week. He also begins seeing a social worker weekly for counseling and attends Narcotics Anonymous meetings 2 to 3 times a week. At a follow-up appointment with you 6 months later, he reports that he has been abstinent from oxycodone for 6 months, his sleep is improved, and he feels better about his chances of finding another job.

Your role in safeguarding the patient

With the rising prevalence of opioid overdose, patient education aimed at crisis prevention is crucial, as well. Warn patients of the risk of accidental overdose, often associated with relapse, stressing the importance of continuing treatment and taking their maintenance medication exactly as prescribed.

There are other steps you can take to safeguard patients—eg, providing naloxone rescue kits to patients and their families when appropriate. You can also institute diversion and overdose prevention measures for patients taking buprenorphine or methadone—providing a lock box for take-home medication, implementing treatment contracts, and using a designated pharmacy to dispense buprenorphine, for example.^26,27,50

Regular monitoring, urine drug screens (see TABLE W1), and random pill counts, in which patients are typically given 24 hours to bring in their prescribed medication so it can be counted, can also help keep patients on track. Treatment for concurrent psychiatric disorders—depression, anxiety, and personality disorders are common among patients with opioid dependence—is likely to improve the outcome of treatment, as well.

TABLE W1
Pharmacokinetics of common opioids: Time detectable in urine*

CORRESPONDENCE Kevin P. Hill, MD, MHS, McLean Hospital, 115 Mill Street, Belmont, MA 02478; [email protected]

Primary care physicians frequently encourage patients to lead a more active, healthy lifestyle. The rise in popularity of endurance events, yoga, and organized gym-based fitness classes has, no doubt, improved the health of those who participate. But what happens when an individual moves too quickly from a sedentary existence to a more physically active one?

In this article we describe 2 clinical cases of rhabdomyolysis that occurred after healthy individuals participated for the first time in a class involving high-intensity stationary cycling, known as “spinning.” This exercise activity originated in California around 1989 when a competitive cyclist introduced variable resistance and speed training to stationary cycle workouts.¹ Over the last 10 years, spinning has gained a worldwide following as a means of building cardiovascular endurance while achieving a significant calorie burn.

CASE 1: Lack of conditioning, improper hydration spell trouble

A previously healthy 38-year-old white man presented with left lower extremity pain and dark urine. Three days earlier, he had participated in a spin class for the first time. Despite a sedentary lifestyle, he had no difficulty completing the session and felt fine during the class. He did feel mildly fatigued afterward. The next day, he played 18 holes of golf in hot, humid weather. He admitted to poor fluid intake, stating he “drank a few beers” during the round. The next day, he began noticing discomfort and swelling in his left knee, which progressed to his anterior thigh. That evening, he became concerned because of a dark red tint to his urine. He was not taking any medications.

The physical exam was unremarkable except for a moderately swollen, tender knee with reduced range of motion. An x-ray of the knee showed a moderate suprapatellar effusion, but no fracture or dislocation. Urinalysis was remarkable for blood and myoglobin. The CPK value was 149,985 U/L (normal, 24-170 U/L), AST was 2234 U/L (normal, 9-25 U/L), ALT was 570 U/L (normal, 7-30 U/L), and BMI was 26.6 kg/m². Renal function was normal, as evidenced by a BUN of 17 mg/dL and a creatinine level of 1.0 mg/dL. He was afebrile and his WBC count was 9.6 x 10³/mm³.

We hospitalized the patient with a diagnosis of rhabdomyolysis and started him on aggressive intravenous (IV) hydration. The patient’s CPK and transaminase levels started trending down the next day, urine output (UOP) remained at goal, and renal function remained stable. Pain and swelling diminished over the next 3 days. He was discharged home on Day 4. At discharge, his CPK level was 26,180 U/L, BUN 10 mg/dL, and creatinine 0.8 mg/dL. At 1 month follow-up, his CPK was within normal limits.

CASE 2: Even those who exercise regularly can overdo it

A previously healthy 26-year-old white woman sought care at our clinic complaining of bilateral leg pain and dark urine. Despite being overweight, she regularly engaged in moderate exercise, and 2 days prior had participated in her first spin class. She felt some discomfort 30 minutes into the class, and the next day noted discomfort in her anterior thighs, which progressively worsened. Two days after the workout, her pain was worse and her urine became reddish-brown. She was not taking any medications.

The physical exam was unremarkable except for antalgic gait and tenderness of the anterior thighs, which were also moderately firm and warm to the touch. Urinalysis showed a large blood concentration and was positive for myoglobin. ALT was 366 U/L, AST was 1383 U/L, CPK was 86,592 U/L, and BMI was 33.36 kg/m². A BUN level of 11 mg/dL and creatinine level of 0.8 mg/dL suggested normal renal function. Her WBC count was 12.2 x 10³/mm³.

We hospitalized the patient for a presumptive diagnosis of rhabdomyolysis, and initiated aggressive IV hydration to achieve a UOP of at least 200 mL/h. CPK levels and renal and liver function were closely monitored. On hospital Day 2, the patient’s thighs were tender and tight, so we consulted orthopedics about possible compartment syndrome. The consultant believed that intervention was unwarranted.

By Day 3, the swelling and pain began to resolve. UOP remained at target, and CPK and transaminase levels continued to trend down. Renal function remained stable. The patient was discharged home on Day 4 with a CPK of 11,388 U/L, BUN of 8 mg/dL, and creatinine of 0.7 mg/dL. At her 2-week follow-up, CPK was down to 772 U/L, and transaminases were within normal limits.

Discussion

Rhabdomyolysis occurs as a result of damage to the striated muscle cell membranes. Such injury releases into the systemic circulation calcium, potassium, phosphate, urate myoglobin, CPK, aldolase, lactate dehydrogenase, AST, and ALT. In the presence of excess calcium, further muscle fiber necrosis occurs and can lead to acute renal failure.^2,3 Serum haptoglobin binding capacity becomes overly saturated. This results in free myoglobin, causing renal tubular obstruction. Myoglobin then dissociates into ferrihemate and globulin. Ferrihemate further exacerbates failure of the renal tubular transport system, eventually resulting in cell death and renal failure.²

Military trainees and casual athletes comprise many of the cases of exercise- induced rhabdomyolysis.^4-6 People who exercise regularly are less likely to develop the condition than their more sedentary counterparts. As with our cases, a sudden increase in the intensity and duration of vigorous exercise, without proper training, may increase the likelihood of rhabdomyolysis.⁶

Other potential underlying causes. In addition to exercise and dehydration as depicted in our cases, rhabdomyolysis can result from burns, shock, acidosis, infections, crush trauma, immobility, malignancy, medications, toxins, abuse of drugs, or pre-existing illness such as sickle cell trait or other metabolic conditions.^7,8

Clinical presentation varies. Regardless of the cause, patients typically present with muscle pain, weakness and cramping, and discolored urine.^4,8 However, many patients will have dark urine associated with other symptoms, such as general malaise, visceral pain, swelling, muscle stiffness and tightness, fever, tachycardia, nausea, and vomiting.^2,3 A careful history may help elucidate the cause.

Laboratory clues. Diagnostic guidelines commonly specify a serum CPK level 5 times the upper limit of normal as an indication of rhabdomyolysis, specifically in the exertional variety.⁹ Typically the level of this is around 1000 U/L.³ However, there is no agreement on what CPK level is diagnostic of rhabdomyolysis. Suggestions range from 1000 to 20,000 U/L.^3,8 A CPK level in excess of 5000 U/L increases the risk for acute renal failure and renal cell death.^3,10 In athletes, an elevated CPK after working out is not uncommon and may be much higher than in other individuals.^6,8 Endurance exercises such as marathon running or cycling have been noted to elevate CPK for up to 2 hours postexercise.⁸

Myoglobin becomes detectable in urine when it exceeds 1.5 mg/dL.¹⁰ Urine becomes tea-colored or reddish-brown when myoglobin is >100 mg/dL.¹⁰

Complications from rhabdomyolysis include compartment syndrome, hyperkalemia, disseminated intravascular coagulation, coagulopathies, and acute renal failure.

Treatment for rhabdomyolysis consists of aggressive IV hydration with normal saline (with variable rate) or crystalloids to maintain a UOP of 200 to 300 mL/h.^2,3,11 Avoid fluid overload in the elderly and those with renal or cardiac disease.² As CPK and myoglobin continue to trend down, it’s important to adjust IV fluids and electrolyte replacement.^2,11 Using bicarbonate to alkalinize the urine is controversial, with no studies showing any benefit.^3,10 In severe situations, consider a nephrology consult for hemodialysis to bring down CPK, which may be secondary to renal failure and hyperkalemia.^2,10 However, renal failure is less likely to occur in physically active, healthy athletes.

Advice after recovery. After an episode of acute rhabdomyolysis, conditioned athletes can return to physical training with resolution of their symptoms or a CPK level from 1000 to 5000 U/L, usually within a week.⁶ A more judicious approach may be needed for less fit individuals. Regardless of their fitness level, advise patients to avoid diuretics and alcohol before exercise, remain hydrated during and after exercise, and avoid overheating to decrease the likelihood of developing rhabdomyolysis.⁴ However, in patients with sickle cell trait, exertional sickling can occur with intensity of exercise without overheating.⁷

In the case of our male patient, poor physical conditioning and intensive, prolonged exercise followed by poor hydration and the diuretic effect of alcohol created the perfect storm for the development of rhabdomyolysis. On the other hand, our female patient routinely exercised, but still pushed herself beyond her limit and went too far too fast. Although BMI may play a role in the development of rhabdomyolysis, it does not appear to be as significant a factor as hydration status and overall physical conditioning.

Our patients’ prompt attention to the need for medical help and the recognition of the problem by their clinicians contributed to good outcomes in both cases.

CORRESPONDENCE Jacqueline DuBose, MD, Department of Family Medicine, Georgia Health Sciences University, 1120 15th Street, Augusta, GA 30912; [email protected]

Primary care physicians frequently encourage patients to lead a more active, healthy lifestyle. The rise in popularity of endurance events, yoga, and organized gym-based fitness classes has, no doubt, improved the health of those who participate. But what happens when an individual moves too quickly from a sedentary existence to a more physically active one?

In this article we describe 2 clinical cases of rhabdomyolysis that occurred after healthy individuals participated for the first time in a class involving high-intensity stationary cycling, known as “spinning.” This exercise activity originated in California around 1989 when a competitive cyclist introduced variable resistance and speed training to stationary cycle workouts.¹ Over the last 10 years, spinning has gained a worldwide following as a means of building cardiovascular endurance while achieving a significant calorie burn.

CASE 1: Lack of conditioning, improper hydration spell trouble

A previously healthy 38-year-old white man presented with left lower extremity pain and dark urine. Three days earlier, he had participated in a spin class for the first time. Despite a sedentary lifestyle, he had no difficulty completing the session and felt fine during the class. He did feel mildly fatigued afterward. The next day, he played 18 holes of golf in hot, humid weather. He admitted to poor fluid intake, stating he “drank a few beers” during the round. The next day, he began noticing discomfort and swelling in his left knee, which progressed to his anterior thigh. That evening, he became concerned because of a dark red tint to his urine. He was not taking any medications.

The physical exam was unremarkable except for a moderately swollen, tender knee with reduced range of motion. An x-ray of the knee showed a moderate suprapatellar effusion, but no fracture or dislocation. Urinalysis was remarkable for blood and myoglobin. The CPK value was 149,985 U/L (normal, 24-170 U/L), AST was 2234 U/L (normal, 9-25 U/L), ALT was 570 U/L (normal, 7-30 U/L), and BMI was 26.6 kg/m². Renal function was normal, as evidenced by a BUN of 17 mg/dL and a creatinine level of 1.0 mg/dL. He was afebrile and his WBC count was 9.6 x 10³/mm³.

We hospitalized the patient with a diagnosis of rhabdomyolysis and started him on aggressive intravenous (IV) hydration. The patient’s CPK and transaminase levels started trending down the next day, urine output (UOP) remained at goal, and renal function remained stable. Pain and swelling diminished over the next 3 days. He was discharged home on Day 4. At discharge, his CPK level was 26,180 U/L, BUN 10 mg/dL, and creatinine 0.8 mg/dL. At 1 month follow-up, his CPK was within normal limits.

CASE 2: Even those who exercise regularly can overdo it

A previously healthy 26-year-old white woman sought care at our clinic complaining of bilateral leg pain and dark urine. Despite being overweight, she regularly engaged in moderate exercise, and 2 days prior had participated in her first spin class. She felt some discomfort 30 minutes into the class, and the next day noted discomfort in her anterior thighs, which progressively worsened. Two days after the workout, her pain was worse and her urine became reddish-brown. She was not taking any medications.

The physical exam was unremarkable except for antalgic gait and tenderness of the anterior thighs, which were also moderately firm and warm to the touch. Urinalysis showed a large blood concentration and was positive for myoglobin. ALT was 366 U/L, AST was 1383 U/L, CPK was 86,592 U/L, and BMI was 33.36 kg/m². A BUN level of 11 mg/dL and creatinine level of 0.8 mg/dL suggested normal renal function. Her WBC count was 12.2 x 10³/mm³.

We hospitalized the patient for a presumptive diagnosis of rhabdomyolysis, and initiated aggressive IV hydration to achieve a UOP of at least 200 mL/h. CPK levels and renal and liver function were closely monitored. On hospital Day 2, the patient’s thighs were tender and tight, so we consulted orthopedics about possible compartment syndrome. The consultant believed that intervention was unwarranted.

By Day 3, the swelling and pain began to resolve. UOP remained at target, and CPK and transaminase levels continued to trend down. Renal function remained stable. The patient was discharged home on Day 4 with a CPK of 11,388 U/L, BUN of 8 mg/dL, and creatinine of 0.7 mg/dL. At her 2-week follow-up, CPK was down to 772 U/L, and transaminases were within normal limits.

Discussion

Rhabdomyolysis occurs as a result of damage to the striated muscle cell membranes. Such injury releases into the systemic circulation calcium, potassium, phosphate, urate myoglobin, CPK, aldolase, lactate dehydrogenase, AST, and ALT. In the presence of excess calcium, further muscle fiber necrosis occurs and can lead to acute renal failure.^2,3 Serum haptoglobin binding capacity becomes overly saturated. This results in free myoglobin, causing renal tubular obstruction. Myoglobin then dissociates into ferrihemate and globulin. Ferrihemate further exacerbates failure of the renal tubular transport system, eventually resulting in cell death and renal failure.²

Military trainees and casual athletes comprise many of the cases of exercise- induced rhabdomyolysis.^4-6 People who exercise regularly are less likely to develop the condition than their more sedentary counterparts. As with our cases, a sudden increase in the intensity and duration of vigorous exercise, without proper training, may increase the likelihood of rhabdomyolysis.⁶

Other potential underlying causes. In addition to exercise and dehydration as depicted in our cases, rhabdomyolysis can result from burns, shock, acidosis, infections, crush trauma, immobility, malignancy, medications, toxins, abuse of drugs, or pre-existing illness such as sickle cell trait or other metabolic conditions.^7,8

Clinical presentation varies. Regardless of the cause, patients typically present with muscle pain, weakness and cramping, and discolored urine.^4,8 However, many patients will have dark urine associated with other symptoms, such as general malaise, visceral pain, swelling, muscle stiffness and tightness, fever, tachycardia, nausea, and vomiting.^2,3 A careful history may help elucidate the cause.

Laboratory clues. Diagnostic guidelines commonly specify a serum CPK level 5 times the upper limit of normal as an indication of rhabdomyolysis, specifically in the exertional variety.⁹ Typically the level of this is around 1000 U/L.³ However, there is no agreement on what CPK level is diagnostic of rhabdomyolysis. Suggestions range from 1000 to 20,000 U/L.^3,8 A CPK level in excess of 5000 U/L increases the risk for acute renal failure and renal cell death.^3,10 In athletes, an elevated CPK after working out is not uncommon and may be much higher than in other individuals.^6,8 Endurance exercises such as marathon running or cycling have been noted to elevate CPK for up to 2 hours postexercise.⁸

Myoglobin becomes detectable in urine when it exceeds 1.5 mg/dL.¹⁰ Urine becomes tea-colored or reddish-brown when myoglobin is >100 mg/dL.¹⁰

Complications from rhabdomyolysis include compartment syndrome, hyperkalemia, disseminated intravascular coagulation, coagulopathies, and acute renal failure.

Treatment for rhabdomyolysis consists of aggressive IV hydration with normal saline (with variable rate) or crystalloids to maintain a UOP of 200 to 300 mL/h.^2,3,11 Avoid fluid overload in the elderly and those with renal or cardiac disease.² As CPK and myoglobin continue to trend down, it’s important to adjust IV fluids and electrolyte replacement.^2,11 Using bicarbonate to alkalinize the urine is controversial, with no studies showing any benefit.^3,10 In severe situations, consider a nephrology consult for hemodialysis to bring down CPK, which may be secondary to renal failure and hyperkalemia.^2,10 However, renal failure is less likely to occur in physically active, healthy athletes.

Advice after recovery. After an episode of acute rhabdomyolysis, conditioned athletes can return to physical training with resolution of their symptoms or a CPK level from 1000 to 5000 U/L, usually within a week.⁶ A more judicious approach may be needed for less fit individuals. Regardless of their fitness level, advise patients to avoid diuretics and alcohol before exercise, remain hydrated during and after exercise, and avoid overheating to decrease the likelihood of developing rhabdomyolysis.⁴ However, in patients with sickle cell trait, exertional sickling can occur with intensity of exercise without overheating.⁷

In the case of our male patient, poor physical conditioning and intensive, prolonged exercise followed by poor hydration and the diuretic effect of alcohol created the perfect storm for the development of rhabdomyolysis. On the other hand, our female patient routinely exercised, but still pushed herself beyond her limit and went too far too fast. Although BMI may play a role in the development of rhabdomyolysis, it does not appear to be as significant a factor as hydration status and overall physical conditioning.

Our patients’ prompt attention to the need for medical help and the recognition of the problem by their clinicians contributed to good outcomes in both cases.

CORRESPONDENCE Jacqueline DuBose, MD, Department of Family Medicine, Georgia Health Sciences University, 1120 15th Street, Augusta, GA 30912; [email protected]

Primary care physicians frequently encourage patients to lead a more active, healthy lifestyle. The rise in popularity of endurance events, yoga, and organized gym-based fitness classes has, no doubt, improved the health of those who participate. But what happens when an individual moves too quickly from a sedentary existence to a more physically active one?

In this article we describe 2 clinical cases of rhabdomyolysis that occurred after healthy individuals participated for the first time in a class involving high-intensity stationary cycling, known as “spinning.” This exercise activity originated in California around 1989 when a competitive cyclist introduced variable resistance and speed training to stationary cycle workouts.¹ Over the last 10 years, spinning has gained a worldwide following as a means of building cardiovascular endurance while achieving a significant calorie burn.

CASE 1: Lack of conditioning, improper hydration spell trouble

A previously healthy 38-year-old white man presented with left lower extremity pain and dark urine. Three days earlier, he had participated in a spin class for the first time. Despite a sedentary lifestyle, he had no difficulty completing the session and felt fine during the class. He did feel mildly fatigued afterward. The next day, he played 18 holes of golf in hot, humid weather. He admitted to poor fluid intake, stating he “drank a few beers” during the round. The next day, he began noticing discomfort and swelling in his left knee, which progressed to his anterior thigh. That evening, he became concerned because of a dark red tint to his urine. He was not taking any medications.

The physical exam was unremarkable except for a moderately swollen, tender knee with reduced range of motion. An x-ray of the knee showed a moderate suprapatellar effusion, but no fracture or dislocation. Urinalysis was remarkable for blood and myoglobin. The CPK value was 149,985 U/L (normal, 24-170 U/L), AST was 2234 U/L (normal, 9-25 U/L), ALT was 570 U/L (normal, 7-30 U/L), and BMI was 26.6 kg/m². Renal function was normal, as evidenced by a BUN of 17 mg/dL and a creatinine level of 1.0 mg/dL. He was afebrile and his WBC count was 9.6 x 10³/mm³.

We hospitalized the patient with a diagnosis of rhabdomyolysis and started him on aggressive intravenous (IV) hydration. The patient’s CPK and transaminase levels started trending down the next day, urine output (UOP) remained at goal, and renal function remained stable. Pain and swelling diminished over the next 3 days. He was discharged home on Day 4. At discharge, his CPK level was 26,180 U/L, BUN 10 mg/dL, and creatinine 0.8 mg/dL. At 1 month follow-up, his CPK was within normal limits.

CASE 2: Even those who exercise regularly can overdo it

A previously healthy 26-year-old white woman sought care at our clinic complaining of bilateral leg pain and dark urine. Despite being overweight, she regularly engaged in moderate exercise, and 2 days prior had participated in her first spin class. She felt some discomfort 30 minutes into the class, and the next day noted discomfort in her anterior thighs, which progressively worsened. Two days after the workout, her pain was worse and her urine became reddish-brown. She was not taking any medications.

The physical exam was unremarkable except for antalgic gait and tenderness of the anterior thighs, which were also moderately firm and warm to the touch. Urinalysis showed a large blood concentration and was positive for myoglobin. ALT was 366 U/L, AST was 1383 U/L, CPK was 86,592 U/L, and BMI was 33.36 kg/m². A BUN level of 11 mg/dL and creatinine level of 0.8 mg/dL suggested normal renal function. Her WBC count was 12.2 x 10³/mm³.

We hospitalized the patient for a presumptive diagnosis of rhabdomyolysis, and initiated aggressive IV hydration to achieve a UOP of at least 200 mL/h. CPK levels and renal and liver function were closely monitored. On hospital Day 2, the patient’s thighs were tender and tight, so we consulted orthopedics about possible compartment syndrome. The consultant believed that intervention was unwarranted.

By Day 3, the swelling and pain began to resolve. UOP remained at target, and CPK and transaminase levels continued to trend down. Renal function remained stable. The patient was discharged home on Day 4 with a CPK of 11,388 U/L, BUN of 8 mg/dL, and creatinine of 0.7 mg/dL. At her 2-week follow-up, CPK was down to 772 U/L, and transaminases were within normal limits.

Discussion

Rhabdomyolysis occurs as a result of damage to the striated muscle cell membranes. Such injury releases into the systemic circulation calcium, potassium, phosphate, urate myoglobin, CPK, aldolase, lactate dehydrogenase, AST, and ALT. In the presence of excess calcium, further muscle fiber necrosis occurs and can lead to acute renal failure.^2,3 Serum haptoglobin binding capacity becomes overly saturated. This results in free myoglobin, causing renal tubular obstruction. Myoglobin then dissociates into ferrihemate and globulin. Ferrihemate further exacerbates failure of the renal tubular transport system, eventually resulting in cell death and renal failure.²

Military trainees and casual athletes comprise many of the cases of exercise- induced rhabdomyolysis.^4-6 People who exercise regularly are less likely to develop the condition than their more sedentary counterparts. As with our cases, a sudden increase in the intensity and duration of vigorous exercise, without proper training, may increase the likelihood of rhabdomyolysis.⁶

Other potential underlying causes. In addition to exercise and dehydration as depicted in our cases, rhabdomyolysis can result from burns, shock, acidosis, infections, crush trauma, immobility, malignancy, medications, toxins, abuse of drugs, or pre-existing illness such as sickle cell trait or other metabolic conditions.^7,8

Clinical presentation varies. Regardless of the cause, patients typically present with muscle pain, weakness and cramping, and discolored urine.^4,8 However, many patients will have dark urine associated with other symptoms, such as general malaise, visceral pain, swelling, muscle stiffness and tightness, fever, tachycardia, nausea, and vomiting.^2,3 A careful history may help elucidate the cause.

Laboratory clues. Diagnostic guidelines commonly specify a serum CPK level 5 times the upper limit of normal as an indication of rhabdomyolysis, specifically in the exertional variety.⁹ Typically the level of this is around 1000 U/L.³ However, there is no agreement on what CPK level is diagnostic of rhabdomyolysis. Suggestions range from 1000 to 20,000 U/L.^3,8 A CPK level in excess of 5000 U/L increases the risk for acute renal failure and renal cell death.^3,10 In athletes, an elevated CPK after working out is not uncommon and may be much higher than in other individuals.^6,8 Endurance exercises such as marathon running or cycling have been noted to elevate CPK for up to 2 hours postexercise.⁸

Myoglobin becomes detectable in urine when it exceeds 1.5 mg/dL.¹⁰ Urine becomes tea-colored or reddish-brown when myoglobin is >100 mg/dL.¹⁰

Complications from rhabdomyolysis include compartment syndrome, hyperkalemia, disseminated intravascular coagulation, coagulopathies, and acute renal failure.

Treatment for rhabdomyolysis consists of aggressive IV hydration with normal saline (with variable rate) or crystalloids to maintain a UOP of 200 to 300 mL/h.^2,3,11 Avoid fluid overload in the elderly and those with renal or cardiac disease.² As CPK and myoglobin continue to trend down, it’s important to adjust IV fluids and electrolyte replacement.^2,11 Using bicarbonate to alkalinize the urine is controversial, with no studies showing any benefit.^3,10 In severe situations, consider a nephrology consult for hemodialysis to bring down CPK, which may be secondary to renal failure and hyperkalemia.^2,10 However, renal failure is less likely to occur in physically active, healthy athletes.

Advice after recovery. After an episode of acute rhabdomyolysis, conditioned athletes can return to physical training with resolution of their symptoms or a CPK level from 1000 to 5000 U/L, usually within a week.⁶ A more judicious approach may be needed for less fit individuals. Regardless of their fitness level, advise patients to avoid diuretics and alcohol before exercise, remain hydrated during and after exercise, and avoid overheating to decrease the likelihood of developing rhabdomyolysis.⁴ However, in patients with sickle cell trait, exertional sickling can occur with intensity of exercise without overheating.⁷

In the case of our male patient, poor physical conditioning and intensive, prolonged exercise followed by poor hydration and the diuretic effect of alcohol created the perfect storm for the development of rhabdomyolysis. On the other hand, our female patient routinely exercised, but still pushed herself beyond her limit and went too far too fast. Although BMI may play a role in the development of rhabdomyolysis, it does not appear to be as significant a factor as hydration status and overall physical conditioning.

Our patients’ prompt attention to the need for medical help and the recognition of the problem by their clinicians contributed to good outcomes in both cases.

CORRESPONDENCE Jacqueline DuBose, MD, Department of Family Medicine, Georgia Health Sciences University, 1120 15th Street, Augusta, GA 30912; [email protected]

Mrs. A, age 68, has a 40-year history of schizoaffective disorder with comorbid anxiety disorder not otherwise specified, type 2 diabetes mellitus, and hypertension. She takes furosemide, 40 mg/d, lisinopril, 20 mg/d, and metformin, 2,000 mg/d, for hypertension and diabetes; lorazepam, 1.5 mg/d, and paroxetine, 40 mg/d, for anxiety; and quetiapine extended release, 800 mg/d, for psychotic features and mood dysregulation with schizoaffective disorder. Mrs. A’s husband died 5 years ago and she lives alone in a senior care facility. Mrs. A uses a weekly pill reminder box because her residential facility does not monitor medication adherence. She sees her psychiatrist once a month and her primary care provider every 3 months. She has no history of illicit drug, alcohol, or tobacco use.

Two weeks ago, Mrs. A was found leaning against the wall in a hallway, complaining of dizziness and disorientation, and unable to find her way back to her apartment. In the emergency department, her serum potassium is low (3.0 mEq/L; normal range: 3.5 to 5.0), fasting glucose is elevated (110 mg/dL; range: 65 to 99), and ECG reveals a prolonged QTc interval of 530 milliseconds. Before this episode, Mrs. A had been medically stable without mood or psychotic symptoms, although her daughter reported medication self-administration was becoming difficult.

Exposure to psychotropics carries a risk of QTc prolongation. The QT interval is an ECG measure of ventricular depolarization and repolarization. The QTc designation indicates a correction for heart rate with increasing heart rate correlating with a shorter QT interval. Readings of 440 milliseconds are considered normal.¹ QTc prolongation is defined as >450 milliseconds for men and >470 milliseconds for women.² An increase in the QT interval is a predictor of serious cardiac events.³

Antidepressants and antipsychotics have been associated with QTc prolongation. When identifying agents that could disrupt cardiac conduction, clinicians need to consider whether the drug’s molecular structure, receptor affinity, or pharmacologic effects are most critical.² Although these may be important, patient-specific variables that increase the risk of QTc prolongation may have greater impact. These include:

• age >65
• female sex
• electrolyte imbalances (specifically low serum potassium and magnesium levels)
• high or toxic serum levels of the suspected drug
• preexisting cardiovascular impairment, such as bradycardia.^4,5

Other risk factors include concurrent use of an agent with similar cardiovascular effects or one that competes for metabolism (either enzymatic or at the binding site), physiologic limitations such as renal insufficiency, and medication changes that may increase or decrease psychotropic clearance.^4,6 Geriatric patients with dementia have an increased risk for cardiovascular-related death.^7,8

Antidepressants

Among tricyclic antidepressants, most reports of QTc prolongation involve amitriptyline and maprotiline.⁹ Risk factors include demographics (eg, female sex, age), personal or family history (congenital long QT syndrome, cardiovascular disease), and concurrent conditions or drug use, particularly those associated with QTc prolongation.³ Desipramine and nortriptyline also have been identified as high-risk agents.¹⁰

QTc prolongation has been reported with all selective serotonin reuptake inhibitors at plasma concentrations above the therapeutic level.¹¹ Fluoxetine-associated QTc prolongation was limited to cases of overdose or when additional risk factors were reported.⁴ QTc prolongation from psychotropics could increase the risk of torsades de pointes, according to an analysis of the FDA Adverse Event Reporting System.¹² In 2011, the FDA reported an increased risk of abnormal heart rhythms—including QTc prolongation—with citalopram doses >40 mg/d.¹³ Although cases of QTc prolongation with paroxetine have not been reported,¹¹ the Arizona Center for Education and Research on Therapeutics lists paroxetine with other agents that may increase the risk for QTc prolongation with concurrent use of medications that may prolong QTc interval.¹⁴ Venlafaxine doses >300 mg/d may require additional cardiac monitoring.^5,12 Data from venlafaxine poisoning case reports found a positive correlation between dose and QTc prolongation.¹⁵ In a review of toxicology database information, Wenzel-Seifert et al⁴ found extended QT interval with citalopram, fluoxetine, and venlafaxine at toxic doses or in the presence of additional risk factors such as sex, older age, or personal or family history of congenital long QT syndrome or cardiovascular disease.

Antipsychotics

Case reports, case series, and research trials have evaluated the risk of QTc prolongation with antipsychotics (Table).^1,2,4,16,17 The first-generation antipsychotics thioridazine,^4,16,18 mesoridazine,^16,18 chlorpromazine,¹⁹ and haloperidol³ warrant cardiac monitoring. The QTc prolongation effects of thioridazine and its active metabolite mesoridazine are well-documented and thioridazine-mediated QTc prolongation increases are dose-dependent.^4,18 ECG monitoring is recommended with IV haloperidol, which is used for delirium in adults.²⁰ QTc prolongation has been associated with long-term ziprasidone use more often than with risperidone, olanzapine, or quetiapine.¹⁹ Ziprasidone prolongs the QTc interval an average of 20 milliseconds,²¹ which could represent a clinically significant change. QTc prolongation for iloperidone is comparable to ziprasidone and haloperidol.²² There is some evidence that aripiprazole may shorten, rather than prolong, the QTc interval.^4,17

Cardiovascular adverse effects associated with clozapine—including QTc prolongation—are dose-dependent.³ Olanzapine prolongs QTc interval, although the mean change is less than with other agents unless other variables were present, such as:

• concomitant use of medications that may prolong QTc interval (ie, amantadine, hydroxyzine, or tamoxifen²)
• preexisting cardiovascular conduction disorders
• higher doses (>40 mg/d).^3,23

In 17 case reports of cardiac changes associated with quetiapine use, doses ranged from 100 mg/d²⁴ to an overdose of 36 g/d.²⁵ Only 1 patient death was reported secondary to overdose and preexisting dysrhythmia and hypertension.²⁶ QTc prolongation associated with risperidone was minor¹ based on oral doses in the normal therapeutic range and incidences of overdose.¹⁰ Paliperidone²⁷ and lurasidone²⁸ are associated with clinically insignificant QTc prolongation. Changes in QTc interval were positively correlated with asenapine dose, although at the highest dose of 40 mg/d, the increase was <5 milliseconds.²⁹

Mrs. A presents with a number of risk factors for QTc prolongation, including older age, female sex, and psychiatric and medical comorbidities that require medication. A pill count revealed that she was taking more than the prescribed daily doses of her medications. During the interview, Mrs. A said that if she missed her medication time, she would take them when she remembered. If she could not remember if she took her pills, she would take them again. Her physicians will explore strategies to increase medication adherence.

Table

Examples of QTc prolongation associated with select antipsychotics^a

Related Resources

• De Hert M, Detraux J, van Winkel R, et al. Metabolic and cardiovascular adverse effects associated with antipsychotic drugs. Nat Rev Endocrinol. 2011;8(2):114-126.
• Vieweg WV, Wood MA, Fernandez A, et al. Proarrhythmic risk with antipsychotic and antidepressant drugs: implications in the elderly. Drugs Aging. 2009;26(12):997-1012.
• Sandson NB, Armstrong SC, Cozza KL. An overview of psychotropic drug-drug interactions. Psychosomatics. 2005;46(5):464-494.

Drug Brand Names

• Amantadine • Symmetrel
• Amitriptyline • Elavil
• Aripiprazole • Abilify
• Asenapine • Saphris
• Chlorpromazine • Thorazine
• Citalopram • Celexa
• Clozapine • Clozaril
• Desipramine • Norpramin
• Fluoxetine • Prozac
• Furosemide • Lasix
• Haloperidol • Haldol
• Hydroxyzine • Atarax, Vistaril
• Iloperidone • Fanapt
• Lisinopril • Prinivil, Zestril
• Lorazepam • Ativan
• Lurasidone • Latuda
• Maprotiline • Ludiomil
• Mesoridazine • Serentil
• Metformin • Glucophage
• Nortriptyline • Pamelor
• Olanzapine • Zyprexa
• Paliperidone • Invega
• Paroxetine • Paxil
• Pimozide • Orap
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Tamoxifen • Nolvadex, Soltamox
• Thioridazine • Mellaril
• Venlafaxine • Effexor
• Ziprasidone • Geodon

Disclosures

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products. No similar work by the authors is under review or in press. No funding was requested or received in conjunction with this manuscript.

Mrs. A, age 68, has a 40-year history of schizoaffective disorder with comorbid anxiety disorder not otherwise specified, type 2 diabetes mellitus, and hypertension. She takes furosemide, 40 mg/d, lisinopril, 20 mg/d, and metformin, 2,000 mg/d, for hypertension and diabetes; lorazepam, 1.5 mg/d, and paroxetine, 40 mg/d, for anxiety; and quetiapine extended release, 800 mg/d, for psychotic features and mood dysregulation with schizoaffective disorder. Mrs. A’s husband died 5 years ago and she lives alone in a senior care facility. Mrs. A uses a weekly pill reminder box because her residential facility does not monitor medication adherence. She sees her psychiatrist once a month and her primary care provider every 3 months. She has no history of illicit drug, alcohol, or tobacco use.

Two weeks ago, Mrs. A was found leaning against the wall in a hallway, complaining of dizziness and disorientation, and unable to find her way back to her apartment. In the emergency department, her serum potassium is low (3.0 mEq/L; normal range: 3.5 to 5.0), fasting glucose is elevated (110 mg/dL; range: 65 to 99), and ECG reveals a prolonged QTc interval of 530 milliseconds. Before this episode, Mrs. A had been medically stable without mood or psychotic symptoms, although her daughter reported medication self-administration was becoming difficult.

Exposure to psychotropics carries a risk of QTc prolongation. The QT interval is an ECG measure of ventricular depolarization and repolarization. The QTc designation indicates a correction for heart rate with increasing heart rate correlating with a shorter QT interval. Readings of 440 milliseconds are considered normal.¹ QTc prolongation is defined as >450 milliseconds for men and >470 milliseconds for women.² An increase in the QT interval is a predictor of serious cardiac events.³

Antidepressants and antipsychotics have been associated with QTc prolongation. When identifying agents that could disrupt cardiac conduction, clinicians need to consider whether the drug’s molecular structure, receptor affinity, or pharmacologic effects are most critical.² Although these may be important, patient-specific variables that increase the risk of QTc prolongation may have greater impact. These include:

• age >65
• female sex
• electrolyte imbalances (specifically low serum potassium and magnesium levels)
• high or toxic serum levels of the suspected drug
• preexisting cardiovascular impairment, such as bradycardia.^4,5

Other risk factors include concurrent use of an agent with similar cardiovascular effects or one that competes for metabolism (either enzymatic or at the binding site), physiologic limitations such as renal insufficiency, and medication changes that may increase or decrease psychotropic clearance.^4,6 Geriatric patients with dementia have an increased risk for cardiovascular-related death.^7,8

Antidepressants

Among tricyclic antidepressants, most reports of QTc prolongation involve amitriptyline and maprotiline.⁹ Risk factors include demographics (eg, female sex, age), personal or family history (congenital long QT syndrome, cardiovascular disease), and concurrent conditions or drug use, particularly those associated with QTc prolongation.³ Desipramine and nortriptyline also have been identified as high-risk agents.¹⁰

QTc prolongation has been reported with all selective serotonin reuptake inhibitors at plasma concentrations above the therapeutic level.¹¹ Fluoxetine-associated QTc prolongation was limited to cases of overdose or when additional risk factors were reported.⁴ QTc prolongation from psychotropics could increase the risk of torsades de pointes, according to an analysis of the FDA Adverse Event Reporting System.¹² In 2011, the FDA reported an increased risk of abnormal heart rhythms—including QTc prolongation—with citalopram doses >40 mg/d.¹³ Although cases of QTc prolongation with paroxetine have not been reported,¹¹ the Arizona Center for Education and Research on Therapeutics lists paroxetine with other agents that may increase the risk for QTc prolongation with concurrent use of medications that may prolong QTc interval.¹⁴ Venlafaxine doses >300 mg/d may require additional cardiac monitoring.^5,12 Data from venlafaxine poisoning case reports found a positive correlation between dose and QTc prolongation.¹⁵ In a review of toxicology database information, Wenzel-Seifert et al⁴ found extended QT interval with citalopram, fluoxetine, and venlafaxine at toxic doses or in the presence of additional risk factors such as sex, older age, or personal or family history of congenital long QT syndrome or cardiovascular disease.

Antipsychotics

Case reports, case series, and research trials have evaluated the risk of QTc prolongation with antipsychotics (Table).^1,2,4,16,17 The first-generation antipsychotics thioridazine,^4,16,18 mesoridazine,^16,18 chlorpromazine,¹⁹ and haloperidol³ warrant cardiac monitoring. The QTc prolongation effects of thioridazine and its active metabolite mesoridazine are well-documented and thioridazine-mediated QTc prolongation increases are dose-dependent.^4,18 ECG monitoring is recommended with IV haloperidol, which is used for delirium in adults.²⁰ QTc prolongation has been associated with long-term ziprasidone use more often than with risperidone, olanzapine, or quetiapine.¹⁹ Ziprasidone prolongs the QTc interval an average of 20 milliseconds,²¹ which could represent a clinically significant change. QTc prolongation for iloperidone is comparable to ziprasidone and haloperidol.²² There is some evidence that aripiprazole may shorten, rather than prolong, the QTc interval.^4,17

Cardiovascular adverse effects associated with clozapine—including QTc prolongation—are dose-dependent.³ Olanzapine prolongs QTc interval, although the mean change is less than with other agents unless other variables were present, such as:

• concomitant use of medications that may prolong QTc interval (ie, amantadine, hydroxyzine, or tamoxifen²)
• preexisting cardiovascular conduction disorders
• higher doses (>40 mg/d).^3,23

In 17 case reports of cardiac changes associated with quetiapine use, doses ranged from 100 mg/d²⁴ to an overdose of 36 g/d.²⁵ Only 1 patient death was reported secondary to overdose and preexisting dysrhythmia and hypertension.²⁶ QTc prolongation associated with risperidone was minor¹ based on oral doses in the normal therapeutic range and incidences of overdose.¹⁰ Paliperidone²⁷ and lurasidone²⁸ are associated with clinically insignificant QTc prolongation. Changes in QTc interval were positively correlated with asenapine dose, although at the highest dose of 40 mg/d, the increase was <5 milliseconds.²⁹

Mrs. A presents with a number of risk factors for QTc prolongation, including older age, female sex, and psychiatric and medical comorbidities that require medication. A pill count revealed that she was taking more than the prescribed daily doses of her medications. During the interview, Mrs. A said that if she missed her medication time, she would take them when she remembered. If she could not remember if she took her pills, she would take them again. Her physicians will explore strategies to increase medication adherence.

Table

Examples of QTc prolongation associated with select antipsychotics^a

Related Resources

• De Hert M, Detraux J, van Winkel R, et al. Metabolic and cardiovascular adverse effects associated with antipsychotic drugs. Nat Rev Endocrinol. 2011;8(2):114-126.
• Vieweg WV, Wood MA, Fernandez A, et al. Proarrhythmic risk with antipsychotic and antidepressant drugs: implications in the elderly. Drugs Aging. 2009;26(12):997-1012.
• Sandson NB, Armstrong SC, Cozza KL. An overview of psychotropic drug-drug interactions. Psychosomatics. 2005;46(5):464-494.

Drug Brand Names

• Amantadine • Symmetrel
• Amitriptyline • Elavil
• Aripiprazole • Abilify
• Asenapine • Saphris
• Chlorpromazine • Thorazine
• Citalopram • Celexa
• Clozapine • Clozaril
• Desipramine • Norpramin
• Fluoxetine • Prozac
• Furosemide • Lasix
• Haloperidol • Haldol
• Hydroxyzine • Atarax, Vistaril
• Iloperidone • Fanapt
• Lisinopril • Prinivil, Zestril
• Lorazepam • Ativan
• Lurasidone • Latuda
• Maprotiline • Ludiomil
• Mesoridazine • Serentil
• Metformin • Glucophage
• Nortriptyline • Pamelor
• Olanzapine • Zyprexa
• Paliperidone • Invega
• Paroxetine • Paxil
• Pimozide • Orap
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Tamoxifen • Nolvadex, Soltamox
• Thioridazine • Mellaril
• Venlafaxine • Effexor
• Ziprasidone • Geodon

Disclosures

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products. No similar work by the authors is under review or in press. No funding was requested or received in conjunction with this manuscript.

Mrs. A, age 68, has a 40-year history of schizoaffective disorder with comorbid anxiety disorder not otherwise specified, type 2 diabetes mellitus, and hypertension. She takes furosemide, 40 mg/d, lisinopril, 20 mg/d, and metformin, 2,000 mg/d, for hypertension and diabetes; lorazepam, 1.5 mg/d, and paroxetine, 40 mg/d, for anxiety; and quetiapine extended release, 800 mg/d, for psychotic features and mood dysregulation with schizoaffective disorder. Mrs. A’s husband died 5 years ago and she lives alone in a senior care facility. Mrs. A uses a weekly pill reminder box because her residential facility does not monitor medication adherence. She sees her psychiatrist once a month and her primary care provider every 3 months. She has no history of illicit drug, alcohol, or tobacco use.

Two weeks ago, Mrs. A was found leaning against the wall in a hallway, complaining of dizziness and disorientation, and unable to find her way back to her apartment. In the emergency department, her serum potassium is low (3.0 mEq/L; normal range: 3.5 to 5.0), fasting glucose is elevated (110 mg/dL; range: 65 to 99), and ECG reveals a prolonged QTc interval of 530 milliseconds. Before this episode, Mrs. A had been medically stable without mood or psychotic symptoms, although her daughter reported medication self-administration was becoming difficult.

Exposure to psychotropics carries a risk of QTc prolongation. The QT interval is an ECG measure of ventricular depolarization and repolarization. The QTc designation indicates a correction for heart rate with increasing heart rate correlating with a shorter QT interval. Readings of 440 milliseconds are considered normal.¹ QTc prolongation is defined as >450 milliseconds for men and >470 milliseconds for women.² An increase in the QT interval is a predictor of serious cardiac events.³

Antidepressants and antipsychotics have been associated with QTc prolongation. When identifying agents that could disrupt cardiac conduction, clinicians need to consider whether the drug’s molecular structure, receptor affinity, or pharmacologic effects are most critical.² Although these may be important, patient-specific variables that increase the risk of QTc prolongation may have greater impact. These include:

• age >65
• female sex
• electrolyte imbalances (specifically low serum potassium and magnesium levels)
• high or toxic serum levels of the suspected drug
• preexisting cardiovascular impairment, such as bradycardia.^4,5

Other risk factors include concurrent use of an agent with similar cardiovascular effects or one that competes for metabolism (either enzymatic or at the binding site), physiologic limitations such as renal insufficiency, and medication changes that may increase or decrease psychotropic clearance.^4,6 Geriatric patients with dementia have an increased risk for cardiovascular-related death.^7,8

Antidepressants

Among tricyclic antidepressants, most reports of QTc prolongation involve amitriptyline and maprotiline.⁹ Risk factors include demographics (eg, female sex, age), personal or family history (congenital long QT syndrome, cardiovascular disease), and concurrent conditions or drug use, particularly those associated with QTc prolongation.³ Desipramine and nortriptyline also have been identified as high-risk agents.¹⁰

QTc prolongation has been reported with all selective serotonin reuptake inhibitors at plasma concentrations above the therapeutic level.¹¹ Fluoxetine-associated QTc prolongation was limited to cases of overdose or when additional risk factors were reported.⁴ QTc prolongation from psychotropics could increase the risk of torsades de pointes, according to an analysis of the FDA Adverse Event Reporting System.¹² In 2011, the FDA reported an increased risk of abnormal heart rhythms—including QTc prolongation—with citalopram doses >40 mg/d.¹³ Although cases of QTc prolongation with paroxetine have not been reported,¹¹ the Arizona Center for Education and Research on Therapeutics lists paroxetine with other agents that may increase the risk for QTc prolongation with concurrent use of medications that may prolong QTc interval.¹⁴ Venlafaxine doses >300 mg/d may require additional cardiac monitoring.^5,12 Data from venlafaxine poisoning case reports found a positive correlation between dose and QTc prolongation.¹⁵ In a review of toxicology database information, Wenzel-Seifert et al⁴ found extended QT interval with citalopram, fluoxetine, and venlafaxine at toxic doses or in the presence of additional risk factors such as sex, older age, or personal or family history of congenital long QT syndrome or cardiovascular disease.

Antipsychotics

Case reports, case series, and research trials have evaluated the risk of QTc prolongation with antipsychotics (Table).^1,2,4,16,17 The first-generation antipsychotics thioridazine,^4,16,18 mesoridazine,^16,18 chlorpromazine,¹⁹ and haloperidol³ warrant cardiac monitoring. The QTc prolongation effects of thioridazine and its active metabolite mesoridazine are well-documented and thioridazine-mediated QTc prolongation increases are dose-dependent.^4,18 ECG monitoring is recommended with IV haloperidol, which is used for delirium in adults.²⁰ QTc prolongation has been associated with long-term ziprasidone use more often than with risperidone, olanzapine, or quetiapine.¹⁹ Ziprasidone prolongs the QTc interval an average of 20 milliseconds,²¹ which could represent a clinically significant change. QTc prolongation for iloperidone is comparable to ziprasidone and haloperidol.²² There is some evidence that aripiprazole may shorten, rather than prolong, the QTc interval.^4,17

Cardiovascular adverse effects associated with clozapine—including QTc prolongation—are dose-dependent.³ Olanzapine prolongs QTc interval, although the mean change is less than with other agents unless other variables were present, such as:

• concomitant use of medications that may prolong QTc interval (ie, amantadine, hydroxyzine, or tamoxifen²)
• preexisting cardiovascular conduction disorders
• higher doses (>40 mg/d).^3,23

In 17 case reports of cardiac changes associated with quetiapine use, doses ranged from 100 mg/d²⁴ to an overdose of 36 g/d.²⁵ Only 1 patient death was reported secondary to overdose and preexisting dysrhythmia and hypertension.²⁶ QTc prolongation associated with risperidone was minor¹ based on oral doses in the normal therapeutic range and incidences of overdose.¹⁰ Paliperidone²⁷ and lurasidone²⁸ are associated with clinically insignificant QTc prolongation. Changes in QTc interval were positively correlated with asenapine dose, although at the highest dose of 40 mg/d, the increase was <5 milliseconds.²⁹

Mrs. A presents with a number of risk factors for QTc prolongation, including older age, female sex, and psychiatric and medical comorbidities that require medication. A pill count revealed that she was taking more than the prescribed daily doses of her medications. During the interview, Mrs. A said that if she missed her medication time, she would take them when she remembered. If she could not remember if she took her pills, she would take them again. Her physicians will explore strategies to increase medication adherence.

Table

Examples of QTc prolongation associated with select antipsychotics^a

Related Resources

• De Hert M, Detraux J, van Winkel R, et al. Metabolic and cardiovascular adverse effects associated with antipsychotic drugs. Nat Rev Endocrinol. 2011;8(2):114-126.
• Vieweg WV, Wood MA, Fernandez A, et al. Proarrhythmic risk with antipsychotic and antidepressant drugs: implications in the elderly. Drugs Aging. 2009;26(12):997-1012.
• Sandson NB, Armstrong SC, Cozza KL. An overview of psychotropic drug-drug interactions. Psychosomatics. 2005;46(5):464-494.

Drug Brand Names

• Amantadine • Symmetrel
• Amitriptyline • Elavil
• Aripiprazole • Abilify
• Asenapine • Saphris
• Chlorpromazine • Thorazine
• Citalopram • Celexa
• Clozapine • Clozaril
• Desipramine • Norpramin
• Fluoxetine • Prozac
• Furosemide • Lasix
• Haloperidol • Haldol
• Hydroxyzine • Atarax, Vistaril
• Iloperidone • Fanapt
• Lisinopril • Prinivil, Zestril
• Lorazepam • Ativan
• Lurasidone • Latuda
• Maprotiline • Ludiomil
• Mesoridazine • Serentil
• Metformin • Glucophage
• Nortriptyline • Pamelor
• Olanzapine • Zyprexa
• Paliperidone • Invega
• Paroxetine • Paxil
• Pimozide • Orap
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Tamoxifen • Nolvadex, Soltamox
• Thioridazine • Mellaril
• Venlafaxine • Effexor
• Ziprasidone • Geodon

Disclosures

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products. No similar work by the authors is under review or in press. No funding was requested or received in conjunction with this manuscript.

In 2006, the FDA issued a warning of the risk of potentially fatal serotonin syndrome when 5-hydroxytryptamine receptor agonist antimigraine medications (triptans) and selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRI) are coprescribed.¹ As a result, most drug interaction programs trigger a serotonin syndrome warning when triptans are prescribed with an SSRI or SNRI.² However, many patients with depression or anxiety also suffer from migraines and require treatment with both triptans and an SSRI or SNRI.^3,4 Kalaydjian et al⁴ found the incidence of major depression and generalized anxiety disorder were approximately 3 times greater in patients with migraines than in those without migraines. Should we avoid coprescribing triptans and SSRIs or SNRIs?

What is serotonin syndrome?

Serotonin syndrome is an adverse drug reaction that results from excessive serotonin stimulation. There are 2 sets of validated diagnostic criteria: the Sternbach Criteria and the Hunter Serotonin Toxicity Criteria; the latter is considered more stringent.^3,5-7 Symptoms of serotonin syndrome include mental status changes, autonomic hyperactivity, and neuromuscular changes such as muscle rigidity.^5-7 Typical manifestations of serotonin syndrome on physical exam include spontaneous and/or inducible clonus, agitation, diaphoresis, tremor, hyperreflexia, hypertonia, and temperature >38°C.⁶ In severe cases, serotonin syndrome can lead to seizures, coma, and death. Management includes supportive treatment, discontinuing the offending agents, controlling agitation with medications such as benzodiazepines, and possibly administering cyproheptadine, a 5HT2A antagonist.⁸ Most cases resolve within 24 hours of discontinuing the offending agents or appropriate treatment.⁵

What did the FDA say?

The 2006 FDA warning initially was based on 27 reports of serotonin syndrome in patients receiving triptans and SSRIs or SNRIs; this was later expanded to include 29 patients.^1,9 No patients died but 13 required hospitalization and 2 had life-threatening symptoms. However, most cases lacked data necessary to diagnose serotonin syndrome.⁹ Further, reviews of the available clinical information have suggested that in some cases, clinicians did not rule out other disorders as required by diagnostic criteria, while others were viral in nature or resolved despite ongoing treatment with the presumed offending agents.^9-11

Some clinicians met the FDA’s assessment with skepticism. Only 10 of the 29 cases met the Sternbach criteria of serotonin syndrome and none met the more rigorous Hunter criteria. Additionally, the theoretical basis has been questioned.^9-11 Available evidence indicates that serotonin syndrome requires activation of 5HT2A receptors and a possible limited role of 5HT1A.^9-12 However, triptans are agonists at the 5HT1B/1D/1F receptor subtypes, with weak affinity for 5HT1A receptors and no activity at the 5HT2 receptors.^13,14 Additionally, triptan medications are used as needed, not as standing treatments, with parameters limiting the maximum dose, dosing interval, and frequency of use. In clinical practice, it appears that these dosing guidelines are being followed: Tepper et al¹⁵ found the typical female patient experiences 1 to 2 migraines per month; on average, patients use 1.2 to 1.8 triptan tablets per month.

Our opinion

We believe it is reasonable to coprescribe SSRIs or SNRIs with triptans because:

• data indicate that many patients are treated with a combination of triptans and SSRIs or SNRIs but the number of reported cases of serotonin syndrome is extremely limited
• the nature of serotonin syndrome cases reported in the literature is questionable
• the interaction is biologically implausible
• triptans remain in the body for a limited time
• triptans are used infrequently.^5-11

This view is supported by the most recent American Headache Society position paper,¹¹ which states that inadequate data are available to assess the risk but current evidence does not support limiting use of triptans with SSRIs and SNRIs.

How we deal with the warning in clinical practice. In practice we are alerted to this interaction by notification in our e-prescribing systems, by pharmacists calling with concerns about dispensing an SSRI or SNRI for a patient already receiving a triptan, and during patient visits that involve prescribing an SSRI or SNRI.

Although it is relatively easy to override a drug interaction warning in our e-prescribing system, we discuss the issue with pharmacists and patients. We provide information about the signs and symptoms of serotonin syndrome and its potential dangerousness. We note that serotonin syndrome is a theoretical concern, but highly unlikely with this combination of medications because of their pharmacologic properties. We explain the parameters of triptan use, recommend that our patients use triptans for migraines when needed, and reassure patients we are available to answer questions. When a patient uses triptans more than twice monthly, we consider discussing this usage with the patient and the treating physician.

Related Resource

• Sclar DA, Robison LM, Castillo LV, et al. Concomitant use of triptan, and SSRI or SNRI after the US Food and Drug Administration alert on serotonin syndrome. Headache. 2012. www.headachejournal.org/SpringboardWebApp/userfiles/headache/file/sclar.pdf.

Drug Brand Name

• Cyproheptadine • Perinctin

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

In 2006, the FDA issued a warning of the risk of potentially fatal serotonin syndrome when 5-hydroxytryptamine receptor agonist antimigraine medications (triptans) and selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRI) are coprescribed.¹ As a result, most drug interaction programs trigger a serotonin syndrome warning when triptans are prescribed with an SSRI or SNRI.² However, many patients with depression or anxiety also suffer from migraines and require treatment with both triptans and an SSRI or SNRI.^3,4 Kalaydjian et al⁴ found the incidence of major depression and generalized anxiety disorder were approximately 3 times greater in patients with migraines than in those without migraines. Should we avoid coprescribing triptans and SSRIs or SNRIs?

What is serotonin syndrome?

Serotonin syndrome is an adverse drug reaction that results from excessive serotonin stimulation. There are 2 sets of validated diagnostic criteria: the Sternbach Criteria and the Hunter Serotonin Toxicity Criteria; the latter is considered more stringent.^3,5-7 Symptoms of serotonin syndrome include mental status changes, autonomic hyperactivity, and neuromuscular changes such as muscle rigidity.^5-7 Typical manifestations of serotonin syndrome on physical exam include spontaneous and/or inducible clonus, agitation, diaphoresis, tremor, hyperreflexia, hypertonia, and temperature >38°C.⁶ In severe cases, serotonin syndrome can lead to seizures, coma, and death. Management includes supportive treatment, discontinuing the offending agents, controlling agitation with medications such as benzodiazepines, and possibly administering cyproheptadine, a 5HT2A antagonist.⁸ Most cases resolve within 24 hours of discontinuing the offending agents or appropriate treatment.⁵

What did the FDA say?

The 2006 FDA warning initially was based on 27 reports of serotonin syndrome in patients receiving triptans and SSRIs or SNRIs; this was later expanded to include 29 patients.^1,9 No patients died but 13 required hospitalization and 2 had life-threatening symptoms. However, most cases lacked data necessary to diagnose serotonin syndrome.⁹ Further, reviews of the available clinical information have suggested that in some cases, clinicians did not rule out other disorders as required by diagnostic criteria, while others were viral in nature or resolved despite ongoing treatment with the presumed offending agents.^9-11

Some clinicians met the FDA’s assessment with skepticism. Only 10 of the 29 cases met the Sternbach criteria of serotonin syndrome and none met the more rigorous Hunter criteria. Additionally, the theoretical basis has been questioned.^9-11 Available evidence indicates that serotonin syndrome requires activation of 5HT2A receptors and a possible limited role of 5HT1A.^9-12 However, triptans are agonists at the 5HT1B/1D/1F receptor subtypes, with weak affinity for 5HT1A receptors and no activity at the 5HT2 receptors.^13,14 Additionally, triptan medications are used as needed, not as standing treatments, with parameters limiting the maximum dose, dosing interval, and frequency of use. In clinical practice, it appears that these dosing guidelines are being followed: Tepper et al¹⁵ found the typical female patient experiences 1 to 2 migraines per month; on average, patients use 1.2 to 1.8 triptan tablets per month.

Our opinion

We believe it is reasonable to coprescribe SSRIs or SNRIs with triptans because:

• data indicate that many patients are treated with a combination of triptans and SSRIs or SNRIs but the number of reported cases of serotonin syndrome is extremely limited
• the nature of serotonin syndrome cases reported in the literature is questionable
• the interaction is biologically implausible
• triptans remain in the body for a limited time
• triptans are used infrequently.^5-11

This view is supported by the most recent American Headache Society position paper,¹¹ which states that inadequate data are available to assess the risk but current evidence does not support limiting use of triptans with SSRIs and SNRIs.

How we deal with the warning in clinical practice. In practice we are alerted to this interaction by notification in our e-prescribing systems, by pharmacists calling with concerns about dispensing an SSRI or SNRI for a patient already receiving a triptan, and during patient visits that involve prescribing an SSRI or SNRI.

Although it is relatively easy to override a drug interaction warning in our e-prescribing system, we discuss the issue with pharmacists and patients. We provide information about the signs and symptoms of serotonin syndrome and its potential dangerousness. We note that serotonin syndrome is a theoretical concern, but highly unlikely with this combination of medications because of their pharmacologic properties. We explain the parameters of triptan use, recommend that our patients use triptans for migraines when needed, and reassure patients we are available to answer questions. When a patient uses triptans more than twice monthly, we consider discussing this usage with the patient and the treating physician.

Related Resource

• Sclar DA, Robison LM, Castillo LV, et al. Concomitant use of triptan, and SSRI or SNRI after the US Food and Drug Administration alert on serotonin syndrome. Headache. 2012. www.headachejournal.org/SpringboardWebApp/userfiles/headache/file/sclar.pdf.

Drug Brand Name

• Cyproheptadine • Perinctin

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

In 2006, the FDA issued a warning of the risk of potentially fatal serotonin syndrome when 5-hydroxytryptamine receptor agonist antimigraine medications (triptans) and selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRI) are coprescribed.¹ As a result, most drug interaction programs trigger a serotonin syndrome warning when triptans are prescribed with an SSRI or SNRI.² However, many patients with depression or anxiety also suffer from migraines and require treatment with both triptans and an SSRI or SNRI.^3,4 Kalaydjian et al⁴ found the incidence of major depression and generalized anxiety disorder were approximately 3 times greater in patients with migraines than in those without migraines. Should we avoid coprescribing triptans and SSRIs or SNRIs?

What is serotonin syndrome?

Serotonin syndrome is an adverse drug reaction that results from excessive serotonin stimulation. There are 2 sets of validated diagnostic criteria: the Sternbach Criteria and the Hunter Serotonin Toxicity Criteria; the latter is considered more stringent.^3,5-7 Symptoms of serotonin syndrome include mental status changes, autonomic hyperactivity, and neuromuscular changes such as muscle rigidity.^5-7 Typical manifestations of serotonin syndrome on physical exam include spontaneous and/or inducible clonus, agitation, diaphoresis, tremor, hyperreflexia, hypertonia, and temperature >38°C.⁶ In severe cases, serotonin syndrome can lead to seizures, coma, and death. Management includes supportive treatment, discontinuing the offending agents, controlling agitation with medications such as benzodiazepines, and possibly administering cyproheptadine, a 5HT2A antagonist.⁸ Most cases resolve within 24 hours of discontinuing the offending agents or appropriate treatment.⁵

What did the FDA say?

The 2006 FDA warning initially was based on 27 reports of serotonin syndrome in patients receiving triptans and SSRIs or SNRIs; this was later expanded to include 29 patients.^1,9 No patients died but 13 required hospitalization and 2 had life-threatening symptoms. However, most cases lacked data necessary to diagnose serotonin syndrome.⁹ Further, reviews of the available clinical information have suggested that in some cases, clinicians did not rule out other disorders as required by diagnostic criteria, while others were viral in nature or resolved despite ongoing treatment with the presumed offending agents.^9-11

Some clinicians met the FDA’s assessment with skepticism. Only 10 of the 29 cases met the Sternbach criteria of serotonin syndrome and none met the more rigorous Hunter criteria. Additionally, the theoretical basis has been questioned.^9-11 Available evidence indicates that serotonin syndrome requires activation of 5HT2A receptors and a possible limited role of 5HT1A.^9-12 However, triptans are agonists at the 5HT1B/1D/1F receptor subtypes, with weak affinity for 5HT1A receptors and no activity at the 5HT2 receptors.^13,14 Additionally, triptan medications are used as needed, not as standing treatments, with parameters limiting the maximum dose, dosing interval, and frequency of use. In clinical practice, it appears that these dosing guidelines are being followed: Tepper et al¹⁵ found the typical female patient experiences 1 to 2 migraines per month; on average, patients use 1.2 to 1.8 triptan tablets per month.

Our opinion

We believe it is reasonable to coprescribe SSRIs or SNRIs with triptans because:

• data indicate that many patients are treated with a combination of triptans and SSRIs or SNRIs but the number of reported cases of serotonin syndrome is extremely limited
• the nature of serotonin syndrome cases reported in the literature is questionable
• the interaction is biologically implausible
• triptans remain in the body for a limited time
• triptans are used infrequently.^5-11

This view is supported by the most recent American Headache Society position paper,¹¹ which states that inadequate data are available to assess the risk but current evidence does not support limiting use of triptans with SSRIs and SNRIs.

How we deal with the warning in clinical practice. In practice we are alerted to this interaction by notification in our e-prescribing systems, by pharmacists calling with concerns about dispensing an SSRI or SNRI for a patient already receiving a triptan, and during patient visits that involve prescribing an SSRI or SNRI.

Although it is relatively easy to override a drug interaction warning in our e-prescribing system, we discuss the issue with pharmacists and patients. We provide information about the signs and symptoms of serotonin syndrome and its potential dangerousness. We note that serotonin syndrome is a theoretical concern, but highly unlikely with this combination of medications because of their pharmacologic properties. We explain the parameters of triptan use, recommend that our patients use triptans for migraines when needed, and reassure patients we are available to answer questions. When a patient uses triptans more than twice monthly, we consider discussing this usage with the patient and the treating physician.

Related Resource

• Sclar DA, Robison LM, Castillo LV, et al. Concomitant use of triptan, and SSRI or SNRI after the US Food and Drug Administration alert on serotonin syndrome. Headache. 2012. www.headachejournal.org/SpringboardWebApp/userfiles/headache/file/sclar.pdf.

Drug Brand Name

• Cyproheptadine • Perinctin

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Patients receiving treatment with epidermal growth factor receptor inhibitors often experience dermatological toxicities. The majority of patients develop skin rash, and may also experience adverse nail and periungual alterations. EGFR inhibitors have become part of the standard of care for several solid tumors, including metastatic colorectal cancer, cancers of the head and neck, and non small-cell lung cancer, thus adequate management of these side effects is necessary to ensure patient compliance to therapy, as well as to maximize patient comfort and quality of life. This review presents a protocol our center optimized to successfully manage cetuximab-associated acneiform rash and nail toxicities.

Click on the PDF icon at the top of this introduction to read the full article.

Patients receiving treatment with epidermal growth factor receptor inhibitors often experience dermatological toxicities. The majority of patients develop skin rash, and may also experience adverse nail and periungual alterations. EGFR inhibitors have become part of the standard of care for several solid tumors, including metastatic colorectal cancer, cancers of the head and neck, and non small-cell lung cancer, thus adequate management of these side effects is necessary to ensure patient compliance to therapy, as well as to maximize patient comfort and quality of life. This review presents a protocol our center optimized to successfully manage cetuximab-associated acneiform rash and nail toxicities.

Click on the PDF icon at the top of this introduction to read the full article.

Patients receiving treatment with epidermal growth factor receptor inhibitors often experience dermatological toxicities. The majority of patients develop skin rash, and may also experience adverse nail and periungual alterations. EGFR inhibitors have become part of the standard of care for several solid tumors, including metastatic colorectal cancer, cancers of the head and neck, and non small-cell lung cancer, thus adequate management of these side effects is necessary to ensure patient compliance to therapy, as well as to maximize patient comfort and quality of life. This review presents a protocol our center optimized to successfully manage cetuximab-associated acneiform rash and nail toxicities.

Click on the PDF icon at the top of this introduction to read the full article.

Hypertension is the force of blood pushing against the walls of the arteries. It is measured as systolic pressure when the heart beats and pumps blood and as diastolic pressure in the arteries when the heart rests between beats. There are 4 stages in blood pressure classification—normal, prehypertension, stage 1, and stage 2. Hypertension affects approximately 50 million people in the United States and 1 billion people worldwide. People who are normotensive at age 55 years have a 90% chance of developing hypertension in their lifetime. Starting with a blood pressure of 115/75 mmHg, the risk of cardiovascular death doubles with each 20/10 mmHg increment...

*For PDFs of the full article and related Commentary, click on the links to the left of this introduction.

Hypertension is the force of blood pushing against the walls of the arteries. It is measured as systolic pressure when the heart beats and pumps blood and as diastolic pressure in the arteries when the heart rests between beats. There are 4 stages in blood pressure classification—normal, prehypertension, stage 1, and stage 2. Hypertension affects approximately 50 million people in the United States and 1 billion people worldwide. People who are normotensive at age 55 years have a 90% chance of developing hypertension in their lifetime. Starting with a blood pressure of 115/75 mmHg, the risk of cardiovascular death doubles with each 20/10 mmHg increment...

*For PDFs of the full article and related Commentary, click on the links to the left of this introduction.

Hypertension is the force of blood pushing against the walls of the arteries. It is measured as systolic pressure when the heart beats and pumps blood and as diastolic pressure in the arteries when the heart rests between beats. There are 4 stages in blood pressure classification—normal, prehypertension, stage 1, and stage 2. Hypertension affects approximately 50 million people in the United States and 1 billion people worldwide. People who are normotensive at age 55 years have a 90% chance of developing hypertension in their lifetime. Starting with a blood pressure of 115/75 mmHg, the risk of cardiovascular death doubles with each 20/10 mmHg increment...

*For PDFs of the full article and related Commentary, click on the links to the left of this introduction.

Patients with glioblastoma and other high-grade gliomas have poor outcomes and are challenging to treat. The relative rarity of these tumors has made large-scale, practice-changing trials difficult to accomplish and has led to the formation of large multinational organizations that focus on neuro-oncology. This has resulted in the rapid completion of several large trials that in some cases have set new standards of care that can offer increased progression-free and overall survivals for some patients. The incorporation of correlative tissue studies in these trials has led to the identification of prognostic and predictive genetic markers that demonstrate the heterogeneity of these tumors and will assist in developing individualized treatment strategies as research continues to uncover new therapeutic targets. This review of recently completed and in-progress phase 3 trials in high-grade gliomas highlights the developments and future directions in the treatment of these tumors...

*For PDFs of the full article and related Commentary, click on the links to the left of this introduction.

Patients with glioblastoma and other high-grade gliomas have poor outcomes and are challenging to treat. The relative rarity of these tumors has made large-scale, practice-changing trials difficult to accomplish and has led to the formation of large multinational organizations that focus on neuro-oncology. This has resulted in the rapid completion of several large trials that in some cases have set new standards of care that can offer increased progression-free and overall survivals for some patients. The incorporation of correlative tissue studies in these trials has led to the identification of prognostic and predictive genetic markers that demonstrate the heterogeneity of these tumors and will assist in developing individualized treatment strategies as research continues to uncover new therapeutic targets. This review of recently completed and in-progress phase 3 trials in high-grade gliomas highlights the developments and future directions in the treatment of these tumors...

*For PDFs of the full article and related Commentary, click on the links to the left of this introduction.

Patients with glioblastoma and other high-grade gliomas have poor outcomes and are challenging to treat. The relative rarity of these tumors has made large-scale, practice-changing trials difficult to accomplish and has led to the formation of large multinational organizations that focus on neuro-oncology. This has resulted in the rapid completion of several large trials that in some cases have set new standards of care that can offer increased progression-free and overall survivals for some patients. The incorporation of correlative tissue studies in these trials has led to the identification of prognostic and predictive genetic markers that demonstrate the heterogeneity of these tumors and will assist in developing individualized treatment strategies as research continues to uncover new therapeutic targets. This review of recently completed and in-progress phase 3 trials in high-grade gliomas highlights the developments and future directions in the treatment of these tumors...

*For PDFs of the full article and related Commentary, click on the links to the left of this introduction.

Adalimumab, a subcutaneously administered tumor necrosis factor blocker, has been approved for treating adults with moderately to severely active ulcerative colitis who have not had an adequate response with conventional treatments, the Food and Drug Administration announced on Sept. 28.

The safety and effectiveness of adalimumab for this patient population was established in two clinical studies of 908 patients with moderately to severely active ulcerative colitis (UC).

Adalimumab, marketed as Humira by Abbott Laboratories, was first approved for treating rheumatoid arthritis in 2002, followed by psoriatic arthritis in 2005, ankylosing spondylitis in 2006, Crohn’s disease in 2007, and plaque psoriasis and juvenile idiopathic arthritis in 2008.

Adalimumab is the second TNF blocker to be approved for ulcerative colitis; infliximab (Remicade), an intravenous TNF blocker, was previously approved for treating UC.

Clinical remission rates in the two studies were significantly greater among patients treated with infliximab than among those who received placebo: In an 8-week study, which did not include patients who had previously been treated with a TNF blocker, the clinical remission rate at 8 weeks was 18.5% among those on adalimumab vs. 9.2% in those on placebo, a 9.3% difference. In the second study, which followed patients for 1 year and included some who had been treated with infliximab, the clinical remission rate at 8 weeks was 16.5% among those on adalimumab, vs. 9.3% among those on placebo, a 7.2% difference.

At a meeting on Aug. 28 held to review these data, the majority of the FDA’s Gastrointestinal Drugs Advisory Committee agreed that these differences represented clinically meaningful benefits and supported approval of adalimumab for this indication. Panelists cited the need for more treatments for UC and for a subcutaneous TNF blocker for these patients, as well as its potential steroid-sparing effects.

In the studies, no new side effects were identified, the agency said. The FDA statement points out that the effectiveness of adalimumab "has not been established in patients with ulcerative colitis who have lost response to or were intolerant to TNF blockers."

The approved dosing regimen for adalimumab is a starting dose of 160 mg, followed by a second dose of 80 mg 2 weeks later and then a maintenance dose of 40 mg every other week. "The drug should only continue to be used in patients who have shown evidence of clinical remission by 8 weeks of therapy," according to the FDA statement.

Adalimumab is the first self-administered biologic treatment for ulcerative colitis to be approved.

Adalimumab, a subcutaneously administered tumor necrosis factor blocker, has been approved for treating adults with moderately to severely active ulcerative colitis who have not had an adequate response with conventional treatments, the Food and Drug Administration announced on Sept. 28.

The safety and effectiveness of adalimumab for this patient population was established in two clinical studies of 908 patients with moderately to severely active ulcerative colitis (UC).

Adalimumab, marketed as Humira by Abbott Laboratories, was first approved for treating rheumatoid arthritis in 2002, followed by psoriatic arthritis in 2005, ankylosing spondylitis in 2006, Crohn’s disease in 2007, and plaque psoriasis and juvenile idiopathic arthritis in 2008.

Adalimumab is the second TNF blocker to be approved for ulcerative colitis; infliximab (Remicade), an intravenous TNF blocker, was previously approved for treating UC.

Clinical remission rates in the two studies were significantly greater among patients treated with infliximab than among those who received placebo: In an 8-week study, which did not include patients who had previously been treated with a TNF blocker, the clinical remission rate at 8 weeks was 18.5% among those on adalimumab vs. 9.2% in those on placebo, a 9.3% difference. In the second study, which followed patients for 1 year and included some who had been treated with infliximab, the clinical remission rate at 8 weeks was 16.5% among those on adalimumab, vs. 9.3% among those on placebo, a 7.2% difference.

At a meeting on Aug. 28 held to review these data, the majority of the FDA’s Gastrointestinal Drugs Advisory Committee agreed that these differences represented clinically meaningful benefits and supported approval of adalimumab for this indication. Panelists cited the need for more treatments for UC and for a subcutaneous TNF blocker for these patients, as well as its potential steroid-sparing effects.

In the studies, no new side effects were identified, the agency said. The FDA statement points out that the effectiveness of adalimumab "has not been established in patients with ulcerative colitis who have lost response to or were intolerant to TNF blockers."

The approved dosing regimen for adalimumab is a starting dose of 160 mg, followed by a second dose of 80 mg 2 weeks later and then a maintenance dose of 40 mg every other week. "The drug should only continue to be used in patients who have shown evidence of clinical remission by 8 weeks of therapy," according to the FDA statement.

Adalimumab is the first self-administered biologic treatment for ulcerative colitis to be approved.

Adalimumab, a subcutaneously administered tumor necrosis factor blocker, has been approved for treating adults with moderately to severely active ulcerative colitis who have not had an adequate response with conventional treatments, the Food and Drug Administration announced on Sept. 28.

The safety and effectiveness of adalimumab for this patient population was established in two clinical studies of 908 patients with moderately to severely active ulcerative colitis (UC).

Adalimumab, marketed as Humira by Abbott Laboratories, was first approved for treating rheumatoid arthritis in 2002, followed by psoriatic arthritis in 2005, ankylosing spondylitis in 2006, Crohn’s disease in 2007, and plaque psoriasis and juvenile idiopathic arthritis in 2008.

Adalimumab is the second TNF blocker to be approved for ulcerative colitis; infliximab (Remicade), an intravenous TNF blocker, was previously approved for treating UC.

Clinical remission rates in the two studies were significantly greater among patients treated with infliximab than among those who received placebo: In an 8-week study, which did not include patients who had previously been treated with a TNF blocker, the clinical remission rate at 8 weeks was 18.5% among those on adalimumab vs. 9.2% in those on placebo, a 9.3% difference. In the second study, which followed patients for 1 year and included some who had been treated with infliximab, the clinical remission rate at 8 weeks was 16.5% among those on adalimumab, vs. 9.3% among those on placebo, a 7.2% difference.

At a meeting on Aug. 28 held to review these data, the majority of the FDA’s Gastrointestinal Drugs Advisory Committee agreed that these differences represented clinically meaningful benefits and supported approval of adalimumab for this indication. Panelists cited the need for more treatments for UC and for a subcutaneous TNF blocker for these patients, as well as its potential steroid-sparing effects.

In the studies, no new side effects were identified, the agency said. The FDA statement points out that the effectiveness of adalimumab "has not been established in patients with ulcerative colitis who have lost response to or were intolerant to TNF blockers."

The approved dosing regimen for adalimumab is a starting dose of 160 mg, followed by a second dose of 80 mg 2 weeks later and then a maintenance dose of 40 mg every other week. "The drug should only continue to be used in patients who have shown evidence of clinical remission by 8 weeks of therapy," according to the FDA statement.

Adalimumab is the first self-administered biologic treatment for ulcerative colitis to be approved.

The first guidelines on the management of gout from the American College of Rheumatology recommend new ways of using old drugs and changes in prophylaxis strategies, among other things.

The two-part guidelines, published online Sept. 28, should help speed up effective treatment of gout and get physicians to treat patients to a target urate level of less than 6 mg/dL in order to improve symptoms, Dr. John D. FitzGerald said in an interview.

"There has been a fair amount of recent movement on gout medications" including new alternatives to allopurinol and colchicine and new data on how to use those traditional drugs in safer ways, said Dr. FitzGerald, acting chief of the rheumatology division at the University of California, Los Angeles. "It’s a fair number of changes for medications that people had been using for decades."

The documents update previous guidelines from medical organizations in Europe, the Netherlands, and Japan. The new guidelines will be published in October 2012 by the journal Arthritis Care & Research.

Part 1 of the American College of Rheumatology (ACR) guidelines covers nonpharmacologic and pharmacologic approaches to managing hyperuricemia (Arthritis Care Res. 2012;64:1431-46 [doi:10.1002/acr.21772]).

Part 2 addresses prophylaxis and treatment for acute gouty arthritis (Arthritis Care Res. 2012;64:1447-61 [doi.wiley.com/10.1002/acr.21773]).

Dr. FitzGerald and two other co-leaders of the project, Dr. Dinesh Khanna of the University of Michigan, Ann Arbor and Dr. Robert Terkeltaub of the University of California, San Diego, reviewed the medical literature on gout from the 1950s to the present and drew up nine clinical case scenarios commonly seen in practice. A task force panel comprising seven rheumatologists, two primary care physicians, a nephrologist, and a patient representative used the scenarios to create consensus recommendations.

Among the recommendations, for example, on the use of allopurinol is to start at a low dose of 100 mg/day (instead of the common practice of starting with 300 mg/day), or even lower for patients with chronic kidney disease, and then gradually titrate upward every 2-5 weeks. That recommendation supports previous statements from the Food and Drug Administration and the European League Against Rheumatism.

Also, allopurinol therapy should be actively managed and patients followed to make sure the uric acid target is achieved. "You can’t just give a prescription and say your job is done," though some recent studies suggest that many physicians do just that, Dr. FitzGerald said. "The corollary would be if someone gave blood pressure medication and then didn’t follow the patient’s blood pressure. That wouldn’t be seen as good medicine."

Maintenance doses of allopurinol to prevent acute gout attacks can exceed 300 mg even in patients with chronic kidney disease provided there is adequate patient education and monitoring.

A new recommendation drops the starting dose of oral colchicine for acute gout attacks to a loading dose of 1.2 mg, followed by 0.6 mg an hour later, and then starting prophylaxis 12 hours later at dosing of 0.6 mg once or twice daily.

"We used to give up to eight tablets a day," Dr. FitzGerald said. "That is dropped down to three to four tablets at the start of an attacks, because of findings that more colchicine didn’t really help outcomes" and that smaller doses are safer. The authors called this recommendation from ACR "a paradigm shift" that’s in accordance with Food and Drug Administration-approved label language.

Other highlights of the new ACR recommendations include sections on screening for HLA-B*5801 in patients at high risk of severe adverse reaction to allopurinol, combination therapy when target urate levels are not achieved, medication options including new drugs, and more.

Although the reports are titled "Guidelines," the text makes clear that they are expert recommendations and that clinicians are expected to take active roles in choosing the best management strategies for their particular patients. The authors were "very concerned" that the guidelines not be used by third-party payers to restrict access to medications or to promote one drug over another if there isn’t clear evidence to support it, Dr. FitzGerald said.

The methodology of the project precluded evaluations of costs and cost effectiveness, instead focusing on efficacy. So, for example, the guidelines say that allopurinol and febuxostat can be used equivalently in some circumstances, but clinicians need to consider all other aspects of these options including cost, patient preference, and more.

The ACR plans to update the guidelines as new data become available. The task force panel did create specific indications for use of imaging studies because results should be available in the next few years from studies on the use of high-resolution ultrasound and dual-energy CT for patients with gout.

In the United States, gout affects an estimated 4% of adults – more than 8 million people.

"I’m most excited and hopeful about trying to get this out to internal medicine and family practice doctors," Dr. FitzGerald said. "They see more gout than rheumatologists."

Dr. FitzGerald reported having no financial disclosures. Some members of the task force reported financial associations with multiple pharmaceutical companies but, by design, a majority of task force members had no perceived potential conflicts of interest. 

The first guidelines on the management of gout from the American College of Rheumatology recommend new ways of using old drugs and changes in prophylaxis strategies, among other things.

The two-part guidelines, published online Sept. 28, should help speed up effective treatment of gout and get physicians to treat patients to a target urate level of less than 6 mg/dL in order to improve symptoms, Dr. John D. FitzGerald said in an interview.

"There has been a fair amount of recent movement on gout medications" including new alternatives to allopurinol and colchicine and new data on how to use those traditional drugs in safer ways, said Dr. FitzGerald, acting chief of the rheumatology division at the University of California, Los Angeles. "It’s a fair number of changes for medications that people had been using for decades."

The documents update previous guidelines from medical organizations in Europe, the Netherlands, and Japan. The new guidelines will be published in October 2012 by the journal Arthritis Care & Research.

Part 1 of the American College of Rheumatology (ACR) guidelines covers nonpharmacologic and pharmacologic approaches to managing hyperuricemia (Arthritis Care Res. 2012;64:1431-46 [doi:10.1002/acr.21772]).

Part 2 addresses prophylaxis and treatment for acute gouty arthritis (Arthritis Care Res. 2012;64:1447-61 [doi.wiley.com/10.1002/acr.21773]).

Dr. FitzGerald and two other co-leaders of the project, Dr. Dinesh Khanna of the University of Michigan, Ann Arbor and Dr. Robert Terkeltaub of the University of California, San Diego, reviewed the medical literature on gout from the 1950s to the present and drew up nine clinical case scenarios commonly seen in practice. A task force panel comprising seven rheumatologists, two primary care physicians, a nephrologist, and a patient representative used the scenarios to create consensus recommendations.

Among the recommendations, for example, on the use of allopurinol is to start at a low dose of 100 mg/day (instead of the common practice of starting with 300 mg/day), or even lower for patients with chronic kidney disease, and then gradually titrate upward every 2-5 weeks. That recommendation supports previous statements from the Food and Drug Administration and the European League Against Rheumatism.

Also, allopurinol therapy should be actively managed and patients followed to make sure the uric acid target is achieved. "You can’t just give a prescription and say your job is done," though some recent studies suggest that many physicians do just that, Dr. FitzGerald said. "The corollary would be if someone gave blood pressure medication and then didn’t follow the patient’s blood pressure. That wouldn’t be seen as good medicine."

Maintenance doses of allopurinol to prevent acute gout attacks can exceed 300 mg even in patients with chronic kidney disease provided there is adequate patient education and monitoring.

A new recommendation drops the starting dose of oral colchicine for acute gout attacks to a loading dose of 1.2 mg, followed by 0.6 mg an hour later, and then starting prophylaxis 12 hours later at dosing of 0.6 mg once or twice daily.

"We used to give up to eight tablets a day," Dr. FitzGerald said. "That is dropped down to three to four tablets at the start of an attacks, because of findings that more colchicine didn’t really help outcomes" and that smaller doses are safer. The authors called this recommendation from ACR "a paradigm shift" that’s in accordance with Food and Drug Administration-approved label language.

Other highlights of the new ACR recommendations include sections on screening for HLA-B*5801 in patients at high risk of severe adverse reaction to allopurinol, combination therapy when target urate levels are not achieved, medication options including new drugs, and more.

Although the reports are titled "Guidelines," the text makes clear that they are expert recommendations and that clinicians are expected to take active roles in choosing the best management strategies for their particular patients. The authors were "very concerned" that the guidelines not be used by third-party payers to restrict access to medications or to promote one drug over another if there isn’t clear evidence to support it, Dr. FitzGerald said.

The methodology of the project precluded evaluations of costs and cost effectiveness, instead focusing on efficacy. So, for example, the guidelines say that allopurinol and febuxostat can be used equivalently in some circumstances, but clinicians need to consider all other aspects of these options including cost, patient preference, and more.

The ACR plans to update the guidelines as new data become available. The task force panel did create specific indications for use of imaging studies because results should be available in the next few years from studies on the use of high-resolution ultrasound and dual-energy CT for patients with gout.

In the United States, gout affects an estimated 4% of adults – more than 8 million people.

"I’m most excited and hopeful about trying to get this out to internal medicine and family practice doctors," Dr. FitzGerald said. "They see more gout than rheumatologists."

Dr. FitzGerald reported having no financial disclosures. Some members of the task force reported financial associations with multiple pharmaceutical companies but, by design, a majority of task force members had no perceived potential conflicts of interest. 

The first guidelines on the management of gout from the American College of Rheumatology recommend new ways of using old drugs and changes in prophylaxis strategies, among other things.

The two-part guidelines, published online Sept. 28, should help speed up effective treatment of gout and get physicians to treat patients to a target urate level of less than 6 mg/dL in order to improve symptoms, Dr. John D. FitzGerald said in an interview.

"There has been a fair amount of recent movement on gout medications" including new alternatives to allopurinol and colchicine and new data on how to use those traditional drugs in safer ways, said Dr. FitzGerald, acting chief of the rheumatology division at the University of California, Los Angeles. "It’s a fair number of changes for medications that people had been using for decades."

The documents update previous guidelines from medical organizations in Europe, the Netherlands, and Japan. The new guidelines will be published in October 2012 by the journal Arthritis Care & Research.

Part 1 of the American College of Rheumatology (ACR) guidelines covers nonpharmacologic and pharmacologic approaches to managing hyperuricemia (Arthritis Care Res. 2012;64:1431-46 [doi:10.1002/acr.21772]).

Part 2 addresses prophylaxis and treatment for acute gouty arthritis (Arthritis Care Res. 2012;64:1447-61 [doi.wiley.com/10.1002/acr.21773]).

Dr. FitzGerald and two other co-leaders of the project, Dr. Dinesh Khanna of the University of Michigan, Ann Arbor and Dr. Robert Terkeltaub of the University of California, San Diego, reviewed the medical literature on gout from the 1950s to the present and drew up nine clinical case scenarios commonly seen in practice. A task force panel comprising seven rheumatologists, two primary care physicians, a nephrologist, and a patient representative used the scenarios to create consensus recommendations.

Among the recommendations, for example, on the use of allopurinol is to start at a low dose of 100 mg/day (instead of the common practice of starting with 300 mg/day), or even lower for patients with chronic kidney disease, and then gradually titrate upward every 2-5 weeks. That recommendation supports previous statements from the Food and Drug Administration and the European League Against Rheumatism.

Also, allopurinol therapy should be actively managed and patients followed to make sure the uric acid target is achieved. "You can’t just give a prescription and say your job is done," though some recent studies suggest that many physicians do just that, Dr. FitzGerald said. "The corollary would be if someone gave blood pressure medication and then didn’t follow the patient’s blood pressure. That wouldn’t be seen as good medicine."

Maintenance doses of allopurinol to prevent acute gout attacks can exceed 300 mg even in patients with chronic kidney disease provided there is adequate patient education and monitoring.

A new recommendation drops the starting dose of oral colchicine for acute gout attacks to a loading dose of 1.2 mg, followed by 0.6 mg an hour later, and then starting prophylaxis 12 hours later at dosing of 0.6 mg once or twice daily.

"We used to give up to eight tablets a day," Dr. FitzGerald said. "That is dropped down to three to four tablets at the start of an attacks, because of findings that more colchicine didn’t really help outcomes" and that smaller doses are safer. The authors called this recommendation from ACR "a paradigm shift" that’s in accordance with Food and Drug Administration-approved label language.

Other highlights of the new ACR recommendations include sections on screening for HLA-B*5801 in patients at high risk of severe adverse reaction to allopurinol, combination therapy when target urate levels are not achieved, medication options including new drugs, and more.

Although the reports are titled "Guidelines," the text makes clear that they are expert recommendations and that clinicians are expected to take active roles in choosing the best management strategies for their particular patients. The authors were "very concerned" that the guidelines not be used by third-party payers to restrict access to medications or to promote one drug over another if there isn’t clear evidence to support it, Dr. FitzGerald said.

The methodology of the project precluded evaluations of costs and cost effectiveness, instead focusing on efficacy. So, for example, the guidelines say that allopurinol and febuxostat can be used equivalently in some circumstances, but clinicians need to consider all other aspects of these options including cost, patient preference, and more.

The ACR plans to update the guidelines as new data become available. The task force panel did create specific indications for use of imaging studies because results should be available in the next few years from studies on the use of high-resolution ultrasound and dual-energy CT for patients with gout.

In the United States, gout affects an estimated 4% of adults – more than 8 million people.

"I’m most excited and hopeful about trying to get this out to internal medicine and family practice doctors," Dr. FitzGerald said. "They see more gout than rheumatologists."

Dr. FitzGerald reported having no financial disclosures. Some members of the task force reported financial associations with multiple pharmaceutical companies but, by design, a majority of task force members had no perceived potential conflicts of interest. 

ANSWER
The correct interpretation includes normal sinus rhythm, right bundle branch block, and left anterior fascicular block. Normal sinus rhythm is evidenced by a rate between 60 and 100 beats/min, with a corresponding P for every QRS and a QRS for every P.

Right bundle branch block is evidenced by a QRS duration > 120 ms, a terminal broad S wave in lead I, and an RSR’ complex in lead V₁. Left anterior fascicular block is evident from the finding that the S waves are greater than the R waves in leads II, III, and aVF.

The presence of a right ventricular block and left anterior fascicular block (bifascicular block) is consistent with a history of a VSD and/or surgical repair. The right and left bundles proceed from the atrioventricular node and bundle of His down the ventricular septum to the Purkinje fibers in the distal ventricular myocardium. Therefore, congenital anomalies of the ventricular septum, and/or surgical intervention within it, often affect conduction of the right and/or left bundle.

This patient’s symptoms were a result of his dilated aorta, and he underwent successful repair, with resolution of his symptoms.

ANSWER
The correct interpretation includes normal sinus rhythm, right bundle branch block, and left anterior fascicular block. Normal sinus rhythm is evidenced by a rate between 60 and 100 beats/min, with a corresponding P for every QRS and a QRS for every P.

Right bundle branch block is evidenced by a QRS duration > 120 ms, a terminal broad S wave in lead I, and an RSR’ complex in lead V₁. Left anterior fascicular block is evident from the finding that the S waves are greater than the R waves in leads II, III, and aVF.

The presence of a right ventricular block and left anterior fascicular block (bifascicular block) is consistent with a history of a VSD and/or surgical repair. The right and left bundles proceed from the atrioventricular node and bundle of His down the ventricular septum to the Purkinje fibers in the distal ventricular myocardium. Therefore, congenital anomalies of the ventricular septum, and/or surgical intervention within it, often affect conduction of the right and/or left bundle.

This patient’s symptoms were a result of his dilated aorta, and he underwent successful repair, with resolution of his symptoms.

ANSWER
The correct interpretation includes normal sinus rhythm, right bundle branch block, and left anterior fascicular block. Normal sinus rhythm is evidenced by a rate between 60 and 100 beats/min, with a corresponding P for every QRS and a QRS for every P.

Right bundle branch block is evidenced by a QRS duration > 120 ms, a terminal broad S wave in lead I, and an RSR’ complex in lead V₁. Left anterior fascicular block is evident from the finding that the S waves are greater than the R waves in leads II, III, and aVF.

The presence of a right ventricular block and left anterior fascicular block (bifascicular block) is consistent with a history of a VSD and/or surgical repair. The right and left bundles proceed from the atrioventricular node and bundle of His down the ventricular septum to the Purkinje fibers in the distal ventricular myocardium. Therefore, congenital anomalies of the ventricular septum, and/or surgical intervention within it, often affect conduction of the right and/or left bundle.

This patient’s symptoms were a result of his dilated aorta, and he underwent successful repair, with resolution of his symptoms.