Research Original Investigation
Tramadol and Hospitalization for Hypoglycemia
Invited Commentary
Tramadol and Hypoglycemia One More Thing to Worry About Lewis S. Nelson, MD; David N. Juurlink, MD, PhD
Pain is one of the leading reasons why patients seek medical attention, and over the past 2 decades, clinicians, health care institutions, medical organizations, and regulators have become increasingly attentive to its management. Yet despite the Related articles pages 186 importance of pain as a clinical and 302 entity, the well of approved pharmacologic options is shallow, consisting principally of acetaminophen, nonsteroidal anti-inflammatory drugs, and opioids, along with off-label alternatives including certain anticonvulsants, antidepressants, and a smattering of other drugs for some types of pain. However, the expectation that analgesics can significantly reduce or abolish pain is often overly optimistic and can lead to the progressive use of higher doses of stronger analgesics without a reasonable benchmark for success or failure. The subjective nature of pain, which can fluctuate and which lacks the objective quantification that many clinicians are accustomed to, further complicates this assessment. Nonpharmacologic approaches such as physical therapy, meditation, exercise, and weight loss are harder to implement than medication because they are time consuming, labor intensive, and often not covered by insurance, even though each is supported by evidence of safety and effectiveness in selected patients. In our desire to alleviate pain—something that clinicians are by nature conditioned to do—we have increasingly resorted to opioids, in part because we perceive them to be the strongest tool at our disposal. Opioid therapy works well for some patients with acute and chronic pain, but for many others it does not. The reasons for therapeutic failure are incompletely characterized but undoubtedly numerous. Yet all patients who take opioids are at risk for the development of tolerance and dependence, as well as the more consequential risks of addiction, overdose, and death. A relative newcomer to our analgesic toolbox is tramadol hydrochloride. First synthesized in the 1970s, it has become especially popular in recent years, in part because it is touted as having a dual mechanism of analgesic action but also because of the widely held perception that it is safer than existing options. Clinical guidelines for the management of chronic pain increasingly advocate the early use of tramadol on this basis. In light of tramadol’s growing popularity, a brief review of its pharmacological properties is warranted. Tramadol itself has low affinity for opioid receptors but inhibits the neuronal reuptake of serotonin and norepinephrine, much like the antidepressant venlafaxine hydrochloride. This mechanism is thought to play a role in tramadol’s use in neuropathic pain. Of its many metabolites, one (O-desmethyltramadol [M1]) binds to μ opioid receptors, as do morphine sulfate, hydromorphone hydrochloride, and other opioids. Importantly, the conversion of tramadol to M1 is cata194
lyzed by cytochrome P450 isoform 2D6 (CYP2D6), the same enzyme responsible for conversion of codeine phosphate to its primary active metabolite, morphine. Herein lies the first problem with tramadol: The expression of CYP2D6 is extremely variable, and the amount of M1 synthesized for a given dose of tramadol is subject to dramatic variability.1 For example, roughly 7% of whites express no functional CYP2D6; these “poor metabolizers” form no M1 and experience less analgesia as a result. In contrast, other patients overexpress CYP2D6 and generate considerably more M1. Approximately 10% of Italians, Portuguese, and Greeks and roughly one-third of people from the Arabian Peninsula and eastern Africa are “ultrarapid metabolizers.”1 Moreover, such patients can be rendered “functional poor metabolizers” by concomitant use of drugs that inhibit CYP2D6, such as paroxetine hydrochloride. The clinical implications of tramadol’s pharmacokinetics are clear: Giving a known dose of tramadol is tantamount to giving an unknown dose of opioid. This is of direct relevance to the drug’s safety and effectiveness. Despite suggestions to the contrary, tramadol displays markers of abuse liability similar to other conventional opioids2 and is widely used for its psychoactive effects. 3 Consequently, in August 2014, tramadol was moved to Schedule IV of the US Controlled Substances Act, reflecting its potential for abuse and diversion. Australia and the United Kingdom have similarly restricted tramadol, although other countries such as Canada have not. The notion that tramadol is safer than other opioids is countered by increasing reports of death involving the drug; in England and Wales, the number of deaths involving tramadol roughly tripled from 2009 to 2013.4 In addition to its unpredictable pharmacokinetics, tramadol therapy is beset by several other important adverse effects. Serotonin syndrome, which can cause life-threatening hyperthermia and multiorgan dysfunction, has been reported in patients taking tramadol, sometimes at very low doses. This is particularly likely when tramadol is combined with antidepressants, a common clinical scenario in patients with chronic pain. Seizures are also a well-described adverse effect of tramadol therapy and can occur even with therapeutic doses. In this issue of JAMA Internal Medicine, Fournier and colleagues5 strengthen the evidence base linking tramadol use with yet another potentially dangerous adverse effect: hypoglycemia. To date, this association has been limited to case reports and case series. By linking prescription claims data and hospital records in the United Kingdom, they found that patients commencing treatment with tramadol were more than 3 times as likely to be hospitalized with hypoglycemia in the subsequent 30 days than those who commenced treatment with codeine. Codeine is a natural comparator for such an analysis; like tramadol, it too is a prodrug converted to a μ opi-
JAMA Internal Medicine February 2015 Volume 175, Number 2 (Reprinted)
Copyright 2015 American Medical Association. All rights reserved.
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Tramadol and Hospitalization for Hypoglycemia
Original Investigation Research
oid agonist (morphine) by CYP2D6. Although hypoglycemia was uncommon in the study of Fournier et al5 (only 8 events were identified in more than 26 000 person-months of tramadol therapy), the true rate is likely higher because hypoglycemia is common, may not be reported in diabetics, and may not be recognized in patients without diabetes. In either case, most instances will not result in hospital admission. Is the association between tramadol use and hypoglycemia a causal one? Perhaps. When the available evidence is considered in toto, many of the fundamental tests of causality are met. In addition to published and unpublished reports suggesting tramadol use as a cause of hypoglycemia, animal studies provide evidence of a complex but incompletely characterized pathophysiologic mechanism. In diabetic rats, tramadol directly reduces hepatic gluconeogenesis and enhances peripheral glucose utilization.6 In a different animal model, tramadol-mediated stimulation of μ receptors in the cerebral cortex and hypothalamus appeared to increase insulin signaling, thereby increasing hepatic sensitivity to insulin.7 In both studies, these effects were blocked by naloxone. What remains unclear is why hypoglycemia is not seen in patients taking other μ agonists such as morphine, oxycodone hydrochloride, and hydrocodone bitartrate. ARTICLE INFORMATION Author Affiliations: Emergency Medicine, New York University School of Medicine, New York, New York (Nelson); General Internal Medicine, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada (Juurlink). Corresponding Author: Lewis S. Nelson, MD, Emergency Medicine, New York University School of Medicine, 455 First Ave, Room 123, New York, NY 10016 ([email protected]). Published Online: December 8, 2014. doi:10.1001/jamainternmed.2014.5260. Conflict of Interest Disclosures: None reported. REFERENCES 1. Kirchheiner J, Keulen JT, Bauer S, Roots I, Brockmöller J. Effects of the CYP2D6 gene
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The increased prescribing of tramadol most likely reflects aggressive marketing coupled with the perception that it is a safe analgesic not prone to abuse. Whereas the drug’s analgesic effects are at best moderate, its toxic effects are dangerous and merit respect, particularly when doses are escalated. Seizures, serotonin syndrome, drug interactions, and opioid-related adverse effects (including addiction, respiratory depression, and death) are now joined by the potential risk of hypoglycemia. Because hypoglycemia can be life threatening, clinicians should remain vigilant for this potential complication of tramadol use, in patients taking the drug as directed, as well as those who abuse it. Whether tramadol therapy should be particularly avoided in patients receiving hypoglycemic drugs is unclear, but given the drug’s limited benefit and unpredictable pharmacological properties, it should be handled at least as carefully in these patients as in others. All opioids carry risks, but the conventional full opioid agonists, used in properly selected patients at appropriate doses, have risks that are more predictable than those of tramadol. If we replace conventional opioids with tramadol, as some guidelines have suggested, we may be left with more unintended consequences of the opioid epidemic to worry about.
duplication on the pharmacokinetics and pharmacodynamics of tramadol. J Clin Psychopharmacol. 2008;28(1):78-83. 2. Babalonis S, Lofwall MR, Nuzzo PA, Siegel AJ, Walsh SL. Abuse liability and reinforcing efficacy of oral tramadol in humans. Drug Alcohol Depend. 2013;129(1-2):116-124. 3. Erowid Experience Vaults. Tramadol. http://www.erowid.org/experiences/subs/exp _Pharms_Tramadol.shtml. Accessed September 15, 2014. 4. Office for National Statistics. Deaths Related to Drug Poisoning, England and Wales—2013. http: //www.ons.gov.uk/ons/rel/subnational-health3 /deaths-related-to-drug-poisoning/england-and -wales---2013/index.html. Accessed September 15, 2014.
5. Fournier J-P, Azoulay L, Yin H, Montastruc J-L, Suissa S. Tramadol use and the risk of hospitalization for hypoglycemia in patients with noncancer pain [published online December 8, 2014]. JAMA Intern Med. doi:10.1001 /jamainternmed.2014.6512. 6. Cheng JT, Liu IM, Chi TC, Tzeng TF, Lu FH, Chang CJ. Plasma glucose-lowering effect of tramadol in streptozotocin-induced diabetic rats. Diabetes. 2001;50(12):2815-2821. 7. Choi SB, Jang JS, Park S. Tramadol enhances hepatic insulin sensitivity via enhancing insulin signaling cascade in the cerebral cortex and hypothalamus of 90% pancreatectomized rats. Brain Res Bull. 2005;67(1-2):77-86.
(Reprinted) JAMA Internal Medicine February 2015 Volume 175, Number 2
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archinte.jamanetwork.com/ by a Fudan University User on 12/06/2016
195
Tramadol and Hospitalization for Hypoglycemia
Invited Commentary
Tramadol and Hypoglycemia One More Thing to Worry About Lewis S. Nelson, MD; David N. Juurlink, MD, PhD
Pain is one of the leading reasons why patients seek medical attention, and over the past 2 decades, clinicians, health care institutions, medical organizations, and regulators have become increasingly attentive to its management. Yet despite the Related articles pages 186 importance of pain as a clinical and 302 entity, the well of approved pharmacologic options is shallow, consisting principally of acetaminophen, nonsteroidal anti-inflammatory drugs, and opioids, along with off-label alternatives including certain anticonvulsants, antidepressants, and a smattering of other drugs for some types of pain. However, the expectation that analgesics can significantly reduce or abolish pain is often overly optimistic and can lead to the progressive use of higher doses of stronger analgesics without a reasonable benchmark for success or failure. The subjective nature of pain, which can fluctuate and which lacks the objective quantification that many clinicians are accustomed to, further complicates this assessment. Nonpharmacologic approaches such as physical therapy, meditation, exercise, and weight loss are harder to implement than medication because they are time consuming, labor intensive, and often not covered by insurance, even though each is supported by evidence of safety and effectiveness in selected patients. In our desire to alleviate pain—something that clinicians are by nature conditioned to do—we have increasingly resorted to opioids, in part because we perceive them to be the strongest tool at our disposal. Opioid therapy works well for some patients with acute and chronic pain, but for many others it does not. The reasons for therapeutic failure are incompletely characterized but undoubtedly numerous. Yet all patients who take opioids are at risk for the development of tolerance and dependence, as well as the more consequential risks of addiction, overdose, and death. A relative newcomer to our analgesic toolbox is tramadol hydrochloride. First synthesized in the 1970s, it has become especially popular in recent years, in part because it is touted as having a dual mechanism of analgesic action but also because of the widely held perception that it is safer than existing options. Clinical guidelines for the management of chronic pain increasingly advocate the early use of tramadol on this basis. In light of tramadol’s growing popularity, a brief review of its pharmacological properties is warranted. Tramadol itself has low affinity for opioid receptors but inhibits the neuronal reuptake of serotonin and norepinephrine, much like the antidepressant venlafaxine hydrochloride. This mechanism is thought to play a role in tramadol’s use in neuropathic pain. Of its many metabolites, one (O-desmethyltramadol [M1]) binds to μ opioid receptors, as do morphine sulfate, hydromorphone hydrochloride, and other opioids. Importantly, the conversion of tramadol to M1 is cata194
lyzed by cytochrome P450 isoform 2D6 (CYP2D6), the same enzyme responsible for conversion of codeine phosphate to its primary active metabolite, morphine. Herein lies the first problem with tramadol: The expression of CYP2D6 is extremely variable, and the amount of M1 synthesized for a given dose of tramadol is subject to dramatic variability.1 For example, roughly 7% of whites express no functional CYP2D6; these “poor metabolizers” form no M1 and experience less analgesia as a result. In contrast, other patients overexpress CYP2D6 and generate considerably more M1. Approximately 10% of Italians, Portuguese, and Greeks and roughly one-third of people from the Arabian Peninsula and eastern Africa are “ultrarapid metabolizers.”1 Moreover, such patients can be rendered “functional poor metabolizers” by concomitant use of drugs that inhibit CYP2D6, such as paroxetine hydrochloride. The clinical implications of tramadol’s pharmacokinetics are clear: Giving a known dose of tramadol is tantamount to giving an unknown dose of opioid. This is of direct relevance to the drug’s safety and effectiveness. Despite suggestions to the contrary, tramadol displays markers of abuse liability similar to other conventional opioids2 and is widely used for its psychoactive effects. 3 Consequently, in August 2014, tramadol was moved to Schedule IV of the US Controlled Substances Act, reflecting its potential for abuse and diversion. Australia and the United Kingdom have similarly restricted tramadol, although other countries such as Canada have not. The notion that tramadol is safer than other opioids is countered by increasing reports of death involving the drug; in England and Wales, the number of deaths involving tramadol roughly tripled from 2009 to 2013.4 In addition to its unpredictable pharmacokinetics, tramadol therapy is beset by several other important adverse effects. Serotonin syndrome, which can cause life-threatening hyperthermia and multiorgan dysfunction, has been reported in patients taking tramadol, sometimes at very low doses. This is particularly likely when tramadol is combined with antidepressants, a common clinical scenario in patients with chronic pain. Seizures are also a well-described adverse effect of tramadol therapy and can occur even with therapeutic doses. In this issue of JAMA Internal Medicine, Fournier and colleagues5 strengthen the evidence base linking tramadol use with yet another potentially dangerous adverse effect: hypoglycemia. To date, this association has been limited to case reports and case series. By linking prescription claims data and hospital records in the United Kingdom, they found that patients commencing treatment with tramadol were more than 3 times as likely to be hospitalized with hypoglycemia in the subsequent 30 days than those who commenced treatment with codeine. Codeine is a natural comparator for such an analysis; like tramadol, it too is a prodrug converted to a μ opi-
JAMA Internal Medicine February 2015 Volume 175, Number 2 (Reprinted)
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archinte.jamanetwork.com/ by a Fudan University User on 12/06/2016
jamainternalmedicine.com
Tramadol and Hospitalization for Hypoglycemia
Original Investigation Research
oid agonist (morphine) by CYP2D6. Although hypoglycemia was uncommon in the study of Fournier et al5 (only 8 events were identified in more than 26 000 person-months of tramadol therapy), the true rate is likely higher because hypoglycemia is common, may not be reported in diabetics, and may not be recognized in patients without diabetes. In either case, most instances will not result in hospital admission. Is the association between tramadol use and hypoglycemia a causal one? Perhaps. When the available evidence is considered in toto, many of the fundamental tests of causality are met. In addition to published and unpublished reports suggesting tramadol use as a cause of hypoglycemia, animal studies provide evidence of a complex but incompletely characterized pathophysiologic mechanism. In diabetic rats, tramadol directly reduces hepatic gluconeogenesis and enhances peripheral glucose utilization.6 In a different animal model, tramadol-mediated stimulation of μ receptors in the cerebral cortex and hypothalamus appeared to increase insulin signaling, thereby increasing hepatic sensitivity to insulin.7 In both studies, these effects were blocked by naloxone. What remains unclear is why hypoglycemia is not seen in patients taking other μ agonists such as morphine, oxycodone hydrochloride, and hydrocodone bitartrate. ARTICLE INFORMATION Author Affiliations: Emergency Medicine, New York University School of Medicine, New York, New York (Nelson); General Internal Medicine, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada (Juurlink). Corresponding Author: Lewis S. Nelson, MD, Emergency Medicine, New York University School of Medicine, 455 First Ave, Room 123, New York, NY 10016 ([email protected]). Published Online: December 8, 2014. doi:10.1001/jamainternmed.2014.5260. Conflict of Interest Disclosures: None reported. REFERENCES 1. Kirchheiner J, Keulen JT, Bauer S, Roots I, Brockmöller J. Effects of the CYP2D6 gene
jamainternalmedicine.com
The increased prescribing of tramadol most likely reflects aggressive marketing coupled with the perception that it is a safe analgesic not prone to abuse. Whereas the drug’s analgesic effects are at best moderate, its toxic effects are dangerous and merit respect, particularly when doses are escalated. Seizures, serotonin syndrome, drug interactions, and opioid-related adverse effects (including addiction, respiratory depression, and death) are now joined by the potential risk of hypoglycemia. Because hypoglycemia can be life threatening, clinicians should remain vigilant for this potential complication of tramadol use, in patients taking the drug as directed, as well as those who abuse it. Whether tramadol therapy should be particularly avoided in patients receiving hypoglycemic drugs is unclear, but given the drug’s limited benefit and unpredictable pharmacological properties, it should be handled at least as carefully in these patients as in others. All opioids carry risks, but the conventional full opioid agonists, used in properly selected patients at appropriate doses, have risks that are more predictable than those of tramadol. If we replace conventional opioids with tramadol, as some guidelines have suggested, we may be left with more unintended consequences of the opioid epidemic to worry about.
duplication on the pharmacokinetics and pharmacodynamics of tramadol. J Clin Psychopharmacol. 2008;28(1):78-83. 2. Babalonis S, Lofwall MR, Nuzzo PA, Siegel AJ, Walsh SL. Abuse liability and reinforcing efficacy of oral tramadol in humans. Drug Alcohol Depend. 2013;129(1-2):116-124. 3. Erowid Experience Vaults. Tramadol. http://www.erowid.org/experiences/subs/exp _Pharms_Tramadol.shtml. Accessed September 15, 2014. 4. Office for National Statistics. Deaths Related to Drug Poisoning, England and Wales—2013. http: //www.ons.gov.uk/ons/rel/subnational-health3 /deaths-related-to-drug-poisoning/england-and -wales---2013/index.html. Accessed September 15, 2014.
5. Fournier J-P, Azoulay L, Yin H, Montastruc J-L, Suissa S. Tramadol use and the risk of hospitalization for hypoglycemia in patients with noncancer pain [published online December 8, 2014]. JAMA Intern Med. doi:10.1001 /jamainternmed.2014.6512. 6. Cheng JT, Liu IM, Chi TC, Tzeng TF, Lu FH, Chang CJ. Plasma glucose-lowering effect of tramadol in streptozotocin-induced diabetic rats. Diabetes. 2001;50(12):2815-2821. 7. Choi SB, Jang JS, Park S. Tramadol enhances hepatic insulin sensitivity via enhancing insulin signaling cascade in the cerebral cortex and hypothalamus of 90% pancreatectomized rats. Brain Res Bull. 2005;67(1-2):77-86.
(Reprinted) JAMA Internal Medicine February 2015 Volume 175, Number 2
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archinte.jamanetwork.com/ by a Fudan University User on 12/06/2016
195
