EM:RAP COMMENTARY
Serotonin Syndrome and Opioids—What’s the Deal? Paul Jhun, MD*; Aaron Bright, MD; Mel Herbert, MD *Corresponding Author. E-mail: [email protected], Twitter: @jhunlikefun. 0196-0644/$-see front matter Copyright © 2015 by the American College of Emergency Physicians. http://dx.doi.org/10.1016/j.annemergmed.2014.12.021
[Ann Emerg Med. 2015;65:434-435.] Editor’s Note: Annals has partnered with EM:RAP, enabling our readers without subscriptions to the EM:RAP service to enjoy their commentary on Annals publications. This article did not undergo peer review and may not reflect the view and opinions of the editorial board of Annals of Emergency Medicine.
WHO CARES? There are myriad (that’s fancy talk for a lot) of medications that can precipitate serotonin syndrome (SS) or serotonin toxicity. Meperidine arguably received the most publicity through the Libby Zion case, which led to regulation of resident physician duty hours.1 Although serotonergic medications obviously play a role in SS, which opioids, aside from meperidine, have been associated with SS? And, given the frequency of pain medication administration in the emergency department, which opioids, if any, are presumably safe to use?
KEY CONCEPTS SS is probably better described as serotonin toxicity. It is not an idiopathic reaction; rather, it’s a predictable response: excess serotonin leads to adverse clinical sequelae (fancy talk for bad stuff), as manifested by the classic triad of altered mental status, autonomic hyperactivity, and neuromuscular excitability. The onset of symptoms is rapid, within minutes to hours after an increase in medication dosage or addition of a serotonergic medication.2,3 The list of medications that have been implicated in SS is a big one: monoamine oxidase inhibitors, tricyclic antidepressants, selective serotonin-reuptake inhibitors, dextromethorphan, drugs of abuse such as cocaine and methamphetamines, triptans, certain antibiotics such as linezolid, certain antiemetics such as ondansetron, several antipsychotics and antiepileptics, etc.2,3 But let’s focus on opioids. Probably the most well-known opioid analgesic to be associated with SS is meperidine. For many reasons, a lot of us do not use meperidine as often as in years past, but do all opioids confer the same risk potential to precipitate SS?
OPIOID TYPES Although the world’s nerd-geniuses are still hard at work trying to fully understand the central nervous system pain pathways, the predominant analgesic effects of opioids are 434 Annals of Emergency Medicine
believed to be mediated through opioid receptors (wow! shocking revelation). One animal study, however, noted that distinct opioid subgroups, with unique chemical structural characteristics, have additional inhibitory effects on serotonin reuptake.4 In other words, certain opioids increase serotonin levels, which increases the risk for developing serotonin toxicity. OK, did you fall asleep a lot in biochemistry? If so, go ahead and skip this next part. The 2 main classes of opioids are phenanthrenes (ie, natural and semisynthetic opiate derivatives) and nonphenanthrenes (ie, synthetic opiate analogs).5 Either makes a nice name for your dog, yes? Of the phenanthrenes, there are 2 distinct subgroups, according to the presence or absence of an oxygen bridge in their chemical structure.4 Phenanthrenes with an oxygen bridge include buprenorphine, codeine, oxycodone, hydrocodone, hydromorphone, morphine,6 naloxone, and naltrexone. Phenanthrenes without one include dextromethorphan. Nonphenanthrenes include fentanyl, meperidine,7 tramadol, methadone, and propoxyphene.8 Are you still awake? Suffice it to say that according to the study by Codd et al,4 phenanthrene opioids with an oxygen bridge did not appear to have any serotonergic effects. Conversely, both phenanthrene opioids lacking the oxygen bridge and nonphenanthrene opioids inhibited serotonin reuptake, leading to increased serotonin levels. In English, we think this structural difference may explain why some opioids can precipitate SS, whereas others do not.
WHAT DOES THE LITERATURE SHOW? MEDLINE was searched with the OvidSP interface on October 16, 2014, for the period 1946 to January, week 5, 2014, combining the Medical Subject Headings terms “serotonin syndrome” and “opioid analgesics.” Of the 70 resulting publications, the specific opioid analgesics reportedly associated with SS (all case reports or series) included tramadol, meperidine, fentanyl, methadone, oxycodone, buprenorphine and naloxone (Suboxone), and hydromorphone. Additional case reports were identified from the reference sections of selected articles. To our knowledge, no case reports have been published of SS associated with morphine, codeine, or hydrocodone. The most commonly reported opioids associated with SS (tramadol, meperidine, fentanyl and methadone) are known to inhibit serotonin reuptake. But there are case reports of SS associated Volume 65, no. 4 : April 2015
Jhun, Bright & Herbert with hydromorphone,9 buprenorphine and naloxone (Suboxone),10 and oxycodone.11-15
WHAT GIVES? If the theory is that phenanthrene opioids with an oxygen bridge do not result in serotonergic effects, these case reports involving oxycodone, buprenorphine and naloxone (Suboxone), and hydromorphone seem to go against that. However, further review of these case reports reveals significant confounding factors, from missing historical and temporal information to potential polypharmacy effects. More studies, both basic science and clinical research, need to be conducted.
THE BOTTOM LINE There are no published case reports or literature associating morphine, codeine, or hydrocodone with SS. “No more clonus” (Norco or hydrocodone, morphine, codeine) is a useful mnemonic to remember which opioids presumably do not cause SS. For patients receiving serotonergic medications, especially a monoamine oxidase inhibitor, who are in need of opioid analgesia, the following opioid classes should be avoided out of concern of precipitating SS: phenanthrenes without an oxygen bridge (eg, dextromethorphan) and nonphenanthrenes (eg, meperidine, fentanyl, tramadol, methadone, propoxyphene).16,17 Author affiliations: From the Department of Emergency Medicine, University of California San Francisco, San Francisco, CA (Jhun); and the Department of Emergency Medicine, University of Southern California, Los Angeles, CA (Bright, Herbert). Funding and support: By Annals policy, all authors are required to disclose any and all commercial, financial, and other relationships in any way related to the subject of this article as per ICMJE conflict of interest guidelines (see www.icmje.org). The authors have stated that no such relationships exist and provided the following details: Dr. Jhun reports other from Hippo Education, Inc., outside the submitted work. Dr. Bright reports other from Hippo Education, Inc., outside the submitted work. Dr. Herbert reports other from EM:RAP and Hippo Education, Inc., outside the submitted work.
Volume 65, no. 4 : April 2015
EM:RAP Commentary REFERENCES 1. Lerner BH. A case that shook medicine. Washington Post. November 28, 2006. Available at: http://www.washingtonpost.com/wp-dyn/ content/article/2006/11/24/AR2006112400985.html. Accessed February 8, 2014. 2. Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med. 2005;352:1112-1120. 3. Boyer EW. Serotonin syndrome. Available at: http://www-uptodatecom.libproxy.usc.edu/contents/serotonin-syndrome?source¼search_ result&search¼serotoninþsyndrome&selectedTitle¼1w150. Accessed February 2, 2014. 4. Codd EE, Shank RP, Schupsky JJ, et al. Serotonin and norepinephrine uptake inhibiting activity of centrally acting analgesics: structural determinants and role in nociception. J Pharmacol Exp Ther. 1995;274:1263-1270. 5. Zichterman A. Opioid pharmacology and considerations in pain management. US Pharmacist. May 2007. Available at: http://www. uspharmacist.com/continuing_education/ceviewtest/lessonid/ 105473/. Accessed February 8, 2014. 6. Wikipedia. Morphine. February 2014. Available at: http://en.wikipedia. org/wiki/Morphine. Accessed February 8, 2014. 7. Wikipedia. Pethidine. February 2014. Available at: http://en.wikipedia. org/wiki/Meperidine. Accessed February 8, 2014. 8. Wikipedia. Dextropropoxyphene. January 2014. Available at: http://en. wikipedia.org/wiki/Propoxyphene. Accessed February 8, 2014. 9. Isenberg D, Wong SC, Curtis JA. Serotonin syndrome triggered by a single dose of Suboxone. Am J Emerg Med. 2008;26:840. e3-e5. 10. Fluoxetine þ hydromorphone: serotonin syndrome? Prescrire Int. 2004;13:57. 11. Walter C, Ball D, Duffy M, et al. An unusual case of serotonin syndrome with oxycodone and citalopram. Case Rep Oncol Med. 2012;2012:261787. 12. Song HK. Serotonin syndrome with perioperative oxycodone and pregabalin. Pain Physician. 2013;16:E362-E363. 13. Karunatilake H, Buckley NA. Serotonin syndrome induced by fluvoxamine and oxycodone. Ann Pharmacother. 2006;40: 155-157. 14. Reich M, Lefebvre-Kuntz D. Serotonergic antidepressants and opiate analgesics: a sometimes painful association. A case report. Encephale. 2010;36(suppl 2):D119-D123. 15. Gnanadesigan N, Espinoza RT, Smith R, et al. Interaction of serotonergic antidepressants and opioid analgesics: is serotonin syndrome going undetected? J Am Med Dir Assoc. 2005;6:265-269. 16. Gillman PK. Monoamine oxidase inhibitors, opioid analgesics and serotonin toxicity. Br J Anaesth. 2005;95:434-441. 17. Sun-Edelstein C, Tepper SJ, Shapiro RE. Drug-induced serotonin syndrome: a review. Expert Opin Drug Saf. 2008;7:587-596.
Annals of Emergency Medicine 435
Serotonin Syndrome and Opioids—What’s the Deal? Paul Jhun, MD*; Aaron Bright, MD; Mel Herbert, MD *Corresponding Author. E-mail: [email protected], Twitter: @jhunlikefun. 0196-0644/$-see front matter Copyright © 2015 by the American College of Emergency Physicians. http://dx.doi.org/10.1016/j.annemergmed.2014.12.021
[Ann Emerg Med. 2015;65:434-435.] Editor’s Note: Annals has partnered with EM:RAP, enabling our readers without subscriptions to the EM:RAP service to enjoy their commentary on Annals publications. This article did not undergo peer review and may not reflect the view and opinions of the editorial board of Annals of Emergency Medicine.
WHO CARES? There are myriad (that’s fancy talk for a lot) of medications that can precipitate serotonin syndrome (SS) or serotonin toxicity. Meperidine arguably received the most publicity through the Libby Zion case, which led to regulation of resident physician duty hours.1 Although serotonergic medications obviously play a role in SS, which opioids, aside from meperidine, have been associated with SS? And, given the frequency of pain medication administration in the emergency department, which opioids, if any, are presumably safe to use?
KEY CONCEPTS SS is probably better described as serotonin toxicity. It is not an idiopathic reaction; rather, it’s a predictable response: excess serotonin leads to adverse clinical sequelae (fancy talk for bad stuff), as manifested by the classic triad of altered mental status, autonomic hyperactivity, and neuromuscular excitability. The onset of symptoms is rapid, within minutes to hours after an increase in medication dosage or addition of a serotonergic medication.2,3 The list of medications that have been implicated in SS is a big one: monoamine oxidase inhibitors, tricyclic antidepressants, selective serotonin-reuptake inhibitors, dextromethorphan, drugs of abuse such as cocaine and methamphetamines, triptans, certain antibiotics such as linezolid, certain antiemetics such as ondansetron, several antipsychotics and antiepileptics, etc.2,3 But let’s focus on opioids. Probably the most well-known opioid analgesic to be associated with SS is meperidine. For many reasons, a lot of us do not use meperidine as often as in years past, but do all opioids confer the same risk potential to precipitate SS?
OPIOID TYPES Although the world’s nerd-geniuses are still hard at work trying to fully understand the central nervous system pain pathways, the predominant analgesic effects of opioids are 434 Annals of Emergency Medicine
believed to be mediated through opioid receptors (wow! shocking revelation). One animal study, however, noted that distinct opioid subgroups, with unique chemical structural characteristics, have additional inhibitory effects on serotonin reuptake.4 In other words, certain opioids increase serotonin levels, which increases the risk for developing serotonin toxicity. OK, did you fall asleep a lot in biochemistry? If so, go ahead and skip this next part. The 2 main classes of opioids are phenanthrenes (ie, natural and semisynthetic opiate derivatives) and nonphenanthrenes (ie, synthetic opiate analogs).5 Either makes a nice name for your dog, yes? Of the phenanthrenes, there are 2 distinct subgroups, according to the presence or absence of an oxygen bridge in their chemical structure.4 Phenanthrenes with an oxygen bridge include buprenorphine, codeine, oxycodone, hydrocodone, hydromorphone, morphine,6 naloxone, and naltrexone. Phenanthrenes without one include dextromethorphan. Nonphenanthrenes include fentanyl, meperidine,7 tramadol, methadone, and propoxyphene.8 Are you still awake? Suffice it to say that according to the study by Codd et al,4 phenanthrene opioids with an oxygen bridge did not appear to have any serotonergic effects. Conversely, both phenanthrene opioids lacking the oxygen bridge and nonphenanthrene opioids inhibited serotonin reuptake, leading to increased serotonin levels. In English, we think this structural difference may explain why some opioids can precipitate SS, whereas others do not.
WHAT DOES THE LITERATURE SHOW? MEDLINE was searched with the OvidSP interface on October 16, 2014, for the period 1946 to January, week 5, 2014, combining the Medical Subject Headings terms “serotonin syndrome” and “opioid analgesics.” Of the 70 resulting publications, the specific opioid analgesics reportedly associated with SS (all case reports or series) included tramadol, meperidine, fentanyl, methadone, oxycodone, buprenorphine and naloxone (Suboxone), and hydromorphone. Additional case reports were identified from the reference sections of selected articles. To our knowledge, no case reports have been published of SS associated with morphine, codeine, or hydrocodone. The most commonly reported opioids associated with SS (tramadol, meperidine, fentanyl and methadone) are known to inhibit serotonin reuptake. But there are case reports of SS associated Volume 65, no. 4 : April 2015
Jhun, Bright & Herbert with hydromorphone,9 buprenorphine and naloxone (Suboxone),10 and oxycodone.11-15
WHAT GIVES? If the theory is that phenanthrene opioids with an oxygen bridge do not result in serotonergic effects, these case reports involving oxycodone, buprenorphine and naloxone (Suboxone), and hydromorphone seem to go against that. However, further review of these case reports reveals significant confounding factors, from missing historical and temporal information to potential polypharmacy effects. More studies, both basic science and clinical research, need to be conducted.
THE BOTTOM LINE There are no published case reports or literature associating morphine, codeine, or hydrocodone with SS. “No more clonus” (Norco or hydrocodone, morphine, codeine) is a useful mnemonic to remember which opioids presumably do not cause SS. For patients receiving serotonergic medications, especially a monoamine oxidase inhibitor, who are in need of opioid analgesia, the following opioid classes should be avoided out of concern of precipitating SS: phenanthrenes without an oxygen bridge (eg, dextromethorphan) and nonphenanthrenes (eg, meperidine, fentanyl, tramadol, methadone, propoxyphene).16,17 Author affiliations: From the Department of Emergency Medicine, University of California San Francisco, San Francisco, CA (Jhun); and the Department of Emergency Medicine, University of Southern California, Los Angeles, CA (Bright, Herbert). Funding and support: By Annals policy, all authors are required to disclose any and all commercial, financial, and other relationships in any way related to the subject of this article as per ICMJE conflict of interest guidelines (see www.icmje.org). The authors have stated that no such relationships exist and provided the following details: Dr. Jhun reports other from Hippo Education, Inc., outside the submitted work. Dr. Bright reports other from Hippo Education, Inc., outside the submitted work. Dr. Herbert reports other from EM:RAP and Hippo Education, Inc., outside the submitted work.
Volume 65, no. 4 : April 2015
EM:RAP Commentary REFERENCES 1. Lerner BH. A case that shook medicine. Washington Post. November 28, 2006. Available at: http://www.washingtonpost.com/wp-dyn/ content/article/2006/11/24/AR2006112400985.html. Accessed February 8, 2014. 2. Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med. 2005;352:1112-1120. 3. Boyer EW. Serotonin syndrome. Available at: http://www-uptodatecom.libproxy.usc.edu/contents/serotonin-syndrome?source¼search_ result&search¼serotoninþsyndrome&selectedTitle¼1w150. Accessed February 2, 2014. 4. Codd EE, Shank RP, Schupsky JJ, et al. Serotonin and norepinephrine uptake inhibiting activity of centrally acting analgesics: structural determinants and role in nociception. J Pharmacol Exp Ther. 1995;274:1263-1270. 5. Zichterman A. Opioid pharmacology and considerations in pain management. US Pharmacist. May 2007. Available at: http://www. uspharmacist.com/continuing_education/ceviewtest/lessonid/ 105473/. Accessed February 8, 2014. 6. Wikipedia. Morphine. February 2014. Available at: http://en.wikipedia. org/wiki/Morphine. Accessed February 8, 2014. 7. Wikipedia. Pethidine. February 2014. Available at: http://en.wikipedia. org/wiki/Meperidine. Accessed February 8, 2014. 8. Wikipedia. Dextropropoxyphene. January 2014. Available at: http://en. wikipedia.org/wiki/Propoxyphene. Accessed February 8, 2014. 9. Isenberg D, Wong SC, Curtis JA. Serotonin syndrome triggered by a single dose of Suboxone. Am J Emerg Med. 2008;26:840. e3-e5. 10. Fluoxetine þ hydromorphone: serotonin syndrome? Prescrire Int. 2004;13:57. 11. Walter C, Ball D, Duffy M, et al. An unusual case of serotonin syndrome with oxycodone and citalopram. Case Rep Oncol Med. 2012;2012:261787. 12. Song HK. Serotonin syndrome with perioperative oxycodone and pregabalin. Pain Physician. 2013;16:E362-E363. 13. Karunatilake H, Buckley NA. Serotonin syndrome induced by fluvoxamine and oxycodone. Ann Pharmacother. 2006;40: 155-157. 14. Reich M, Lefebvre-Kuntz D. Serotonergic antidepressants and opiate analgesics: a sometimes painful association. A case report. Encephale. 2010;36(suppl 2):D119-D123. 15. Gnanadesigan N, Espinoza RT, Smith R, et al. Interaction of serotonergic antidepressants and opioid analgesics: is serotonin syndrome going undetected? J Am Med Dir Assoc. 2005;6:265-269. 16. Gillman PK. Monoamine oxidase inhibitors, opioid analgesics and serotonin toxicity. Br J Anaesth. 2005;95:434-441. 17. Sun-Edelstein C, Tepper SJ, Shapiro RE. Drug-induced serotonin syndrome: a review. Expert Opin Drug Saf. 2008;7:587-596.
Annals of Emergency Medicine 435
