Advertisement

Tramadol: Understanding the Risk of Serotonin Syndrome and Seizures

      Abstract

      Tramadol is commonly prescribed for pain control because it presents a lower risk for addiction and respiratory depression compared to other opioids. However, tramadol's serotonin and norepinephrine reuptake inhibitory effects result in a unique adverse effect profile. Two such adverse events are serotonin syndrome and seizures. The prevalence of tramadol-induced serotonin syndrome and seizures is modest in the general population, but if left untreated, the morbidity and mortality can be high; therefore, prompt recognition and management is essential. Various risk factors such as medical comorbidities, use or abuse of supratherapeutic doses of tramadol, and concomitant administration of proconvulsant serotonergic cytochrome P-450 inhibitors will help clinicians identify individuals at an elevated risk for serotonin toxicity and seizures. Serotonin syndrome and seizures can be effectively treated by administering benzodiazepines, providing supportive care, and discontinuing tramadol and other contributing agents. Cyproheptadine should be administered in moderate to severe cases of serotonin syndrome. Our objective is to summarize the literature on the pharmacology, epidemiology, risk factors, clinical presentations, and evidence-based management of tramadol-related seizures and serotonin syndrome.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to The American Journal of Medicine
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Sansone RA
        • Sansone LA
        Tramadol: seizures, serotonin syndrome, and coadministered antidepressants.
        Psychiatry (Edgmont). 2009; 6: 17-21
        • Reeves RR
        • Cox SK
        Similar effects of tramadol and venlafaxine in major depressive disorder.
        South Med J. 2008; 101: 193-195
        • Schug SA
        The role of tramadol in current treatment strategies for musculoskeletal pain.
        Ther Clin Risk Manag. 2007; 3: 717-723
        • Duehmke RM
        • Derry S
        • Wiffen PJ
        • Bell RF
        • Aldington D
        • Moore RA
        Tramadol for neuropathic pain in adults.
        Cochrane Database Syst Rev. 2017; 6CD003726
        • Cepeda MS
        • Camargo F
        • Zea C
        • Valencia L
        Tramadol for osteoarthritis: a systematic review and metaanalysis.
        J Rheumatol. 2007; 34: 543-555
        • Kaynar M
        • Kilic O
        • Yurdakul T
        On-demand tramadol hydrochloride use in premature ejaculation treatment.
        Urology. 2012; 79: 145-149
        • Bhatnagar S
        • Saxena A
        • Kannan TR
        • Punj J
        • Panigrahi M
        • Mishra S
        Tramadol for postoperative shivering: a double-blind comparison with pethidine.
        Anaesth Intensive Care. 2001; 29: 149-154
        • Shapira NA
        • Verduin ML
        • DeGraw JD
        Treatment of refractory major depression with tramadol monotherapy.
        J Clin Psychiatry. 2001; 62: 205-206
        • Tamaskar R
        • Parran Jr., TV
        • Heggi A
        • Brateanu A
        • Rabb M
        • Yu J
        Tramadol versus buprenorphine for the treatment of opiate withdrawal: a retrospective cohort control study.
        J Addict Dis. 2003; 22: 5-12
      1. Agency Medical Directors' Group. Opioid Dose Calculator. http://www.agencymeddirectors.wa.gov/calculator/dosecalculator.htm. 2015.

        • Beakley BD
        • Kaye AM
        • Kaye AD
        Tramadol, pharmacology, side effects, and serotonin syndrome: a review.
        Pain Physician. 2015; 18: 395-400
      2. Food and Drug Administration. FDA Adverse Event Report System.https://fis.fda.gov/sense/app/777e9f4d-0cf8-448e-8068-f564c31baa25/sheet/7a47a261-d58b-4203-a8aa-6d3021737452/state/analysis. 2018.

        • Boyer EW
        • Shannon M
        The serotonin syndrome.
        New Engl J Med. 2005; 352: 1112-1120
        • Frank C
        Recognition and treatment of serotonin syndrome.
        Can Fam Physician. 2008; 54: 988-992
        • Miotto K
        • Cho AK
        • Khalil MA
        • Blanco K
        • Sasaki JD
        • Rawson R
        Trends in tramadol: pharmacology, metabolism, and misuse.
        Anesth Analg. 2017; 124: 44-51
        • Raffa RB
        • Friderichs E
        • Reimann W
        • et al.
        Complementary and synergistic antinociceptive interaction between the enantiomers of tramadol.
        J Pharmacol Exp Ther. 1993; 267: 331-340
        • Dean L
        Tramadol therapy and CYP2D6 genotype.
        in: Pratt V McLeod H Dean L Malheiro A Rubinstein W Medical Genetics Summaries. National Center for Biotechnology Information (US), Bethesda, MD2012: 397-403
        • Grond S
        • Sablotzki A
        Clinical pharmacology of tramadol.
        Clin Pharmacokinet. 2004; 43: 879-923
      3. Food and Drug Administration (FDA). ULTRAM (tramadol hydrochloride) Tablets Full Prescribing Information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020281s032s033lbl.pdf. 2009. pp 1–22.

        • Zanger UM
        • Raimundo S
        • Eichelbaum M
        Cytochrome P450 2D6: overview and update on pharmacology, genetics, biochemistry.
        Naunyn Schmiedeberg Arch Pharmacol. 2004; 369: 23-37
        • Fawzi MM.
        Some medicolegal aspects concerning tramadol abuse: the new Middle East youth plague 2010. An Egyptian overview.
        Egypt J Forensic Sci. 2011; 1: 99-102
        • Nelson EM
        • Philbrick AM
        Avoiding serotonin syndrome: the nature of the interaction between tramadol and selective serotonin reuptake inhibitors.
        Ann Pharmacother. 2012; 46: 1712-1716
        • Volpi-Abadie J
        • Kaye AM
        • Kaye AD
        Serotonin syndrome.
        Ochsner J. 2013; 13: 533-540
        • Boyer E
        Serotonin syndrome.
        (Available at: Accessed September 17, 2013.)
        • Rehni AK
        • Singh I
        • Kumar M
        Tramadol-induced seizurogenic effect: a possible role of opioid-dependent gamma-aminobutyric acid inhibitory pathway.
        Basic Clin Pharmacol Toxicol. 2008; 103: 262-266
        • Kenicer D
        • Krishnadas R
        Recognition and management of serotonin syndrome.
        Prescriber. 2015; 26: 31-34
        • Houlihan DJ
        Serotonin syndrome resulting from coadministration of tramadol, venlafaxine, and mirtazapine.
        Ann Pharmacother. 2004; 38: 411-413
        • Park SH
        • Wackernah RC
        • Stimmel GL
        Serotonin syndrome: is it a reason to avoid the use of tramadol with antidepressants?.
        J Pharm Pract. 2014; 27: 71-78
        • Buckley NA
        • Dawson AH
        • Isbister GK
        Serotonin syndrome.
        BMJ. 2014; 348: g1626
        • Takeshita J
        • Litzinger MH
        Serotonin syndrome associated with tramadol.
        Prim Care Companion J Clin Psychiatry. 2009; 11: 273
        • Tashakori A
        • Afshari R
        Tramadol overdose as a cause of serotonin syndrome: a case series.
        Clin Toxicol (Philadelphia). 2010; 48: 337-341
        • Dunkley E
        • Isbister G
        • Sibbritt D
        • Dawson A
        • Whyte I
        The Hunter Serotonin Toxicity Criteria: simple and accurate diagnostic decision rules for serotonin toxicity.
        QJM. 2003; 96: 635-642
        • Ables AZ
        • Nagubilli R
        Prevention, recognition, and management of serotonin syndrome.
        Am Fam Physician. 2010; 81: 1139-1142
        • Kapur S
        • Zipursky RB
        • Jones C
        • Wilson AA
        • DaSilva JD
        • Houle S
        Cyproheptadine: a potent in vivo serotonin antagonist.
        Am J Psychiatry. 1997; 154: 884
        • Graudins A
        • Stearman A
        • Chan B
        Treatment of the serotonin syndrome with cyproheptadine.
        J Emerg Med. 1998; 16: 615-619
        • Marquardt KA
        • Alsop JA
        • Albertson TE
        Tramadol exposures reported to statewide poison control system.
        Ann Pharmacother. 2005; 39: 1039-1044
        • Spiller HA
        • Gorman SE
        • Villalobos D
        • et al.
        Prospective multicenter evaluation of tramadol exposure.
        J Toxicol Clin Toxicol. 1997; 35: 361-364
        • Boostani R
        • Derakhshan S
        Tramadol induced seizure: A 3-year study.
        Caspian J Intern Med. 2012; 3: 484-487
        • Gardner JS
        • Blough D
        • Drinkard CR
        • et al.
        Tramadol and seizures: a surveillance study in a managed care population.
        Pharmacotherapy. 2000; 20: 1423-1431
        • Jick H
        • Derby LE
        • Vasilakis C
        • Fife D
        The risk of seizures associated with tramadol.
        Pharmacotherapy. 1998; 18: 607-611
        • Farajidana H
        • Hassanian-Moghaddam H
        • Zamani N
        • Sanaei-Zadeh H
        Tramadol-induced seizures and trauma.
        Eur Rev Med Pharmacol Sci. 2012; 16: S34-S37
        • Kahn LH
        • Alderfer RJ
        • Graham DJ
        Seizures reported with tramadol.
        JAMA. 1997; 278: 1661
        • Talaie H
        • Panahandeh R
        • Fayaznouri MR
        • Asadi Z
        • Abdollahi M
        Dose-independent occurrence of seizure with tramadol.
        J Med Toxicol. 2009; 5: 63-67
        • Talaie H
        • Panahandeh R
        • Fayaznouri M
        • Asadi Z
        • Abdollahi M
        Dose-independent occurrence of seizure with tramadol.
        J Med Toxicol. 2009; 5: 63-67
        • Taghaddosinejad F
        • Mehrpour O
        • Afshari R
        • Seghatoleslami A
        • Abdollahi M
        • Dart RC
        Factors related to seizure in tramadol poisoning and its blood concentration.
        J Med Toxicol. 2011; 7: 183-188
        • Gasse C
        • Derby L
        • Vasilakis-Scaramozza C
        • Jick H
        Incidence of first-time idiopathic seizures in users of tramadol.
        Pharmacotherapy. 2000; 20: 629-634
      4. National Institute on Drug Abuse Pain and Opiophobia. Research Report Series—Prescription Drugs: Abuse and Addiction.

        • Jovanovic-Cupic V
        • Martinovic Z
        • Nesic N
        Seizures associated with intoxication and abuse of tramadol.
        Clin Toxicol (Philadelphia). 2006; 44: 143-146
        • Shadnia S
        • Soltaninejad K
        • Heydari K
        • Sasanian G
        • Abdollahi M
        Tramadol intoxication: a review of 114 cases.
        Hum Exp Toxicol. 2008; 27: 201-205
        • Shadnia S
        • Brent J
        • Mousavi-Fatemi K
        • Hafezi P
        • Soltaninejad K
        Recurrent seizures in tramadol intoxication: implications for therapy based on 100 patients.
        Basic Clin Pharmacol Toxicol. 2012; 111: 133-136