Rebellion in EM 2019: Why Tramadol Should Be Called Tramadon’t…The Dirty Truth


  • Tramadol is a centrally acting synthetic opioid analgesic approved for use in the United States in 1995 by the Food and Drug Administration.
  • In 2014, the Drug Enforcement Agency classified tramadol as a Schedule IV controlled substance.
  • ~41 million prescriptions for tramadol were dispensed in the United States in 2017.

Rebellion in EM 2019: Why Tramadol Should Be Called Tramadon’t…The Dirty Truth via Deanna Turner, PharmD


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Critical Point #1:  Tramadol has a dual analgesic mechanism of action (MOA) and unpredictable pharmacokinetics.

  • MOA #1: Tramadol is metabolized in the liver by CYP2D6 to its primary active metabolite O-desmethyltramadol (M1).
    • Tramadol (parent compound) has very low affinity for m-opioid receptors.
    • M1 binds m-opioid receptors with ~300-fold higher affinity than tramadol and is more potent in producing analgesia.
  • MOA #2: Tramadol inhibits serotonin and norepinephrine reuptake suggesting analgesic activity by inhibition of central nervous system pain transmission.
  • Variation in CYP2D6 activity leads to unpredictable metabolism and production of active metabolites resulting in phenotypic differences in toxicity and efficacy.

Critical Point #2:  Common misconception?  Tramadol is a weak opioid and has a more favorable safety profile.

  • Tramadol has atypical risks compared to other opioids due to inhibition of serotonin and norepinephrine uptake, including serotonin syndrome.
  • Hypoglycemia is a potential serious complication reported with use in both diabetic and non-diabetic patients.
  • New-onset seizures have been reported in patients taking therapeutic doses.
  • Physical dependence and addiction are possible consequences of tramadol use.
  • Abrupt cessation can cause unpleasant opioid andSSRI-like withdrawal symptoms.

Guest Post By:

DeAnna W. Turner, PharmD, BCPS
Clinical Pharmacist Emergency Medicine
Methodist Hospital Emergency Medicine Department
San Antonio, Texas


  1. Drug Enforcement Administration Diversion Control Division. Drug and Chemical Evaluation Section.  Tramadol (Trade Names:  Ultram®, Ultracet®).  October 2018 update. Accessed April 25, 2019. Link is HERE
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  6. Odonkor CA, Chhatre A. What’s tramadol got to do with it?  A case report of rebound hypoglycemia, a reappraisal and review of potential mechanisms.  Pain Physician.2016;19:e1215-e1220. PMID: 27906953
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  9. 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(1):71-78.  PMID: 24153222
  10. Ryan NM, Isbister GK. Tramadol overdose causes seizures and respiratory depression but serotonin toxicity appears unlikely.  Clin Toxicol (Phila).  2014;53(6):545-550.  PMID: 25901965
  11. Nelson EM, Philbrick AM. Avoiding serotonin syndrome:  The nature of the interaction between tramadol and selective serotonin reuptake inhibitors.  Ann Pharmacother.  2012;46(12):1712-1716.  PMID: 23212934
  12. Epstein DH, Preston KL, Jasinski DR. Abuse liability, behavioral pharmacology, and physical-dependence potential of opioids in humans and laboratory animals: lessons from tramadol.  Biol Psychol.  2006;73(1):90-99.  PMID: 16497429
  13. Senay EC, Adams EH, Geller A, et al. Physical dependence on Ultram (tramadol hydrochloride): both opioid-like and atypical withdrawal symptoms occur.  Drug Alcohol Depend.  2003;69(3):223-241.  PMID: 12633909

Post Peer Reviewed By: Salim R. Rezaie, MD (Twitter: @srrezaie)

Cite this article as: Salim Rezaie, "Rebellion in EM 2019: Why Tramadol Should Be Called Tramadon’t…The Dirty Truth", REBEL EM blog, September 12, 2019. Available at:

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