- 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
- 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
- Gong L, Stamer UM, Tzvetkov MV, et al.PharmGKB: Tramadol pathway. Pharmacogenet Genomics. 2014;24(7):374-380. PMID: 24849324
- Miotto K, Cho AK, Khalil MA, et al.Trends in tramadol: Pharmacology, metabolism, and misuse. Anesth Analg.2017;124:44-51. PMID: 27861439
- Fournier JP, Azoulay L, Yin H, et al. Tramadol use and the risk of hospitalization for hypoglycemia in patients with noncancer pain. JAMA Intern Med. 2015;175(2):186-193. PMID: 25485799
- Golightly LK, Simendinger BA, Barber GR, et al. Hypoglycemic effects of tramadol analgesia in hospitalized patients: a case-control study. J Diabetes Metab Disord. 2017;16:30. PMID: 28748177
- 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
- Labate A, Newton MR, Vernon GM, et al. Tramadol and new-onset seizures. Med J Aust. 2005;182(1):42-43. PMID: 15651948
- Hassamal S, Miotto K, Dale W, et al. Tramadol: Understanding the risk of serotonin syndrome and seizures. Am J Med. 2018;131(11):1382.e1-1382.e6. PMID: 29752906
- 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
- 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
- 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
- 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
- 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)