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

Background:

• 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

References:

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
2. Gong L, Stamer UM, Tzvetkov MV, et al.PharmGKB: Tramadol pathway. Pharmacogenet Genomics.  2014;24(7):374-380.  PMID: 24849324
3. Miotto K, Cho AK, Khalil MA, et al.Trends in tramadol:  Pharmacology, metabolism, and misuse.  Anesth Analg.2017;124:44-51.  PMID: 27861439
4. 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
5. 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
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
7. Labate A, Newton MR, Vernon GM, et al. Tramadol and new-onset seizures.  Med J Aust. 2005;182(1):42-43.  PMID: 15651948
8. 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
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)

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