Contributor: Taylor Lynch, MD

Educational Pearls:

• Tramadol is a Schedule IV opioid analgesic used for moderate pain and is often perceived as safer than other opioids due to lower abuse potential.

• It is a prodrug with weak direct μ-opioid receptor activity.

• The parent compound also inhibits serotonin and norepinephrine reuptake, giving it SSRI/SNRI-like properties.

• Tramadol is metabolized by CYP2D6 into O-desmethyltramadol (ODT), which has significantly stronger μ-opioid receptor agonism than the parent drug.

• Ultrarapid CYP2D6 metabolizers (more common in Middle Eastern and North African populations) rapidly convert tramadol to ODT, increasing the risk of opioid toxicity.

• Poor CYP2D6 metabolizers generate little ODT and may experience primarily serotonergic effects, increasing the risk of serotonin syndrome, especially when combined with SSRIs or SNRIs.

• CYP2D6 inhibitors (e.g., bupropion, paroxetine, terbinafine, celecoxib) can block tramadol's conversion to ODT, potentially precipitating opioid withdrawal or increasing serotonergic toxicity.

• Tramadol is also associated with an increased risk of first-time seizures, even at therapeutic doses.

• Tramadol's effects are highly unpredictable, varying from minimal analgesia to exaggerated opioid effects depending on metabolism.

• Drug–drug interactions can lead to serotonin syndrome or opioid withdrawal.

• Despite its Schedule IV classification and reputation for safety, alternative analgesics may be preferable in many patients.

References

1. DailyMed - TRAMADOL HYDROCHLORIDE tablet, coated. Accessed January 10, 2026. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=61fb5ba7-6896-4ee4-83de-caee69b06a8e#ID57

2. Dean L, Kane M. Tramadol Therapy and CYP2D6 Genotype. In: Pratt VM, Scott SA, Pirmohamed M, Esquivel B, Kattman BL, Malheiro AJ, eds. Medical Genetics Summaries. National Center for Biotechnology Information (US); 2012. Accessed January 10, 2026. http://www.ncbi.nlm.nih.gov/books/NBK315950/

3. Aly SM, Tartar O, Sabaouni N, Hennart B, Gaulier JM, Allorge D. Tramadol-Related Deaths: Genetic Analysis in Relation to Metabolic Ratios. J Anal Toxicol. 2022;46(7):791-796. doi:10.1093/jat/bkab096

Summarized and edited by Dan Orbidan OMS2

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