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

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

Episode 990: Tramadol, or rather, Trama-don't

Emergency Medical Minute