Tramadol Is an Opioid

During the recent postoperative course of a family member, I was repeatedly assured that tramadol is not an opioid and would not cause constipation. That seems to be a common misconception, possibly related to tramadol’s designation by the DEA as a Schedule IV controlled substance, a class that includes various benzodiazepines, but no other opioids. Before 2014, tramadol was not classified as a controlled substance at all. It is still not a controlled substance in Canada.

Tramadol is a weak mu opioid agonist, but it is a prodrug with pharmacologically active metabolites. Tramadol is metabolized in the liver by CYP2D6 to O-desmethyltramadol(M1), a more potent opioid agonist that is mainly responsible for the drug’s analgesic effects and its toxicity. The efficiency of CYP2D6 metabolism varies from poor metabolizers to intermediate, extensive (normal), and ultra-metabolizers. Ultra-metabolizers treated with tramadol gain the most analgesic benefit, but also have the most side effects, including constipation. Poor metabolizers or those taking a CYP2D6 inhibitor may not experience an analgesic effect.

Tramadol has a second mechanism of action: it inhibits the uptake of both serotonin and norepinephrine, which makes it an SNRI like venlafaxine and duloxetine. That may provide some additional analgesic effect in neuropathic pain, but also brings up the possibility of a new set of side effects and drug interactions. Concomitant use of tramadol with other serotonergic drugs can cause serotonin syndrome, which can be fatal. These include not only serotonin reuptake inhibitor antidepressants, but also antipsychotics, anticonvulsants, antiparkinson drugs, cough suppressants, and monoamine oxidase inhibitors (K Miotto et al. Trends in Tramadol: Pharmacology, Metabolism, and Misuse. Anesthesia and Analgesia 2017; 14:44).

Tramadol can cause some other problems. It has been associated with hypoglycemia. It lowers the threshold for seizures, and interactions with a number of psychiatric and other drugs can lower it further still. Naloxone, which conceivably could be used to treat a tramadol overdose, can increase the risk of a seizure. Some children appear to be particularly sensitive to tramadol-induced respiratory depression. Because of reports of deaths and near-deaths, tramadol is now contraindicated for any use in children under 12 and for use after tonsillectomy or adenoidectomy in children 12-18.

Tramadol is an opioid, with abuse potential, opioid side effects, and some other concerns as well. Read our recent article on Opioids for Pain.

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