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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Comments

  1. Francis Dann MD says:

    Tramadol, without doubt, can cause constipation.

  2. Ann Sullivan says:

    Just some things I’ve found interesting:

    Tramadol was not given an MME until recently, and I’ve never found an affinity or efficacy measurement for Tramadol or M1 at the mu-opioid receptor, despite every other opioid having these values.

    The Human Metabolome Database states:
    “The analgesic properties of tramadol can be attributed to norepinephrine and serotonin reuptake blockade in the CNS, which inhibits pain transmission in the spinal cord” and calls Tramadol and M1 “selective, weak OP-3 receptor agonists.” (http://www.hmdb.ca/metabolites/HMDB0014339)

    As for the side-effect of constipation, it’s worth noting that most of the serotonin in the human body is in the gut, and that, in addition to serotonin’s known stimulation of GI motility and other GI activity, targeted serotonergic drugs are used to treat diarrhea or constipation caused by various disorders.

    This may all be more or less anecdotal, but the recent efforts condemning/restricting opioids ostensibly for the sake of Americans have run over so many of those same Americans and continue on without looking back despite demonstrable harm and the (quiet) acknowledgment by the CDC that a previously alleged contributor to opioid overdoses and perennial target for anti-opoid legislation, high prescribing rates, is not related at all; prescribing rates have been declining for years and are at their lowest in years, which the CDC realized after discovering it has chronically misinterpreted its data. (See April 2018 issue of American Journal of Public Health for paper by CDC employees; https://ajph.aphapublications.org/doi/full/10.2105/AJPH.2017.304265).

    Please forgive the length of this post, but it’s this kind of bias/confusion from involved (and possibly well-meaning) parties that can lead to giving something a label that’s convenient but not accurate, and I think it’s worth considering how much of an opioid Tramadol really is

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