Genetic polymorphisms in opioid metabolism

The article about serotonergic interactions between antidepressants and opioids¹ was a concise depiction of the influence of enzyme inhibitors and inducers of cytochrome P450 (CYP) 2D6 on the extent of the serotonergic, noradrenergic or opioid effects of codeine and tramadol. However, it is not simply drug–drug interactions, but also genetic polymorphisms that dictate the prevalence of serotonergic, noradrenergic, or opioid metabolites.

Equivalent drug doses can produce vastly different degrees of analgesia or serotonergic toxicity if the patient is an ultra-rapid metaboliser of CYP2D6 (the incidence is 1–28% of the worldwide population), or a poor metaboliser.^2,3 Without this caveat, it could be misleading to label codeine and tramadol as ‘weak’ analgesics.³

Codeine is a prodrug metabolised to therapeutically active morphine. In ultra-rapid metabolisers it can be a potent analgesic with risks that may not be appreciated if it is considered as a ‘weak’ opioid.² In contrast, codeine offers negligible analgesia to poor metabolisers.

Tramadol’s opioid activity is dependent on metabolism to O-desmethyltramadol via CYP2D6. Ultra-rapid metabolisers experience a lower risk of serotonergic and noradrenergic adverse effects yet greater risks of mu-opioid-receptor agonism and respiratory depression.⁴

The table in the article showed the ‘triptan’ class of drugs as being ‘likely’ to increase the risk of serotonin toxicity.¹ They are primarily agonists of 5-HT_1B and 5-HT_1D subtypes, while the harms of serotonin toxicity are believed to be primarily mediated through 5-HT_1A and 5-HT_2A (as the authors note in other work).^5,6 Due to the clinical benefit of having a triptan and opioid analgesic available for the treatment of severe migraine, it may be counterproductive to suggest they should be combined only cautiously.

Tiernan McDonough
Community pharmacist, Kenmore Discount Drug Stores, Kenmore, QLD

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