A retrospective analysis supports this drug-drug interaction.

Opioids and antidepressants are often coprescribed. However, some anti­depressants (e.g. fluoxetine) inhibit CYP2D6, an enzyme involved in metabolism of several prescription opioids (e.g. codeine). This drug-­drug interaction has been linked to opioid toxicity and worsened pain control, possibly caused by attenuated conversion of these opioids to active forms (NEJM JW Psych 1 Apr 2019 and PLoS One 2019; 14: e0210575).

In this retrospective cohort study, researchers identified 29,000 US nursing home residents (age, 65 years and older) who were prescribed CYP2D6­ metabolised opioids (i.e. codeine, hydro­codone, oxycodone or tramadol) plus antidepressants. During one year of follow up after antidepressant initiation, residents who received CYP2D6­ inhibiting antidepressants (i.e. bupropion, doxepin, duloxetine, fluoxetine or paroxetine) were more likely to have worsening pain (33% vs 29%), pain­related hospitalisations (1.5% vs 1.1%) and pain-­related emergency department visits (0.9% vs 0.6%) than were residents who received other antidepressants. Rates of opioid overdose were similar between the two antidepressant groups. 

Comment: These results are worth considering when selecting anti­depressants for patients who take opioids. There is probably no downside to erring on the side of using CYP2D6­ neutral antidepressants in patients who take CYP2D6­-metabolised opioids. But keep in mind that various confounding factors might have influenced these findings. For example, because duloxetine is often used to treat both pain and depression, patients who received that drug might have been at higher baseline risk for pain-­related complications, independent of its inhibition of CYP2D6.

Christopher W. Goodman, MD, Clinical Assistant Professor of Internal Medicine, University of South Carolina School of Medicine, Columbia, USA.

Wei Y-JJ, et al. Clinical and adverse outcomes associated with concomitant use of CYP2D6-metabolized opioids with antidepressants in older nursing home residents: a target trial emulation study. Ann Intern Med 2024; 177: 1058-1068.

This summary is taken from the following Journal Watch titles: General Medicine, Ambulatory Medicine, Hospital Medicine.