New depression diagnosis following prescription of codeine, hydrocodone or oxycodone

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Longer duration of prescription opioid use is associated with risk of major depression after controlling for daily morphine equivalent dose and pain. It is not known if risk of depression varies as a function of the type of opioid prescribed.


A retrospective cohort design was used to model onset of new depression diagnosis among 11 462 Veterans Health Administration (VA) patients who were prescribed only codeine, only hydrocodone or only oxycodone for >30 days. Patients were free of prevalent opioid use and depression at baseline (2000–2001). Follow-up was 2002–2012. Propensity scores and weighting were used to balance covariates across opioid type. Cox-proportional hazard models were computed, using weighted data and additional adjustment for morphine equivalent dose (MED), duration of use, and pain after opioid initiation, to estimate the risk of new depression diagnosis among patients prescribed only codeine, only oxycodone vs. those prescribed only hydrocodone.


After controlling for confounding, we observed that patients prescribed codeine, compared to hydrocodone, were significantly more likely to have a new depression diagnosis (HR = 1.27; 95%CI: 1.12–1.43). Oxycodone was significantly associated with onset of new depression diagnosis when exposure was modeled as total days exposed in post-hoc analysis, but not when exposure was duration of incident period of use.


Although codeine is a less potent opioid, after controlling for MED, chronic use of this agent is associated with nearly a 30% greater risk of depression compared to hydrocodone. Additional research is needed to determine the mechanisms for this association. Copyright © 2016 John Wiley & Sons, Ltd.

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