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Antidepressants May Lower Prodrug Opioid Effects

Alternative methods should be considered for patients taking SSRIs

A PPM Brief

Selective serotonin reuptake inhibitor (SSRI) antidepressants were shown in a recent study1 to dampen the effects of prodrug opioids, resulting in less effective pain management. Widely prescribed prodrugs such as hydrocodone require conversion by liver enzyme CYP-2D6 to exert their analgesic effects. Commonly prescribed for depression, SSRIs are known to inhibit CYP-2D6 activity and, therefore, may reduce opioid efficacy when both drug types are used in combination.

Researchers, largely based at Stanford University, used a machine learning approach to identify patients prescribed both SSRIs and prodrugs post-operatively, examining the effect of this combination on postoperative pain control. Using electronic health record (EHR) data, they identified patients receiving surgery over a 9-year period. A natural language processing (NLP) algorithm was developed to extract depression-related information (such as diagnosis, SSRI use, and associated symptoms), and researchers aimed to find the difference between preoperative pain score and post-operative pain at discharge, 3 weeks, and 8 weeks. They predicted the increase or decrease in post-operative pain across these three time points by using the patient’s EHR data captured before surgery.

Direct-acting opioids may be a better options for depressed patients on SSRIs. (Source: 123RF)

Approximately 4,306 surgical patients had symptoms of depression; a total of 14.1% were prescribed both an SSRI and a prodrug opioid, 29.4% were prescribed an SSRI and a non-prodrug opioid, 18.6% were prescribed just a prodrug opioid, and 37.5% were prescribed just a non-prodrug opioid. The NLP algorithm identified depression with an F1 score of 0.95 against manual annotation of 300 randomly sampled clinical notes.

On average:

  • Patients receiving prodrug opioids alone had lower average pain scores (p < 0.05), with the exception of those also on an SSRI at 3-weeks
  • The SSRI and prodrug group had significantly worse pain control at discharge, 3-week and 8-week follow-up (p < 0.01) compared to patients on SSRIs alone, whereas there was no difference in pain control among those on just prodrug opioids (p > 0.05).

According to the researchers, the algorithm accurately predicted the increase/decrease of the discharge, 3-week, and 8-week follow-up pain scores compared to preoperative pain scores using 10-fold cross-validation. Preoperative pain, surgery type, and opioid tolerance were all found to be strong predictors of postoperative pain control.

“We provide the first direct clinical evidence that the known ability of SSRIs to inhibit prodrug opioid effectiveness is associated with worse pain control among depressed patients,” the researchers concluded in their paper. “The study results imply that prescribers might instead choose direct-acting opioids (eg oxycodone or morphine) in depressed patients on SSRIs.”

Last updated on: February 26, 2019
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