Taking Both CYP2D6 Opioids and Antidepressants Leads to Risk for Older Adults

The concomitant use of CYP2D6-metabolized opioids and CYP2D6-inhibiting antidepressants is linked to worse pain and increased risk for opioid-related adverse events among older nursing home residents, a new study found.^1,2

“The present study provided referential data for clinicians about which antidepressants are effective and safer for co-use with CYP2D6-metabolized opioids for older [nursing home] residents, particularly those with comorbid chronic pain and neuropsychiatric symptoms that required treatment with both medications,” wrote investigators, led by Yu-Jung Jenny Wei, PhD, from the Division of Outcomes and Translational Sciences at College of Pharmacy at The Ohio State University.

Not a lot of evidence exists on the safety of pharmacokinetic interactions of cytochrome P450 (CYP) 2D6 (CYP2D6)-metabolized opioids with antidepressants among older nursing home residents. Thus, investigators sought to assess the link between concomitant use of CYP2D6-metabolized opioids and antidepressants with clinical outcomes and opioid-related adverse events.

The team conducted a retrospective cohort study using a target trial emulation framework and including a sample of 29435 long-term nursing home residents on Medicare from the Minimum Data Set from 2010 – 2021. Participants were aged ≥ 65 years and received CYP2D6-metabolized opioids concomitantly with antidepressants for at least 1 day. The mean age was 84.9 years.

In total, 28,123 residents had ≥ 1 Minimum Data Set 3.0 assessment in follow-up, and there were 38,613 patient episodes to analyze. Investigators compared residents receiving CYP2D6-metabolized opioids with CYP2D6-inhibiting antidepressants (n = 5293; 17.6%) with the comparison group, residents receiving CYP2D6-metabolized opioids with CYP2D6-neutral antidepressants (n = 24,863; 82.4%).

Investigators analyzed data on worsening pain, physical function, and depression from baseline to quarterly Minimum Data Set assessments using modified Poisson regression models. They also analyzed data on opioid-related adverse events, such as counts of pain-related hospitalizations and emergency department visits, opioid use disorder, and opioid overdose using negative binomial or Poisson regression models.

Among the nursing home residents, the use of concomitant use of CYP2D6-metabolized opioids and CYP2D6-inhibiting antidepressants, compared to CYP2D6-neutral antidepressants, was associated with poorer clinical and ORAE outcomes. The CYP2D6-inhibiting antidepressant group had greater crude percentages of residents who experienced worsening pain (35% vs 28%) and a greater crude incidence rate per 1000 patient-years for pain-related hospitalization (19.79 vs. 12.55), pain-related emergency department visit (11.50 vs. 7.20), opioid use disorder (42.73 vs. 17.18). The CYP2D6-inhibiting antidepressant group also had lower rates of worsening physical function (62.6% vs. 65%), depressive symptoms (29.5% vs 29.3%), and opioid overdose (7.94 vs. 8.12 per 1000 patient-years).

After adjusting for covariates, investigators found the concomitant use of CYP2D6-metabolized opioids and CYP2D6-inhibiting antidepressants was linked to a greater worsening pain (adjusted rate ratio [aRR], 1.13; 95% confidence interval [CI], 1.09 – 1.17l; P < .001), pain-related hospitalization (aRR, 1.37; 95% CI, 1.19 – 1.59; P < .001), pain-related emergency department visit (adjusted incidence rate ratio [aIRR], 1.49; 95% CI, 1.24 – 1.80; P < .001), and opioid use disorder (aIRR, 1.93; 95% CI, 1.37 – 2.73; P < .001). Between participants on CYP2D6-inhibiting antidepressants versus CYP2D6-neutral antidepressants, there was no difference in physical function (aRR, 0.99; 95% CI, 0.97 – 1.01; P = .55), depression (aRR, 1.03; 95% CI, 0.99 – 1.07; P = .106, and opioid overdose (aIRR, 0.88; 95% CI, 0.57 – 1.37; P = 0.57).

Investigators pointed out multiple limitations of the study, including unavailable data on drugs consumed, whether medications were given as needed or around the clock and genetic information about people’s capacity for metabolizing opioids and antidepressants. Additionally, the results can only be generalized to older nursing home residents on Medicare.

“When co-use of CYP2D6-metabolized opioids and antidepressants is clinically needed, selection of CYP2D6-neutral antidepressants, rather than CYP2D6-inhibiting antidepressants, may provide better pain control and prevent pain-related hospital and [emergency room] visits and [opioid use disorder],” investigators concluded.

References

1. ^{Wei, Y, Winterstein, A, Schmidt, S, et al. Clinical and Adverse Outcomes Associated with Concomitant Use of CYP2D6-Metabolized Opioids with Antidepressants in Older Nursing Home Residents. Ann Intern Med. doi:10.7326/M23-3109.}
2. ^{Co-Use Of CYP2D6-Metabolized Opioids And Antidepressants Associated With Adverse Events In Older Nursing Home Patients. Newswise. July 16, 2024. https://www.newswise.com/articles/co-use-of-cyp2d6-metabolized-opioids-and-antidepressants-associated-with-adverse-events-in-older-nursing-home-patients. Accessed July 22, 2024.}