Use of oxycodone with fluoxetine or paroxetine increases risk for opioid overdose

Patients who started oxycodone while taking fluoxetine or paroxetine were at increased risk for opioid overdose compared with those who were taking other selective serotonin reuptake inhibitors, a cohort study showed.

According to Ismaeel Yunusa, PharmD, PhD, an assistant professor in the department of clinical pharmacy and outcomes sciences at the University of South Carolina College of Pharmacy, and colleagues, the selective serotonin reuptake inhibitors (SSRIs) fluoxetine and paroxetine are “potent inhibitors” that metabolize oxycodone through the cytochrome-P450 2D6 (CYP2D6) enzyme.

“Although pharmacokinetic studies have found increased plasma concentrations of oxycodone in the presence of CYP2D6 or CYP3A4 inhibition, no population-based study has examined whether concomitant use of oxycodone and CYP-inhibiting SSRIs is associated with opioid overdose,” Yunusa and colleagues wrote in JAMA Network Open.

The researchers reviewed data from three health insurance databases on 2,037,490 patients who received a prescription for oxycodone while receiving a SSRI. The cohort had a mean age of about 50 years and about 72% were women. Some of the most common comorbidities among the cohort were back and neck pain, arthritis, arthropathies, musculoskeletal pain, anxiety and depression.

At the time of oxycodone initiation, 12% of the patients were receiving paroxetine, 18.4% were receiving fluvoxamine and the remaining were taking another SSRI. All the patients were followed for up to 1 year after initiating oxycodone.

The researchers reported that 0.05% of the entire cohort experienced an overdose event during the follow-up period. There were 381 crude overdose events during 40,053 person-years of follow-up in the patients who were administered fluoxetine or paroxetine and 654 such events observed during 90,125 person-years of follow-up in the patients who were administered all other SSRIs (adjusted HR = 1.2; 95% CI, 1.06-1.36).

The adjusted incidence rate of opioid overdose was higher in those who received fluoxetine or paroxetine at the time oxycodone was started than those who received other SSRIs (9.47 per 1,000 person-years vs. 7.66 per 1,000 person-years). According to the researchers, this signified a small but significant increased risk for opioid overdose among patients receiving fluoxetine or paroxetine and oxycodone (adjusted HR = 1.23; 95% CI, 1.06-1.31).

“The higher overdose rate found in our study may have been caused, at least partially, by increased oxycodone plasma concentration from the inhibition of its metabolism by paroxetine or fluoxetine,” Yunusa and colleagues wrote. “In addition to strongly inhibiting CYP2D6, both paroxetine and fluoxetine mildly inhibit CYP3A4, which may further increase oxycodone concentration in blood. The narrow therapeutic index of oxycodone may have contributed to the increased risk of overdose.”

The researchers added that study limitations included the lack of other clinical information regarding the overdoses, as well as the small confidence intervals.