Comparative risk of opioid overdose in patients who initiated antibiotics for urinary tract infection while on long-term opioid therapy.

Sulfamethoxazole/trimethoprim, a commonly used antibiotic, has been associated with opioid overdose in patients with long-term opioid use, based on a prior drug-drug interaction screening study. To evaluate whether this finding represents a false-positive signal due to potential confounding, we assessed the safety of sulfamethoxazole/trimethoprim relative to 2 comparable antibiotic treatments in patients receiving long-term opioid therapy. We used data from 4 large administrative claims databases spanning 2000-2019. The study population was restricted to patients aged 18 years or older with urinary tract infection and at least 90 days of continuous prescription opioid use who initiated sulfamethoxazole/trimethoprim, nitrofurantoin, or fluoroquinolone therapy. We used propensity score matching weights to adjust for confounding and Cox proportional hazards models to estimate weighted hazard ratios (HRs) and 95% CIs in a 30-day intention-to-treat analysis. Cumulative 30-day opioid overdose risk ranged between 0.04% and 0.12% across databases and did not differ between antibiotics. Relative to sulfamethoxazole/trimethoprim, the weighted HR of opioid overdose was 1.09 (95% CI, 0.79-1.50) for nitrofurantoin and 0.94 (95% CI, 0.68-1.31) for fluoroquinolones. Potential safety signals identified in high-throughput screening studies, especially for medication combinations with limited biologic plausibility of drug-drug interaction and high frequency of use, should be interpreted with caution. .