Identification and quantification of prescription opioid-related drug-drug interactions in electronic healthcare data
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CitationKhan, Nazleen. 2021. Identification and quantification of prescription opioid-related drug-drug interactions in electronic healthcare data. Doctoral dissertation, Harvard University Graduate School of Arts and Sciences.
AbstractPolypharmacy is common among patients taking prescription opioids long-term, and the co-dispensing of interacting medications may further increase opioid overdose risk. To identify non-opioid medications that may increase opioid overdose risk in this population, we conducted a case-crossover-based screening of electronic claims data from IBM® MarketScan® and Optum© Clinformatics® Data Mart spanning 2003 through 2019. Eligible patients were 18 years of age or older and had at least 180 days of continuous enrollment and 90 days of prescription opioid use immediately before an opioid overdose resulting in an emergency room visit or hospitalization. The main analysis quantified the odds ratio (OR) between opioid overdose and each non-opioid medication dispensed in the 90 days immediately before the opioid overdose date after adjustment for prescription opioid dosage and benzodiazepine co-dispensing. Additional analyses restricted to patients without cancer diagnoses and individuals who used only oxycodone for 90 days immediately before the opioid overdose date. The false discovery rate (FDR) was used to account for multiple testing. We identified 24,866 individuals who experienced opioid overdose. Baclofen (OR 1.56; FDR 0.01; 95% confidence interval (CI), 1.29 to 1.89), lorazepam (OR 1.53; FDR 0.01; 95% CI, 1.25 to 1.88), and gabapentin (OR 1.16; FDR = 0.09; 95% CI, 1.04 to 1.28), among other non-opioid medications, were associated with opioid overdose. Similar patterns were observed in non-cancer patients and individuals who used only oxycodone. Interventions may focus on prescribing safer alternatives when a potential for interaction exists.
The concomitant use of prescription opioids and skeletal muscle relaxants has been associated with opioid overdose. Little data exist on the head-to-head safety of these drug combinations. Our objective was to compare the risk of opioid overdose among patients on long-term opioid therapy who concurrently initiate skeletal muscle relaxants. We conducted a new user, active comparator cohort study spanning data from 2000 to 2019. The primary analysis quantified opioid overdose risk across seven prescription opioid-skeletal muscle relaxant therapies and a negative control outcome (sepsis) to assess potential confounding by unmeasured illicit opioid use. Secondary analyses evaluated two- and five-group comparisons in patients with similar baseline characteristics; individuals without prior recorded substance abuse; and subgroups stratified by baseline opioid dosage, benzodiazepine co-dispensing, and oxycodone or hydrocodone use. We used healthcare utilization data from four US commercial and public insurance databases. Individuals were required to have at least 180 days of continuous enrollment and at least 90 days of continuous prescription opioid use immediately before and on the date of skeletal muscle relaxant initiation. Exposures included the concomitant use of prescription opioids and skeletal muscle relaxants. The main outcomes and measures were the hazard ratio (HR) and bootstrapped 95% confidence interval (CI) of opioid overdose resulting in an emergency visit or hospitalization. The weighted HR of opioid overdose relative to cyclobenzaprine was 2.52 (95% CI 1.29-4.90) for baclofen; 1.64 (95% CI 0.81-3.34) for carisoprodol; 1.14 (95% CI 0.53-2.46) for chlorzoxazone/orphenadrine; 0.46 (95% CI 0.17-1.24) for
metaxalone; 1.00 (95% CI 0.45-2.20) for methocarbamol; and 1.07 (95% CI 0.49-2.33) for tizanidine in the 30-day intention-to-treat analysis. Findings were similar in the as-treated analysis, two- and five-group comparisons, and in patients without prior recorded substance abuse. None of the therapies relative to cyclobenzaprine were associated with sepsis, and no subgroups indicated increased risk of opioid overdose. Concomitant use of prescription opioids and baclofen relative to cyclobenzaprine is associated with opioid overdose. Clinical interventions may focus on prescribing alternatives in the same drug class or providing access to opioid antagonists if treatment with both medications is necessary for pain management.
The concomitant use of prescription opioids and select antibiotics has been associated with opioid overdose. It is unclear whether this increased risk persists after accounting for underlying infection. Our objective was to compare the risk of opioid overdose among patients who concurrently initiate antibiotics on long-term opioid therapy. We conducted a new user, active comparator cohort study spanning data from 2000 to 2019. The primary analysis quantified the relative risk of opioid overdose between sulfamethoxazole/trimethoprim, nitrofurantoin, and fluoroquinolones among patients diagnosed with urinary tract infection (UTI). Matching weights were used to adjust for confounding, and intention-to-treat analyses were conducted with a maximum follow-up of 30 days immediately after antibiotic initiation. Secondary analyses evaluated the comparative risk of sepsis as a negative control outcome to account for unmeasured confounding; subgroups stratified by baseline opioid dosage; and patients without prior recorded substance abuse. We used healthcare utilization data from four US commercial and public insurance databases. Individuals were required to have at least 180 days of continuous enrollment and 90 days of continuous prescription opioid use immediately before and on the date of antibiotic initiation. Diagnosis for UTI was required within three days prior to or on the antibiotic dispensing date. Exposures included the concomitant use of prescription opioids and antibiotics. The main outcomes and measures were the weighted hazard ratio (HR) and 95% bootstrapped confidence interval (CI) for emergency department visits or hospitalizations for opioid overdose. We identified 555,183 UTI patients across the three treatment groups who contributed to the weighted analysis. The mean age at antibiotic initiation was 65 years, and 93% were female in the weighted population. Co-prescription of opioids and nitrofurantoin relative to sulfamethoxazole/trimethoprim was unassociated with opioid overdose (pooled weighted HR 1.06, 95% CI 0.77-1.46). Results were similar for fluoroquinolones relative to sulfamethoxazole/trimethoprim. Nitrofurantoin co-prescription relative to sulfamethoxazole/trimethoprim was associated with sepsis (pooled weighted HR 1.18, 95% CI 1.07-1.30), which persisted in patients without prior recorded substance abuse. No increased risk of opioid overdose was observed for patients prescribed high opioid dosages. Additional studies are needed to disentangle drug-drug interactions from underlying infection in potentially increasing opioid overdose risk.
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