Purpose: In drug studies, research designs requiring no prior exposure to certain drug classes may restrict important populations. Since abuse-deterrent formulations (ADF) of opioids are routinely prescribed after other opioids, choice of study design, identification of appropriate comparators, and addressing confounding by “indication” are important considerations in ADF post-marketing studies. Methods: In a retrospective cohort study using claims data (2006-2018) from a North Carolina private insurer [NC claims] and Merative MarketScan [MarketScan], we identified patients (18-64 years old) initiating ADF or non-ADF extended-release/long-acting (ER/LA) opioids. We compared patient characteristics and described opioid treatment history between treatment groups, classifying patients as traditional (no opioid claims during prior six-month washout period) or prevalent new users. Results: We identified 8,415 (NC claims) and 147,978 (MarketScan) ADF, and 10,114 (NC claims) and 232,028 (MarketScan) non-ADF ER/LA opioid initiators. Most had prior opioid exposure (ranging 64-74%), and key clinical differences included higher prevalence of recent acute or chronic pain and surgery among patients initiating ADFs compared to non-ADF ER/LA initiators. Concurrent immediate-release opioid prescriptions at initiation were more common in prevalent new users than traditional new users. Conclusions: Careful consideration of the study design, comparator choice, and confounding by “indication” is crucial when examining ADF opioid use-related outcomes.

Purpose: Long-term opioid therapy (LTOT) has been shown to be associated with opioid overdose, but the definition of LTOT varies widely across studies. We use a rigorous LTOT definition to examine risk of opioid overdose by duration of treatment. Methods: Data were from a large private health insurance provider in North Carolina linked to mortality records from 2006-2018. Eligible patients were adults (18-64) newly initiating opioid therapy after a pain diagnosis or surgery. We defined LTOT as ≥1 opioid prescription per month totaling ≥60 days’ supply within 90 days. We used inverse probability- (IP) weighted cumulative incidence functions to estimate three-year risk of opioid overdose and IP-weighted Fine-Gray models to estimate subdistribution hazard ratios, comparing LTOT to short- to medium-term opioid therapy (SMTOT). We also examined modification by derived indication of acute pain or surgery versus chronic pain. Results: We identified 491,369 patients, and 1.7% were exposed to LTOT. The three-year risk of opioid overdose was 0.3 percentage points (RD w= 0.003, 95% CI: 0.001, 0.005) higher in LTOT patients compared to patients with SMTOT. The weighted hazard of opioid overdose was 4.4 times as high (HR w 4.42, 95% CI 2.41, 8.11) among patients exposed to LTOT versus SMTOT. We did not find meaningful modification by clinical indication for opioid therapy. Conclusions: Exposure to LTOT was associated with increased risk of opioid overdose in this population of privately insured patients using a rigorous definition of LTOT. These findings confirm the importance of guidelines to minimize duration of opioid therapy whenever possible.