Hao Jiang,1,* Xiaomin Zhang,2,* Jian Zhang,1 Jie Liang,1 Liping Wang1 

1Department of Anesthesiology, Harbin Medical University Cancer Hospital, Harbin, People’s Republic of China; 2Department of Anesthesiology, Beidahuang Industry Group General Hospital, Harbin, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Liping Wang; Jie Liang, Department of Anesthesiology, Harbin Medical University Cancer Hospital, No. 150 of Haping Road, Nangang District, Harbin, Heilongjiang, 150081, People’s Republic of China, Email applew708@126.com; 830625@hrbmu.edu.cn

Background: Opioids and benzodiazepines are frequently prescribed for managing pain and anxiety in chronic obstructive pulmonary disease (COPD) patients. This study aimed to determine whether opioid use, with or without benzodiazepine use, is associated with increased all-cause mortality in COPD patients.
Methods: This prospective cohort study included adults aged ≥ 20 years with COPD from the US National Health and Nutrition Examination Survey 2007– 2012. The primary outcome was all-cause mortality, which were obtained through linkage to registries. Weighted Cox proportional hazards regression models were used to evaluate hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause mortality. Additionally, subgroup and sensitivity analyses were used to evaluate the robustness of our findings.
Results: This study enrolled 811 participants, representing 10.84 million COPD individuals in the United States (mean [standard error] age, 58.7 [0.6] years). During a median follow-up of 9.6 years, mortality rates were 57.8 per 1000 person-years in patients using only opioids, 41.3 per 1000 person-years in patients using only benzodiazepines, 45.7 per 1000 person-years in patients using both opioids and benzodiazepines, and 27.0 per 1000 person-years in patients using neither. In the fully adjusted model, COPD patients prescribed both opioids and benzodiazepines (HR: 1.76; 95% CI: 1.11– 2.78) and those prescribed opioids only (HR: 1.68; 95% CI: 1.13– 2.49) had significantly higher all-cause mortality compared to non-users. After adjusting for propensity scores, the mortality risk for opioid-only users slightly increased (HR: 1.87; 95% CI: 1.25– 2.81). Further, subgroup analysis revealed an elevated mortality risk in patients over 60 years receiving coprescriptions or opioids only, but not in younger participants. In contrast, benzodiazepine-only users aged 60 or younger showed increased mortality risk.
Conclusion: Opioid use, with or without benzodiazepine use, was associated with higher mortality in COPD patients over 60, while benzodiazepine-only use was associated with higher mortality aged 60 or younger.

Keywords: opioid, benzodiazepine, chronic obstructive pulmonary disease, mortality, national health and nutrition examination survey, NHANES