Co-prescribing of opioids and benzodiazepines/Z-drugs associated with all-cause mortality-A population-based longitudinal study in primary care with weak opioids most commonly prescribed

Kristjan Linnet; Heidrun Sjofn Thorsteinsdottir; Johann Agust Sigurdsson; Emil Larus Sigurdsson; Larus Steinthor Gudmundsson

doi:10.3389/fphar.2022.932380

Co-prescribing of opioids and benzodiazepines/Z-drugs associated with all-cause mortality-A population-based longitudinal study in primary care with weak opioids most commonly prescribed

Front Pharmacol. 2022 Sep 6:13:932380. doi: 10.3389/fphar.2022.932380. eCollection 2022.

Authors

Kristjan Linnet¹, Heidrun Sjofn Thorsteinsdottir², Johann Agust Sigurdsson^{1

3}, Emil Larus Sigurdsson^{1

4}, Larus Steinthor Gudmundsson²

Affiliations

¹ Development Centre for Primary Healthcare in Iceland, Primary Health Care of the Capital Area, Reykjavik, Iceland.
² Faculty of Pharmaceutical Sciences, School of Health Sciences, University of Iceland, Reykjavik, Iceland.
³ General Practice Research Unit, Department of Public Health and Nursing, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.
⁴ Department of Family Medicine, Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland.

Abstract

Introduction: The risk of mortality associated with the co-prescribing of benzodiazepines and opioids has been explored in a number of papers mainly focusing on strong opioids. The mortality risk associated with the use of weak opioids has not been dealt with to a similar extent. Objective: To assess the mortality risk in primary care patients with consistent 3-year co-prescribing of benzodiazepine/Z-drugs (benzodiazepine receptor modulators) and mainly weak opioids (codeine, tramadol). Methods: Of 221,804 patients contacting the primary healthcare centres, 124,436 were selected for further analysis, 88,832 participants fulfilled the inclusion criteria, aged 10-69 years and were divided into four groups with neither any use of benzodiazepines/Z-drugs nor opioids as Group 1, 3 years' use of opioids and no/minimal benzodiazepines/Z-drugs as Group 2, with benzodiazepines/Z-drugs and no/minimal opioids as Group 3, and finally both benzodiazepines/Z-drugs and opioids as Group 4. Hazard ratios were calculated with the no-drug group as a reference, using Cox proportional hazards regression model adjusted for age, sex, number of chronic conditions and cancer patients excluded (n = 87,314). Results: Hazard ratios for mortality increased both in Group 3 where it was 2.66 (95% CI 2.25-3.09) and in Group 4 where it was 5.12 (95% CI 4.25-6.17), with increased dose and higher number of chronic conditions. In Group 4 an opioid dose-dependent increase in mortality among persons using >1000 DDDs benzodiazepines/Z-drugs was observed when those on less than ≤300 DDDs of opioids with HR 4.94 (95% CI 3.54-6.88) were compared to those on >300 DDDs with HR 7.61/95% CI 6.08-9.55). This increase in mortality was not observed among patients on <1000 DDDs of benzodiazepines/Z-drugs. Conclusion: The study supports evidence suggesting that mortality increases in a dose-dependent manner in patients co-prescribed benzodiazepines/Z-drugs and weak opioids (codeine, tramadol). An association between the number of chronic conditions and a rise in mortality was found. Long-term use of these drugs should preferably be avoided. Non-pharmacological therapy should be seriously considered instead of long-term use of benzodiazepines/Z-drugs, and deprescribing implemented for chronic users of these drugs when possible.

Keywords: benzodiazepines/Z-drugs; long-term co-prescribing; mortality risk; primary care; weak opioids.