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Opioid Initiation and the Hazard of Falls or Fractures Among Older Adults with Varying Levels of Central Nervous System Depressant Burden



Co-prescription of opioids with other central nervous system (CNS) depressants is common but the combination may increase the risk for adverse events such as falls and fractures, particularly among older adults. We explored the risk of fall- or fracture-related hospital visits after opioid initiation among older adults with varying degrees of concomitant CNS depressant burden.


We used population-based administrative health data from Ontario, Canada, to examine the relationship between hospital visits for falls or fractures at different levels of CNS burden among individuals aged 66 and older who started prescription opioids between March 1, 2008, and March 31, 2019. For comparison, we identified individuals starting prescription non-steroidal anti-inflammatory drugs (NSAIDs). The outcome was a hospital visit for falls or fractures within 14 days after starting analgesic therapy. We stratified the cohort according to additional CNS burden: none, low (one concurrent CNS depressant drug class) and high (≥ 2 concurrent CNS depressant classes) on the index date. We balanced opioid and NSAID recipients using inverse probability of treatment weighting and reported weighted hazard ratios from Cox proportional hazards models. We then used pairwise comparisons to determine differences between hazard ratios at different levels of CNS burden.


The cohort included 1,066,692 older adults, with 562,692 new opioid recipients and 504,000 new NSAID recipients. Among opioid recipients, 83 % had no additional CNS burden, 13 % had low burden and 4 % had high burden. The short-term rate of falls or fractures for new opioid recipients increased by CNS burden from 97 per 1000 person-years (no burden) to 233 per 1000 person-years (high CNS burden). Opioid recipients had a similarly elevated hazard of falls or fractures within each CNS burden level compared to NSAID recipients (adjusted hazard ratio [aHR] 1.62, 95 % CI 1.50–1.76 for no burden; aHR 1.69, 95 % CI 1.45–1.97 for low burden; aHR 1.40, 95 % CI 1.08–1.82 for high burden).


Among older adults, initiation of opioids is associated with an increased hazard of falls; however, this hazard is not modified by different levels of CNS depressant burden. This suggests that it remains important for physicians, patients, and caregivers to be vigilant when starting new opioid therapy regardless of other CNS medications taken concurrently.

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We thank IQVIA Solutions Canada Inc. for use of their Drug Information File, Marie McMillan and Pat Messner for their input and insight throughout this study as patient contributors, and Peter Austin for his input on the statistical methods.

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Correspondence to Qi Guan.

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This study was supported by ICES, which is funded by an annual grant from the Ontario Ministry of Health (MOH) and the Ministry of Long-Term Care (MLTC). This study also received funding from grant 153070 from the Canadian Institutes of Health Research (CIHR). Parts of this material are based on data and information compiled and provided by the Ontario Ministry of Health and CIHI. The analyses, conclusions, opinions, and statements expressed herein are solely those of the authors and do not reflect those of the funding or data sources; no endorsement is intended or should be inferred. Adapted from Statistics Canada, Postal Code Conversion File, 2016. This does not constitute an endorsement by Statistics Canada of this product.

Conflicts of interest

Hannah Wunsch was supported by a Canada Research Chair [Tier 2] in Critical Care Organization and Outcomes and by a Merit Research Award from the Department of Anesthesiology and Pain Management, University of Toronto. Tara Gomes was supported by a Tier 2 Canada Research Chair in Drug Policy Research and Evaluation.

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Author contributions

QG, TG, and DNJ developed the research question while QG led the study design, analysis, interpretation, and manuscript preparation. All authors contributed to study design, interpretation, and manuscript preparation.

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The dataset from this study is held securely in coded form at ICES. While legal data sharing agreements between ICES and data providers (e.g., healthcare organizations and government) prohibit ICES from making the dataset publicly available, access may be granted to those who meet pre-specified criteria for confidential access, available at (email: The full dataset creation plan and underlying analytic code are available from the authors upon request, understanding that the computer programs may rely upon coding templates or macros that are unique to ICES and are therefore either inaccessible or may require modification.

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Guan, Q., Men, S., Juurlink, D.N. et al. Opioid Initiation and the Hazard of Falls or Fractures Among Older Adults with Varying Levels of Central Nervous System Depressant Burden. Drugs Aging 39, 729–738 (2022).

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