Opioids and Dementia in the Danish Population.

Importance: Opioids have been studied as a potential risk factor for dementia, but evidence concerning long-term noncancer opioid use and exclusive use of weak opioids and associated dementia risk is sparse.

Objective: To assess the association between cumulative noncancer use of opioids and risk of age-related all-cause dementia.

Design, setting, and participants: This nested case-control study within a population-based cohort included 1 872 854 individuals without previous dementia, cancer, opioid addiction, or opioid use in terminal illness. Data were obtained from national Danish registers. Each individual who developed dementia during follow-up was incidence-density matched to 5 dementia-free controls. Statistical analysis was performed from August 2023 to March 2024.

Exposure: Cumulative opioid exposure was based on filled prescriptions available from 1995 through 2020.

Main outcomes and measures: Conditional logistic regression provided adjusted incidence rate ratios (IRRs) for associations between opioids and dementia.

Results: Among 1 872 854 individuals without previous dementia, cancer, opioid addiction, or opioid use in terminal illness included in the study, 93 638 (5.0%) developed all-cause dementia during follow-up (51 469 [55.0%] female; median [IQR] age, 78.1 [73.0-82.8] years) and were matched to 468 190 control individuals (257 345 [55.0%] female; median [IQR] age, 78.0 [73.0-82.8] years). Opioid use up to 90 total standardized doses (TSDs) was not consistently associated with dementia risk. Opioid exposure above 90 TSDs yielded increased IRRs of dementia occurring before age 90 years ranging from 1.29 (95% CI, 1.17-1.42) for 91 to 200 TSDs to 1.59 (95% CI, 1.44-1.76) for greater than 500 TSDs for age-band 60 to 69 years at dementia diagnosis. Corresponding IRRs were 1.16 (95% CI, 1.11-1.22) to 1.49 (95% CI, 1.42-1.57) for age-band 70 to 79 years and 1.08 (95% CI, 1.03-1.14) to 1.21 (95% CI, 1.16-1.27) for 80 to 89 years. Sensitivity analyses corroborated associations in individuals with chronic noncancer pain and with use of weak opioids.

Conclusions and relevance: This study found that opioid use of less than 90 TSDs was not significantly associated with increased dementia risk. Above 90 TSDs of opioid use was associated with an elevated dementia risk before age 90 years, which persisted in individuals with chronic noncancer pain and in individuals solely exposed to weak opioids. Further research should ascertain whether the findings denote causality between opioids and dementia risk.