Prescription Opioids and Longitudinal Changes in Cognitive Function in Older Adults

A Population-based Observational Study

Nafisseh S. Warner MD; Andrew C. Hanson MS; Phillip J. Schulte PhD; Elizabeth B. Habermann PhD; David O. Warner MD; Michelle M. Mielke PhD


J Am Geriatr Soc. 2022;70(12):3526-3537. 

In This Article

Abstract and Introduction


Background: Opioids are frequently prescribed to alleviate pain in older adults, yet the relationships between prescription opioids and long-term cognitive function are unclear.

Methods: In this analysis of the Mayo Clinic Study of Aging, a longitudinal population-based cohort study of older adults with formal neuropsychological testing and cognitive evaluations performed every 15 months, the associations between prescription opioids, global and domain-specific cognitive function, and mild cognitive impairment were evaluated through time-dependent linear mixed effects and Cox proportional hazards models.

Results: Four thousand two hundred eighteen participants (51% male) were included with enrollment between 11/1/2004 and 4/1/2019 and median age of 76 (interquartile range 72, 82) years. Two thousand nine hundred seventy-seven subjects (71%) received at least 1 opioid prescription during a median follow-up of 7.5 (5.0, 10.7) years. Overall, there was an estimated 0.096 reduction in the global cognitive Z-score per year, including decreases of 0.050 in memory, 0.080 in language, 0.044 in visual–spatial cognition, and 0.112 in attention. In multivariable analyses, each receipt of an opioid prescription resulted in an additional −0.007 (95% CI −0.009, −0.005) change in global cognitive Z-score (p < 0.001), with significant effects seen in the domains of memory (−0.005, 95% CI −0.007, −0.003; p < 0.001), language (−0.002, 95% CI −0.003, 0.000; p = 0.024) and attention (−0.004, 95% CI −0.006, −0.002; p < 0.001) but not visual–spatial function (0.000, 95% CI −0.001, 0.001; p = 0.897). Opioid prescriptions were associated with incident mild cognitive impairment (MCI) in adjusted analysis (hazard ratio 1.21, 95% CI 1.04, 1.42; p = 0.014).

Conclusion: Prescription opioids are associated with small but statistically significant declines in long-term cognitive function in older adults, which may represent effects of opioids or other related factors.


Chronic pain is common in older adults, with a prevalence of bothersome pain for those ≥65 years exceeding 50%.[1–3] Pain in this population is associated with decreased quality of life,[4–6] inferior perception of health,[7] and increased healthcare resource utilization.[5] Persistent pain symptoms may also be associated with accelerated cognitive decline.[8–11] Thus, it is critically important to optimize analgesic outcomes for older adults.

Opioids are frequently prescribed in older adults to treat pain symptoms. Approximately 10% of US adults >60 years of age are using opioids at any given time.[12] Despite it being known that a single therapeutic dose of opioid causes transient declines in attention, working memory, and verbal memory in older adults,[13] the long-term effects of opioids on cognitive performance, including the development of mild cognitive impairment (MCI) or dementia, is unclear. The limited evidence suggests that opioid use may be a risk factor for long-term cognitive impairment in older adults.[14–16] However, most data are based on the utilization of cognitive screening tools rather than longitudinal assessment of global and domain-specific cognitive function and with limited adjustment for important covariates that may influence propensity for opioid use and/or cognitive function.

In this study, we determined the associations between prescription opioid availability, longitudinal changes in global and domain-specific cognitive function, and incident MCI utilizing data from a longitudinal population-based cohort study, the Mayo Clinic Study of Aging (MCSA). We hypothesized that opioid availability in older adults would be associated with accelerated cognitive decline and an increased risk of incident MCI. In addition, we describe patterns of opioid prescribing in this population-based cohort to provide insights into current prescribing practices in older adults.