Prescription Opioids and Risk of Dementia or Cognitive Decline

A Prospective Cohort Study

Sascha Dublin, MD, PhD; Rod L. Walker, MS; Shelly L. Gray, PharmD, MS; Rebecca A. Hubbard, PhD; Melissa L. Anderson, MS; Onchee Yu, MS; Paul K. Crane, MD, MPH; Eric B. Larson, MD, MPH


J Am Geriatr Soc. 2015;63(8):1519-1526. 

In This Article


This population-based cohort study found a slightly higher risk of dementia or AD in people with the highest cumulative use of prescription opioids than in those with little to no use (aHR for all cause dementia = 1.29, 95% CI = 1.02–1.62). A similar pattern was observed for NSAIDs, another widely used class of analgesics (aHR for all cause dementia = 1.31, 95% CI = 1.07–1.62). Recent opioid use was not associated with markedly higher dementia risk. People with the heaviest opioid use did not demonstrate more-rapid decline in cognitive scores with age.

There are several possible explanations for the small elevation in risk seen with heavy use of opioids or NSAIDs. It may be that heavy cumulative use of either medication class truly increases dementia risk. This would presumably require the drugs to act through different mechanisms, because they act on different targets and biological pathways. Alternatively, there could be residual confounding. Participants with heavier opioid or NSAID use were more likely to be in poor health than those with little to no use. Although many potential confounders, including comorbidity, depressive symptoms, physical activity, and smoking status, were adjusted for, other factors might not have been accounted for. Measures of pain, including severity and duration, were lacking. Studies have shown that chronic pain is associated with structural brain changes, including a global decrease in gray matter volume and density and decreases in gray matter in specific brain regions, particularly areas related to pain processing.[26–31] Some of these areas are also important for memory and executive function.[27] Studies have also suggested that impairments in cognitive function are associated with chronic pain.[26,27] These studies have important limitations. Most were cross-sectional, making it difficult to determine whether brain changes preceded or were caused by pain. Also, most studies were small, and many did not exclude individuals using opioids or account for opioid use, so it is difficult to distinguish the effects of pain from those of its treatment.

Strengths of the current study include that it is population based and ascertained outcomes in a rigorous manner. It was possible to study subclinical cognitive decline and dementia. Detailed pharmacy data going back many years provided a unique opportunity to study long-term medication exposures. Many studies assess medication use through self-report or periodic medication inventory at study visits and thus lack detailed information about cumulative exposure. ACT collects data about a wide range of potential confounders including depressive symptoms.

Limitations include that information about pain, including its chronicity, duration, and severity, were lacking. There could be residual confounding by pain or other characteristics. Few participants had very heavy opioid use. Throughout much of the study period, NSAIDs were available over the counter, so there could be misclassification of NSAID use, although GH members often purchase over-the-counter medications at health plan pharmacies, and these purchases are recorded in the computerized pharmacy database, improving data capture. Most participants were Caucasian, which may limit generalizability.

In this study—the first to examine opioids and dementia risk—there was not convincing evidence that prescription opioid use hastens cognitive decline or increases dementia risk. Although a modestly higher dementia risk was found in participants with the heaviest exposure to opioids, several aspects argue against a causal relationship. A similar pattern was seen for NSAIDs (the finding was not specific to opioids), there was no pattern of increasing risk across categories of greater cumulative opioid exposure, and recent opioid use was not associated with higher risk. Studies of this topic share a common challenge: the difficulty of untangling the effect of pain from the effect of its treatments. Together with the existing literature, this work suggests that, although there are other risks associated with opioid use in older adults, the evidence thus far does not suggest that opioid use conveys substantial long-term cognitive harm.