Prescription opioids, brain structure, and cognition in older adults with chronic pain - Project Summary/Abstract Chronic pain is experienced by more than 30% of older adults (>65 years of age), many of whom receive prescription opioids despite well-described adverse effects including gastrointestinal distress, constipation, physical dependence, and respiratory depression. More recently, longitudinal observational studies led by our group and others have highlighted that prescription opioids are associated with accelerated cognitive decline in older adults, including increased risk for mild cognitive impairment or dementia. However, two critical gaps remain in our understanding of the relationship between prescription opioids and cognition. First, existing observational studies are unable to adequately distinguish the effects of opioids from those of underlying chronic pain necessitating opioids (i.e., confounding by indication). Second, the biological mechanisms driving the relationships between opioids and cognition are unknown. We find in prior work that prescription opioids are associated with decreased white matter integrity in major axonal pathways, including the corpus callosum and other pathways integral to cognitive and emotional processing. These findings are consistent with preclinical studies showing the opioids impair myelin production by oligodendrocytes. However, as with cognition, these observational data cannot be used to distinguish the potential causative effects of opioids from the effects of underlying pain. The overall purpose of this project is to test the hypothesis that opioid-mediated impairments in myelin production and/or other direct or indirect effects on axonal integrity mediate opioid- associated cognitive impairment. We will conduct a single-center, double-blinded, placebo-controlled trial including 200 participants with chronic pain secondary to osteoarthritis. The primary aim is to determine whether exposure to prescription opioids is associated with brain structural changes on magnetic resonance imaging (MRI), with the primary outcome of white matter integrity as measured by fractional anisotropy of the corpus callosum. The secondary outcome will be global cognition. Exploratory outcomes include several patient-centered outcomes (mental health, physical function, quality of life, sleep). All participants will receive evidence-based, tiered interventions to treat their pain under the direction of the study team (experts in pain management for older adults). In addition, they will be randomized to receive either opioids or placebo over a 6 week treatment period with titration of study medication based on pain scores per a defined protocol. All participants will undergo MRI imaging at enrollment and again at 12-months to evaluate the primary outcome. Participants will also undergo neurocognitive testing and assessment of exploratory patient-centered outcomes (e.g., quality of life). Our team has the requisite experience and expertise to perform this innovative research, whose findings will have a major impact on clinical practice and shared clinical decision making, regardless of study results.
