Opioids and Accelerated Brain Aging: The White Matter Matters

Prescription Opioids and Brain Structure in Community-Dwelling Older AdultsMayo Clinic ProceedingsVol. 99Issue 5PreviewTo evaluate the associations between prescription opioid exposures in community-dwelling older adults and gray and white matter structure by magnetic resonance imaging. Full-Text PDF Opioids are most highly prescribed in older adults, and because of aging and multimorbidity, this demographic is also most likely to suffer adverse events from this drug class. The article by Warner et al1Warner N.S. Hanson A.C. Schulte P. et al.Prescription opioids and brain structure in community-dwelling older adults.Mayo Clin Proc. 2024; 99: 716-726Abstract Full Text Full Text PDF Scopus (1) Google Scholar reports on the cross-sectional associations between prescription opioid exposures in community-dwelling older adults (older than 65 years) and gray and white matter structure assessed by magnetic resonance imaging. The primary exposure was the duration of opioid availability with a secondary exposure of total morphine milligram equivalents (MME). Multivariable models were used to assess associations between opioid exposures and brain structures. No significant associations were found between opioid exposures and gray matter structure; however, increased opioid duration and MME were associated with decreased white matter fractional anisotropy (FA) in a little more than one-third of regions assessed. Opioid duration and MME were also associated with greater white matter hyperintensity volume. The authors concluded that both the duration and dose of prescription opioids in community-dwelling older adults are associated with changes in white matter structure or function and may provide a mechanism for clinical opioid and cognition relationships. Although observational studies suggest an association between opioid use and long-term cognitive impairment, this report by Warner et al takes a first, comprehensive examination of the relationship between opioid use and structural changes in the brains of older, community-dwelling adults. The results are somewhat unexpected on the basis of previous studies in younger individuals but also have important clinical implications, including that (1) opioids affect white matter tracts that are known to be involved in cognition; (2) magnetic resonance imaging of the brain may be a way to identify older individuals susceptible to the deleterious effects of opioids on cognitive function; and (3) there may be a threshold effect, using opioid duration or dose, that could guide prescriptive use of opioids in older adults. White matter injury, either concurrent with or independent of gray matter involvement, is known to be associated with cognitive deficits and dementia. Because patients with dementia at enrollment were excluded in this study, it is intriguing that the opioid-induced changes observed in white matter structure are in the axonal tracts involved in cognitive, sensory, and emotional processing domains commonly affected in dementia that contribute to executive dysfunction, hallucinations, and behavioral disturbances, respectively. One of the most provocative and perhaps clinically applicable finding is that each 10-day increase in annual opioid exposure or 400-MME increase is associated with approximately the equivalent of 1 additional year of cognitive aging. Important caveats are that opioids may simply serve as a marker for other factors (ie, pain, medical or psychiatric comorbidities) that drive structural changes and that those receiving opioids in this cohort were modestly older and had greater cardiovascular risk factors than those not receiving opioids. Nevertheless, these caveats do not easily explain the dose relationship or why those with cardiovascular risk factors would preferentially require opioids. This study strongly suggests that potential opioid-related changes in brain structure in older adults may be limited to white matter. Supporting evidence indicates that these changes are also similar to those alterations related to brain aging, dementia, and drug dependence. For example, several reports have identified the corpus callosum as the white matter region with the most substantial changes in FA with aging.2Abe O. Aoki S. Hayashi N. et al.Normal aging in the central nervous system: quantitative MR diffusion-tensor analysis.Neurobiol Aging. 2002; 23: 433-441Crossref PubMed Scopus (349) Google Scholar,3Sullivan E.V. Pfefferbaum A. Diffusion tensor imaging in normal aging and neuropsychiatric disorders.Eur J Radiol. 2003; 45: 244-255Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar Furthermore, the role of white matter injury in cognitive decline appears to be related to inadequate communication between important regions in gray matter connected by white matter tracts.4Filley C.M. Fields R.D. White matter and cognition: making the connection.J Neurophysiol. 2016; 116: 2093-2104Crossref PubMed Scopus (241) Google Scholar,5Horne A. Ding J. Schnur T.T. Martin R.C. White matter correlates of domain-specific working memory.Brain Sci. 2023; 13: 19Crossref Scopus (2) Google Scholar Whereas the association between prescription opioids and longitudinal cognitive decline has previously been described,6Warner N.S. Hanson A.C. Schulte P.J. Habermann E.B. Warner D.O. Mielke M.M. Prescription opioids and longitudinal changes in cognitive function in older adults: a population-based observational study.J Am Geriatr Soc. 2022; 70: 3526-3537Crossref PubMed Scopus (6) Google Scholar,7Dublin S. Walker R.L. Gray S.L. et al.Prescription opioids and risk of dementia or cognitive decline: a prospective cohort study.J Am Geriatr Soc. 2015; 63: 1519-1526Crossref PubMed Scopus (79) Google Scholar the imaging study reported by Warner et al now suggests that disruption in white matter structure-function relationships may be a prominent mechanism for opioid-induced cognitive decline in older adults. Another clinical correlate that may, at least in part, be explained by this study is opioid dependence, in which decreased FA in white matter tracts involved in the limbic system, internal capsule, and body of the corpus callosum has been reported.8Upadhyay J. Maleki N. Potter J. et al.Alterations in brain structure and functional connectivity in prescription opioid-dependent patients.Brain. 2010; 133: 2098-2114Crossref PubMed Scopus (290) Google Scholar This latter observation is potentially extended to other substance use disorders, perhaps mediated by myelin degeneration.9Archibong V.B. Usman I.M. Lemuel A.M. Prolonged codeine administration causes degeneration of myelinated axons and motor dysfunction in Wistar rats.Subst Abuse Rehabil. 2022; 13: 73-81Crossref PubMed Google Scholar Warner et al have provided initial findings that may suggest a future imaging-based way to evaluate older patients predisposed to the untoward complications of opioid-associated cognitive dysfunction. More immediately, their study also suggests that opioid dosage and duration need to be carefully assessed and weighed against clinical benefit. Although future studies with longitudinal imaging and clinically meaningful correlations are warranted to further translate this information into the clinic, the key messages are clear, namely, opioids are very likely contributing to accelerated brain aging, and white matter injury is a prominent mediator of this process. The author reports no competing interests.