Meta-Analysis: Prescription Opioid and Morphine Use and Risk of Stroke

Abstract Prescription opioid analgesics are widely used for the management of acute, chronic, and cancer-related pain, yet their potential association with cerebrovascular events remains uncertain. This meta-analysis evaluated the association between prescription opioid/morphine exposure and incident stroke in adults. Eligible observational studies reporting adjusted effect estimates for incident stroke among prescription opioid or morphine users were included, while studies focused on heroin, illicit opium, passive exposure, or opioid use disorder without separable prescription-opioid exposure were excluded from the primary analysis. Adjusted effect estimates were synthesized using generic inverse-variance random-effects methods, with restricted maximum likelihood estimation and Hartung–Knapp inference used for the principal analysis. Four independent studies contributed to the primary meta-analysis of overall incident stroke. Prescription opioid/morphine exposure was associated with a modest increase in stroke risk, with a pooled adjusted relative effect of 1.10 (95% CI 1.03–1.18). Statistical heterogeneity was low (I² = 0% in the conventional analysis). The association remained above the null when the analysis was restricted to studies reporting hazard ratios (1.11, 95% CI 1.03–1.19) and after exclusion of the largest, highly weighted cohort (1.16, 95% CI 1.05–1.29). Additional evidence suggested associations with specific ischemic and hemorrhagic stroke outcomes; however, differences in study design, opioid exposure, populations, and outcome definitions precluded reliable subtype-specific pooling. Overall, prescription opioid/morphine exposure was associated with a small but consistent elevation in incident stroke risk. Nevertheless, the exclusively observational evidence remains susceptible to residual confounding, confounding by indication, and exposure misclassification and therefore does not establish causality. Further prospective studies incorporating opioid type, dose, duration, cumulative exposure, and time-varying use are required to define the cerebrovascular implications of prescription opioid therapy more precisely. Keywords: Prescription opioids; Morphine; Stroke; Cerebrovascular disease; Ischemic stroke; Hemorrhagic stroke; Opioid analgesics; Morphine and Stroke, Opioid and Stroke.