The Association of Neurocognitive Symptoms With Opioid Overdose Events Among Patients on Long-Term Opioid Therapy

BACKGROUND: Neurocognitive symptoms (NCS)-including difficulties with attention, memory, and executive functioning-are common among patients receiving long-term opioid therapy (LTOT) for pain. Although cognitive impairment may influence safety, its relationship to opioid overdose has not been evaluated at scale. This study assessed whether NCS are associated with opioid overdose among Veterans prescribed LTOT. METHODS: We conducted a retrospective cohort study using national Veterans Health Administration (VHA) data. Patients prescribed LTOT (≥90 days of continuous opioid prescriptions) in 2018 were included. NCS during LTOT episodes were measured via diagnostic codes and natural language processing. The primary outcome was fatal and nonfatal opioid overdose, identified through ICD codes. A Cox proportional hazards model estimated the association between NCS and overdose events, adjusting for demographics, co-occurring diagnoses, VHA visits, opioid dose, and LTOT duration. RESULTS: The opioid overdose risk for patients with NCS, compared with those without, during LTOT receipt was higher, risk ratio (95% CI) = 5.80 (3.99-8.41). Cox regression analysis showed that adjusted hazard ratio (aHR) of opioid overdose was significantly higher for patients with NCS during LTOT (aHR 2.54 [2.10-3.06]). Factors associated with increased overdose risk included black race, presence of a substance use disorder, cardiovascular disease, chronic obstructive pulmonary disease, chronic kidney disease, opioid dose >50 mg morphine equivalent daily dose, and LTOT duration of 12 months or fewer. Sensitivity analyses yielded similar results. Age between 45 and 64 (vs 75 and older) was associated with decreased overdose risk. CONCLUSION: Neurocognitive symptoms are independently associated with increased risk of opioid overdose among Veterans receiving LTOT. Incorporating cognitive screening into opioid safety assessments may help identify individuals at heightened risk and inform tailored risk mitigation strategies.