OBJECTIVE: Neurocognitive symptoms (NCSs) may be early indicators of opioid-related harm. We aimed to evaluate the incidence and potential attribution of opioid-related NCS among patients on long-term opioid therapy (LOT) by using natural language processing to extract data from the electronic health records within the Veterans Health Administration. METHODS: We conducted a retrospective cohort study of patients prescribed LOT in 2018. NCS were identified from clinical notes across 3 periods: 6 months before LOT initiation, during LOT, and 1-year post-LOT discontinuation. Opioid-related NCS included cognitive impairment, sedation, light-headedness, altered mental status, and intoxication. We calculated incidence rates, incidence rate ratios, and hazard ratios to evaluate the occurrence and potential opioid attribution of NCS across these periods. RESULTS: Among 55,652 patients, 3.1% experienced opioid-related NCS, with the highest incidence observed during LOT. Prevalence of NCS was greater in patients who were: between 55 and 64 (3.6%) or 65 and 74 years old (3.2%), Asian (4.8%, P = 0.02), and had received treatment for substance use disorders (7.1%, P = 0.01). In adjusted proportional hazards models, identified Asian race (hazard ratio: 2.20 [95% CI: 1.09-4.44], P = 0.03), and cooccurring conditions dementia (1.50 [1.12-2.00], 0.01), depression (1.31 [1.14-1.49], <
0.01), posttraumatic stress disorder (1.18 [1.02-1.37], 0.02), substance use disorder (1.62 [1.36-1.92], 0.01), cardiovascular disease (1.18 [1.01-1.37], 0.04), chronic obstructive pulmonary disease (1.16 [1.01-1.33], 0.03), cirrhosis (1.73 [1.34-2.24], 0.01), chronic kidney disease (1.41 [1.19, 1.66]
0.01) and traumatic brain injury (1.42 [1.06-1.91], 0.02) were associated with increased likelihood of NCS. Likelihood of NCS increased with LOT dose and decreased with LOT duration. CONCLUSION: This study suggests that opioid-related NCS are most likely to occur during LOT, indicating a potential temporal association with opioid use. These findings highlight the importance of monitoring NCS in patients on LOT as part of a broader strategy to mitigate opioid-related harms.