Comparative risk of delirium among opioid users for non-cancer pain: a retrospective cohort study

Opioid use for chronic non-cancer pain remains common in the UK, despite limited evidence of long-term effectiveness. Delirium, a serious acute confusional state associated with increased mortality, is a known adverse effect of opioid use. Pharmacological differences between opioids may influence delirium risk, but comparative evidence is scarce. This study evaluated the association of opioid type and dosage with the risk of in-hospital delirium in non-cancer patients.

We conducted a retrospective cohort study using electronic health records (EHRs) from a tertiary care hospital in northwest England (September 26, 2014-December 31, 2020). Adult (≥ 18 years) without cancer who were administered with opioids during admission were included. Delirium was identified using the 4 'A's Test or through a combination of ICD-10 codes and new-onset confusion scores (= 3) on the National Early Warning Score. Daily opioid doses were converted to daily morphine milligram equivalents (MME/day) to assess the effect of dose across different opioid types. Incidence rates were calculated by opioid type and opioid dosage. Cox regression models, adjusted for confounders, were used to evaluate delirium risk.

Among 50,586 opioid-exposed patients (mean [SD] age, 55 [20] years; 53% female), 867 patients (1.7%) experienced delirium during their first hospital admission (mean [SD] age, 75.1 [16.7] years). Compared to codeine, oxycodone (hazard ratio [HR] 3.52, 95% CI 2.77-4.46), fentanyl (HR 2.45, 95% CI 1.71-3.51), buprenorphine (HR 2.43, 95% CI 1.54-3.82), combination opioids (HR 2.22, 95% CI 1.63-3.02), and morphine (HR 2.15, 95% CI 1.65-2.79) were associated with significantly higher delirium risk. No clear dose-response association was observed: doses of 50-119 MME/day were not associated with a significant increase in risk compared to < 50 MME/day (HR 0.96, 95% CI 0.66-1.39).

Using in-hospital medication administration records to capture opioid exposure, we found that oxycodone, fentanyl, buprenorphine, morphine, and combination opioids were associated with increased delirium risk compared with codeine. Oxycodone was associated with a higher risk of delirium compared with both codeine and morphine. These findings support personalised opioid prescribing in non-cancer pain and can inform shared clinical decision-making to prevent delirium in patients prescribed opioids.