Opioid-specific risk of respiratory depression in non-cancer pain: a retrospective cohort study

Opioids are associated with serious adverse outcomes, including premature death. Respiratory depression is among the most severe opioid-related events, yet data on its incidence in non-cancer pain remain limited. Pharmacological differences suggest varying respiratory risks across opioid drugs. This study evaluated the comparative risk of respiratory depression by opioid drug and dose, and the impact of concomitant gabapentinoids and benzodiazepines in hospitalised patients with non-cancer pain.

A retrospective cohort study was conducted using electronic health records from a large tertiary hospital in Northwest England. Adult inpatients (≥ 18 years) receiving opioids for non-cancer pain were included. Opioid exposure was defined from drug administration records. Respiratory depression was identified using National Early Warning Scores or naloxone administration. Incidence rates were estimated by time-varying opioid exposure, opioid drug, and daily morphine milligram equivalent (MME). Associations with incident respiratory depression were examined using a Cox regression adjusted for confounders. Effect modifiers including co-administration of gabapentinoids or benzodiazepines were assessed for their impact on respiratory depression risk, in addition to opioids.

Among 32,909 inpatients, fentanyl (HR: 3.36, 95% CI 2.70-4.18), combination opioids (HR: 2.74, 95% CI 2.38-3.15), oxycodone (HR: 2.10, 95% CI 1.74-2.54), and morphine (HR: 1.84, 95% CI 1.59-2.12) were associated with a significantly higher risk compared with codeine. Relative to morphine, fentanyl (HR: 1.85, 95% CI 1.50-2.27) and combination opioids (HR: 1.49, 95% CI 1.32-1.69) remained associated with higher risk. Concomitant opioid-gabapentinoid use was associated with an increased risk compared to opioid use alone (HR: 1.73; 95% CI: 1.53-1.96). Doses ≥ 120 MME/day doubled the risk compared with < 50 MME/day (HR: 2.06, 95% CI 1.81-2.35), with evidence of increased risk at lower doses (31-60 MME/day) when examined using narrower dose categories.

Our study highlights the increased risk of respiratory depression associated with specific opioid drugs, particularly fentanyl and combination opioids, compared with codeine or morphine. Even moderate doses (31 to 60 MME/day) were associated with an increased risk, while co-prescription of gabapentinoids with opioids was associated with a higher risk compared with opioids alone.