Regular use of pharmaceutical opioids and subsequent risk of cancer: a prospective cohort study and Mendelian randomization analysis.

BACKGROUND

Opium consumption was classified as "carcinogenic to humans" by the International Agency for Research on Cancer (IARC). We investigated whether use of pharmaceutical opioids, derived from or synthesized to mimic opium, is associated with cancer risk using separate observational and genetic analyses.

METHODS

Observational analysis included 472,955 participants in the UK Biobank prospective cohort (2006-2022). Genetic analysis included 2-sample Mendelian Randomization (MR) analyses using data from 14 independent genome-wide-association-studies (N = 9931-357,292). Adjusted hazard ratios (a-HR) or odds ratios (ORs) associated with regular opioid use were assessed for six established opium-related cancers (lung, pancreatic, bladder, esophageal, oropharyngeal, and laryngeal) and seven non-opium-related cancers (prostate, breast, colon, endometrial, kidney, ovarian, and brain).

FINDINGS: In UK Biobank, regular opioid use was associated with increased risk of opium-related cancers among ever-smoking [a-HR = 1.33 (95% CI = 1.22-1.43)] and never-smoking participants [a-HR = 1.32 (1.10-1.59)], but not non-opium-related cancers [a-HR = 0.96 (0.91-1.02)]. Risk increased with opioid strength [a-HR = 1.30 (1.20-1.40) for weak opioids; a-HR = 1.86 (1.43-2.40) for strong opioids, p-trend < 0.0001] and duration of action [a-HR = 1.32 (1.22-1.42) for short-acting; a-HR = 1.65 (1.24-2.18) for long-acting opioids, p-trend < 0.0001]. Both observational and genetic analyses showed increased risks for most opium-related cancers, including lung [a-HR = 1.39 (1.27-1.53); MR-Odds Ratio (OR) = 1.17 (1.07-1.29)], pancreas [a-HR = 1.24 (1.01-1.52); MR-OR = 1.34 (1.11-1.62)], bladder [a-HR = 1.26 (1.02-1.56); MR-OR = 1.15 (1.03-1.29)], esophagus [a-HR = 1.18 (0.94-1.49); MR-OR = 1.24 (1.01-1.52)], and larynx [a-HR = 1.37 (0.85-2.20); MR-OR = 1.29 (1.04-1.61)]. Except for an inverse association with prostate cancer [a-HR = 0.83 (0.76-0.91); MR-OR = 0.99 (0.92-1.05)], associations were null for non-opium-related cancers.

INTERPRETATION: Regular use of pharmaceutical opioids was associated with elevated risk for cancers caused by opium, but not other cancers.

FUNDING: US National Institutes of Health, French National Cancer Institute.