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

Summary

In 472,955 UK Biobank participants, regular pharmaceutical opioid use was associated with higher risks of cancers known to be caused by opium, with dose-response patterns by strength and duration of action. Two-sample Mendelian randomization supported causal links for several opium-related cancers.

Key Findings

• Regular opioid use increased risk of opium-related cancers in both ever- and never-smokers (a-HR ~1.32–1.33); no increase for non-opium-related cancers.
• Dose-response observed: higher risk with strong vs weak opioids and with long- vs short-acting agents (p-trend < 0.0001).
• Mendelian randomization supported increased risks for lung, pancreatic, bladder, esophageal, and laryngeal cancers.

Clinical Implications

Chronic opioid prescribing should incorporate cancer risk into shared decision-making, favor opioid-sparing multimodal analgesia, and prioritize periodic deprescribing assessments, particularly for strong and long-acting formulations.

Limitations

• Potential residual confounding and exposure misclassification in observational data
• MR assumptions (e.g., no horizontal pleiotropy) may not fully hold for all instruments

Future Directions

Mechanistic studies on opioid-related carcinogenesis, evaluation of risk by dose-duration thresholds, and clinical guidelines integrating cancer risk in chronic pain management.