Mahdi Sheikh

Supplementary Table S1. Multiplicative interaction analyses between tobacco products and opium use in the multivariable Cox proportional hazards models.

Supplementary Table S2. Sensitivity analysis using current and former cigarette smoking classifications

Background:Tobacco and opium consumption are prevalent in Iran and have been linked to increased risk of upper gastrointestinal (GI) cancers. To investigate their role in lower GI cancers, the associations of tobacco and opium use with liver and colorectal cancer mortality were examined in this study. Methods:From 2004 to 2008, participants of 40 to 75 years of age were recruited through random systematic cluster sampling and primary healthcare worker contact in Golestan, Iran. Baseline assessment of tobacco and opium use, demographic information, and cancer-relative risk factors were conducted through validated questionnaires. Cancer diagnoses and deaths were collected through regular follow-up between 2004 and March 6, 2023. Multivariate Cox proportional regression model evaluated the association between tobacco and opium use and liver and colorectal cancer mortality. Results:During a median follow-up of 15 years, 112 participants developed liver cancer and 201 developed colorectal cancer. Cigarette smoking [hazard ratio (HR) = 1.76; 95% confidence interval (CI), 1.05–2.94] and water-pipe smoking (HR = 3.20; 95% CI, 1.12–9.13) were associated with liver cancer. Opium was not associated with liver cancer. We observed no associations between tobacco or opium use and risk of colorectal cancer. Conclusions:Cigarette and water-pipe smoking were associated with increased liver cancer mortality, whereas no significant associations were observed for tobacco and opium use and colorectal cancer mortality. Impact:Tobacco control could be a strategy for reducing liver cancer mortality in high-risk populations. Larger prospective studies are required to confirm the associations of tobacco and opium use with lower GI cancers.

Supplementary Table S3. Quartile dose-response associations between different measures of tobacco use and the risk of different cancers

Background: Tobacco and opium consumption are prevalent in Iran and have been linked to increased risk of upper gastrointestinal (GI) cancers. To investigate their role in lower GI cancers, the associations of tobacco and opium use with liver and colorectal cancer mortality were examined in this study. Methods: From 2004 to 2008, participants of 40 to 75 years of age were recruited through random systematic cluster sampling and primary healthcare worker contact in Golestan, Iran. Baseline assessment of tobacco and opium use, demographic information, and cancer-relative risk factors were conducted through validated questionnaires. Cancer diagnoses and deaths were collected through regular follow-up between 2004 and March 6, 2023. Multivariate Cox proportional regression model evaluated the association between tobacco and opium use and liver and colorectal cancer mortality. Results: During a median follow-up of 15 years, 112 participants developed liver cancer and 201 developed colorectal cancer. Cigarette smoking [hazard ratio (HR) = 1.76; 95% confidence interval (CI), 1.05–2.94] and water-pipe smoking (HR = 3.20; 95% CI, 1.12–9.13) were associated with liver cancer. Opium was not associated with liver cancer. We observed no associations between tobacco or opium use and risk of colorectal cancer. Conclusions: Cigarette and water-pipe smoking were associated with increased liver cancer mortality, whereas no significant associations were observed for tobacco and opium use and colorectal cancer mortality. Impact: Tobacco control could be a strategy for reducing liver cancer mortality in high-risk populations. Larger prospective studies are required to confirm the associations of tobacco and opium use with lower GI cancers.

Evidence from experimental studies suggests that pain may influence cancer development. We conducted a systematic review (registration osf.io/ms437) of the epidemiological studies assessing whether chronic pain, with minimal or non-inflammatory features, increases the risk of cancer incidence or mortality. The search used Scopus and Web of Science up to 11/03/2025. Quality assessment used the Newcastle–Ottawa Scale. Study characteristics and outcomes were analysed using narrative synthesis, with random-effects meta-analysis and meta-regression conducted where appropriate. A total of 23 studies (12 prospective, 11 retrospective) met the inclusion criteria, of which six were rated as high quality. The outcome data synthesis indicates a small increase in cancer mortality rate ratios, and a potential increase in a subset of organs. A total of three body site-specific analyses suggest that chronic pain may be associated with higher incidence for breast (SIR 2.12–4.8) and prostate (SIR 1.49–5.59) cancers, and with increased mortality for lung cancer (MRR 3.09, 95% CI 1.45–6.62). Ten studies were included for meta-analysis, including four studies rated as high quality. Meta-analysis of hazard ratios showed no association between cancer-related mortality and pain (HR 1.00, 95% CI 0.97–1.04), with consistent estimates across pain subtypes in meta-regression. Our review and meta-analysis do not support an overall association between chronic pain and increased risk of cancer mortality or incidence and highlight multiple methodological and conceptual obstacles to exploring this relationship, including reverse causation and confounding factors such as pain and opioid use association. High-quality studies that rigorously address reverse causation and confounding are warranted.