Is Long-term Use of Benzodiazepine a Risk for Cancer?

AbstractThe carcinogenicity of benzodiazepines (BZDs) is still unclear. We aimed to assess whether long-term benzodiazepines use is risk for cancer.We conducted a longitudinal population-based case-control study by using 12 years from Taiwan National Health Insurance database and investigated the association between BZDs use and cancer risk of people aged over 20 years. During the study period, 42,500 cases diagnosed with cancer were identified and analyzed for BZDs use. For each case, six eligible controls matched for age, sex, and the index date (ie, free of any cancer in the date of case diagnosis) by using propensity score. For appropriate risk estimation, we observed the outcomes according to their length of exposure (LOE) and defined daily dose (DDD). To mimic bias, we adjusted with potential confounding factors such as medications and comorbid diseases which could influence for cancer risk during the study period. The data was analyzed by using Cox proportional hazard regression and conditional logistic regression.The finding unveils benzodiazepines use into safe and unsafe groups for their carcinogenicity. The use of diazepam (HR, 0.96; 95%CI, 0.92–1.00), chlorodizepoxide (HR, 0.98; 95%CI, 0.92–1.04), medazepam (HR, 1.01; 95%CI, 0.84–1.21), nitrazepam (HR, 1.06; 95%CI, 0.98–1.14), oxazepam (HR, 1.05; 95%CI, 0.94–1.17) found safer among BZDs. However, clonazepam (HR, 1.15; 95%CI, 1.09–1.22) were associated with a higher risk for cancers. Moreover, specific cancer risk among BZDs use was observed significantly increased 98% for brain, 25% for colorectal, and 10% for lung, as compared with non-BZDs use.Diazepam, chlordiazepoxide, medazepam, nitrazepam, and oxazepam are safe among BZDs use for cancer risk. Our findings could help physicians to select safer BZDs and provide an evidence on the carcinogenic effect of benzodiazepines use by considering the LOE and DDD for further research.

[1]  L. Bero,et al.  Healthcare outcomes assessed with observational study designs compared with those assessed in randomized trials. , 2014, The Cochrane database of systematic reviews.

[2]  J. Concato,et al.  Randomized, controlled trials, observational studies, and the hierarchy of research designs. , 2000, The New England journal of medicine.

[3]  G. Nahler defined daily dose (DDD) , 2009 .

[4]  A Volkman,et al.  The influence of diazepam administration in rats bearing the R3230AC mammary carcinoma. , 1979, Prostaglandins and medicine.

[5]  K. Tomer,et al.  Changes in global gene and protein expression during early mouse liver carcinogenesis induced by non-genotoxic model carcinogens oxazepam and Wyeth-14,643. , 2003, Carcinogenesis.

[6]  I. Miyawaki,et al.  Mechanism of clobazam-induced thyroidal oncogenesis in male rats. , 2003, Toxicology letters.

[7]  Kuan-Pin Su,et al.  Benzodiazepine use possibly increases cancer risk: a population-based retrospective cohort study in Taiwan. , 2012, The Journal of clinical psychiatry.

[8]  D F Horrobin,et al.  The possible effect of diazepam on cancer development and growth. , 1981, Medical hypotheses.

[9]  P. Triozzi,et al.  Contributions of benzodiazepines to cancer therapy. , 1988, Cancer investigation.

[10]  Jesper Hallas,et al.  Use of benzodiazepines or benzodiazepine related drugs and the risk of cancer: a population-based case-control study. , 2013, British journal of clinical pharmacology.

[11]  J. Tong,et al.  Distinct DNA methylation epigenotypes in bladder cancer from different Chinese sub-populations and its implication in cancer detection using voided urine , 2011, BMC Medical Genomics.

[12]  C. Mackenzie,et al.  A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. , 1987, Journal of chronic diseases.

[13]  Phung Anh Nguyen,et al.  The impact of benzodiazepines on occurrence of pneumonia and mortality from pneumonia: a nested case-control and survival analysis in a population-based cohort , 2013, Thorax.

[14]  D. Kripke,et al.  Evidence for harm, comment on ‘Use of benzodiazepines or benzodiazepine related drugs and the risk of cancer: a population-based case-control study’. , 2014, British journal of clinical pharmacology.

[15]  C. Körber,et al.  An investigation of micronucleus and mutation induction by oxazepam in mammalian cells. , 1993, Mutagenesis.

[16]  W. Hsiao,et al.  Does universal health insurance make health care unaffordable? Lessons from Taiwan. , 2003, Health affairs.

[17]  M. Cotterchio,et al.  Benzodiazepines and risk for breast cancer. , 2006, Annals of epidemiology.

[18]  D. Kripke,et al.  Hypnotics' association with mortality or cancer: a matched cohort study , 2012, BMJ Open.

[19]  D. Rubin,et al.  Reducing Bias in Observational Studies Using Subclassification on the Propensity Score , 1984 .

[20]  S. Madhusoodanan,et al.  Safety of benzodiazepines in the geriatric population , 2004, Expert opinion on drug safety.

[21]  J. Collet,et al.  Use of antidepressants and risk of colorectal cancer: a nested case-control study. , 2006, The Lancet. Oncology.

[22]  Phung Anh Nguyen,et al.  Influenza vaccination and reduction in risk of ischemic heart disease among chronic obstructive pulmonary elderly , 2013, Comput. Methods Programs Biomed..

[23]  Keh‐ming Lin,et al.  Characteristics associated with benzodiazepine usage in elderly outpatients in Taiwan. , 2007, International journal of geriatric psychiatry.

[24]  M. Bouchard,et al.  The global diversion of pharmaceutical drugs
non-medical use and diversion of psychotropic prescription drugs in North America: a review of sourcing routes and control measures. , 2010, Addiction.

[25]  D. Cramer,et al.  Self-reported use of antidepressants or benzodiazepine tranquilizers and risk of epithelial ovarian cancer: evidence from two combined case-control studies (Massachusetts, United States) , 1995, Cancer Causes & Control.

[26]  Daniel F. Kripke Evidence That New Hypnotics Cause Cancer , 2008 .

[27]  D. Kripke Risks of Chronic Hypnotic Use , 2006 .

[28]  S. Bojesen,et al.  Statin use and reduced cancer-related mortality. , 2012, The New England journal of medicine.

[29]  S. Shapiro,et al.  Risk of ovarian cancer according to use of antidepressants, phenothiazines, and benzodiazepines (United States) , 2000, Cancer Causes & Control.

[30]  D. Rubin,et al.  The central role of the propensity score in observational studies for causal effects , 1983 .

[31]  S Shapiro,et al.  Relation of benzodiazepine use to the risk of selected cancers: breast, large bowel, malignant melanoma, lung, endometrium, ovary, non-Hodgkin's lymphoma, testis, Hodgkin's disease, thyroid, and liver. , 1995, American journal of epidemiology.

[32]  M. Lader Benzodiazepines revisited--will we ever learn? , 2011, Addiction.