br Use of hypnotic sedative
Use of hypnotic-sedative medications can be a proxy for inter-rupted circadian rhythm, which is related to decreased length of nightly fasting. Shortened time of night fasting can disrupt meta-bolic factors, including glucoregulation . Increases in the insulin/insulin-like growth factor system may increase the risk for a majority of cancers . In addition, a number of adverse psychi-atric symptoms, including insomnia and depression, which are known to be associated with overuse of alcohol , and cigarette
Outcomes: individual cancers Exposure: any hypnotic use (ref.: no hypnotic use)
Case (N) Crude HR
Case (N) Crude HR
Ovarian cancer NA
CI, confidence interval; HR, hazard ratio; NA, not applicable. a Adjusted for socio-economic status and comorbidity status using the Charlson Comorbidity Index. Age was considered as the time scale.
smoking , can be relieved after administration of sedative-hypnotics. It is possible that people with diminished symptoms consume less alcohol and fewer cigarettes compared to patients without a prescription, which can lead to decreased incidence of certain cancers, such as gastric or colon cancer. In addition, people who visit a psychiatric clinic to get sedative-hypnotic prescriptions may be more sensitive to their health, use medical facilities frequently, or have been exposed more to early screening for pre-cancerous lesions using endoscopy, resulting in an overall dimin-ished incidence rate for gastric and colon cancers.
Circadian rhythms are also known to affect androgen levels and modulate the development and progression of prostate cancer , and an interrupted circadian rhythm can break the expression of related genes, altering breast biology and advancing cancer . Individuals who use sedative-hypnotics, especially benzodiaze-pines, tend to have multiple psychiatric comorbidities, including substance use disorders , and possibly have altered immune function . With regard to decreased immune function, several studies have suggested an association between infection and use of various sedative-hypnotics [36,37], as medications such as benzo-diazepines worsen sleep FG-4592 and provoke hypoxia followed by inflammation, which increases the risk of cancer . Certain behavioral conditions, such as cigarette smoking and high alcohol consumption, co-exist with the use of sedative-hypnotics, resulting in increased risk of lung and liver cancers. A few studies have dis-cussed the direct independent effect of sedative-hypnotics, including benzodiazepines, on individual disease onset; two early animal studies proposed an interaction between benzodiazepines and liver cancer [39e41].
This study has several strengths. First, we utilized a large, representative population-based sample, as the NHIS covers almost every population in South Korea. This granted sufficient power to observe increased risk for certain cancers that were not found in previous studies. This study was also able to assess the sedative-hypnotics categorized by drug mechanisms. Detailed information about participant sedative-hypnotic prescriptions was also employed in the analyses. We considered the effect of other comorbidities in the association between sedative-hypnotics and overall/specific cancers, and we were also able to assess specific types of cancer in relation to sedative-hypnotic use. In this way, we found the use of sedative-hypnotics to increase the likelihood of sex-specific cancers, such as breast and ovary cancer among women and prostate cancer among men. For example, the effect of abnormal circadian rhythm ion androgen levels has been investi-gated, inducing a carcinogenetic change in the prostate .
However, this study also has some limitations. Because we used only national insurance claims data, we could not obtain informa-tion on other demographic or lifestyle factors, such as body mass index, physical activity, alcohol consumption habits, or cigarette smoking habits and, thus, could not consider these factors as covariates. In addition, the diagnosis codes in the NHIS data are entered with the primary purpose of administrative billing, which can be different from the actual clinical diagnosis, further requiring validation. To address this concern, we compared incidence of cancer as defined in our data with Korean Central Cancer Registry data (results not shown). The overall cancer incidence rate in the current study exceeded the reported rate from the cancer registry, although the differences decreased as age increased, regardless of sex. If the cancer code in the NHIS dataset was inaccurate, the incidence of cancer and/or associations between sedative-hypnotic use and overall cancer may have been overestimated. However, certain cancers such as breast, lung, prostate, and thyroid cancer showed very similar incidence rates between the current study and the cancer registry, which provides external validity for our ana-lyses. Additionally, we could not find a significant doseeresponse