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催眠药物的死亡风险:证据的优势与局限

Mortality Risk of Hypnotics: Strengths and Limits of Evidence.

作者信息

Kripke Daniel F

机构信息

UCSD, 8437 Sugarman Drive, La Jolla, CA, 92037-2226, USA.

Scripps Clinic Viterbi Family Sleep Center, La Jolla, USA.

出版信息

Drug Saf. 2016 Feb;39(2):93-107. doi: 10.1007/s40264-015-0362-0.

Abstract

Sleeping pills, more formally defined as hypnotics, are sedatives used to induce and maintain sleep. In a review of publications for the past 30 years, descriptive epidemiologic studies were identified that examined the mortality risk of hypnotics and related sedative-anxiolytics. Of the 34 studies estimating risk ratios, odds ratios, or hazard ratios, excess mortality associated with hypnotics was significant (p < 0.05) in 24 studies including all 14 of the largest, contrasted with no studies at all suggesting that hypnotics ever prolong life. The studies had many limitations: possibly tending to overestimate risk, such as possible confounding by indication with other risk factors; confusing hypnotics with drugs having other indications; possible genetic confounders; and too much heterogeneity of studies for meta-analyses. There were balancing limitations possibly tending towards underestimates of risk such as limited power, excessive follow-up intervals with possible follow-up mixing of participants taking hypnotics with controls, missing dosage data for most studies, and over-adjustment of confounders. Epidemiologic association in itself is not adequate proof of causality, but there is proof that hypnotics cause death in overdoses; there is thorough understanding of how hypnotics euthanize animals and execute humans; and there is proof that hypnotics cause potentially lethal morbidities such as depression, infection, poor driving, suppressed respiration, and possibly cancer. Combining these proofs with consistent evidence of association, the great weight of evidence is that hypnotics cause huge risks of decreasing a patient's duration of survival.

摘要

安眠药,更正式的定义为催眠药,是用于诱导和维持睡眠的镇静剂。在对过去30年出版物的回顾中,发现了一些描述性流行病学研究,这些研究考察了催眠药及相关镇静抗焦虑药的死亡风险。在34项估计风险比、比值比或风险率的研究中,24项研究显示与催眠药相关的额外死亡率显著(p<0.05),其中包括所有14项规模最大的研究,相比之下,没有任何研究表明催眠药能延长寿命。这些研究有许多局限性:可能倾向于高估风险,比如可能存在与其他风险因素的指征混杂;将催眠药与有其他适应证的药物混淆;可能存在基因混杂因素;以及用于荟萃分析的研究异质性过大。也存在可能导致风险低估的局限性,比如检验效能有限、随访间隔过长,可能导致服用催眠药的参与者与对照组的随访混淆、大多数研究缺少剂量数据,以及对混杂因素过度调整。流行病学关联本身并不足以证明因果关系,但有证据表明催眠药会导致过量用药死亡;人们对催眠药如何使动物安乐死和致人死亡有透彻的了解;并且有证据表明催眠药会导致潜在致命的病症,如抑郁、感染、驾驶能力下降、呼吸抑制,甚至可能致癌。将这些证据与一致的关联证据相结合,大量证据表明催眠药会带来极大风险,降低患者的生存时长。

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