Menopause Live (09 April, 2012)

Sleep disturbances may be bothering enough to lead to substantial impairment of quality of life. Perimenopausal and postmenopausal women typically complain of sleep problems and therefore are often prescribed with hypnotics. Many previous studies have pointed at the serious adverse effects of prolonged use of hypnotics [1], but the impact of those data on clinical practice has not been significant. A new study from the USA may again raise attention to the risks of hypnotics [2]. Study participants included 10,529 adults (63% women, mean age 54 years) who received hypnotic prescriptions and 23,676 matched controls with no hypnotic prescriptions, followed for an average of 2.5 years. Data were adjusted for age, gender, smoking, body mass index, ethnicity, marital status, alcohol use and prior cancer. Patients prescribed any hypnotic had substantially elevated hazards of dying compared to those prescribed no hypnotics. For groups prescribed < 18, 18–132 and > 132 doses/year, hazard ratios (95% confidence intervals) were 3.6 (2.9–4.4), 4.4 (3.7–5.4) and 5.3 (4.5–6.3), respectively, demonstrating a dose–response association. Hazard ratios were elevated in separate analyses for several common hypnotics, including zolpidem, temazepam, eszopiclone, zaleplon, other benzodiazepines, barbiturates and sedative antihistamines. Hypnotic use in the upper third was associated with a significant elevation of incident cancer (hazard ratio 1.35; 95% confidence interval 1.2–1.5). Results were robust within groups suffering each co-morbidity, indicating that the death and cancer hazards associated with hypnotic drugs were not attributable to pre-existing disease.

Comment
Sleep pills are among the most frequently used medications, with up to 10% of the adult population exposed to the various brands of hypnotics. Prior studies have shown multiple causal pathways by which hypnotics might raise the risk for death [3]. For example, controlled trials have shown that hypnotics impair motor and cognitive skills, such as driving. Use of hypnotics has been linked to an increase in automobile crashes and an increase in falls and fractures due to hangover sedation. In some patients, hypnotics may increase or prolong sleep apneas and suppress respiratory drive. They may also increase incident depression. These data, which are well known and scientifically well established, have not had a large impact on consumption of hypnotics so far. It seems that the benefit–risk balance for those who really suffer from insomnia favors the use of hypnotics after all. But now we are faced with impressive mortality and cancer data that might change our views. Three to five times higher risk for users of all kinds of hypnotics, no matter the annual number of pills/dosage (even less than 18 pills per year), no matter the age (not only in the old population) certainly deserves second thoughts. Note that the current study by Kripke and colleagues [2] has its limitations: it analyzed an insurance database, it was impossible to control for psychiatric conditions and anxiety, which is an area of significant concern to this study population, and users of hypnotics had a greater rate of several co-morbid health problems than the control group (i.e. cardiovascular disease, chronic obstructive pulmonary disease and asthma), suggesting they were a sicker population. Guidelines and recommendations on the use of sleeping pills usually state that efforts should be made to prescribe the lowest effective dose of medication and to reduce the medication’s usage when conditions allow. In my experience as a primary care physician, I know that it is sometimes difficult to avoid the use of hypnotics, yet, wherever applicable, patients should be investigated for potential causes of sleep disturbances (stress, anxiety, pain, hot flushes and sweating, nocturia, etc.) which should be treated first. Patients must be aware of the potential adverse effects and risks and should make an effort to reduce consumption of medications as much as possible.

Amos Pines
Department of Medicine ‘T’, Ichilov Hospital, Tel-Aviv, Israel