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Sleep‐promoting medications: Weighing the hazards of use versus non‐use

Hypnotic drugs – medications intended to initiate and sustain sleep – have returned to the regulatory and public health radar screen. Retail pharmacy data for calendar year 2010 shows in excess of 50 million retail prescriptions for the most commonly used hypnotics: zolpidem (immediate-release and controlled-release), temazepam, and eszopiclone (Table 1). Another 18.8 million prescriptions were written for trazodone, also prescribed for sleep disorders though not officially labeled as such. The public health hazard identified by the Food and Drug Administration is the risk of impaired automobile operation in the daytime hours following use of a hypnotic drug the night before. The FDA Drug Safety Communication dated January 10, 2013, had a principal focus on zolpidem, the most widely-prescribed hypnotic, but more generally stated: “... all drugs taken for insomnia can impair driving and activities that require alertness the morning after use. Drowsiness is already listed as a common side effect in the drug labels of all insomnia drugs, along with warnings that patients may still feel drowsy the day after taking these products. Patients who take insomnia drugs can experience impairment of mental alertness the morning after use, even if they feel fully awake.” The FDA Communication, and a later editorial in the New England Journal of Medicine, further propose that women are at greater risk for residual daytime impairment following nighttime use of zolpidem. The agency has accordingly required a 50% reduction in recommended zolpidem dosage for adult women compared to adult men. At a later time we will consider whether medical or scientific evidence actually establishes an increased risk associated with zolpidem use among women. Here we will consider the more global question of whether the risk of impaired driving from not using a hypnotic medication actually exceeds the risk of using the medication. Sleep deprivation itself – hypnotic drugs aside – is of medical and public health concern. Insufficient sleep causes unintended and unwanted daytime sleepiness, reduced alertness, and an increased risk of unsafe automobile operation (see path a on the right side of Figure 1). With appropriate use and a “just right” dose, hypnotic drugs have the potential to improve the duration and quality of sleep (path b). The link between sleep deprivation and daytime drowsiness is interrupted (path c), daytime alertness is restored (path d), and the probability of safe driving is increased. A hypnotic medication ideally will shorten the time to sleep onset, reduce nocturnal awakenings, prolong total sleep duration, and yield “restorative” sleep. At the same time, the probability of residual daytime sedative and performance-impairing effects should be minimal or zero. Favorable effects on sleep, as well as residual sedative effects, will depend on the dose of the medication as well as its pharmacokinetic properties – rate of absorption, extent of distribution, and elimination half-life. Individual sensitivity, duration of treatment, and other co-ingested medications are other critical factors that influence therapeutic response and adverse reactions. Given the overall biomedical complexity, the “just right” dose may not be straightforwardly predictable, and in fact complete attainment of the ideal therapeutic result may not be realistically possible. In any case, if the dose turns out to be “too much” for a given patient, therapeutic benefits on sleep are outweighed by residual daytime drug effects, and the medication itself may be the cause of daytime drowsiness and impaired driving (path e). This risk can be diminished or eliminated altogether by using a dose that is too small to be clinically effective or, in the extreme, by using nomedication at all (path f), in which case the FDA, Clinical Pharmacology in Drug Development 3(3) 167–169 © 2014, The American College of Clinical Pharmacology DOI: 10.1002/cpdd.127