Benzodiazepines are one of the most widely used drug classes for the short-term treatment of insomnia. These agents bind to gamma-aminobutyric acid (GABA) receptors in the central nervous system (CNS), causing inhibition of neuronal excitation. Benzodiazepines affect sleep by increasing total sleep time and shortening sleep latency.[9,10]
There are five benzodiazepines that are FDA approved for the treatment of insomnia, and all are schedule IV controlled substances. Recommended doses, onset and duration of action, half-life, and insomnia indication for these drugs are outlined in TABLE 1.
Benzodiazepines are safe and effective for the treatment of insomnia when used short-term at recommended doses; however, due to their mechanism of action, a number of adverse effects can occur. These may include changes in sleep architecture (mainly shortened time in both deep and rapid eye movement [REM] sleep and increased time in intermediate sleep), subsequent daytime hangover, anterograde amnesia, mental status changes, psychomotor impairment, rebound insomnia, and withdrawal symptoms upon discontinuation. Other common adverse effects include drowsiness, dizziness, and headache. Subsequent daytime hangover is particularly problematic when using benzodiazepines with long durations of action (e.g., flurazepam [Dalmane]). Long half-life agents also increase the risk for poor outcomes in elderly patients, including increased risk of drug accumulation, falls, and confusion.[8,10] Since the side effects are mostly dose related, patients should be maintained on the lowest effective dose for the shortest period of time that is necessary to treat the insomnia complaints. The choice of the agent should be patient specific; benzodiazepines should be avoided in pregnancy (Category D or X), in those with a history of substance abuse, and in sleep apnea.
Nonbenzodiazepines, also known as z-hypnotics, are a relatively new class of drugs for the treatment of insomnia. The mechanism of action of nonbenzodiazepines is similar to that of benzodiazepines but with less severe side effects. Similarly to benzodiazepines, z-hypnotics work through the potentiation of GABA, but they are more selective to the alpha1 subunit of the GABA receptor, which may be more specific for sedation and cause fewer adverse effects.[9,10] Since the approval of the first z-hypnotic in 1993, the use of benzodiazepines for the management of insomnia has declined.
There are three z-hypnotics that are FDA approved for the treatment of insomnia. Like benzodiazepines, they are schedule IV controlled substances. Recommended doses, onset and duration of action, half-life, and insomnia indication for various nonbenzodiazepines are outlined in TABLE 2.[9,10] Compared to benzodiazepines, z-hypnotics are generally associated with less rebound insomnia and potential for abuse, as well as less risk of dependency, tolerance, and hangover effect. All three z-hypnotics have different pharmacologic properties, adverse effects, and clinical activity.
Zolpidem and Extended-release Zolpidem: Zolpidem (Ambien) works mainly to induce sleep due to its relatively quick onset of action. Its duration of action may be as long as 8 hours in some patients and therefore may increase total sleep time as well. Extended-release (ER) zolpidem was FDA approved in 2005 for the treatment of insomnia that is characterized by difficulties in falling asleep and/or staying asleep. Zolpidem ER is a bilayered tablet with the first layer dissolving quickly to help with sleep onset. The second layer gradually releases active drug to help maintain sleep. An important difference is that the ER labeling does not restrict use to the short term, while FDA-approved labeling for immediate-release zolpidem is for short-term use only. These agents have not been shown to have deleterious effects on sleep architecture. The adverse effects of zolpidem and zolpidem ER are similar and include headache, drowsiness, fatigue, and dizziness. Postmarketing reports revealed that zolpidem may cause parasomnias such as sleep walking and sleep-related eating disorders.[10,15]
Zaleplon: Zaleplon (Sonata) has a rapid onset of action and a very short duration of action, making it an ideal drug for patients with insomnia characterized by difficulty with sleep onset. Due to the pharmacokinetic profile of zaleplon, there is virtually no next-day hangover effect. It can be taken within 4 to 5 hours of wake time, if needed, without the risk of next-day drowsiness, and should be taken on an empty stomach for optimal absorption. Zaleplon is not associated with tolerance or rebound insomnia and is relatively well tolerated, with the side-effect profile similar to that of placebo. Dose-dependent headache appears to be the most common complaint, although a small percentage of patients have reported CNS changes such as drowsiness, incoordination, hallucinations, dizziness, and ataxia.
Eszopiclone: Eszopiclone (Lunesta) has a rapid onset that helps improved sleep onset, as well as an intermediate duration of action that helps with sleep maintenance. In contrast to other z-hypnotics, the dose can be adjusted to the desired effect. The 1- and 2-mg doses are used to improve sleep onset, while the 3-mg dose can be used for sleep maintenance. Eszopiclone is associated with minimal rebound insomnia, withdrawal, and tolerance. It is important to note that the eszopiclone labeling does not restrict it for short-term use. The most common adverse effects include unpleasant taste, headache, and dry mouth.
Ramelteon (Rozerem) is the only FDA-approved melatoninreceptor (MT) agonist. It works by binding to the MT1 and MT2 receptors. These receptors are involved in the maintenance of circadian rhythm, which help regulate the sleep-wake cycle. Ramelteon promotes sleep by agonizing the MT1 and MT2 receptors, therefore helping to regulate the sleep-wake cycle. Recommended doses, onset and duration of action, half-life, and insomnia indication for ramelteon are outlined in TABLE 3. Ramelteon does not bind to the GABA receptors; therefore, the side-effect profile differs from that of the benzodiazepines and non-benzodiazepines. It is the only hypnotic sleep agent that is not classed as a controlled substance by the FDA, and it is well tolerated, with the most common side effects including headache, somnolence, dizziness, and fatigue. It is does not cause rebound insomnia or next-day hangover effect. Patients should be instructed to avoid taking ramelteon after a high-fat meal, as this may interfere with absorption. There is also a potential for drug interactions, because ramelteon is metabolized by CYP1A2, and it should avoided in patients with severe liver disease.
US Pharmacist © 2011 Jobson Publishing