Benzodiazepine hypnotics can be categorized into three groups based on their pharmacokinetic characteristics: short-acting, intermediate-acting, and long-acting. Short-acting benzodiazepines such as triazolam (Pfizer’s Halcion, generics) generally have elimination half-lives of 6 hours or less; intermediate-acting benzodiazepines such as temazepam (Mallinckrodf s Restoril, generics), oxazepam (Wyeth’s Serax / Serepax, Boehringer-Ingelheim’s Adumbran, generics), and lormetazepam (Wyeth’s Loramet, Schering’s Noctinamid, generics) have elimination half-lives of 6 to 12 hours; and long-acting benzodiazepines such as lorazepam (Biovail’s Ativan, Wyeth’s Tavor / Temesta / Wypax, generics), flurazepam(Valeant’s Dalmane, generics), and nitrazepam (Valeant’s Mogadon, generics) have half-lives exceeding 12 hours. (Note: Flurazepam is classified as long-acting because of the extended half-life of its active metabolite.)
Short-acting benzodiazepine hypnotics are rapidly absorbed and eliminated and so are particularly useful for treating sleep-onset insomnia (i.e., difficulty falling asleep) and are virtually devoid of residual next-day sedative effects. However, short-acting agents have the notable disadvantage of being associated with rebound insomnia if treatment is suddenly withdrawn. Longer-acting benzodiazepines, by contrast, tend to be more slowly absorbed and eliminated and therefore have less of a beneficial effect on sleep latency but greater efficacy in maintaining sleep throughout the night. They also have less of a tendency than short-acting agents to induce rebound insomnia. However, longer-acting agents also cause more unwanted residual effects (e.g., daytime sleepiness, dizziness Aight headedness, cognitive impairment) than short-acting agents because they remain in the system longer.
All benzodiazepines in current clinical use alter sleep architecture and, with prolonged administration, reduce the quantity and quality of rapid eye movement and slow-wave (non-rapid eye movement stages 3 and 4) sleep. Researchers believe this deficit may contribute to the “hangover” effect experienced by many patients taking benzodiazepine hypnotics; they hypothesize that the disruption in sleep architecture caused by the benzodiazepines leads to unrefreshing sleep and, in some patients, memory impairment, that ultimately prove detrimental to daytime functioning. In contrast, abrupt withdrawal of a benzodiazepine can lead to the opposite effect — specifically, prolonged rebound in rapid eye movement sleep (i.e., increased time in rapid eye movement sleep), which can be associated with unpleasant dreams and anxiety upon awakening.
Traits that have marred the reputation of benzodiazepines, especially over the last decade since the introduction of the non-benzodiazepine hypnotics (discussed earlier), include their propensity to induce tolerance and physical dependence. Benzodiazepines can produce a feeling of pleasure or a “high” that leads to drug-seeking behavior in some individuals, especially those with addictive personalities (e.g., alcoholics, drug abusers). They can also lead to tolerance in some individuals, leading to the requirement of steadily increasing doses to obtain the desired therapeutic effect. This effect is why all benzodiazepine hypnotics are classified as controlled substances, meaning that they have the potential to lead to dependence and abuse; this status limits the frequency and duration of prescriptions for these agents.
Other adverse events reported with traditional benzodiazepines include retrograde amnesia, mood changes, decreased cognitive function, and impairment of reaction times. benzodiazepines are also associated with several clinically significant interactions with other prescription drugs (e.g., certain antidepressants) and alcohol that can produce either inhibitory or facilitatory actions on the hypnotic effect of the benzodiazepines. Finally, benzodiazepines must be administered with caution in patients with respiratory impairment (e.g., chronic obstructive pulmonary disease, upper airway resistance syndrome, sleep apnea syndrome) because they have been shown to worsen such conditions.
Mechanism of Action
Benzodiazepines act nonselectively at two central receptor binding sites — benzodiazepine type-1 (or omega 1) and benzodiazepine type-2 (or omega 2) — located on the gamma aminobutyric acid-A receptor complex (but in different areas of the central nervous system). Activation of these receptors facilitates the binding of the endogenous transmitter GAB A and the subsequent opening of chloride channels; benzodiazepines thus have agonistic actions. Gamma aminobutyric acid-A activation results in increased inhibition of activating neuronal inputs to the ascending reticular activating system. Researchers suspect that the hypnosedative action of benzodiazepines results from their activity at benzodiazepine-1 receptors and that these agents’ action at benzodiazepine-2 receptors mediates their negative effects on psychomotor performance and memory, as well as their habit-forming effects.
Triazolam (Pfizer’s Halcion, generics) is a short-acting benzodiazepine that has been marketed for the short-term treatment of insomnia for more than 20 years. The drug is available in all major markets except the United Kingdom, where it was withdrawn from the market in the late 1990s because of safety issues (i.e., reports of transient global amnesia, or “blackouts,” occurring up to 11 hours after the drug was taken). Because of the availability of newer and safer short-acting alternatives (i.e., zolpidem, zopiclone, and zaleplon), triazolam is no longer widely prescribed for the treatment of insomnia.
Like other traditional benzodiazepines, triazolam elicits its hypnotic activity by binding nonselectively at the benzodiazepine-1 and benzodiazepine-2 binding sites located on the gamma aminobutyric acid-A receptor complex. The drug’s efficacy in treating insomnia reflects its clinical pharmacology in the sense that its rapid absorption leads to a notable reduction in sleep latency; however, after several days of use, no significant differences in terms of side effects and clinical efficacy are found between triazolam and longer-acting benzodiazepines such as temazepam and flurazepam, despite differences in half-lives. Nevertheless, investigators suspect that triazolam’s short half-life (two to three hours) does, in fact, give the drug a higher incidence of rebound insomnia following discontinuation compared with longer-acting benzodiazepines, even after only brief, intermittent use. In addition, triazolam has been associated with all of the standard drawbacks of other traditional benzodiazepines (e.g., tolerance, dependence, memory impairment, cognitive impairment). These drawbacks now preclude the use of triazolam as a first-line prescription hypnotic in favor of one of the newer non-benzodiazepine hypnotics.
Temazepam (Mallinckrodt’s Restoril, generics) (), one of the minor metabolites of diazepam (Roche’s Valium, generics), is an intermediate-acting benzodiazepine that, like triazolam, has been marketed for the short-term treatment of insomnia for more than 20 years. Temazepam is classified as an intermediate-acting benzodiazepine because its mean elimination half-life is eight to nine hours.
Like other traditional benzodiazepines, temazepam elicits its hypnotic activity by binding nonselectively at the benzodiazepine-1 and benzodiazepine-2 binding sites located on the gamma aminobutyric acid-A receptor complex. In clinical trials in insomniacs, temazepam has been shown to significantly improve overall sleep quality (i.e., sleep latency, sleep duration, and nocturnal and early morning awakenings) compared with placebo and has a low occurrence of side effects. It has also shown hypnotic efficacy comparable to zopiclone in several small trials in insomniacs. However, like other traditional benzodiazepines, temazepam carries the potential for physical dependence and abuse and, like triazolam, can cause rebound insomnia when abruptly discontinued. It can also cause residual sedation and dizziness — more so than the newer, shorter-acting non-benzodiazepine hypnotics such as zolpidem and zaleplon. Nevertheless, temazepam is still frequently prescribed in certain countries, despite the availability of the newer non-benzodiazepine hypnotics. This is particularly true in the United States and the United Kingdom, where temazepam is prescribed more frequently than any other traditional benzodiazepine for the treatment of insomnia.
Flurazepam (Valeant’s Dalmane, generics) is a long-acting benzodiazepine that has been marketed for the treatment of insomnia for more than 30 years. It is classified as a long-acting benzodiazepine because of the extended half-life (40-100 hours) of its major active metabolite, Nl-desalkylflurazepam. In clinical studies, flurazepam has been shown to have a cumulative effect over several nights of use as well as a lasting hypnotic effect for one or two nights following discontinuation, supporting a long therapeutic half-life. Like other traditional benzodiazepines, flurazepam elicits its hypnotic activity by binding nonselectively at the benzodiazepine-1 and benzodiazepine-2 binding sites located on the gamma aminobutyric acid-A receptor complex. Numerous clinical studies support flurazepam’s efficacy in improving sleep duration and overall quality of sleep in individuals with insomnia. However, flurazepamis generally less effective than some of the shorter-acting benzodiazepine and non-benzodiazepine hypnotics in reducing sleep latency. Several studies also show that flurazepam causes a significant “hangover” effect (e.g., daytime sleepiness, impaired coordination) at the standard 30 mg dose. The most common side effects associated with flurazepam are daytime drowsiness, dizziness, and headache; these occur infrequently and generally decrease in frequency and intensity after several days of therapy.
Like most other traditional benzodiazepines, flurazepam is not as widely prescribed by physicians as are the newer, non-benzodiazepine hypnotics. This is primarily because of the drug’s higher propensity to cause residual next-day impairment and because of its association with the standard drawbacks of all of the older benzodiazepines — specifically, the potential for physical dependence and abuse with long-term use.