Drug Criteria & Outcomes

Sleep for Sale: An Evaluation of Sedative Hypnotics for the Treatment of Insomnia

By Erin Bedard, PharmD Candidate
Auburn (AL) University Harrison School of Pharmacy

Last year, 42 million prescriptions were filled for sleeping medications, more than doubling the number filled in the year 2000.1 The prescribing of these agents probably will continue to increase as the baby boomer population ages, because the elderly suffer from insomnia more often than do younger populations.

Insomnia and its impact

Insomnia is defined as difficulty falling asleep, difficulty staying asleep, or experiencing disturbed sleep patterns resulting in insufficient sleep. Insomnia affects 50-70 million Americans, is associated with many health problems (such as hypertension, obesity, and depression), and adversely affects quality of life.2,3

The costs from insomnia are extraordinary in the United States: More than $100 billion annually in direct and indirect costs, most of which is attributed to increased hospitalizations, reduced workplace productivity, motor vehicle and other accidents, and medical comorbidities.3

Pharmacological treatment options

Over-the-counter agents. Before visiting a physician for a prescription agent, many patients first turn to over-the-counter (OTC) sleep aids, most of which contain the antihistamine diphenhydramine (Benadryl®) or a similar agent. These products do effectively induce sleep, but they cause a daytime residual effect, or "hangover effect" in an estimated 50% of patients and tolerance may develop within one to two weeks with continued use.4 Furthermore, diphenhydramine is not recommended for use in the elderly due to its high anticholinergic activity. OTC aids are easily obtained, are inexpensive, and may be most appropriately used by young patients with acute insomnia. However, their disadvantages make them undesirable in many patients, especially for long-term use.

Alternative medications also may be an effective treatment for insomnia. The two most commonly used products are melatonin and valerian root.5 Melatonin is an endogenous hormone derived from tryptophan and is released by the pineal gland to regulate circadian rhythm.6 Its secretion is stimulated by darkness and is thought to increase binding of GABA to its receptors, thereby inducing sleep. Supplementation of 5 mg before bedtime may be effective for improving subjective measures associated with insomnia, but may not improve time to sleep onset or total sleep time. Use of melatonin has been studied for up to nine months and generally is well tolerated. The most common side effects include daytime drowsiness, headache, and dizziness. Melatonin should not be taken by women who are pregnant or breast-feeding, and it is unknown whether melatonin disrupts gonadal development when taken by younger adults. Melatonin also may increase insulin resistance, prolong clotting time, and increase risk for seizures, and should not be taken with fluvoxamine or nifedipine.5

Valerian root, like melatonin, is thought to improve subjective sleep measures but also may decrease time to sleep onset at doses ranging from 400 to 900 mg up to two hours before bedtime. Valerian has GABA agonist activity by possible inhibition of GABA catabolism and may bind to GABA receptors directly. Valerian is safe for short-term use up to 28 days, but long-term safety is unknown. Significant improvement of insomnia may not be seen until taken nightly for three days to four weeks. Valerian is hepatically metabolized and is an inhibitor of the cytochrome 3A4 enzyme, resulting in significant drug interactions with other medications such as the azole antifungals, statins, and macrolide antibiotics. Valerian may cause daytime drowsiness and should be tapered when discontinued to prevent withdrawal symptoms.5

Benzodiazepines. Benzodiazepines have traditionally been used for the treatment of insomnia, but carry the same disadvantages as the OTC agents such as next-day drowsiness, fatigue, headache, and lethargy.4 These side effects may be most pronounced in the elderly who are not as efficient at metabolizing the drug; in this population the effects may linger much longer than in the average patient.7 Thus, short- to intermediate-acting agents like temazepam (Restoril®) are preferred. The benzodiazepines also are associated with tolerance and rebound insomnia when discontinued following long-term administration and therefore are only appropriate for use on an as-needed basis.7

Nonbenzodiazepine GABA-A agonists. Zolpidem (Ambien®) was the first nonbenzodiazepine sedative hypnotic to be approved by the FDA and remains the most commonly prescribed hypnotic in the United States and Europe.3 Since zolpidem's release, zaleplon (Sonata®), eszopiclone (Lunesta) and zolpidem controlled release (Ambien CR) have joined this drug class (see Table 1 for comparison).

The agents in this class bind to the GABA-A benzodiazepine receptors, but have greater selectivity for specific subunits of the GABA complex, which is thought to account for the fewer adverse effects associated with this group of hypnotic agents.8 In contrast to the benzodiazepines that disrupt the restorative sleep stages, the newer agents induce sleep that has a more natural pattern and may result in a more refreshing night's sleep.8

Case reports have shown that zolpidem has the potential to cause delirium, sleepwalking, or visual hallucinations, especially in patients who discontinue use abruptly or are already taking psychotropic medications.9-11 Over the past 10 years, the Huntsville Hospital adverse drug reaction monitoring program has received similar numbers and types of reports with temazepam and zolpidem.

These newer agents can be distinguished from each other by their pharmacokinetic characteristics. Zolpidem, zaleplon, and eszopiclone have a similar onset of 30 minutes, but differ in their elimination time, or half-life.8 Zolpidem has a half-life of 2.5 hours and may be appropriate for patients with nighttime awakening.12 Zolpidem also is available in a controlled release formulation (Ambien CR). The immediate and controlled release formulations have similar half-lives, but the controlled release has biphasic absorption, releasing some of the drug immediately and then slowly releasing the remaining drug to maintain plasma concentrations for over three hours.12 Both tablets have been shown to improve sleep maintenance, and there have been no comparative trials to support the controlled release tablets over the immediate release.

Eszopiclone's half-life of six hours13 decreases sleep latency and improves sleep maintenance; however, this long half-life may cause the patient to have undesirable residual effects for up to 12 hours following administration,8 especially in patients with hepatic dysfunction. Eszopiclone, unlike the other GABA-A agonists, has been studied for long-term use up to six months.14

Zaleplon has the shortest half-life of one hour.15 This agent is most appropriate for patients with sleep onset insomnia, because the drug can induce sleep and then be quickly eliminated. Zaleplon does not increase sleep time or decrease nighttime awakenings, but patients who wake in the middle of the night can take an additional dose if at least four hours left of sleeptime remains.8 According to some studies, zaleplon may have less of an effect on memory and psychomotor function compared to zolpidem and eszolpiclone.8

Indiplon, another GABA-A agonist, has been approved by the FDA and should enter the market by the end of the 2006. Indiplon's onset of action is similar to the other nonbenzodiazepine agents, and its half-life of 1.5 hours is most similar to zaleplon. Because of its short half-life, indiplon had minimal effect on next-day functioning during clinical trials and like zaleplon can be taken during the night as long as the patient has at least four hours to sleep. Studies suggest that indiplon may be appropriate for chronic use, unlike most other agents that are only recommended for short-term treatment. Another possible benefit of indiplon is that the half-life was not prolonged in the elderly, but this finding should be studied further.16

Melatonin agonist. Ramelteon (Rozerem®) is a new agent that has a distinct mechanism of action from other sedative-hypnotics. Ramelteon is a melatonin receptor agonist for melatonin-1 and melatonin-2 receptors, which leads to its sleep-promoting action.6 Ramelteon's hypnotic effects are seen within 30-40 minutes after administration and its half-life is about 2.5 hours, leaving little potential for next-day sedation.

Studies suggest that Ramelteon may be used safely for up to one year with no evidence of rebound insomnia following discontinuation. Ramelteon has little addictive potential and is not a controlled substance, unlike the benzodiazepines and other GABA agonists.17,18

Ramelteon is metabolized by the cytochrome enzymes 1A2, 3A4, 2C9, and 2D6 leading to some important drug interactions. Ramelteon should not be used with fluvoxamine, and should be used with caution with agents such as ketoconazole, fluconazole, and fluoxetine.17

Due to the cost of ramelteon (about $80 per month), melatonin supplements might be considered for initial treatment due to the similarity in their mechanisms of action. An advantage of ramelteon compared with OTC melatonin supplements is that safety and efficacy has been studied more extensively. In addition, ramelteon is an FDA-approved product that provides consistent, reliable dosing free from impurities, which is not guaranteed with individual melatonin supplements.

Cognitive behavioral therapy

Cognitive behavioral therapy (CBT) is commonly overlooked as an available treatment, and some small studies suggest that it may be more effective than pharmacotherapy, especially in terms of long-term efficacy.19,20

In one of these studies 63 patients suffering from insomnia were randomized to receive zolpidem, CBT, a combination, or placebo and were followed for six weeks. CBT alone was found to be the most effective treatment for decreasing time to sleep onset and improving sleep efficiency, and effects were maintained at 12 months. CBT treatment consisted of many aspects including cognitive and behavioral components to improve what is commonly referred to as sleep hygiene (see Table 2 for details). The researchers of the study argue that CBT should be the first-line intervention for insomnia, because it improves insomnia, is cost-effective, and is free of adverse effects.

Conclusion and clinical application

As the baby boomer population ages, the incidence of insomnia will continue to increase, and as more and more treatment options become available, selecting an appropriate agent will be increasingly difficult. The type of insomnia (sleep onset or sleep maintenance) should be identified and the need for acute or chronic therapy should be established.

Before using pharmacotherapy, obstacles to sleep should be identified and CBT should be considered. If a patient is a candidate for pharmacological therapy, he or she should be counseled on appropriate use of the drug to maximize efficacy and limit adverse effects. In addition, the patients should be counseled on appropriate sleep hygiene.


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