Medication

Pharmacology of sedative-hypnotic medications

Gamma-aminobutyric acid (GABA) is the most widely distributed inhibitory neurotransmitter in the central nervous system (CNS). The GABA_A receptor consists of 5 protein subunits arranged in a ring around a central pore. Most GABA_A receptors consist of 2 alpha, 2 beta, and 1 gamma subunits. Upon GABA_A receptor activation, chloride ions flow into the cell, resulting in neuronal hyperpolarization.

Benzodiazepine receptor agonists (BZRAs) enhance the effect of GABA by lowering the concentration of GABA required to open the GABA channel. BZRAs bind to a modulatory site on the GABA_A receptors that is distinct from the GABA binding site and changes the receptor complex allosterically to increase the affinity of the receptor to GABA, thus producing a larger postsynaptic current prolonging inhibition. Although BZRAs do not directly open the chloride channel, they modulate the ability of GABA to do so, thus enhancing its inhibitory effect.

A receptor complex subunits and sc...">

GABA_A receptor complex subunits and schematic representation of agonist binding sites.

Synaptic GABA_A receptors typically contain a γ in combination with an α₁, α₂, and α₃ subunit. Most GABA_Areceptors expressed in the CNS are α₁ β₂ γ₂, α₂ β₃ γ₂, α₃ β₃ γ₂, α₅ β₃ γ_2. While GABA binds at the junction between subunits α and β, BZRAs bind at the interface between α and γ. The alpha subunits of the GABA_Areceptor mediate sedative, amnestic, anxiolytic, myorelaxant, ataxic, and sedative effects. GABA_A receptors containing the α₁ subunit mediate the sedative-hypnotic and amnestic effects and, to some degree, the anticonvulsant effects of BZRAs.

For example, studies of knockout mice that express a benzodiazepine insensitive α₁ subunit fail to show the sedative, amnestic effects of diazepam. The nonbenzodiazepine receptor agonists (ie, zaleplon, zolpidem, eszopiclone) have relative selectivity for GABA_A receptors containing the α₁ subunit, thereby producing fewer adverse effects (ie, ataxia, anxiolytic, myorelaxation properties) than nonselective BZRAs.

A receptor subunit function(s).">

GABA_A receptor subunit function(s).

Practical medical management of insomnia

The pharmacologic treatment of insomnia has made great advances in the last 2 decades. In the early 19^thcentury, alcohol and opioids were used as sleeping medications. In the late 19^th century, chloral hydrate and alcohol were used in combination “Mickey Finn,” and in the early 20^th century, barbiturates were used until the early 1960s when benzodiazepine receptor agonists (BZRAs) were first FDA-approved for the treatment of insomnia (flurazepam and quazepam).

Typically, BZRAs include long-acting forms (flurazepam and quazepam that are rarely used today for insomnia because of daytime sedation, cognitive impairment, and increased risk for falls in elderly patients); intermediate-acting forms (temazepam, estazolam) and short-acting (triazolam). BZRAs were commonly used until the 1980s, when concerns about tolerance, dependence, and daytime side effects were recognized as major limitations of these agents, particularly those with long elimination half lives. Temazepam is still used for a short-term course (ie, days to 1-2 w).

Subsequently, in the 1990s, antidepressants were widely used for primary insomnia, and they continue to be widely used, despite the fact that no randomized controlled trials have demonstrated their efficacy in treating primary insomnia.

Sedative-hypnotic medications do not cure insomnia, but they can provide symptomatic relief as sole therapy or as an adjunct with cognitive behavioral therapy (CBT). Furthermore, some patients cannot adhere or do not respond to CBT and are candidates for these agents, particularly NBRAs. The most appropriate use of BZRA drugs is for transient and short-term insomnia in combination with nonpharmacologic treatment. Most authorities now agree that they should infrequently be the only therapy for chronic insomnia.

In the past, most studies of the efficacy of sedative-hypnotics had been short-term trials, generally less than 4 weeks. However, recent studies have indicated that nonbenzodiazepine benzodiazepine receptor agonists (NBBRAs) have long-term efficacy for 6-12 months without the development of tolerance. Eszopiclone was the first sedative-hypnotic to be tested over a 6-month period.¹³ This study showed continued efficacy over the 6-month period. Recent evidence shows continued efficacy at 12 months.

More recently, Krystal et al showed long-term efficacy and safety of zolpidem-CR for 6 months in a double-blind, placebo-controlled trial.¹⁴ A multicenter, randomized, placebo-controlled trial of long-term (6 mo) eszopiclone showed improved quality of life, reduced work limitations and reduced global insomnia severity.¹⁵ In summary, eszopiclone and zolpidem are believed to be less habit forming than benzodiazepines and, therefore, represent important advances in the long-term treatment of chronic insomnia.

Zolpidem can be dosed at 5 or 10 mg at bedtime for sleep-onset insomnia, and zolpidem-controlled release at doses of 6.25 mg or 12.5 mg can be used for patients with sleep maintenance insomnia or patients with both sleep onset and maintenance insomnia. Eszopiclone has a half-life of 5-7 hours, and can be used for sleep-maintenance insomnia. It can be used starting with either a 2 mg or 3 mg dose at bedtime or a 1 mg starting dose in elderly or debilitated patients. Zaleplon has a very short half-life of 1 hour and is indicated for sleep-onset insomnia at doses ranging from 5-20 mg. It can also be used for sleep-maintenance insomnia if taken at the time of awakening during the night. However, the patient should allow at least 4 hours for remaining sleep to avoid possible daytime sedation.

Intermediate-acting BZRAs, such as temazepam, are still sometimes used in a short course at a dose of 15-30 mg at bedtime.

Some general precautions should be followed for the use of sedative-hypnotics, as follows:

• Therapy should be instituted and maintained with the smallest effective dose.
• Nightly use should be discouraged in most patients.
• It can be used for 3-4 weeks, however, the need for long-term use needs to be assessed on a regular basis.
• A hypnotic free of residual effects in the morning is preferable (eg, zolpidem, zaleplon, triazolam, eszopiclone, ramelteon).
• Hypnotics with a rapid onset of action, such as zolpidem, zaleplon, triazolam, and eszopiclone, are preferable when the problem is falling asleep. If the problem is staying asleep, a hypnotic with longer actions, such as zolpidem-CR or eszopiclone, can be used. Alternatively, zaleplon can be used for sleep maintenance insomnia with a dose given at the time of awakening as long as the time for remaining sleep is at least 4 hours in duration. If the patient is depressed, an antidepressant with sedative properties, such as trazodone or mirtazapine, may be useful.
• Hypnotics should never be used with alcohol since this can produce excess sedation or the development of parasomnias.
• In general, pregnancy is a contraindication.
• Benzodiazepines should be used with caution in patients with mild sleep apnea and avoided in patients with known or suspected moderate to severe sleep apnea since they can worsen sleep apnea or render their usual continuous positive airway pressure (CPAP) settings less effective.
• Smaller doses should be used in elderly patients, and used very cautiously, if at all, in patients with gait disorders or a history of recurrent falls.
• In most patients, the risk of dependency is low (most rarely escalate the dose or use more frequently than prescribed). However, avoid use in patients with a history of substance abuse.
• Rebound insomnia may develop when the medication is withdrawn abruptly in some patients. This is more likely to occur with large doses, short-acting agents, and long-term use. Using smaller doses and tapering the drug can avoid rebound insomnia.

Sedating antidepressants

Although there is a paucity of clinical data for the treatment of primary insomnia without mood disorders, sedating antidepressants are still sometimes used. Many clinicians believe that sedating antidepressants have fewer side effects that NBZRAs; however, this is not the case. Sedating tricyclic antidepressants, such as amitriptyline, nortriptyline, and doxepin and the tetracyclic drug mirtazapine have been used. Tricyclic drugs and mirtazapine can cause daytime sedation, weight gain, dry mouth, postural hypotension, and cardiac arrhythmias. Trazodone can cause priapism in men, daytime sedation, and hypotension.

Melatonin has become a popular over-the-counter sleep aid. Melatonin is a naturally occurring hormone secreted by the pineal gland. The concentration of melatonin is highest in the blood during normal times of sleep and lowest during normal times of wakefulness. The general consensus is that melatonin given during normal waking hours has hypnotic properties. However, the timing of evening administration is critical as to whether a hypnotic effect occurs. Melatonin given early in the evening appears to increase sleep time; however, administration 30 minutes before a normal bedtime has not resulted in a decreased sleep latency or an increase in sleep time.

However, studies of melatonin in individuals with chronic insomnia have not demonstrated objective changes in patient sleep habits or changes in mood or alertness the day after treatment. In addition, a dose-response relationship has not been determined. OTC melatonin is also sold at doses much higher than those that naturally occur in the blood. Therefore, at this time, most authorities do not recommend melatonin for the treatment of chronic insomnia.

Melatonin receptor agonists

Ramelteon is a specific melatonin receptor agonist that binds to the melatonin MT1 and MT2 receptors. It has a half-life of 1-3 hours. The MT1 receptor attenuates the alerting signal of the suprachiasmatic nucleus (SCN) clock and the MT2 receptor phase shifts (advances) the SCN clock to promote sleep. Controlled trials have shown a decrease in sleep latency, but no change in wake time after sleep onset. This medication is suited for patients with sleep-onset insomnia, and particularly for elderly patients with gait disorders who have an increased fall risk and in patients with a history of substance abuse.

The typical starting dose is 8 mg prior to bedtime. It is effective for sleep-onset insomnia and not for sleep maintenance insomnia.

Common OTC remedies ¹⁶

First generation H1-receptor antagonists (eg, diphenhydramine, hydroxyzine, doxylamine) are not indicated for the treatment of insomnia. Antihistamines are the major ingredient of OTC sleep aids and are the ingredient in cold and sinus formulas sold as bedtime-use medications. While H1-receptor antagonists have sedative effects in healthy individuals, no study has established a dose range over which the hypnotic effect is effective in patients with insomnia. Thus, their regular use in individuals with insomnia is not advised. These agents may have some subjective benefit, but long-term efficacy has not been demonstrated and they are not recommended.

Studies of melatonin can reduce sleep latency in patients with circadian rhythm disorders but have conflicting efficacy in primary insomnia. Herbal remedies, such as chamomile and St. Johns Wort, have also not shown efficacy for insomnia with the exception of valerian root where some evidence suggests some benefit. Furthermore, potential risks were associated with the use of some OTC remedies such as dogwood, kava kava, alcohol, and l-tryptophan.¹⁶