Sedative hypnotics, intermediate-acting benzodiazepine receptor agonists

These agents have been the hypnotics of choice for many years because of their relative safety compared with the barbiturates. By binding to specific subunits of GABA_A receptor sites, these agents appear to potentiate the effects of GABA and facilitate inhibitory GABA neurotransmission by increasing the frequency of chloride channel opening. The older sedative hypnotics have prolonged half-life with an increased risk for next day sedation, daytime psychomotor impairment, and an increased risk for abuse and dependence.

Useful in sleep-onset insomnia.

Estazolam (ProSom)

Intermediate acting with slow onset of action and long duration; good agent for sleep-maintenance insomnia.

Temazepam (Restoril)

Short to intermediate acting with longer latency to onset and half-life; may be more helpful in sleep-maintenance insomnia.

Tricyclic antidepressants

Drugs in this category are not FDA approved treatment of insomnia, and there have been no randomized placebo controlled trials demonstrating efficacy for insomnia.

Amitriptyline (Elavil)

Tricyclic antidepressant with sedative effects. Inhibits reuptake of serotonin and/or norepinephrine at presynaptic neuronal membrane, which increases concentration in CNS.

Doxepin (Adapin, Sinequan)

Increases concentration of serotonin and norepinephrine in the CNS by inhibiting their reuptake by presynaptic neuronal membrane. These effects are associated with a decrease in symptoms of depression.

Nortriptyline (Aventyl HCl, Pamelor)

Has demonstrated effectiveness in the treatment of chronic pain.
By inhibiting the re-uptake of serotonin and/or norepinephrine by the presynaptic neuronal membrane, this drug increases the synaptic concentration of these neurotransmitters in the CNS.
Pharmacodynamic effects such as the desensitization of adenyl cyclase and downregulation of beta-adrenergic receptors and serotonin receptors also appear to play a role in its mechanisms of action.

Non-tricyclic antidepressants

The side effect of drowsiness seen with some antidepressants can be used to benefit the patient in the treatment of sleep-maintenance insomnia or insomnia associated with depression.

Trazodone (Desyrel)

Nontricyclic antidepressant with short onset of action; consolidates sleep. Antagonist at 5-HT2 receptor and inhibits reuptake of 5-HT. Also has negligible affinity for cholinergic and histaminergic receptors.

Nefazodone (Serzone)

Withdrawn from market in May 2004 due to hepatotoxicity risk. Inhibits serotonin reuptake and is potent antagonist at type 2 serotonin (5-HT) receptor. Also has negligible affinity for cholinergic, histaminic, or alpha-adrenergic receptors.

Antidepressant, alpha-2 antagonists

This drug is not an FDA approved treatment for insomnia, and no randomized, placebo-controlled trials have demonstrated its efficacy for insomnia.

In patients with depression, the sedative properties of the drug may help with sleep-onset insomnia.

Mirtazapine (Remeron, Remeron SolTab)

Exhibits both noradrenergic and serotonergic activity. In cases of depression associated with severe insomnia and anxiety, shown to be superior to other SSRI drugs.

Selective melatonin agonists

Indicated for insomnia characterized by difficulty with sleep onset.

Ramelteon (Rozerem)

Melatonin receptor agonist with high selectivity for human melatonin MT₁ and MT₂ receptors. MT₁ and MT₂ are thought to promote sleep and be involved in maintenance of circadian rhythm and normal sleep-wake cycle. Stimulation of the MT1 receptor in the suprachiasmatic nucleus (SCN) inhibits neuronal firing (reduces alerting affect of the SCN) and stimulation of the MT2 receptor in the SCN affects the circadian rhythm causing a phase advance (earlier sleep time).
Ramelteon has a short half-life of 1-2.6 hours. Its active metabolite M-II has a half-life of 2-5 hours. It has a 3-5 times greater affinity for the melatonin receptor and is up to 17 times more potent than melatonin.

Sedative Hypnotics, Nonbenzodiazepine Receptor Agonists

These agents have a nonbenzodiazepine structure and bind more specifically to the alpha 1 subunit of the GABA _Areceptor, which is associated with sedation. This class of drugs is called nonbenzodiazepine receptor agonists. They are excellent choices for treatment of sleep-onset insomnia.

Both eszopiclone and zolpidem-CR are effective for both sleep-onset and sleep-maintenance insomnia, with a reduced abuse potential and long-term efficacy up to 6 months as compared with nonselective benzodiazepine receptor agonists.

Zaleplon (Sonata)

Sedative-hypnotic of pyrazolopyrimidine class; rapid onset of action with ultra-short duration of action; good choice for treatment of sleep-onset insomnia. Second dose can be used during middle of night without residual sedation in morning (believed to be an advantage of this hypnotic over others).

Zolpidem (Ambien, Ambien CR)

Sedative-hypnotic of imidazopyridine class; has rapid onset and duration of action; good first choice for treatment of sleep-onset insomnia; has no significant residual sedation in morning. The extended-release product (Ambien CR) consists of a coated 2-layer tablet and is useful for insomnia characterized by difficulties with sleep onset and/or sleep maintenance. The first layer releases drug content immediately to induce sleep; the second layer gradually releases additional drug to provide continuous sleep.

Eszopiclone (Lunesta)

Nonbenzodiazepine hypnotic pyrrolopyrazine derivative of the cyclopyrrolone class. The precise mechanism of action is unknown but is believed to interact with GABA-receptor at binding domains close to or allosterically coupled to benzodiazepine receptors. Indicated for insomnia to decrease sleep latency and improve sleep maintenance. Short half-life of 6 h. Higher doses (ie, 2 mg for elderly adults and 3 mg for nonelderly adults) are more effective for sleep maintenance, whereas lower doses (ie, 1 mg for elderly adults and 2 mg for nonelderly adults) are suitable for difficulty in falling asleep.

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

Treatment Of Insomnia

Medical Care

Practical management of insomnia

Even when comorbid causes of insomnia (ie, medical, psychiatric) are treated, variable degrees of insomnia persist that require additional interventions.

• The management of insomnia depends upon its etiology. However, even comorbid insomnia can benefit from cognitive behavioral therapy and a short-term course of a sedative-hypnotic or melatonin receptor agonist.
  • If the patient has a comorbid medical, neurologic, or sleep disorder, treatment should be directed at that disorder.
  • In the case of a psychiatric disorder (eg, depression or anxiety), treatment should be directed at the disorder. This may involve medications, psychotherapy, and, if possible, referral to a psychiatrist, psychologist, or therapist. A short-term sedative-hypnotic in conjunction with an antidepressant can be beneficial.
  • If the insomnia is related to medication or drug abuse, the offending medication or drug must be slowly tapered and withdrawn.
• The treatment of primary insomnia begins with education about the sleep problem and appropriate sleep hygiene measures (elements of good sleep hygiene are described in Patient Education).
• Before instituting therapy, most patients are asked to maintain a sleep diary for 2-4 weeks (see Sleep diary). This gives the physician a clearer picture of the degree of sleep disturbance and allows him or her to better tailor the treatment.

Cognitive behavior therapy (CBT)

CBT is a group of techniques that regardless of predisposing or precipitating factors is used to ameliorate factors that perpetuate or exacerbate chronic insomnia, such as poor sleep habits, hyperarousal, irregular sleep schedules, inadequate sleep hygiene, and misconceptions about sleep and the consequences of insomnia. While CBT is most effective for primary insomnia, it can also be effective for comorbid insomnia as adjunctive therapy.

CBT consists of the following components:

• Sleep hygiene education addresses behaviors that are incompatible with sleep (eg, caffeine or alcohol use, environmental noise, room temperature, watching TV in bed) (see Patient Education).
• Cognitive therapy: The patient is educated to correct inaccurate beliefs about sleep and to reduce catastrophic thinking and excessive worrying about the consequences of failing to obtain adequate sleep.
• Relaxation therapy: In progressive relaxation, the patient is taught to recognize and control tension through a series of exercises that consist of first tensing and then relaxing each muscle group in a systematic way.
  • Guided imagery and meditation teach the patient how to focus on neutral or pleasant targets in place of racing thoughts.
  • Biofeedback techniques can also be used. These techniques have the advantages of providing the patient with immediate feedback regarding his or her level of tension and rapidly teaching the patient how to relax.
• Stimulus control therapy: This works to reassociate the bed with sleepiness instead of arousal. Rules for its use include the following:
  • Use the bed only for sleeping and sexual activity (no reading, TV, eating, or working in bed)
  • Go to bed only when sleepy.
  • If unable to fall asleep in 15-30 minutes, get out of bed to do something relaxing until sleepy; this can be repeated as often as needed.
  • Do not spend more time in bed than is needed by establishing a standard wake-up time.
  • Refrain from daytime napping.
• Sleep-restriction therapy: This is based upon the fact that excessive time in bed often perpetuates the insomnia. Limiting time in bed leads to more efficient sleep that is both consolidated and more regular and predictable. Time in bed is allowed to increase as the patient demonstrates a continuing ability to sleep in an efficient and consolidated manner. This treatment plan consists of limiting time in bed to the patient's estimated total sleep time (not less than 5 h) and increasing it by 20 minutes for a given week when the patient estimates that their sleep efficiency (SE; ratio of time asleep to time in bed) has reached greater than 85%. The amount of time in bed remains the same when the SE falls between 80 and 85%, and is decreased by 20 minutes for a given week when the SE is less than 85%. Periodic (weekly) adjustments are made until the optimal sleep duration is achieved.

Multiple, randomized, controlled trials have demonstrated the efficacy of CBT. Sleep latency, total sleep time, duration of wakefulness, and sleep quality improve compared with placebo treatment. 50-75% of patients attain clinically significant improvement. CBT also improves the absolute amount of slow-wave sleep by 30%. Six-month follow-up has shown sustained efficacy for this treatment modality. The AASM evidence-based practice parameter found that CBT (all components), as well as individual components of stimulus-control, paradoxical intention, relaxation training, and biofeedback were effective.⁷ CBT has also been shown to be better in weaning patients from hypnotics compared with tapering medications alone. Most studies of CBT used trained psychologists to work with patients over an average of 5.7 sessions over 6.5 weeks. At this time, how practical or effective this treatment can be when administered by a healthcare provider is not known.

Preliminary evidence by Morin indicated that providing written information about CBT can be helpful.⁸ In summary, CBT should be an integral component of therapy for any patient with insomnia, whether it be primary insomnia or comorbid insomnia.

Efficacy of CBT versus sedative hypnotics for primary insomnia

Several randomized trials comparing CBT against hypnotics for primary insomnia have been published. Morin and colleagues compared temazepam with CBT in older patients and found similar short-term effects, but continued efficacy after discontinuation of therapy in the CBT group only. Another study by Jacobs et al comparing zolpidem with CBT showed continued efficacy for the patients treated with CBT.⁹

A European study by Sivertsen and colleagues showed that CBT was superior to zopiclone. In fact, zopiclone was no different than placebo on 3 of 4 outcome measures.¹⁰ CBT, on the other hand, reduced total wake time by 52%, improved sleep efficiency, and increased slow-wave sleep. At 6 months, sleep efficiency was still improved with CBT. The limitation of this last study was that it only consisted of 44 older subjects using zolpicone (not available in the US). Zopiclone is a racemic mixture of an inactive and an active isomer with the active isomer equivalent to eszopiclone. Furthermore, the dose used was slightly higher than the maximal recommended dose of eszopiclone.

Efficacy of combined CBT and sedative hypnotics

Several studies have demonstrated that after 10-24 months follow-up, the CBT group demonstrated sustained benefit that wasn’t seen in the combined CBT-hypnotic group. This could be due to patients being less willing to practice CBT techniques during the initial phase if they have obtained rapid, short-term improvement of sleep with a sedative hypnotic.

In this regard, many sleep experts feel that CBT should be considered as initial therapy for primary insomnia and adjunctive therapy for secondary insomnia. A limitation of CBT is that it requires someone who is trained in CBT and requires approximately 6 sessions over 6 weeks with each session lasting at least 20-40 minutes. A study by Edinger et al showed that 4 biweekly individual treatments represents the optimal dosing of CBT. Obviously, this is not practical for most primary care or neurology specialists.¹¹ Some sleep centers have specialized behavioral medicine specialists who can administer CBT. Preliminary evidence suggests that the use of written information may be beneficial.⁸ An internet-based CBT learning program for patients is also available for a nominal cost (seeCBTforINSOMNIA.com).

[#CombinedTherapy]CBT and hypnotic medications are efficacious for short-term treatment of insomnia, but few patients achieve complete remission with any single treatment. Morin et al studied 160 adults with persistent insomnia and demonstrated that CBT used singly or in combination with zolpidem produced significant improvements in sleep latency, time awake after sleep onset, and sleep efficiency during initial therapy (all P <0.001). p =" .05)." style="font-size: 0.85em; line-height: 0; ">12

Surgical Care

No surgical intervention is warranted, unless the patient has another medical condition or sleep disorder contributing to insomnia that warrants surgical therapy.

Consultations

Primary care physicians should be able to diagnose and treat transient or short-term insomnia. Chronic insomnia is often more difficult to treat and when primary or associated with a sleep or psychiatric disorder, referral to an appropriate specialist may be indicated.

Patients should be referred to a sleep specialist in the following cases:

• If history suggests obstructive sleep apnea or restless legs syndrome/periodic leg movement disorder
• In cases of primary insomnia, particularly if it is psychophysiologic insomnia and of long duration.
• The patient requires daily or near-daily sedative-hypnotics for insomnia for 30 days or more.
• Many sleep centers have a staff psychologist who specializes in treating insomnia. The advantages include experience in cognitive-behavioral techniques and providing sleep education, greater available time for the often-frequent follow-up that is needed, and the ability to ascertain if other psychological factors are present that may need further evaluation by a psychiatrist.
• Patients with a history of depression should be treated with an antidepressant or referred to a psychiatrist based on the physician's comfort level in treating depression, the severity of depression, and the response to therapy. Furthermore, patients with a history of substance abuse or another major psychiatric disorder should also be referred to a psychiatrist.

Diet

• Avoid caffeinated beverages in the late afternoon or evening since the stimulant activity of adenosine antagonism can promote hyperarousal.
• Avoid alcohol in the evening since this can worsen sleep disordered breathing leading to frequent arousals. Furthermore, while alcohol promotes sleep early in the night, it leads to more sleep disruption later in the evening.
• Avoid large meals near bedtime, particularly in patients with gastroesophageal reflux disease or delayed gastric emptying.

Activity

Exercise in the late afternoon or early evening (at least 6 hours before bedtime) can promote sleep. However, vigorous physical activity in the late evening (<>