The Evolution and Development of Insomnia Pharmacotherapies

The National Institutes of Health (NIH) 2005 State of the Science Conference on the Manifestations and Management of Chronic Insomnia in Adults panel report concluded that insomnia is a problem, at least occasionally, for approximately 30% of adults in the general population, that insomnia is a chronic problem for about 10% of adults, and that in clinical settings the insomnia prevalence is roughly 50%.¹ The report reinforced the view that insomnia should be appreciated as more than just a nighttime nuisance, but rather a condition that also affects daytime functioning, quality of life, and other mental and physical health outcomes.²

Insomnia sometimes is described as a contemporary problem resulting from modern-day societal stressors. However, it is hard to imagine that famine, warfare, pestilence, and other health concerns have not contributed to insomnia throughout the history of mankind. No doubt, processes of psychological conditioning also have perpetuated chronic insomnia throughout human history. People likely have sought relief with a wide assortment of substances. Fermented beverages have been available for millennia and alcohol remains a popular, though problematic, choice in the attempt to achieve improved sleep. Likewise, the sedative properties of opium were noted in ancient writings.

With the Industrial Revolution came a variety of compounds that were packaged and marketed as sleep aids. While the effects of opium were known for thousands of years, it became a patent medicine product in the 1800s when it was combined with alcohol and sold as laudanum. Although an efficacious hypnotic, there were serious safety problems, including dependency and respiratory depression. Label prescribing guidelines included doses for infants and young children, and many deaths were associated with its use. Chloral hydrate, another abusable sedating medicine employed to induce sleep, became widely used beginning in the mid-19th century. Barbiturates were developed in the early 20^th century and remained the primary prescribed hypnotic medications until the 1960s. Other past hypnotics included glutethimide, ethchlorvynol, paraldehyde and bromide preparations. All of these substances have had reasonable efficacy in promoting sleep, but there have been serious safety concerns with each medication. The evolution of insomnia treatment with pharmaceutical approaches in recent decades primarily has been manifest in major improvements in safety.

This review will focus on the pharmacological characteristics and clinical value of the medications and related substances that currently are used with the intention of helping with difficulty falling asleep or remaining asleep. The efficacy of these compounds ranges from negligible to well established, and several have significant safety issues. Compounds recommended for insomnia include widely available unregulated substances and over-the-counter (OTC) medications, as well as prescription medicines that are used either off-label or with a US Food and Drug Administration (FDA) approved indication for the treatment of insomnia. Currently the only medications approved for the treatment of insomnia are benzodiazepine receptor agonist hypnotics and a selective melatonin receptor agonist.

UNREGULATED SUBSTANCES

Dietary supplements, herbal compounds, and homeopathic preparations often are promoted as sleep aids. Ingredients may include valerian, kava-kava, hops, lavender, passion flower, skullcap, and melatonin. Since they are not regulated by the FDA, there may be variability in the purity of concentration of these products. Few efficacy studies have been performed with these substances and none has demonstrated convincing benefits in improving sleep. Although these products generally are regarded as safe, most have not been thoroughly evaluated regarding adverse events or interactions with other substances or medications. In fact, the FDA has issued a safety warning regarding reports of liver toxicity with kava-kava. The 2005 NIH chronic insomnia state-of-the-science panel report specifically noted the inadequate efficacy evidence for all compounds in this class.¹

REGULATED OTC SLEEP AIDS

The OTC sleep aids that are regulated by the FDA are all antihistamines. Most of these products contain diphenhydramine, although some have doxylamine as the active ingredient. The antihistamine sleep aids are available alone or in combination with analgesics. Although they may be sedating initially, tolerance to the sedating effects of these compounds may occur.³ The relatively long elimination half-life may lead to next-morning grogginess following bedtime use. Post-synaptic muscarinic receptor blockade may result in anticholinergic side effects, including dry mouth, blurred vision, constipation, urinary retention, confusion, and delirium, especially when coadministered with other medications with anticholinergic effects. In reviewing the antihistamine sleep aids, the recent NIH chronic insomnia state-of-the-science panel noted the lack of systematic efficacy evidence and the significant safety concerns and risks.¹

PRESCRIPTION OFF-LABEL MEDICATIONS

Medications from several different psychotropic classes indicated for other disorders sometimes are prescribed on an off-label basis with the primary intention of promoting sleep and treating insomnia.⁴ Patients with comorbid psychiatric disorders may experience improved sleep from sedating antidepressants, antipsychotics, and mood stabilizers. However, individuals without psychiatric disorders are exposed to a less favorable risk-benefit ratio when prescribed these medications solely for the treatment of insomnia. The practice is complicated by the paucity of insomnia treatment efficacy data and safety evaluation with these medications in non-psychiatric populations.

An analysis of 2002 prescribing practices in the US found that 3 of the top 4 medications prescribed for insomnia were antidepressants—trazodone, amitriptyline, and mirtazapine.⁴ Among the problems patients may experience with certain sedating antidepressants are daytime residual sedation, orthostatic hypotension, cardiac arrhythmias, and anticholinergic effects. Trazodone has the added risk of priapism, and it may also contribute to the serotonin syndrome when coadministered with other serotonergic medications. Only two relatively short-term insomnia efficacy trials with trazodone in non-depressed patients have been performed, and these have not demonstrated continued benefits in improving sleep. The NIH chronic insomnia panel noted that “all antidepressants have potentially significant adverse effects, raising concerns about the risk-benefit ratio.”¹

The risk-benefit ratio problem is even more pronounced with the use of sedating antipsychotic medications to treat insomnia in patients with no psychiatric comorbidity. Atypical antipsychotics, such as quetiapine, sometimes are prescribed as first-line agents to treat insomnia in non-psychiatric patients. While the exposure to potential acute and chronic adverse effects may be appropriate in patients with psychotic and related disorders, this may not be the case with insomnia patients in the general population. The NIH chronic insomnia panel stated that “all of these agents have significant risks, and thus their use in the treatment of chronic insomnia cannot be recommended.”¹

FDA-APPROVED INSOMNIA TREATMENT MEDICATIONS

Currently the FDA-approved insomnia treatment medications include several benzodiazepine receptor agonists and one selective melatonin receptor agonist.⁵ These medications can be differentiated based upon their mechanisms of action, pharmacokinetic and pharmacologic characteristics, potential adverse effects, specific indications, and Drug Enforcement Administration (DEA) scheduling (Table 1).

Table 1.

US FDA-Approved Insomnia Treatment Medications⁵

Medication	Brand Name	Available Doses (mg)	Elimination Half-Life (hr)	DEA Schedule
Benzodiazepine Receptor Agonists
Immediate-Release Benzodiazepines
Estazolam	ProSom	1, 2	8 – 24	IV
Flurazepam	Dalmane	15, 30	48 – 120	IV
Quazepam	Doral	7.5, 15	48 – 120	IV
Temazepam	Restoril	7.5, 15, 22.5, 30	8 – 20	IV
Triazolam	Halcion	0.125, 0.25	2 – 4	IV
Immediate-Release Nonbenzodiazepines
Eszopiclone	Lunesta	1, 2, 3	5 – 7	IV
Zaleplon	Sonata	5, 10	1	IV
Zolpidem	Ambien	5, 10	1.5 – 2.4	IV
Modified-Release Nonbenzodiazepines
Zolpidem ER	Ambien CR	6.25, 12.5	2.8 – 2.9	IV
Selective Melatonin Receptor Agonist
Ramelteon	Rozerem	8	1 – 2.6	None

Benzodiazepine Receptor Agonists

Benzodiazepine medications became available in the 1960s and first were promoted for the treatment of insomnia in the early 1970s with the introduction of flurazepam. The benzodiazepine receptor agonist hypnotics approved by the FDA for the treatment of insomnia now include 5 medications that are structurally benzodiazepines and 4 formulations of newer generation nonbenzodiazepine hypnotics (see Table 1). However, other benzodiazepines, such as diazepam, lorazepam, and alprazolam also are sometimes prescribed for insomnia symptoms.⁵

All of the benzodiazepine receptor agonist hypnotics share fundamental pharmacodynamic characteristics. They function as positive allosteric modulators of gamma-aminobutyric acid (GABA) responses at the GABA_Areceptor complex. GABA is the most widespread CNS inhibitory neurotransmitter. Several different types of GABA receptors have been identified, and these may exist in different configurations. GABA_A and GABA_C receptors are ligand-gated ion channel receptors. The GABA_B type is a G protein-coupled receptor.^6,7

The GABA_A receptor has a transmembrane pentameric structure (Figure 1). The most common configuration includes 2 alpha, 2 beta, and 1 gamma subunit. The binding of GABA at its recognition site on the GABA_A receptor complex allows negative chloride ions to enter the cell through a central ion channel. The extracellular-intracellular ion balance affects the degree of membrane polarization and the likelihood of an action potential. GABA_A agonists promote greater polarization and therefore have an inhibitory effect. Benzodiazepine receptor agonists interact with an allosteric recognition site at the interface of alpha and gamma subunits in the GABA_A receptor complex. With the presence of a benzodiazepine receptor agonist, a greater number of chloride ions are able to enter the cell. Medications and other substances that enhance GABA activity may function as sedatives, muscle relaxants, anxiolytics, and anticonvulsants, as well as hypnotics. While there may be a generalized cortical sedating effect that contributes to the hypnotic action of benzodiazepine receptor agonists, there likely is an important targeted action at the ventrolateral preoptic nucleus, which is a key structure involved in the coordination of sleep and wakefulness.

Figure 1.

Structure of the GABA_A receptor^{6, 14}; BZ = benzodiazepine

Although the benzodiazepine and nonbenzodiazepine hypnotics share fundamental pharmacodynamic properties, the nonbenzodiazepine medications can be differentiated from the earlier benzodiazepines with regard to GABA_A receptor subunit subtype selectivity. Eszopiclone, zaleplon, and zolpidem all have some degree of selectivity for GABA_A receptor configurations that include the alpha-1 subtype. In contrast, the benzodiazepines do not discriminate among several of the alpha subtypes. This nonbenzodiazepine alpha-1 selectivity may contribute to the improved tolerability, decreased adverse effects, and lack of withdrawal effects on discontinuation.

The traditional benzodiazepine hypnotics include flurazepam, temazepam, triazolam, estazolam, and quazepam. The elimination half-lives of these hypnotics range from a few hours (triazolam) to a few days (flurazepam and quazepam). All are available in generic formulations, although some dosages may exist only as branded medicines. The nonbenzodiazepine hypnotics, which first became available in the US in the early 1990s with the release of zolpidem, include the 2 zolpidem formulations (immediate and extended release), zaleplon, and eszopiclone. These newer generation hypnotics also can be differentiated with regard to elimination half-life and range from about 1 hour for zaleplon to eszopiclone at approximately 5 to 7 hours, with the 2 zolpidem formulations falling between this range.⁵

All of the benzodiazepine receptor agonist hypnotics are relatively rapidly absorbed and all may be beneficial for sleep onset. The duration of action in promoting sleep will be influenced by the elimination half-life and the dose taken. Longer half-life hypnotics may provide greater efficacy with sleep maintenance; however, this must be balanced with the potential for undesirable residual sedation the following morning. Until recently, all of the hypnotics demonstrated standard pharmacodynamics with a steady decline in the blood level after reaching the maximum concentration early during the night. Controlled-release hypnotic formulations now have been developed with the goal of promoting sleep later during the night while minimizing residual morning sedation. At present, zolpidem extended release is the only hypnotic with this controlled-release approach, although others are being investigated.

Prescribing guidelines for the benzodiazepine receptor agonist hypnotics include taking the medication when the patient is going to bed. Earlier dosing may increase the risk of impairment before the patient goes to bed. Generally, patients should be prepared to spend at least 7 to 8 hours in bed after taking a hypnotic. The one exception is the very short half-life zaleplon, which should no longer be active 4 hours after ingestion. While none of these hypnotics specifically is indicated for middle-of-the-night dosing, the short half-life of zaleplon does offer greater flexibility in the timing of the dose. It is likely that hypnotics indicated for nighttime awakenings will be available in the future. Studies with alternate delivery strategies allowing very rapid onset of action have been reported, although it is unclear whether these ultimately will be approved. The current benzodiazepine receptor agonist hypnotics are all available in standard adult doses and lower doses for elderly and medically debilitated patients.

Generally, the benzodiazepine receptor agonist hypnotics are well tolerated. Adverse effects may include somnolence, headache, dizziness, nausea, diarrhea, and anterograde amnesia. Rarely patients may exhibit sleepwalking or confused behaviors within a few hours after taking a hypnotic dose. The medications in this class may be associated with a rebound insomnia of worse sleep for several nights following abrupt discontinuation. Tapering the dose may reduce the magnitude of this effect.⁵

Until 2005, all of the benzodiazepine receptor agonist hypnotics were approved with indications for the short-term treatment of insomnia. The most recently approved hypnotics in this category, eszopiclone and zolpidem extended release, no longer have the “short term” wording in the indication and therefore have no implied limitation on their duration of use. Long-term placebo-controlled efficacy studies and even longer open-label safety studies have been published. These have confirmed long-term efficacy without the development of tolerance for up to 6 months and a generally positive safety profile for up to 1 year. Recent placebo-controlled efficacy studies have included one for the nightly use of eszopiclone for 6 months and one for zolpidem extended-release as-needed use (3 to 7 tablets per week) for 24 weeks.^8,9 Safety was monitored in these long-term efficacy studies. Additionally, safety was assessed in a 6-month open-label extension following the 6-month eszopiclone efficacy trial and in a 1-year open-label zaleplon study of elderly insomnia subjects.^9,10

Another recent development with the benzodiazepine receptor agonist hypnotics has been the specific indications for sleep onset and sleep maintenance. The latency to sleep onset and total sleep time had been the standard parameters demonstrating hypnotic efficacy. They did not directly reflect the ability of a hypnotic to help maintain sleep later during the night. Wake time after sleep onset (WASO) began to be calculated as representative of sleep maintenance efficacy. The approved indications for both eszopiclone and zolpidem extended-release include sleep maintenance in addition to sleep onset.

In summary, the evolution of the benzodiazepine receptor agonist hypnotics has included the trend toward moderately short half-life medications, alpha-1 receptor selectivity, an indication supporting longer-term use when appropriate, longer-term efficacy and safety trials, specific indications for sleep onset and maintenance, and the development of controlled-release formulations. Future additions may include hypnotics specifically designed for middle-of-the-night use and some with alternate delivery systems.

Selective Melatonin Receptor Agonist

In 2005 the FDA approved ramelteon as the first insomnia treatment medication with an entirely new mechanism of action in several decades. It functions as an agonist for selected melatonin (MT₁ and MT₂) receptors, which are present in the suprachiasmatic nucleus (SCN) and play key roles in the regulation of the sleep-wake cycle. The pharmacologic and clinical characteristics, as well as the safety profile, are quite different from the previous hypnotics.¹¹

The rationale for the use of a selective melatonin receptor agonist is based in the two-process model of the regulation of the sleep-wake cycle. Two processes contribute to the experience of sleepiness and wakefulness, resulting in the normal pattern of sleep during the nighttime and waking during the day and evening. A homeostatic process represents the balance of waking and sleep. The homeostatic sleep drive accumulates during waking. Prolonged wakefulness results in excessive sleepiness. Humans require approximately 8 hours of sleep per 24-hour cycle for optimum waking functioning. Hypothetically, the homeostatic sleep drive could be satisfied with sleep at any time of the day or night; however, sleep normally occurs at nighttime. While the homeostatic process determines the amount of sleep, the circadian system optimizes sleep during the nighttime. The circadian system is biologically entrained to the photoperiod from light exposure sensed through the retina and transmitted through the retinohypothalamic tract to the SCN in the anterior hypothalamus. A complex transcription-translation feedback loop within the SCN neurons maintains the clock-like approximately 24-hour periodicity. The SCN in turn controls the activity of the pineal gland in producing and releasing melatonin into the cerebrospinal fluid and bloodstream. Typically the melatonin level is very low throughout the daytime, gradually increases as bedtime approaches, plateaus during the normal nighttime sleep period, and declines as the normal waking time approaches.¹²

The typical experience for an individual is to feel fully awake throughout the morning. This is due to the homeostatic sleep drive being satisfied by the sleep that occurred the previous night. However, the homeostatic drive for sleep increases as the day continues. People may experience a dip in alertness in the early- to mid-afternoon, but then by late afternoon or evening often will feel that they have a “second wind.” Most people are more awake and alert in the evening than at any other time throughout the 24-hour cycle. This alertness would be paradoxical just from the homeostatic perspective; however, it occurs due to the circadian arousal, which peaks late in the day and helps to offset the homeostatic sleep drive that has accumulated. As bedtime approaches the circadian arousal decreases, allowing the homeostatic sleep drive to promote a rapid sleep onset when the person goes to bed. The decrease in the circadian arousal occurs in part due to the effects of endogenous melatonin interacting with the melatonin receptors within the SCN. The melatonin cycle controlled by the SCN contributes to the robustness of the circadian cycle and its influence on the normal sleep-wake cycle. It has been shown that agonists for the MT₁ melatonin receptor subtype decreases the firing rate of the SCN neurons. Presumably this activity enhances the sleep onset process. The MT₂ receptor subtype influences the phase or timing of the circadian system. On a nightly basis, as endogenous melatonin rises it promotes sleep as well as the likelihood that sleepiness will occur again the next night at approximately the same time.

Ramelteon is an agonist for the MT₁ and MT₂ receptor subtypes and has little affinity for other melatonin binding sites.¹³ It also does not interact to a significant degree with other neurotransmitter systems. Accordingly, it has very targeted action that minimizes the potential for adverse effects. It has a greater affinity for the receptors than melatonin, and it has one active metabolite that has the same pharmacodynamic activity. Ramelteon promotes sleep through its selective melatonin receptor agonist activity. Unlike all other approved insomnia treatment medications, ramelteon does not improve sleep through a sedating effect. Therefore, there is little potential for pharmacodynamic drug interactions.

The FDA-approved ramelteon indication is for the treatment of insomnia characterized by difficulty with sleep onset. Like the recently approved benzodiazepine receptor agonist hypnotics, ramelteon has no implied limitation on duration of use. As suggested by the mechanism of action, ramelteon is able to enhance sleep onset through agonist activity by decreasing the arousal generated by the SCN. Therefore, ramelteon should be beneficial in helping people fall asleep and remain asleep during the early part of the night. Unlike the benzodiazepine receptor agonist hypnotics, which are Schedule IV controlled substances due to abuse liability, ramelteon has been shown to have no abuse potential and, therefore, is classed as nonscheduled by the Drug Enforcement Administration.

INSOMNIA PHARMACOTHERAPY AND THE FUTURE

Advancing knowledge of neural mechanisms affecting the regulation of sleep and wakefulness will foster the development of new pharmacologic strategies for the treatment of insomnia. Insomnia is a common condition with a multitude of potential causes. There may be specific genetic or acquired vulnerabilities that have key roles for subpopulations of insomnia sufferers, and for these individuals, targeted pharmacotherapeutic strategies may be possible. New general insomnia treatments with efficacy for a broad range of patients will continue to be investigated.

Scores of compounds currently are being examined as possible insomnia treatment medications. Studies range from preclinical to phase III clinical trials. Among the possibilities are an extrasynaptic GABA agonist, 5-HT_2A receptor antagonists, ultra-low-dose doxepin, orexin antagonists, neurosteroids, corticotropin-releasing factor antagonists, selective histamine H₁ receptor antagonists, and histamine H₃ agonists.

CONCLUSIONS

Compared with older insomnia treatment medications, the current generation of medications maintain efficacy, but have greatly improved safety profiles. The diversity of approved agents allows for the medication selection to be customized for individual patients depending upon their clinical histories. In recent years there have been significant advances in both pharmacodynamic and pharmacokmetic approaches in promoting improved sleep. The most recently approved insomnia treatment medications no longer have an implied limitation on their duration of use, and the indications specifically note efficacy for sleep onset and sleep maintenance. New pharmacologic approaches continue to be developed.