Insomnia

Etiology and Pathophysiology

Insomnia is characterized by difficulty initiating and/or maintaining restorative sleep. Common symptoms are trouble falling asleep, difficultly staying asleep, early awakening, and intermittent wakefulness. Most insomniacs report negative daytime consequences as a result of their inability to achieve a full night’s sleep. Different types of insomnia are classified based on duration and/or cause, as follows:

• Transient insomnia — insomnia that lasts for a few days or weeks and usually results from stress, environmental changes, or temporary conditions.
• Chronic insomnia — insomnia that persists for months and may be classified as either primary or secondary:
• Primary chronic insomnia — insomnia that persists for several months and does not arise from any known cause, but rather results from internal abnormalities in mechanisms that control sleeping and waking.
• Secondary chronic insomnia — insomnia that persists for several months and arises from another underlying medical, psychiatric, behavioral, or environmental condition.

Longitudinal results from the Wisconsin Sleep Cohort Study (WSCS) — which included survey responses from more than 2,300 subjects to three sleep surveys conducted over a period of up to 12 years — suggest that approximately 45% of those who initially report insomnia symptoms (Survey 1) continue to report symptoms 5 years later (Survey 2) and 9-12 years later (Survey 3). Additionally, more than 80% of those who report insomnia symptoms say they suffer from at least two of the three insomnia types defined in the study (i.e., sleep onset insomnia, sleep maintenance insomnia , and early morning awakening insomnia ).

Etiology

While most cases of insomnia are caused by one or more physical, psychological, or environmental conditions, some cases are of unknown origin.

Misalignment of one’s internal circadian clock with one’s external environment is a trigger of insomnia. Circadian rhythms are patterns generated within the body that last approximately 24 hours and regulate cycles of wake and sleep, body temperature, and hormone secretion. Normal circadian rhythms keep physiological processes in synchrony with one another and allow different systems of the body to work in harmony. External time cues or zeitgebers (meaning “time givers” in German) such as daily activities, environmental conditions, and social factors can adjust the biological clock.

Light is the most dominant zeitgeber and may reset one’s circadian rhythm. Delayed and advanced sleep phase syndrome are persistent circadian rhythm disturbances. Common transient circadian rhythm disorders are sleep difficulties resulting from nightly shift work and jet lag. Night-shift workers often fail to adapt fully to their altered schedules and fail to sleep during the daytime. Jet lag results from crossing time zones and having difficulty resetting the biological clock.

Other factors that contribute to secondary insomnia include medical conditions such as depression, anxiety, and chronic pain. In fact, researchers have identified a strong link between insomnia and depression; however, the exact relationship between the two conditions remains unclear.

Nearly 30% of insomniacs suffer from depression and/or anxiety and close to 90% of patients with major depression experience sleep disturbances. Depressed individuals typically experience shallow, fragmented sleep and often awaken frequently throughout the night. Because insomnia and depression are frequently present together, they have been suggested to share similar pathologies. Both depression and insomnia have been reported to be associated with elevated activity within the hypothalamic-pituitary-adrenal axis and increased production of the stress hormone cortisol .

Hyperarousal may also be a principal trigger for insomnia; hyperarousal results from medical conditions, psychiatric disorders, or other psychological factors (e.g., stress). Many studies find heightened physiological activity (e.g., elevated heart rate, increased metabolic activity, higher cortical activation) in insomniacs. Chronic insomnia is suggested to be correlated to abnormally high activity within the stress system (hypothalamic-pituitary-adrenal axis and the autonomic nervous system).

In a recent study, increased production of two stress-related chemicals in the body, acetylcholine and cortisol, was found to be associated with chronic persistent insomnia in humans. Additional studies are needed to further identify brain structures and mechanisms involved in arousal and their relation to insomnia.

Pathophysiology

Normal Sleep Stages

During sleep, the brain cycles through two distinct phases: non-rapid eye movement sleep and rapid eye movement sleep. Different levels of physiological activity (e.g., brain activity, cardiac rate, respiratory rhythm, temperature regulation) take place during non-rapid eye movement and rapid eye movement sleep.

Normal nocturnal sleep in adults is highly organized and cycles between periods of non-rapid eye movement and rapid eye movement sleep. Non-rapid eye movement sleep consists of four stages. Higher stages of non-rapid eye movement are deeper states of sleep and are characterized by slower brain wave patterns and higher arousal thresholds. Each stage of sleep is associated with distinct brain wave activity:

• Stage 1 of non-rapid eye movement is the initial and lightest stage of sleep. It is the transition stage from wakefulness to sleep. During this stage, alpha brain wave activity (present during wakefulness) decreases and theta (high amplitude, slow) wave activity increases. Approximately 5-10% of the night is spent in stage 1 sleep.
• Stage 2 of non-rapid eye movement is the intermediate stage of sleep and accounts for approximately 40% of total sleep time. This stage is characterized by the presence of sleep spindles (brief bursts of activity) and K-complexes (a recurrent pattern of a negative sharp wave followed by a positive wave).
• Stages 3 and 4 of non-rapid eye movement are called delta sleep, or slow-wave sleep. These stages of sleep are important for physical restoration and for maintaining normal health. Slow-wave sleep is the deepest state of sleep and it is the phase from which it is most difficult to wake. Delta sleep is characterized by high amplitude low frequency waves and constitutes approximately 25% of nightly sleep.

Stage 1 of non-rapid eye movement marks sleep onset; it is the start of the first cycle of sleep and may not appear in subsequent sleep cycles. In the first sleep cycle, sleepers sequentially advance through the four stages of non-rapid eye movement sleep and then go back through stages 3 and 2. Rapid eye movement sleep follows non-rapid eye movement sleep and completion of this phase marks the end of the first cycle of sleep.

Four to six sleep cycles, each approximately 90 minutes long, occur during normal continuous sleep. Each successive sleep cycle has a longer rapid eye movement period and a shorter period of slow-wave (stages 3 and 4 of non-rapid eye movement) sleep. Toward morning, the duration of stage 4 declines and the duration of rapid eye movement increases. Overall, approximately 75% of total sleep time is spent in non-rapid eye movement sleep.

Rapid eye movement is the deepest stage of sleep and constitutes approximately 20-25% of total sleep time. Approximately 90 minutes after sleep onset, the first rapid eye movement sleep episode of the night begins. Signals from the brainstem are sent to the thalamus and cerebral cortex and control rapid eye movement induction. Rapid eye movement sleep is characterized by the presence of darting movements of the eyes, fast low-voltage unsynchronized brain waves (similar to those observed during wakefulness) and high physiologic activity.

The rapid eye movement period is termed “paradoxical sleep” because heart rate, respiration, blood pressure, body temperature, and brain waves during this state are similar to those during wakefulness. The majority of dreaming occurs during this state and is associated with heightened brain activity. During rapid eye movement sleep, muscle tone drops and reflex-excitability is virtually eliminated, preventing the sleeper from acting out dreams. Inhibitory signals initiating in the pons area of the brain shut off neurons in the brainstem and spinal cord, causing temporary paralysis of limb muscles.

Neuronal Systems and Neurotransmitters Involved in Sleep. Multiple mechanisms work together to control sleep and wakefulness. While investigators have yet to identify any one unique underlying cause of insomnia, they have identified several systems, structures, and chemical messengers that may be linked to the condition.

Reticular Activating System

Both conscious alertness and sleep are largely regulated by the reticular activating system, also known as the ascending reticular formation. The reticular activating system consists of networks of multisynaptic neurons located in various divisions of the brain including the cerebral cortex, thalamus, hypothalamus, medulla, pons, and basal forebrain. These neurons communicate through various chemical messengers such as acetylcholine, serotonin, gamma aminobutyric acid, and norepinephrine. These chemical messengers in normal sleep and their influences on specific brain structures within this system.

Acetylcholine

States of arousal are regulated through interaction between cholinergic and monoaminergic (i.e., serotoninergic, noradrenergic and histaminergic) neurons. Cholinergic neurons important in sleep originate in the dorsal pons and relay information to the thalamus, basal forebrain, and tectum (located at the top of the midbrain). Acetylcholine concentrations are most elevated during wakefulness and rapid eye movement  and are involved in many physiological activities that occur during this phase of sleep.

Cholinergic signals prevent gamma aminobutyric acid from exerting its inhibitory activity on thalamocortical cells and, hence, allow these neurons to fire freely in a desynchronous manner during wakefulness and rapid eye movement sleep. Cholinergic neurons projecting to the tectum direct the rapid eye movement during rapid eye movement sleep. Activity within these neurons is also vital for the temporary paralysis observed during this phase. Signals initiating in the cholinergic cells are sent to the magnocellular nucleus of the medulla (in the hindbrain), which inhibit motor neurons of the spinal cord.

Serotonin

Serotonergic neurons involved in the sleep pathway originate in the dorsal raphe nucleus and project directly onto cholinergic neurons. Serotonin (5-hydroxytriptamine, or 5-HT) is a neurotransmitter synthesized from the amino acid tryptophan in the raphe nucleus of the reticular formation. Serotoninergic neurons fire in synchrony with adrenergic neurons (located in the locus coeruleus) and histaminergic neurons (in the pontomesencephalon).

Firing of these monoaminergic neurons is highest during states of wakefulness, decreased during non-rapid eye movement sleep, and low in rapid eye movement sleep. Animal studies suggest that an inverse relationship exists between levels of serotonin in the brainstem and number of rapid eye movement episodes experienced during sleep. Researchers suspect that adequate levels of serotonin concentrations are associated with normal sleep in humans.

Gamma Aminobutyric Acid

Gamma aminobutyric acid, the main inhibitory neurotransmitter in the central nervous system, directs shifting between different stages of sleep. During sleep, this neurotransmitter acts on many cells within the reticular activating system to stop neurotransmission that facilitates arousal. At the onset of sleep, GABAergic neurons hyperpolarize thalamic relay neurons, which in turn stop sensory information from being transmitted to the cerebral cortex.

During non-rapid eye movement sleep, GABAergic neurons in the thalamic reticular nucleus regulate the firing rates of thalamocortical neurons, causing the synchronized slow brain waves observed at this phase. In contrast, high frequency brain waves present in rapid eye movement sleep are caused by the deactivation of these GABAergic neurons by cholinergic neurons.

Gamma aminobutyric acid’s effects in sleep-wake regulation are mediated via binding to gamma aminobutyric acid receptors. The three types of gamma aminobutyric acid receptors are as follows:

• gamma aminobutyric acid-A receptors, which are ligand-gated chloride channels.
• gamma aminobutyric acid-B receptors, which are Germany-protein-coupled receptors linked to calcium and potassium channels (gamma aminobutyric acid is least sensitive to these receptors).
• gamma aminobutyric acid-C receptors, which are ligand-gated chloride channels (gamma aminobutyric acid is most sensitive to these receptors).

Although gamma aminobutyric acid-A receptors are present throughout the brain, they are most heavily concentrated in the cerebellum, thalamus, and cerebral cortex. The gamma aminobutyric acid-A receptor complex consists of five protein subunits that surround a chloride channel. When the gamma aminobutyric acid-A receptor is activated, the chloride channel opens, permitting chloride ions to cross the membrane.

The inflow of chloride ions mediates an inhibitory response that stops excitatory activity in target cells. Benzodiazepines, barbiturates, and neurosteroids enhance gamma aminobutyric acid’s ability to activate its receptors and hence the increase inhibitory activity within the central nervous system. These compounds alter the shape of gamma aminobutyric acid-A receptors and allow gamma aminobutyric acid to attach more readily to its binding site.

There are 17 different types of gamma aminobutyric acid-A receptors, each composed of a different combination of alpha (α), beta (β), and gamma (y) subunits. Gamma aminobutyric acid-A receptors with similar subunits are commonly concentrated together in localized brain regions. Different receptor subunits of the gamma aminobutyric acid-A receptor are associated with distinct behavioral effects. The α subunit is the main modulatory sites of the gamma aminobutyric acid-A receptor. gamma aminobutyric acid-A subunits are shown to be involved in sedation and a1 subunits mediate anxiolysis and muscle relaxation.

Control of Biological Rhythms Affecting Sleep.

The SuprachiasmatiC Nucleus

The suprachiasmatic nucleus, located in the hypothalamus above the optic chiasm, is the primary circadian clock and pacemaker of the mammalian brain. Cells within the suprachiasmatic nucleus self-generate circadian rhythms and synchronize many rhythms of the body. suprachiasmatic nucleus signals are sent to neuroendocrine organs (such as the pineal and pituitary glands) and regulate body temperature, levels of hormone secretion, and sleep cycles. The suprachiasmatic nucleus is responsive to light intensity and paces rhythms of the body to daily patterns of light.

The suprachiasmatic nucleus regulates activity cycles by receiving, both directly and indirectly, visual input from the retina. Light levels absorbed in the retina and are sent along the retinohypothalmic tract to the suprachiasmatic nucleus. Glutamate mediates activity within the retinohypothalmic tract tract by activating N-mefhyl-D-aspartate and non-N-mefhyl-D-aspartate receptors. Indirectly, the suprachiasmatic nucleus receives visual input via the geniculohypothalamic tract, which originates in the lateral geniculate body of the thalamus and is mediated by the neurotransmitter neuropeptide Y.

The FOS protein is a transcription factor that accumulates in recently activated neurons in the suprachiasmatic nucleus. The cellular expression of the FOS protein has been used widely by researchers to study factors involved in “phase-shifting” circadian rhythms. Researchers have shown by staining for FOS that light pulses lead to a period of neural activity. Interference in the suprachiasmatic nucleus (e.g., by medication including GABAergic drugs or by electrical stimulation) prevents the FOS protein from being produced and can lead to a shift in the timing of circadian rhythms.

The Pineal Gland and Melatonin

The pineal gland is a small neuroendocrine organ located on top of the midbrain that produces the hormone melatonin at night in response to the neural output of the suprachiasmatic nucleus. Serotonin  is converted into melatonin primarily via the enzyme serotonin N-acetyltransferase.

Norepinephrine is another neurotransmitter that assists in melatonin production by binding to beta-adrenergic receptors in cells of the pineal gland and initiating signal transduction pathways that increase the concentration of cyclic adenosine monophosphate within these cells. The cyclic adenosine monophosphate signal transduction pathway plays a critical role in stimulating melatonin synthesis. Because light-dependent signals originating in the suprachiasmatic nucleus inhibit the adrenergic neurons that are responsible for producing norepinephrine, secretion of norepinephrine is highest at night.

While suprachiasmatic nucleus output regulates melatonin synthesis, melatonin modulates suprachiasmatic nucleus output through its “resynchronizing/resetting” effect on this intrinsic biological clock. Melatonin receptors in the suprachiasmatic nucleus provide a means by which melatonin may feed back to the body’s pacemaker and shift the circadian rhythm. High-affinity Germany-protein-coupled receptors mediate the effects of melatonin and are highly concentrated in the suprachiasmatic nucleus. Given that melatonin secretion occurs only at night and is active in regulating the suprachiasmatic nucleus only during the hours surrounding the day/night transition, melatonin’s function may involve the synchronization of humans or animals to the time of nightfall.

The low nocturnal production of melatonin in many insomniacs and the sleep-promoting effects of melatonin in individuals experiencing sleep difficulties  suggest that melatonin may help maintain regular sleep in some individuals. The efficacy of melatonin replacement treatment in the elderly is of current interest. Although some studies report that melatonin treatment improves sleep in elderly insomniacs, other studies do not support these findings. Properly timed melatonin administration may be able to readjust sleep-wake patterns and realign the circadian clock with the environmental rhythm. At present, several chemically modified melatonin agonists are under investigation in clinical trials for insomnia.

Current Therapies

Most individuals who suffer from insomnia either self-treat with nonprescription sleep aids (e.g., antihistamines, herbal remedies), use alcohol as a sedative, or take no drug therapy at all. For those who do seek professional help (approximately one-third of insomniacs), the majority receive physician-prescribed benzodiazepine or non-benzodiazepine sedative hypnotics to treat their insomnia. Such hypnotic agents produce drowsiness and facilitate the onset and maintenance of sleep from which the individual may be easily aroused.

Historically, prior to the advent of the benzodiazepines, low-dose barbiturates and alcohols (e.g., chloral hydrate) were widely used to treat insomnia. Today, however, these agents are rarely used because they are associated with several adverse reactions (e.g., addiction, respiratory suppression, hepatic disease, unexpected deaths) and because newer, safer hypnotics such as the benzodiazepines and non-benzodiazepine hypnotics are available.

TABLE . Prescription Drugs Used for Insomnia

Agent	Company/Brand	Daily Dose(a)	Availability
Benzodiazepine hypnotics
Triazolam	Pfizer’s Halcion, generics	0.25-0.5 mg	US, France, Germany, Italy,Spain, Japan
Temazepam	Mallinckrodt’s Restoril, generics	30 mg	US, France, Germany, Italy, UK
Flurazepam	Valeant’s Dalmane, generics	15-30mg	US, Germany, Italy, Spain, UK, Japan
Sedating antidepressants
Trazodone	Aventis’s Molipaxin,Bristol-Myers Squibb’s Desyrel, generics	50-100 mg	US, Germany, Italy, Spain, UK, Japan
Mirtazapine	Organon’sRemeron/Remergil/Zispan, generics	15-30mg	US, France, Germany, Italy,Spain, UK

Medication is generally taken shortly before bedtime; elderly patients frequently take lower doses (i.e., one-half the strength) than those cited here for the benzodiazepine (benzodiazepine) and non-benzodiazepine hypnotics.

Sanofi-Synthelabo will officially become Sanofi-Aventis by year-end 2004.

As a result of the Sanofi-Aventis merger (approved by the European Commission in April 2004), Aventis will divest itself of all marketing rights for Imovane (zopiclone) in European countries.

Numerous benzodiazepines are used to treat insomnia (see text discussion of benzodiazepine hypnotics); the three presented in this table are among the most widely prescribed.

Other antidepressants with sedating properties, such as the tricyclic antidepressants amitriptyline (Roche’s Laroxyl, AstraZeneca’s Elavil, generics), doxepin (Roerig’s Sinequan, generics), and trimipramine (Aventis’s Surmontil, generics) are also used to treat insomnia. Doses used for insomnia are lower than those used for depression.

Benzodiazepines, introduced in the early 1960s, were the first class of relatively selective hypnotics available. By the late 1980s, even more-selective non-benzodiazepine hypnotics such as zopiclone (Aventis’s Imovane/Amoban, Chugai’s Amban, generics) and zolpidem (Sanofi-Synfhelabo’s Ambien/Stilnox, Fujisawa’s Myslee, generics) became available. Today, these traditional benzodiazepines and non-benzodiazepine hypnotics constitute the bulk of physician prescriptions for the short-term treatment of insomnia. (Traditional benzodiazepine and non-benzodiazepine hypnotics are not indicated for long-term treatment of insomnia.)

Less frequently prescribed for insomnia are the sedating antidepressants such as trazodone (Bristol-Myers Squibb’s Desyrel, Aventis’s Molopaxin, generics), mirtazapine (Organon’s Remeron/Remergil), and amitriptyline (Roche’s Laroxyl, AstraZeneca’s Elavil, generics), among others. Physicians sometimes prescribe these agents in place of the sedative hypnotics for patients who suffer from comor-bid depression and insomnia or for patients who require long-term treatment for insomnia.

Finally, physicians sometimes recommend natural remedies such as herbal drugs and, in certain markets (primarily the United States), melatonin, to individuals suffering from insomnia who prefer not to take a chemical drug. This practice is particularly common in France and Germany, where physicians use herbal remedies such as valerian and crataegus oxaycantha nearly as frequently as they use prescription hypnotics. However, these remedies can be purchased without a prescription in most countries; these products are not discussed further here because the focus is on prescription drugs for insomnia.

Nonbenzodiazepine Hypnotics

Benzodiazepine Hypnotics

Sedating Antidepressants

Nonpharmacological Approaches

Behavioral therapies are occasionally used to manage patients with insomnia. Such therapies are designed to change bad sleep habits and alter dysfunctional beliefs and attitudes that contribute to insomnia. Behavioral therapies used to manage insomnia include sleep hygiene, relaxation therapy, sleep restriction therapy, stimulus control therapy, and cognitive therapy. Bright light therapy is another nonpharmacological approach that is occasionally recommended for insomnia related to altered circadian rhythms, as well as certain depressive states (e.g., seasonal affective disorder).

Emerging Therapies

Most of the late-stage compounds in clinical development for insomnia are non-benzodiazepine  gamma-aminobutyric acid -acting agents. These drugs’ developers are hoping that their new compounds, once approved, will achieve less restrictive labeling from regulatory authorities than the currently marketed benzodiazepine and non-benzodiazepine hypnotics — most of which have short-term prescribing limits and all of which are classified as “controlled substances” because of their abuse potential.

While the newer compounds are unlikely to be “unscheduled” (i.e., devoid of the “controlled substance” classification) because of their class association (i.e., they are considered to be in the same class as zolpidem [Sanofi-Aventis’s Ambien/Stilnox, Fujisawa’s Myslee, generics], zopiclone [Sanofi-Aventis’s Imovane/Amoban, Chugai’s Amban, generics], and zaleplon [Wyeth and King Pharmaceuticals’ Sonata]), the relaxing of prescribing limits in terms of how long the drugs should be used is a definite possibility. More specifically, for chronic insomniacs, some of the newer drugs may be indicated for use for several months rather than just several weeks.

A second and also important differentiating factor in terms of labeling for the newer compounds will be more-expansive labeling to cover “sleep maintenance” in addition to “sleep onset.” Neither zolpidem nor zaleplon is labeled for sleep maintenance because of these agents’ short duration of action. Zopiclone, the other marketed non-benzodiazepine hypnotic, is labeled for use in inducing and maintaining sleep, but this agent is not available on the U.Spain. market.

Aside from the fact that many of these next-generation non-benzodiazepine hypnotics have been studied for longer durations in clinical trials, there is little to differentiate them from the first generation of non-benzodiazepine hypnotics (i.e., zolpidem, zopiclone, and zaleplon) in terms of safety and efficacy. Nevertheless, robust data from longer-term (i.e., 3-, 6-, and 12-month) clinical trials along with aggressive marketing once these compounds reach the market may be enough to afford the newer non-benzodiazepine hypnotics a competitive edge over the current agents. Indeed, this new generation of non-benzodiazepine hypnotics may expand the overall prescription drug market for insomnia simply by providing physicians with a greater number of treatment choices for patients suffering from chronic insomnia.

Also under investigation for insomnia are clinical-stage compounds with non-gamma aminobutyric acid mechanisms, such as the melatonin agonists and 5-НТгА antagonists. These novel agents hold the promise of offering sleep-enhancing effects without the potential for abuse and/or dependence associated with long-term use of benzodiazepine and even non-benzodiazepine hypnotics. However, these agents may prove useful in only certain segments of the insomnia population and may not be as effective as the benzodiazepine and non-benzodiazepine hypnotics, so their future in the insomnia market is less clear.

Table Emerging Therapies in Development for Insomnia summarizes the drug therapies in development for insomnia.

TABLE . Important Drug Labeling Considerations That May Differentiate Emerging Hypnotics from Currently Marketed Agents

HypnoticMarketed	U.Spain. LabelingActual Labeling
Zolpidem	Indication: sleep onset (but used for sleep maintenance)
	Recommended treatment duration: 7-10 days
	Controlled substance status: Schedule IV
Zopiclone(outside of U.Spain.)	Indication: sleep onset/sleep maintenance
	Recommended treatment duration: 7-10 days
	Controlled substance status: Equivalent of Schedule IV in U.Spain.
Zaleplon	Indication: sleep onset
	Recommended treatment duration: 7-10 days
	Controlled substance status: Schedule IV
In Development	Potential Labeling
Indiplon immediate-release	Indication: sleep onset
	Recommended treatment duration: several weeks/months
	Controlled substance status: Schedule IV
Zolpidem modified-release	Indication: sleep onset/sleep maintenance
	Recommended treatment duration: several weeks/months
	Controlled substance status: Schedule IV
Zaleplon extended-release	Indication: sleep onset/sleep maintenance
	Recommended treatment duration: several weeks/months
	Controlled substance status: Schedule IV
Eszopiclone	Indication: sleep onset/sleep maintenance
	Recommended treatment duration: several weeks/months
	Controlled substance status: Schedule IV
Indiplon modified-release	Indication: sleep onset/sleep maintenance
	Recommended treatment duration: several weeks/months
	Controlled substance status: Schedule IV
Gaboxadol	Indication: sleep onset/sleep maintenance
	Recommended treatment duration: several weeks/months
	Controlled substance status: Schedule IV or possibly no restrictions
Tiagabine	Indication: sleep onset/sleep maintenance
	Recommended treatment duration: several weeks/months
	Controlled substance status: no restrictions
TAK-375	Indication: sleep onset/sleep maintenance
	Recommended treatment duration: several weeks/months
	Controlled substance status: no restrictions
PD-6735	Indication: sleep onset/sleep maintenance
	Recommended treatment duration: several weeks/months
	Controlled substance status: no restrictions
M-100907	Indication: sleep maintenance
	Recommended treatment duration: several months
	Controlled substance status: no restrictions

Nonbenzodiazepine Gamma Aminobutyric Acid-A Agonists

Gamma Aminobutyric Acid Reuptake Inhibitors

Overview

Like non-benzodiazepine gamma aminobutyric acid-A agonists, gamma aminobutyric acid reuptake inhibitors essentially enhance the activity of the inhibitory neurotransmitter gamma aminobutyric acid and therefore possess sleep-enhancing properties. At present, the only gamma aminobutyric acid reuptake inhibitor under clinical investigation for insomnia is tiagabine (Cephalon’s Gabitril).

Mechanism Of Action

Gamma aminobutyric acid reuptake inhibitors enhance the activity of gamma aminobutyric acid. They do so by binding to recognition sites associated with the gamma aminobutyric acid uptake carrier and blocking uptake into presynaptic nerve cells. When gamma aminobutyric acid reuptake is blocked, more gamma aminobutyric acid is available to post-synaptic nerve cells, which leads to an inhibition of nerve impulses.

Tiagabine

Tiagabine  was launched extensively for epilepsy by Novo Nordisk and Abbott in Europe and the United States by the end of 1997. In November 2000, Abbott licensed U.Spain. rights to the compound to Cephalon, which planned to pursue development for nonepilepsy indications, and by January 2002, Cephalon had acquired worldwide rights to tiagabine (excluding Canada, Latin America, and Japan). By 2004, Cephalon had announced positive preliminary data from Phase II trials in insomnia, generalized anxiety disorder, and neuropathic pain, and large Phase II trials for insomnia are underway.

As mentioned, tiagabine elicits its sedative effects via gamma aminobutyric acid reuptake blocking activity and subsequent potentiation of the inhibitory effects of gamma aminobutyric acid. More specifically, it produces an increase in extracellular gamma aminobutyric acid by inhibiting reuptake on the gamma aminobutyric acid-1 transporter (GAT-1). The drug has no effect on noradrenaline or dopamine reuptake and binds weakly to benzodiazepine, histamine HI, and 5-HTi receptors. Tiagabine is rapidly absorbed (T-max of 45 minutes) and has a plasma half-life of seven to nine hours (longer in those with hepatic dysfunction); investigators have, however, noted substantial inter-individual variability (4.5-13 hours) when the drug has been used as an antiepileptic.

Cephalon presented clinical data from its initial insomnia trials at the 2004 annual meeting of the APSS. In the first double-blind, placebo-controlled, dose-response Phase II study, 58 subjects with primary insomnia were given 4, 8, 12, and 16 mg doses of tiagabine for two consecutive nights followed by a 5-12 day washout between treatment periods. Investigators assessed sleep using polysomnographic and next-day psychomotor performance using the Digit Symbol Substitution Test (DSST). Efficacy data were presented for treatment period one (11-12 subjects per group) and safety data were presented for all subjects who received at least one dose of tiagabine (n = 58).

Findings presented by study investigators showed that the 8 mg and 12 mg doses achieved a significant reduction in WASO. A dose-related decrease in number of awakenings was noted, as was a dose-related increase in percentage of sleep time in slow-wave sleep (with dose-related reductions in all other stages of sleep). Tolerability was also dose-related, with the two highest doses causing residual effects. The most common adverse effects (adverse events) were dizziness, nausea, and daytime somnolence.

Additional findings from a smaller dose-response analysis (n = 26) of older adults (i.e., 60-80 years) revealed that the 4 mg and 8 mg doses of tiagabine have positive effects on sleep maintenance with minimal adverse effects. Larger trials examining these doses in elderly insomniacs are being planned.

Although it is clear that tiagabine has sleep-enhancing properties, it remains to be seen whether the drug provides comparable efficacy and tolerability to the non-benzodiazepine hypnotics on the market and in clinical development. If not, tiagabine will have little chance of carving out a niche in the insomnia marketplace. In addition, its status as an antiepileptic drug may limit its acceptance among GPs and PCPs, who might perceive the drug as one that falls within the realm of the specialist.

Cephalon could potentially capitalize on two important factors: (1) tiagabine’s status as a nonscheduled drug, and (2) specialists’ familiarity with the drug — some already prescribe it on occasion for insomnia. Cephalon has an increasing presence in the sleep disorders arena with its recently marketed drug modafanil (Provigil) — which is now marketed for excessive sleepiness associated with narcolepsy, obstructive sleep apnea/hypopnea syndrome, and moderate to severe chronic shift work sleep disorder — and will have an established sales-force with expertise in this arena by the time tiagabine is approved for insomnia (if it is, in fact, approved). That said, based on its current pricing for epilepsy, tiagabine may be considerably more expensive than other available sleep aids.

Melatonin Agonists/Analogues

5-НТ2 Antagonists

Overview

Drugs that act as 5-НТ2a and/or 5-НТ2c antagonists are under investigation for insomnia because they have exhibited sedative effects when used as treatments for anxiety and depression. For example, NV Organon has initiated Phase II trials with the single enantiomer version (Spain-isomer) of its widely marketed antidepressant mirtazapine (Organon’s Remeron/Remergil, generics) — a 5-НТ2f and alpha-2 adrenergic antagonist — because the parent drug has been shown to promote sleep in depressed patients. Similarly, Sanofi’s investigational 5-НТ antagonist eplivanserin — which was originally being developed for depression and anxiety — is reportedly back in development for insomnia. Sanofi-Aventis also has a 5-HT2A antagonist called M-100907 in Phase II trials for anxiety, depression, and insomnia. Because there are scant available data for any of these compounds in treating insomnia, only one of them is profiled in detail in the following section — Sanofi-Aventis’s M-100907.

Mechanism Of Action

Investigators suspect that 5-НТг antagonists exert their sedative effects by enhancing slow-wave sleep. In particular, 5-НТ2 antagonists may tone down serotonin-induced arousal, which is part of the sleep-wake cycle.

M-100907

Sanofi-Aventis’s highly selective 5-HT₂a antagonist M-100907 is in Phase lib trials for insomnia. The drug was originally being developed for schizophrenia and had reached Phase III trials for that indication, but development ceased in 1999 following interim analysis of results that suggested a lack of efficacy.

According to Sanofi-Aventis, M-100907 significantly increased slow-wave sleep and reduced the number of nighttime awakenings in a small crossover trial in elderly adults (n = 13). These findings were reportedly confirmed in another small trial. Based on the drug’s half-life of eight hours, it is reasonable to assume that it will provide a full night’s effect in individuals with insomnia. However, it could also cause residual sedative effects. In schizophrenia trials, the most common adverse effects were headache and constipation.

One potential benefit of the drug compared with other sedative hypnotics could be its lack of gamma aminobutyric acid-related effects such as the propensity to be habit-forming or to cause rebound insomnia upon discontinuation. However, in the absence of more evaluable data from clinical trials in insomniacs, it is too early to determine whether the drug will even provide meaningful sedative effects in this population.