Before any consideration can be given to treating insomnia, a          comprehensive evaluation is mandatory.

In his 2001 best-selling novel The Corrections, Jonathan Franzen tells the story of an older couple who embark on a cruise along the coast of New England. The Parkinson-afflicted husband presents a constant challenge to the patience, understanding, and caretaking abilities of his wife. As his sleep becomes disturbed by violent tremors and frightening hallucinations, so too does hers. Exhausted and emotionally drained, she secretly consults the ship’s doctor, who entices her with a mysterious medication that promises relief far beyond her initial complaints of anxiety and lost sleep. In the doctor’s words, this is “state-of-the-art psychopharmacology that Pleasurelines is proud to make available to its discerning clientele.”

When asked how it works, he responds that “it switches your anxiety to the Off position. Turns that little dial right down to zero.” When asked how quickly it exerts its effects, he answers, “the action is effective instantaneously.” Before long, she succumbs to his persuasive skills, exchanges cash for pills, and heads back to her cabin. Here, the author writes, “how sweet the optimism of the person carrying a newly scored drug that she believed would change her head... no exertion more strenuous than raising hand to mouth, no act more violent than swallowing... was required to experience a pill’s transformative blessings. She couldn’t wait to take it.” Upon awakening the following morning, she says to her husband, “I had the most wonderful night’s sleep.”¹

The pursuit of the perfect hypnotic is far from fiction. For decades, doctors and patients alike have searched for a safe and effective cure for the curse of insomnia.

Pharmacologically, the ideal medication would be one quickly absorbed and metabolized, possessing a relatively short half-life, and completely eliminated from the body by morning. The dream of sleep practitioners would be a drug that reduces sleep latency, preserves normal sleep architecture, and causes no residual daytime symptoms—with little potential for tolerance, dependence, abuse, or rebound insomnia. In layman’s terms, a pill that would hasten sleep onset, eliminate nocturnal awakenings, and leave the patient mentally alert and physically energized the next day.²

Such goals have steered the course of pharmacologic research for insomnia over the past 50 years. And while newer agents come closer than ever to achieving these targets, shortcomings remain that propel the ongoing search. Clearly, the problem is not a lack of interest or potential market. The National Sleep Foundation estimates that more than 80 million Americans suffer from some degree of insomnia, with close to 30% of the adult population experiencing symptoms nearly every night.³

Despite this widespread incidence, the vast majority of insomniacs remain undiagnosed and untreated. Approximately 5% of patients with symptoms of insomnia have ever received a confirmed diagnosis, with only 3% to 4% having received some form of professional treatment. The reasons for this discrepancy are many, including the continued stigma of being labeled with a “psychological” disorder, a fear of “bothering” physicians with such trivial complaints, and a hesitancy to embark on a course of pharmacotherapy offering immediate symptomatic relief but fraught with complications down the road.⁴

Insomnia: Symptom or Syndrome?
Insomnia presents with a variety of chief complaints including trouble falling asleep, difficulty with sleep maintenance, early morning awakenings, and unrefreshing or nonrestorative sleep. From the perspective of duration, it is typically classified as transient, short-term, or chronic.

Before any consideration can be given to treatment, a comprehensive evaluation is mandatory. Despite tremendous advances in technology, a thorough clinical history remains the most indispensable tool in the diagnostic process. A detailed examination of the patient’s medical, psychological, and sleep-related complaints yields far more valuable data than polysomnography (which is typically indicated only in select cases).⁵ The primary goal of the clinical evaluation is the often-difficult differentiation between primary and secondary insomnia.

Table 1. Causes of secondary insomnia.

In secondary insomnia, the sleep disturbance is best viewed as a symptom resulting from an underlying medical, psychological, pharmacological, or environmental factor. A representative, but not exhaustive, list appears in Table 1. Recent research suggests that approximately 58% of patients with secondary insomnia suffer from an underlying psychological disorder, while 25% have an undiagnosed sleep disorder, and 8% are attributable to a pharmacologic agent.⁶

Once the etiology has been determined, treatment should first be directed at resolution of the underlying disorder, or change in the offending environmental or pharmacological factor. Premature initiation of hypnotic therapy leaves the underlying disorder untreated and places the patient at risk for associated complications. While a nighttime sedative may suppress nocturnal awakenings from hyperthyroidism, it does nothing to address the core cause and related symptoms. Worse yet, some conditions may be exacerbated with the use of sleeping medications. A prime example is obstructive sleep apnea, often made worse by the muscle relaxant properties of many hypnotics.

Only approximately one third of all patients with a chief complaint of insomnia suffer from true primary insomnia.6 Technically speaking, the disorder is classified as psychophysiological insomnia, characterized by a conditioning process in which the patient associates the bed with wakefulness, anxiety, and heightened arousal rather than sleep.⁷ Patients with psychophysiological insomnia engage in a nightly pattern of worry and rumination about the elusiveness of sleep, which serves only to increase sympathetic activation incompatible with sleep. This “self-fulfilling prophecy” reinforces the patient’s belief that their sleep system is broken or defective, and that nights of sound sleep are somehow a thing of the past. Once this mind-set becomes entrenched in the patient’s psyche, insomnia may persist well beyond the resolution of the precipitating factor. Not uncommonly, this process transforms a simple case of transient or short-term insomnia into an intractable chronic syndrome.

Table 2. General features of available sleep medications relative to ideal hypnotic.

Past Sleep Aids
The pursuit of a medicinal sleep aid is certainly not new to 21st-century society. The history of medicine is replete with substances alleged to induce a restful slumber. While alcohol has been used for centuries to induce sleepiness, it is now known to generally cause more harm than good by fragmenting sleep during the second half of the night. The 1900s brought the development of barbiturates, which remained in favor until the 1960s, when their safety profile came under serious attack and newer, safer options emerged on the scene.⁸

Current Agents
The pharmacological treatment of insomnia flourished in the last decades of the 20th century with the introduction of a new class of hypnotics—benzodiazepines.

These medications bind to GABA receptors in the brain, which potentiates neuronal inhibition and induces sleep. The benzodiazepines continue to be a mainstay in the treatment of insomnia, despite significant drawbacks making them far from ideal. While typically effective in shortening sleep latency and reducing nighttime awakenings, they typically reduce slow wave and rapid eye movement (REM) sleep at the expense of increasing stage two. Furthermore, most benzodiazepines cause at least some degree of morning grogginess, daytime fatigue, dizziness, confusion, and impaired motor coordination (particularly in elderly patients).⁹

Most of the adverse effects noted above are a function of a prolonged elimination half-life, creating “therapeutic” effects beyond the desired morning waketime. Those with a long half-life (such as flurazepam) are more prone to creating a significant daytime “hangover effect,” while shorter-acting benzodiazepines (such as triazolam) produce a greater likelihood of rebound insomnia.¹⁰

Despite these shortcomings, Americans spend more than $400 million per year on benzodiazepine medications. Current FDA guidelines recommend only short-term use of the benzodiazepines for a maximum period of 4 weeks; however, in practice many patients persist with nightly use of these drugs for months or even years. The controversy persists as to whether some patients continue to obtain true therapeutic effects with long-term use of benzodiazepines, or whether the sustained response simply represents an enduring placebo effect.¹¹

When benzodiazepines are indicated, they should be used for brief periods of time, on an intermittent basis, and at the lowest dose possible. These guidelines will help the medication maintain its effectiveness, reduce side effects, and minimize the possibility of tolerance and dependence.11

The 1990s introduced two newer drugs classified as “nonbenzodiazepine” hypnotics including zolpidem and zaleplon. Both are benzodiazepine receptor agonists that bind selectively to the BZ1 receptors.8 As effective as the first generation of benzodiazepines, these new agents offer several distinct advantages, including rapid absorption and onset of action, short half-lives, minimal daytime impairment, and a low potential for abuse and dependence. The particularly short half-life of zaleplon (approximately 1 hour) provides a unique option for patients suffering from middle-of-the-night awakenings with difficulty returning to sleep (provided it is taken at least 4 hours before the scheduled morning waketime).¹² The combination of efficacy with a positive safety profile makes these medications the most commonly prescribed hypnotics today.

Antidepressants as Sleep Aids
Due to the concerns of habituation and dependence on the benzodiazepine hypnotics, many physicians have turned to tricyclic antidepressants in the treatment of insomnia. The sedating side effect of these medications (often a stumbling block in the treatment of depression) is here viewed as an advantage in inducing and sustaining sleep. The antidepressants most commonly used for this purpose are amitriptyline, doxepin, and trazodone.¹³ Typically, these medications are prescribed at very low doses for the treatment of insomnia, and clinicians should be mindful that treatment with such subtherapeutic doses is not an effective means of managing the truly depressed patient with complaints of insomnia. And although relatively safe, these medications are not without their own risk of cardiovascular and anticholingeric side effects. Furthermore, tricyclics are known to aggravate periodic limb movements and restless legs syndrome, and are therefore contraindicated in such patients.¹⁰

Over-the-Counter Sleep Aids
At one time or another, most patients with ongoing insomnia have purchased some form of over-the-counter medication for relief of their symptoms. The active ingredient in most of these sleep aids is the antihistamine, diphenhydramine. While effective in producing drowsiness and inducing sleep, their benefit:side effect ratio makes them a poor choice for ongoing treatment. Most produce anticholinergic side effects such as urinary retention, dry mouth, and constipation, and their extended half-life may cause next-day impairments in memory, concentration, and general alertness.¹⁴

Surely, the most popular of the “natural” remedies for insomnia is melatonin, readily available at most drug and health food stores. Melatonin is a hormone secreted by the pineal gland that plays a well-documented role in the regulation of sleep and wake. Although supplemental melatonin is generally well tolerated, there is limited data on its clinical effectiveness. Some evidence exists for its effectiveness in elderly patients with presumed melatonin deficiency (blood levels decrease with age),¹⁵ but its value in treating insomniacs with normal melatonin levels remains unknown. Furthermore, melatonin is not FDA-regulated, and therefore has not undergone the rigorous testing for efficacy and safety required of prescription hypnotics. For similar reasons, there is little quality control in the manufacturing of over-the-counter melatonin products, leaving consumers uncertain as to purity and concentration.¹⁶

New developments
Clearly, we have yet to witness the arrival of an ideal hypnotic. Insomnia has existed since the beginning of time; the field of sleep medicine is a mere half-century old. The pressure to treat the millions of individuals suffering from insomnia may have exceeded our available knowledge base of the underlying science of sleep; however, recent advances in the neurochemistry of sleep have led to exciting new pharmacological developments currently under investigation.

• Eszopliclone is a novel nonbenzodiazepine hypnotic with demonstrated efficacy in reducing sleep latency, increasing total sleep time, and improving overall sleep maintenance. Next-day residual effects are reportedly minimal, and the overall safety profile appears excellent. Initial studies indicate a lack of tolerance, with positive treatment responses sustained across a 6-month trial.¹⁷

• Indiplon is a nonbenzodiazepine GABA-A receptor modulator with purported hypnotic properties. Cumulative results from recent clinical trials indicate significant improvements in sleep onset and sleep maintenance, with no residual side effects and adverse events no different than those for placebo.^18,19

• One of the newer SSRI medications, mirtazapine, was first introduced in 1996 for treatment of depression. Anecdotal evidence of its sedative properties prompted a recent investigation that supports its effectiveness in improving sleep efficiency, compared to both placebo and temazepam.²⁰

• Exogenous melatonin is a fairly non-specific agent likely to bind to multiple receptor sites in the brain; however, a newly developed product known as TAK-375 is a novel melatonin receptor agonist, with high affinity for ML1 receptors located in the cells of the suprachiasmatic nucleus. The results from multiple clinical trials suggest significant reductions in latency to persistent sleep in subjects with both transient and chronic insomnia. The most common adverse event was headache, and TAK-375 produced no significant residual daytime effects.²¹

Future Direction
Hypnotic medications are not the only effective means of treating insomnia, although by far they represent the fastest and easiest path to symptom relief. Significant advances have been made in recent years in the behavioral and psychological treatment of insomnia. Although a thorough review of such treatment is beyond the scope of this article, a body of evidence is emerging that supports the effectiveness of cognitive-behavioral therapy for insomnia. These techniques have been shown to produce treatment effects comparable to pharmacotherapy, yet without the associated risks.²²

Several studies have examined the effectiveness of combining hypnotic medication with cognitive-behavioral therapy. In this way, the patient is provided with immediate symptom relief, yet equipped with the necessary skills to combat the problem when the medication is discontinued, or when similar symptoms develop down the road. The results are thus far equivocal, and long-term effectiveness has yet to be substantiated.²³

Such findings may strip insomnia of its uniqueness, placing it squarely in a broader grouping of psychophysiological disorders such as hypertension, diabetes, headache, and erectile dysfunction; disorders where medicine and psychology converge to create the desired synergistic effect; disorders where no single pill offers a wholly satisfying outcome, without a concomitant dose of will power, stress reduction, lifestyle changes, and common sense.

Michael J. Neeb, PhD, is a Diplomate ABSM and certified as a behavioral sleep medicine specialist; is director of the St Vincent Mercy and St Charles Mercy Sleep Centers; and is codirector of Mercy Children’s Hospital Sleep Disorders Program, all in Toledo, Ohio.

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