Melatonin and Insomnia

by Dimitri Papadimitriou, Ph.D.

Insomnia is a common subjective complaint of inadequate non-restorative sleep. Individual sleep needs vary widelyanywhere from four hours to nine hours of night sleepmaking insomnia distinguishable only as a result of daytime consequences such as restlessness, irritability and impaired social and occupational functioning. Insomnia contributes to an increased rate of absenteeism, health care utilization and social disability.1 The direct cost of insomnia in the United States for 1995 was approximately $11 billion, including costs of medical care from self-treatment, by health care providers and insurance.2 The overall annual economic impact may be as high as $30 billion.

Insomnia is the most common sleep complaint, affecting 26 percent of the adult population; of those affected, 17 percent consider the problem serious, lasting more than six months.3 Those at greatest risk for insomnia include the elderly, women, shift workers and persons with psychiatric disorders. Disturbances in sleep are experienced by more than 50 percent of the elderly, resulting in an increase in daytime napping and further increases in frequency and duration of nighttime awakenings. Insomnia and excessive daytime sleepiness among the elderly are the leading predictors of institutionalization.4 The origins of insomnia stem from multiple causes, including medical conditions (i.e., pain, urinary disorders, menopause, fibromyalgia, irritable bowel syndrome), psychological problems (i.e., depression, anxiety, substance abuse, medications) and breathing disorders.5

Healthy sleep is regulated by circadian rhythms as defined by an individuals biological clock, which is set at a 24-hour cycle. Typically, a person is awake during the daytime and falls asleep at night. Sleep is divided in five stages. Stage 1 initiates sleep and lasts between 15 and 30 minutes. Stage 2, known as intermediate or rapid wave sleep, totals 50 percent of overall sleep time. Stages 3 and 4 make up 15 percent to 20 percent of total sleep time, and are the delta or deep sleep stages. Finally, Stage 5, or REM sleep, is an active sleep state when dreams occur. It is periodicevery 90 minutes throughout sleep timeand is regulated by the hypothalamus and the biological clock. Achieving REM sleep is critical for learning and mood regulation.

There are two means of treating insomnia: psycho-behavioral and medical interventions. The first involves psychological tools such as going to sleep only when sleepy, creating a dark, comfortable environment, and establishing a bed time ritual. Behavioral changes also include decreasing excessive time in bed, decreasing the use of caffeine and alcohol, avoiding nicotine and not getting in bed after a large meal or being hungry. Medical intervention involves administration of one of a variety of preparations, including natural remedies (i.e., valerian, kava, melatonin), homeopathic remedies, conventional pharmacotherapy, over-the-counter (OTC) agents or prescription drugs (i.e., chloral hydrate, barbiturates, benzodiazepines).

Ideally, a hypnotic agent would have a rapid onset of action, prevent night and early morning awakening, would not cause daytime sedation or adverse effects, and have no potential for abuse tolerance or rebound insomnia after discontinuing therapy. Unfortunately, no hypnotic agent currently on the market possesses all these properties. Therefore, a risk-to-benefit analysis should be conducted when selecting a remedy, particularly when working with the elderly.

A lack of active metabolites in any hypnotic is important. One would look for a compound with a clean profile with defined duration of action and few, if any, residual effects. Preferably, the hypnotic should be metabolized through a mechanism other than the liver enzymes to minimize possible drug-hypnotic interactions. This is particularly important in the elderly population, which is often exposed to multiple drug regimens. Finally, the hypnotic should be of a fixed dose without the need for age-dose adjustment.

Other than the benzodiazepines and some newer hypnotic agents, the use of drugs has been diminished due to high incidence of adverse effects, rapid development of tolerance or chemical dependence, and withdrawal symptoms. The mainstay of pharmacotherapy treatment for insomnia is the benzodiazepines. They have been shown effective in inducing and maintaining sleep. However, all benzodiazepines given at night impair next day performance. This is further exacerbated due to the long acting metabolites (with half-lives ranging from eight hours to 150 hours) that accumulate, causing daytime sedation, amnesia and psychomotor impairment. These side effects pose significant risk in the patient, especially in elderly patients, due to possible falls and fractures. Newer hypnotics are given in low doses (between 5 mg and 10 mg), with side effects of reduced performance and memory loss lasting less than five hours.6 Most hypnotic drugs are given in anticipation of sleep difficulty prior to bedtime and not during the night or repeated at night for fear of residual hangover effects.

Given the drug issues, many consumers experiencing sleep difficulties turn to self-medication with OTC products and natural remedies. Skeptics of this path tend to emphasize the risks associated with adverse effects and possible interactions between existing pharmaceutical regimens and natural sleep therapies. In addition, skeptics raise concerns about a lack of regulatory control during the manufacture of natural remedies, resulting in doubtful purity, safety and efficacy. The issuance of federal good manufacturing practice (GMP) requirements should quell this part of the discussion.

There are three popular natural remedies for treating insomnia. They include the botanicals valerian and kava, and the endogenous human hormone melatonin. This hormone, secreted by the brains pineal gland, is necessary to induce sleep. Its synthesis and release are stimulated by darkness and inhibited by light. Melatonins effect to relieve primary insomnia is not yet established due to variable efficacy compared to currently used hypnotics.7 For this reason, it can be classified as a hypnotic aid recommended for treating abnormalities related to circadian rhythmicity of sleep during the 24- hour day. Disorders of the 24-hour sleep/wake cycle include disorders initiating and maintaining sleep, disorders of excessive sleepiness, disruption of the sleep/wake cycle and parasomnias.

Melatonin acts as an adaptation hormone because it synchronizes the adaptive response of the organism to environmental variables. Normal circadian cycle melatonin levels are low during the day and elevated in the evening. An oral dose of 2.5 mg/d to 5 mg/d raises the serum physiological levels for several hours, rising 40 minutes post administration, peaking at 70 minutes and leveling after four hours. Kinetic studies of circulating melatonin following intravenous or subcutaneous bolus administration demonstrated an elimination phase of 44 minutes in humans.8 Concerns that doses greater than 3 mg can induce hypothermia and daytime sleepiness due to elevated blood melatonin levels are speculative and do not extend to the next days awakening.9,10

This collection of disorders are due to a misalignment between the phase of the individuals sleep/wake cycle. Melatonin has a phase advancing capacity, making it particularly useful for delayed sleep phase, jet lag and work shift and irregular sleep wake pattern. It is also recommended for reducing insomnia of the blind. It is suspected the exact timing of exogenous melatonin administration is critical to its efficacy to induce sleep, with optimal administration prior to the rise of endogenous melatonin levels.11

The effects of exogenous melatonin on body temperature have been extensively studied.12 There is an inverse relationship between melatonin levels and body temperature. The fact that humans fall asleep when the body temperature drops and awaken when body temperature rises suggests sleep may be enhanced by substances, such as melatonin, that reduce body temperature.13 Findings that sleep is disrupted following administration of nonsteroidal anti-inflammatory drugs (NSAIDs) supports this hypothesis, since these drugs decrease melatonin synthesis and are also associated with an increase of body temperature.14 Melatonin levels decrease with age, and elevated body temperatures are often associated with degradation in sleep quality.15 Higher overall body temperatures have been reported for those suffering from insomnia.16

Melatonins side effects are transient, with the most common effects being grogginess, headache and lethargy. These side effects tend to be dose dependent, appearing at high levels approaching gram quantities. Most usage concerns stem from melatonins inconsistent efficacy when used to induce sleep for treating sleep disorders. Some of this poor performance stems from the variable absorption and bioavailability of melatonin due to delivery system and timing of administration. For instance, daytime melatonin administration can have opposite effects, distorting circadian rhythms, inducing fatigue and slowing reaction times.

Oral administration is the conventional and convenient mode of delivery, though it does not always give rise to sufficient plasma concentrations to be effective. Absorption may also be unpredictable. It is believed melatonin must be accessible to all cells and cross all physiological barriers readily, including the blood-brain barrier, to be effective. It therefore makes sense to administer melatonin proximal to the site of its activity. An oral route of absorption fulfills this purpose. The oral cavity is moistened by saliva and is very vascular, making it highly permeable to substances through diffusion. Two potential routes across the mucosa are recognized. The first is the non-polar route, involving partitioning and diffusion through the lipid bilayer of the cells or the intercellular lipid matrix. In this situation, the absorbed material needs to be lipid/oil soluble. The second polar route involves passage of a hydrophilic material through aqueous pores in the cell membrane of individual cells or the ionic channels in the intercellular spaces of the epithelium. In this instance, the absorbed material needs be water-soluble. Melatonin has limited solubility in both water and oil. Lab measurements reveal the following solubilities in specific solvents:

One of the major advantages of oral absorption is the rapid onset of response. When only small amounts of an agent such as melatonin are required to gain access to the blood, absorption typically occurs within 15 minutes from a properly formulated product. Oral absorption provides systemic action, avoiding the acidic, enzymatic environment of the gastrointestinal tract and potentially reducing melatonins side effects. The key is proper formulation. Mixing melatonin with few soluble ingredients and compressing a soluble tablet results in an inadequate product. Melatonin needs to be in a stable soluble form prior to being incorporated in a pleasantly flavored, small, soluble tablet that dissolves completely to allow for complete absorption.

Melatonin meets several criteria of an ideal hypnotic, though it is not considered as such and acts in a supportive capacity by normalizing the inherent body capabilities to shut off in order to rest. People who are stressed and worried during the night experience diminishing melatonin function. In this instance, melatonin tablets would function as a sleeping aid rather than a sleeping pill. The adequate dose of melatonin for treating sleep disorders has yet to be determined; however, most melatonin products on the market range from 1 mg to 10 mg per dose. Care should be exercised for special populations such as children and pregnant women. However available reports indicate positive effects in sleep disorders for children.17

Overall, melatonin is a safe compound and the risk-to-benefit ratio significantly favors the benefit for this important hormone.

Sleeping disorders are a widespread problem that take a serious toll on society and compromise an individuals quality of life. It is imperative these disorders are recognized and treated. Given the plethora of abnormalities that can underlie a restless sleep, it is best to handle the complaint with a combination of approaches. Properly formulated melatonin supplements may be an effective path for some individuals, due to melatonins high benefit-to-risk ratio and its natural approach to re-establishing a healthy sleep pattern.

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