Nonprescription Pharmacotherapies: Alcohol, Over-the-Counter, and Complementary and Alternative Medicines

By | January 19, 2015

A large percentage of individuals with insomnia self-medicate with alcohol, over-the-counter (OTC) antihistamines, or complementary and alternative preparations. In the United States, the formulation and manufacture of OTC products are regulated by the U.S. Food and Drug Administration (FDA). Other products not requiring a prescription, such as dietary supplements, are unregulated. The National Center for Complementary Health and Alternative Medicine (NCCAM) at the National Institutes of Health (NIH) defines “complementary and alternative medicine (CAM)” as “practices that are unproven by science and not presently considered an integral part of conventional medicine”. CAM encompasses a variety of dietary supplements, herbal compounds, or formulations containing a mixture of these. Individuals seeking relief from insomnia may also combine two or more of any agents for insomnia (including prescription medications, OTC agents, alcohol, and CAM preparations). Alcohol is the substance most commonly used to self-medicate for insomnia. Some 1.6 million non-institutionalized adults with insomnia are estimated to use complementary and alternative medicine to treat their insomnia or difficulties in sleeping; 20% of the population using herbals alone. The popularity of CAM in general is increasing; a 2007 national survey of adults and children found that 38.3% of U.S. adults using any CAM increased from 36% in 2002. Of those individuals using CAM in 2007, 1.4% of adults and 1.8% of children were doing so for insomnia. Nonvitamin, nonmineral products accounted for most (17%) CAM use.

Despite the perceived efficacy of these agents by the individuals who use them, there are several concerns associated with their use. There have been very few controlled studies conducted on most of these substances, and the available evidence has demonstrated little or no clinical efficacy. Safety data are similarly scant or lacking. Since CAM preparations are not regulated by the FDA, the consistent potency and product purity are not assured. Compounding this, many herbal products are mixtures of more than one type of herb. The FDA may intervene to remove a product from the market or issue advisories or warnings only when significant safety concerns are evident, as was the case with tryptophan in 1990 and kava kava in 2002. Although generally regarded as benign, the use of complementary and alternative medicine substances may be associated with clinically important and sometimes lethal adverse effects, such as the liver toxicity reported for kava kava, as well as the myriad problems associated with excessive alcohol use. CAM tends to be used more by individuals experiencing insomnia comorbid with other chronic conditions, particularly psychiatric illness (e.g., anxiety and mood disorders), congestive heart failure, hypertension, and obesity. Apart from the fact that comorbid conditions themselves may lower the risk threshold associated with use of certain OTC and CAM products (such as CNS and GI effects with antihistamine use or hepatotox-icity with kava kava), the potential for pharmacologic interactions is also significant. St. John’s wort, for example, is an inducer of cytochrome P450 isoenzymes and has the potential to interfere with protease inhibitors, chemotherapeutic agents, and oral contraceptives. Kava kava, valerian, and St. John’s wort may interact with anesthetics, and tryptophan may have toxic effects when used concomitantly with certain psychiatric medications. Further complicating these issues, most of the OTC and CAM products are perceived by patients to be safe, as they often are touted to be “natural”, or are not considered dangerous since they do not require a prescription. Frequently patients do not report their use of these agents to their physicians when listing their “real” medications and physicians are not necessarily aware that they should inquire about them.

Alcohol

Large-scale studies have estimated that 13% to 28% of individuals with insomnia use alcohol specifically to induce sleep. One Japanese study reported the use of alcohol as a sleep-promoting agent in 48% of male survey respondents. A National Sleep Foundation (NSF) survey conducted in 1991 found that some 30% of their respondents with chronic insomnia used alcohol as a sleep aid, and that 67% of them found it to be effective in reducing sleep latency. Alcohol is a CNS depressant; its hypnotic properties may be a consequence of multiple pharmacologic effects, including its interaction with gamma-aminobutyric acid (GABA) and glutamate. Its effects on sleep have been investigated for decades, often in controlled trials, but frequently with conflicting results. Some studies have shown that alcohol does, in fact, decrease sleep latency, while others have shown that it does not. The effects of alcohol on sleep typically are dose dependent and may also depend upon the chronicity of the insomnia as compared with individuals without insomnia. While total sleep time (total sleep time) is not usually affected by alcohol intake, a dose-dependent redistribution of REM sleep and NREM sleep stages is common, although this has not been demonstrated consistently. A common finding is REM suppression during the first half of the night, followed by REM rebound (or “mini withdrawal”) during the latter half of the night as the alcohol is metabolized and the serum level decreases. An increase in NREM stages 3 and 4 sleep during the first half of the night may be associated with alcohol ingestion, as may an increase in NREM stage 1 and waking in the latter half of the night. Low doses of alcohol have been shown to increase total sleep time and therefore, may result in mildly beneficial effects. Development of tolerance to alcohol develops quickly, often within three nights in healthy volunteers, and is associated with a concomitant return to normal sleep architecture. Use of alcohol as a sleep aid has also been shown to impair secretion of growth hormone (GH), independent of slow wave sleep (slow wave sleep) alterations; exacerbate snoring and sleep apnea; and worsen restless legs syndrome (RLS). Nightly use of alcohol can cause or worsen insomnia or exacerbate other psychiatric conditions such as depression or anxiety. Chronic use of alcohol for insomnia may lead to the development of alcohol dependence. Finally, it has been argued that an improved mood associated with the use of alcohol may be contributing to beneficial effects on sleep. Given the potentially significant problems associated with the regular use of alcohol as a sleep-inducing agent, its use should be discouraged.

Antihistamines

First-generation antihistamines, such as diphenhydramine, doxylamine, chlorpheniramine (as well as the prescription drugs hydroxyzine and doxepin), are pharmacodynamic antagonists at central histamine Hi receptors. The first-generation antihistamines are liposoluble and readily cross the blood-brain barrier, and may be associated with significant anticholinergic and sedative effects, hence their popularity as OTC sleep aids (. Diphenhydramine is by far the most common antihistamine encountered in OTC sleep aids, either by itself (e.g., Nytol ®, Sominex ®) or in combination with pain relievers in “nighttime” or “PM” formulations (e.g., Tylenol PM ®). Diphenhyd ramine has a tmax of 1.7 (±1) hours, a t½ of 9.2 (±2.5) hours, and a duration of action of approximately 12 hours. Subjective improvement of sleep onset and sleep quality are common in subjects taking diphenhydramine (typically at a dose of 25-50 mg), but few randomized, placebo-controlled studies assessing the safety and efficacy of diphenhydramine in the treatment of insomnia have been conducted. Efficacy in at least one sleep parameter has been demonstrated in populations of adults, geriatric subjects (including those in long-term care), pediatric subjects, and psychiatric patients. A 1983 double-blind, placebo-controlled, crossover study evaluated the use of diphenhydramine 50 mg in adult subjects complaining of difficulty with sleep onset. On the basis of subjective assessments (daily sleep logs), diphenhydramine was significantly more effective than placebo at decreasing sleep latency, decreasing frequency of awakenings, decreasing wake time after sleep onset (WASO), increasing sleep duration, and increasing quality of sleep. Subjective physician assessment of efficacy was similar.

While diphenhydramine has been shown to be associated with sedation and improvement in sleep parameters such as sleep onset, duration, and quality, it also is associated with significant safety concerns regarding its relatively long half-life and its anticholinergic properties resulting from postsynaptic muscarinic receptor antagonism. Complaints of residual sedation, drowsiness, or grogginess during the morning or daytime following bedtime use are common. The anticholinergic activity has the potential to cause other side effects, such as diminished cognitive function and delirium, dry mouth, blurred vision, urinary retention, constipation, and risk of increased intraocular pressure in individuals with narrow-angle glaucoma. Undesired sedation, delirium, and anticholinergic effects are of particular concern in geriatric patients. Additionally, there are potential pharmacokinetic and pharmacodynamic interactions with concomitant medications, complementary and alternative medicine substances, and alcohol. Caution is advised when patients are taking other medications with anticholinergic effects. Diphenhydramine also exacerbates the adverse effects of ethanol upon oculomotor coordination, cognitive function, and driving ability. An additional concern with the use of diphenhydramine as a sleep aid is the possible development of tolerance to its sedating effects. In one study in healthy volunteers, diphenhydramine was administered 50 mg twice daily and sleepiness was assessed both objectively and subjectively throughout the day. Development of tolerance to the sedating effects of diphenhydramine was observed after administration of the medication for four consecutive days. The development of tolerance results in reduced efficacy and may contribute to the development of dependence or abuse. Tolerance to the antihistamine sedating effects may lead to dose escalation and other possible reinforcing effects, such as euphoria. Antihistamine abuse has been documented; case reports exist for doses of diphenhydramine as high as 3000 mg per day. The position of the American Academy of Sleep Medicine (AASM) on diphenhydramine is as follows: “Sufficient evidence does not exist to support over-the-counter (OTC) sleep aids … OTC sleep aids that contain antihistamine may provide modest, short-term benefits for adults with mild cases of insomnia. It is important to be aware, however, that the use of antihistamines may produce a variety of side effects”.

Melatonin

Melatonin is a pineal hormone involved in the regulation of circadian rhythms. Although it has sleep-promoting effects on healthy volunteers and has been assessed in a small number of controlled clinical trials, its efficacy in the treatment of insomnia has not been well established, and some controlled studies have shown it to be indistinguishable from placebo. Melatonin generally is considered to be safe, but its safety in long-term use has not been demonstrated. Melatonin is a very popular dietary supplement. The 2002 Alternative Health / Complementary and Alternative Medicine Supplement to the National Health Interview Survey (NHIS) interviewed an age and socioeconomically representative population of 31,044 individuals about use of 25 pharmacologic and nonpharmacologic complementary and alternative medicine therapies, including melatonin. The use of melatonin was reported by 5.2% of the respondents and of those individuals, 27.5% identified insomnia as at least one reason for its use. Most melatonin use occurred without physician consultation. A retrospective meta-analytic study was conducted in 2005 by Buscemi and colleagues evaluating the safety and efficacy of melatonin in the treatment of primary insomnia. Initially, 1884 melatonin studies were identified; however, only 14 met the randomized-controlled trial criteria for assessment of efficacy and only 10 met the criteria for safety assessment. Mean improvement of sleep latency was 11.7 minutes. Two studies in the insomnia meta-analysis also investigated the efficacy of melatonin in shortening sleep onset in subjects with delayed sleep phase syndrome (DSPS). Subjects with DSPS taking melatonin experienced an average improvement in sleep latency of 38.8 minutes, as compared with 7.2 minutes in subjects with insomnia. The meta-analysis also assessed secondary outcome measures such as sleep efficiency, sleep quality, wakefulness after sleep onset (WASO), total sleep time, and percentage of time spent in REM sleep. None of these secondary measures reached statistical significance. Safety assessment (headache, nausea, dizziness, drowsiness) showed no significant difference in adverse events between melatonin and placebo. The study group for the meta-analysis concluded that there was little evidence supporting the use of melatonin as an exogenous sleep aid, although it might be useful for treating DSPS. The researchers also concluded that melatonin appears to be safe, at least for short-term use (up to three months).

A second meta-analysis by Brzezinski and colleagues evaluated the effects of exogenous melatonin on sleep in 17 randomized, double-blind, placebo-controlled trials using objective measures of sleep evaluation and including at least six adult subjects with no severe disabling systemic disease. Crossover and parallel group designs were included, but case studies were not. This meta-analysis was a review of the trials investigating the effects of melatonin on sleep and not on insomnia per se. However, nine of the trials in this meta-analysis involved participants with insomnia (five of the insomnia studies were also included in the Buscemi meta-analysis). In a subanalysis of healthy subjects with no relevant medical condition other than insomnia, subjects administered exogenous melatonin had shorter sleep onset by an average of 3.9 minutes, higher sleep efficiency by an average of 3.1%, and a longer total sleep time by an average of 13.7 minutes. The authors concluded that there was statistically significant evidence demonstrating that the use of exogenous melatonin improves sleep latency, sleep efficiency, and total sleep time. However, it remains unclear whether these modest changes represent clinically significant improvements. The meta-analysis authors also concluded that melatonin generally is safe, at least for short-term use in adults.

The role of melatonin in sleep-wake regulation and the use of exogenous melatonin and melatonin agonists as sleep aids is discussed further in site.

L-tryptophan

L-tryptophan is an essential amino acid and dietary precursor of serotonin. The role it plays in the biochemistry of sleep and its impact on sleep architecture have not been fully elucidated, although it has been regarded as a “natural” sleep aid. Its purported positive effects on sleep onset and maintenance are based on very few and mostly uncontrolled clinical studies that often included noninsomniac subjects. L-tryptophan may be most beneficial in subjects with mild insomnia or in normal subjects with situational insomnia accompanied by longer-than-average sleep onset. Tryptophan generally is considered to be safe and reportedly is not associated with visuomotor, cognitive, or memory impairment. However, L-tryptophan as a supplement was removed from the market in 1989 because of the development of an often serious and sometimes fatal (37 attributed deaths) eosinophilia myalgia syndrome (EMS) in some individuals who had taken one of several tryptophan-containing products. The cause of the eosinophilia myalgia syndrome was ultimately traced to a contaminant from a single manufacturer, and L-tryptophan is once again available. Nevertheless, the NIH chronic insomnia State-of-the-Science summary report cautions against the use L-tryptophan due to possible adverse effects, particularly if used in conjunction with psychiatric medications. When concern about L-tryptophan developed and its availability became limited, 5-hydroxy-L-tryptophan (5-HTP, the immediate precursor to serotonin, or 5-HT) grew in popularity as a “natural hypnotic.” After the L-tryptophan recall, scrutiny of 5-HTP for serious adverse events was high, but no definitive toxicity with use of the agent has been confirmed. 5-HTP is commercially produced by extraction from the seeds of Griffonia simplicifolia, a woody African shrub. Effects of 5-HTP on insomnia are inconclusive.

Herbal Preparations And Dietary Supplments

Summary

A variety of nonprescription pharmacologic agents are widely used as sleep aids (Table Nonprescription Pharmacotherapeutic Agents used as Sleep Aids). Although the most frequently used substance to induce sleep, alcohol has not been determined to be safe or efficacious as a sleep aid or in the treatment of insomnia. OTC antihistamine sleep aids may be popular because they are readily accessible, do not require a prescription, and are perceived to be safe. Herbal and dietary supplements, such as melatonin and valerian, may be appealing to consumers because they are viewed as “natural” products. Accordingly, it are not surprising that the use of OTC and CAM compounds is widespread. However, data are scant or lacking on the safety and efficacy of most of these agents, some can have serious side effects or cause significant drug interactions, and consistent purity and concentration of the unregulated marketed agents are not assured. Increased awareness of the potential safety issues associated with OTC and complementary and alternative medicine agents is required by both consumers and health care professionals alike.

Table Nonprescription Pharmacotherapeutic Agents used as Sleep Aids

Nonprescription agent Reported effects on sleep in > 1 study Safety concerns
Alcohol
Alcohol Decreases sleep latency

Does not decrease sleep latency

↑ Total sleep time by low doses

↓ REM first half of night

↑ REM latter half of night

↑ NREM 3 / 4 first half of night

↑ NREM 1, ↑ waking in second half of night

Tolerance

↓ Secretion GH

↑ Snoring, sleep apnea

Worsens RLS

Cause or worsen insomnia

Exacerbate comorbid psychiatric conditions

Dependence

Antihistamines
Diphenhydramine Subjective (physician and subject) improvement of sleep onset and quality, ↓ awakenings, ↑ total sleep time

Efficacy in at least one sleep parameter seen in adults, geriatric subjects, pediatric subjects, and psychiatric patients

Anticholinergic effects, particularly in older individuals

Residual sedation, grogginess; long half-life

Interaction with concomitant medications, CAM agents, alcohol

Tolerance

Abuse

Dietary Supplements
Melatonin ↓ Onset in some studies

Effective in DSPS

Essentially not different from placebo; safe in short-term (< 3 months)
L-tryptophan Might be beneficial in mild or situational insomnia Removed from market in 1989 due to fatality-related impurities; has since been restored with caveats

Possible interactions if used with psychiatric medicines

Valerian Significant improvements in both objective and subjective measures of sleep onset, WASO, and sleep quality have been reported

Not been shown to affect sleep architecture

Potential interaction with alcohol, anesthetics, the CYP3A4 metabolic pathway, and sedatives

Hallucinations, hepatotoxicity, and withdrawal effects have been reported

Kava kava Sleep-promoting effects have been observed in anecdotal / uncontrolled studies

Improvement in stress-related insomnia symptoms in 1 trial

Interaction with CNS depressants and

dopamine antagonists

Significant hepatotoxicity that can lead to liver transplantation and death

Warning: do not take with hepatic impairment

St. John’s wort Inconsistent results of ↑ latency to REM sleep, ↑ % slow wave sleep Fatigue, Gl upset, dizziness, anxiety, headache, photosensitivity, phototoxicity

Significant concern with drug interactions; induces several CYP450 enzymes, especially CYP3A4

Studies: may cause decreased concentrations of or have significant interactions with certain prescription medications

Warning: do not take concomitantly with medications that are metabolized by the CYP 450 system

Nicotinamide ↑ REM sleep (68; small, uncontrolled trial)

↑ Sleep efficiency (68; small, uncontrolled trial)

 

Abbreviations: CAM, complementary and alternative medicine; DSPS, delayed sleep phase syndrome; GH, growth hormone; Gl, gastrointestinal; NREM, non rapid-eye movement (sleep); REM, rapid-eye movement (sleep); RLS, restless leg syndrome; slow wave sleep, slow wave sleep; total sleep time, total sleep time; WASO, wakefulness after sleep onset.