Download Over-the-Counter Sleep Aid Medications and Insomnia

CLINICAL FOCUS
CME
Primary Psychiatry. 2008;15(5):52-58
3
Over-the-Counter Sleep Aid
Medications and Insomnia
Surilla Randall, PhD, Timothy A. Roehrs, PhD, and Thomas Roth, PhD
ABSTRACT
Needs Assessment: Chronic insomnia is reported by 10% to 15% of the population
insomnia self treatment are ineffectiveness, tolerance, dependency,
and the morbidity of untreated insomnia is now well documented. Beyond the quality
of life and psychosocial risks, insomnia is associated with increased risk of psychiatric
disorders and exacerbation of medical disorders. Medical treatment of chronic insomnia with Food and Drug Administration-indicated drugs is not common, but insomniacs
do use other available substances and physicians prescribe off-label medications.
Insomniacs’ use of ineffective and in some cases potentially dangerous self treatments
is not fully appreciated as a risk of not treating the patient presenting with insomnia.
Insomniacs use various over-the-counter medications and herbal substances for which
there is limited data regarding their efficacy and safety. This article provides an overview of the available information regarding these various self-treatments.
and potentially harmful side effects. Studies of OTC sleep aids and
Learning Objectives:
Insomnia is defined as difficulty initiating or maintaining sleep
and/or nonrestorative sleep which impairs daytime function. Self
treatment with over-the-counter (OTC) sleep aids, herbal and dietary
supplements, and/or alcohol is common. Problems associated with
• List the major categories of over-the-counter (OTC) sleep aids.
• Describe the current hypotheses of the mechanisms in which the various OTC sleep
aids work.
• Explain the concerns regarding the safety and efficacy of insomnia self treatment.
other non-prescription sleep aids such as antihistamines, valerian,
melatonin, and L-tryptophan have inconsistent results and lack
objective data on both their efficacy and safety. Lastly, alcohol
should never be used as a sleep aid due to its abuse liability.
Target Audience: Primary care physicians and psychiatrists.
CME Accreditation Statement: This activity has been planned and implemented in
INTRODUCTION
Credit Designation: The Mount Sinai School of Medicine designates this educational
accordance with the Essentials and Standards of the Accreditation Council for Continuing
Medical Education (ACCME) through the joint sponsorship of the Mount Sinai School of
Medicine and MBL Communications, Inc. The Mount Sinai School of Medicine is accredited
by the ACCME to provide continuing medical education for physicians.
activity for a maximum of 3 AMA PRA Category 1 Credit(s)TM. Physicians should only claim
credit commensurate with the extent of their participation in the activity.
The Diagnostic and Statistical Manual of Mental Disorders,
Fourth Edition, Text Revision,1 defines primary insomnia as
difficulty initiating or maintaining sleep and/or poor quality
(nonrestorative) sleep for at least 1 month, which has some
daytime consequences. The duration of insomnia can be transient (days to several weeks) or chronic (≥1 month). Insomnia is
associated with impairments in social, occupational, and other
areas of functioning. Sleep disturbances can have a significant
negative impact on daytime function, evident by mental slowing, reduced concentration, memory lapses, and decreased
motivation. Insomnia can be associated with medical conditions, medication use, psychiatric disorders, substance abuse, or
other primary sleep disorders (eg, sleep apnea, restless leg syndrome). However, primary insomnia is a disorder independent
of these other conditions.
Epidemiologic studies report varying estimates of insomnia
prevalence. The estimates are dependent upon whether the
Faculty Disclosure Policy Statement: It is the policy of the Mount Sinai School
of Medicine to ensure objectivity, balance, independence, transparency, and scientific
rigor in all CME-sponsored educational activities. All faculty participating in the planning or implementation of a sponsored activity are expected to disclose to the audience
any relevant financial relationships and to assist in resolving any conflict of interest
that may arise from the relationship. Presenters must also make a meaningful disclosure to the audience of their discussions of unlabeled or unapproved drugs or devices.
This information will be available as part of the course material.
This activity has been peer-reviewed and approved by Eric Hollander, MD, chair and
professor of psychiatry at the Mount Sinai School of Medicine, and Norman Sussman,
MD, editor of Primary Psychiatry and professor of psychiatry at New York University
School of Medicine. Review Date: March 27, 2008.
Drs. Hollander and Sussman report no affiliation with or financial interest in any
organization that may pose a conflict of interest.
To receive credit for this activity: Read this article and the two CME-des-
ignated accompanying articles, reflect on the information presented, and then
complete the CME posttest and evaluation found on page 85. To obtain credits,
you should score 70% or better. Early submission of this posttest is encouraged:
please submit this posttest by May 1, 2010 to be eligible for credit. Release date:
May 1, 2008. Termination date: May 31, 2010. The estimated time to complete all three
articles and the posttest is 3 hours.
Dr. Randall is postdoctoral fellow in the Sleep Disorders and Research Center at the Henry Ford Hospital in Detroit, MI. Dr. Roehrs is director of research at the Sleep Disorders and Research Center at the Henry Ford
Hospital and professor of psychiatry in the Department of Psychiatry and Behavioral Neuroscience at Wayne State University School of Medicine in Detroit. Dr. Roth is director of the Sleep Disorders and Research
Center at the Henry Ford Hospital and professor of psychiatry in the Department of Psychiatry and Behavioral Neuroscience at Wayne State University School of Medicine.
Disclosure: The authors report no affiliation with or financial interest in any organization that may pose a conflict of interest.
Please direct all correspondence to: Surilla Randall, PhD, Henry Ford Hospital Sleep and Research Center, CFP-3, 2799 West Grand Blvd, Detroit, MI 48202; Tel: 313-916-5301: Fax: 313-916-2508;
E-mail: [email protected].
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Over-the-Counter Sleep-Aid Medication and Insomnia
data come from patient care settings; female, elderly, or general
populations; or the study’s definition of insomnia.2 Taking into
consideration the various adult insomniac populations, prevalence estimates range from approximately 10% to 50%. When
including only chronic insomnia the prevalence range decreases
from 10% to 15%.3-6
Insomnia predisposes one to psychiatric disorders, aggravates
medical conditions, decreases the quality of life, and increases
the risk of drug and alcohol abuse.7 Greater than 50% of those
with depression, psychosomatic disorders, anxiety disorders,
neuroses, dementia, and schizophrenia have insomnia complaints.8 In some cases, treating the underlying mental disease
may not improve the insomnia.
Self treatment with over-the-counter (OTC) sleep aids,
herbal and dietary supplements, and/or alcohol is common
among insomniacs. It is thought that the availability of these
products, decreased cost compared to prescription sleep aids,
and importantly, perceived safety results in the great usage of
OTC sleep aids.9-11 A metropolitan Detroit study10 showed that
25.9% of respondents reported using some substance to aid
their sleep. Of those who used medications (either prescription, OTC sleep aids, or both) to improve sleep, 57% reported
using OTC sleep aids. In a recent study,12 approximately 25%
of patients with insomnia used OTC sleep aids, and 5% used
these drugs several times a week. A study of insomniac women
≥85 years of age noted that the respondents reported they did
not see a physician or nurse practitioner for insomnia until the
self treatment (with alcohol, OTC sleep aids, or both) was no
longer effective.13 The problems associated with insomnia self
treatment are use at higher than recommended doses, tolerance
resulting from loss of efficacy, and the development of dependency in at-risk populations. There are even greater concerns
with alcohol used as a sleep aid. Ineffective and potentially
harmful self treatment is not fully appreciated as a risk of not
treating insomnia medically with drugs exhibiting efficacy
and safety profiles. This article provides an overview of what
is known regarding the efficacy and safety of popular nonprescription products used for insomnia.
Diphenhydramine
In 1982, the Food and Drug Administration authorized the
initial marketing of diphenhydramine HCl and diphenhydramine citrate as active ingredients in non-prescription sleep
aids. Other general medical uses include relief of allergies,
motion sickness, and coughing. Table 1 lists the various OTC
products and their doses. For sleep, the available dose range of
diphenhydramine is 25–50 mg, with 50 mg being the maximum dose to be taken 30–60 minutes before bed.14,15 While
marketed for allergy relief, Benadryl, which contains 12.5 or
25 mg of diphenhydramine depending on the formulation, is
commonly used for sleep. Diphenhydramine citrate is often
combined with an analgesic; together they are advertised to
provide pain relief and induce sleep (Table 1).
Diphenhydramine has a half-life of 5–12 hours and has significant anticholinergic activity. Consequently, its use is associated with next-day mild-to-moderate side effects, namely residual morning sedation, dry mouth, grogginess, and malaise.15,16
Importantly, it has not been determined which aspects of its
pharmacologic activity are mediated by H1 receptors and which
are mediated by cholinergic receptors. Despite the reported side
effects of diphenhydramine, virtually all OTC sleep aids contain
diphenhydramine as the active ingredient (Table 1).
The use of diphenhydramine is common, but the number
of controlled trials that support its efficacy are limited and
many lack objective data. Several studies show evidence of
sedative properties. One-week administration of diphenhydramine (50 mg) significantly decreased self-reported
sleep latency and improved sleep depth and quality.16
Similar results were reported in psychiatric patients with
insomnia following nightly administration of 12.5–50 mg
of diphenhydramine for 2 weeks. Sleep quality, duration
of sleep, and severity of insomnia symptoms significantly
improved as measured by self reports.15 Interestingly, global
improvements in sleep were significantly greater in those
who had not received previous treatment for insomnia.15
This finding suggests drug tolerance, cross-drug tolerance,
or that the efficacy of diphenhydramine is not as robust
as other pharmamocologic treatments. Tolerance to the
hypnotic effects of diphenhydramine was evident on both
objective and subjective measures of sleepiness following
3–4 days of administration.17 Thus, only short-term use is
recommended since physical tolerance, can develop.17,18
For several reasons, it is advised that those with chronic
medical conditions should not take diphehydramine, and
specific precautions should be considered in those with cardiovascular disease, hypertension, or lower respiratory disease.
Diphenhydramine produces additive central nervous system
effects when taken concomitantly with alcohol, hypnotics, anxiolytics, narcotic analgesics, and neuroleptic drugs. Similarly,
significant interactions may occur if the drug is taken concomitantly with anticholinergic agents or tricyclic antidepressants.
ANTIHISTAMINES
Antihistamines consist of a broad class of pharmacologic
agents that include the first-generation, central acting histamine
(H)1 receptor antagonists. The primary action of this drug class
is to block the effects of histamine, which reduces congestion,
sneezing, coughing, and allergy symptoms. Centrally, these
drugs block histamine receptors, histamine being one of the
major alerting central neurotransmitters. Due to the sedative
action of antihistamines, they are widely used as non-prescription sleep aids. Evidence appears to suggest that antihistamines
may be useful for insomnia for 1–2 nights, but not efficacious
in treating chronic insomnia.
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S. Randall, T.A. Roehrs, T. Roth
Doxylamine
TABLE 1
Active Ingredients
Brand Name
Dose (mg)
Diphenhydramine HCl
Nytol Sleep Aid
(Regular Strength)
Sominex Original Formula
Tylenol Simply Sleep
Nytol Sleep Aid
(Extra Strength)
Sominex
Maximum Strength Formula
Unisom
SleepGels Maximum Strength
25
Doan’s PM Nighttime Back
Pain Relief & Sleep Aid
Legatrin PM
25
Diphenhydramine Citrate
(pain relief with sleep
aid)
Excedrine PM
Advil PM
Bayer PM
38
38
38.8
In 1978, the FDA approved doxylamine succinate as an active
ingredient for OTC sleep aid use. Doxylamine succinate mediates its activity through the H1 receptor. Doxylamine has minimal
effects on sleep onset due to its relatively long time to maximum
plasma concentration. The time for sleep to be achieved is 45–60
minutes after oral administration. The peak plasma concentration
is not reached until 90 minutes after administration. Using patient
report outcomes, doxylamine (25 mg) for 1 week significantly
decreased sleep latency.19 The authors of this article are unaware of
any further published OTC efficacy studies for doxylamine. The
elimination half-life is 10.1 hours. Thus, upon waking, plasma
levels of doxylamine are present; consequently, residual daytime
sedation is a documented side effect. Doxylamine is also potentially
dangerous in accidental or intentional overdose. Rhabdomyolysis
and secondary acute renal failure are rare but potentially serious
complications, making early recognition and treatment essential.20
H1 antihistamines are not recommended for the elderly due to
potential adverse effects and drug interactions. Doxylamine shares
the same mechanism of action as diphenhydramine and the potential for tolerance to doxylamine’s sedative effects exists.
Doxylamine Succinate
(pain relief with sleep aid)
Unisom SleepTabs
Goodsense Sleep Aids Tablets
Kirkland Nighttime Sleep Aid
25
25
25
SUPPLEMENTS AND HERBS
OTC SLEEP-AID MEDICATIONS*
Antihistamines
Diphenhydramine HCl
(pain relief with sleep aid)
25
25
50
50
50
50
In the United States, usage of complementary and alternative
medicines showed a secular upward trend from 33.8% to 42.1%
for treatment of any health condition between 1990 and 1997.
In comparison, treatment for insomnia rose from 20.4% in
1990 to 26.4% in 1997.21 Supplements and herbs are perceived
as “natural” and, therefore, a safe alternative to prescription
medications and some OTC products. The FDA does not rigorously test or regulate manufacturing of supplements and herbs.
Currently, no FDA regulations specific to dietary supplements
require a minimum standard for manufacturing of dietary supplements. Thus, the manufacturer is responsible for the strength,
purity, composition, and safety of their products. According to
FDA regulations, supplement manufacturers are forbidden to
market their product as a treatment, prevention, or cure, for any
medical disorder, including insomnia.
Supplements and herbs have reported side effects and inconsistent clinical findings, so the risk to benefit is questionable.
Care should be used when taking these substances because they
still cause physiologic changes in the body and can interact
with other medications (Table 2).
Herbs and Supplements
Melatonin
Melatonex
Nature’s Bounty
Natrol
Nature Made
GNC Melatonin
3
1/3/5†
3/5†
3
1/3†
Valerian
Nature Made
Nature’s Resource Valerian
Herbal Plus Valerian Root
Nature’s Fingerprint
Valerian Root
400
400
500
500
St. John’s Wort
Nature Made
Sundown
Nature’s Resource Time Release
Nature’s Fingerprint
150
300
450
500
Tryptophan
Cyence Labs L-Tryptophan 500
Xenadrine Sleep Plus with LTryptophan
Cyence Labs L-Tryptophan 1,000
500
500
1,000 mg
Valerian
* This table is not exhaustive, but it represents active ingredients found in OTC sleep-aid
medications that purport sleep-inducing properties.
Valerian is a flowering plant that includes >200 species. The
species Valeriana officinalis is most often used in the treatment
of anxiety and insomnia. Valerian preparation methods vary
with several different extraction methods used. The aqueous
† Can be purchased at multiple doses.
OTC=over-the-counter; GNC=General Nutrition Centers.
Randall S, Roehrs TA, Roth T. Primary Psychiatry. Vol 15, No 5. 2008.
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Over-the-Counter Sleep-Aid Medication and Insomnia
extraction method produces doses range from 270–900 mg
and ethanolic valerian extraction doses range from 300–600
mg.22 Other valerian species (V. edulis and V. wallichii) have
active ingredients that are minimally present in V. officinalis.
The chemical ingredients in valerian products vary depending on the plant species and the extraction method. Valerian
roots are prepared as teas and dried plant material and extracts
are compounded into capsules or incorporated into tablets. A
possible mechanism in which valerian causes sedation is by
inhibition of the breakdown of γ-aminobutyric acid (GABA)
or GABA-like metabolites.23
The sleep research evaluating the efficacy of valerian as a
sleep aid has produced inconsistent results. Variations in study
participants, study design, and methodology; valerian preparation; dose; and sleep assessment measures likely account for the
mixed results for valerian.
Valerian 400 mg administered on three nonconsecutive nights
produced a significant decrease in self-reported sleep latency,
which was notable in people >40, men, and those who considered themselves poor or irregular sleepers. Poor or irregular
sleepers and those who considered themselves as having long
sleep latencies also reported significant improvements in sleep
quality.24 Significant decreases in self-reported sleep latencies
were also found in healthy subjects without major sleep disturbances following one valerian dose of either 450 or 900 mg.
Only the 900 mg dose reduced wake time after sleep onset using
self reports. The self ratings of sleep quality were not significantly
different among treatments (0, 450, and 900 mg).
In an uncontrolled case study, insomniacs receiving mental
health services took valerian for 14 days to supplement their
psychotropic regimen. Doses of valerian started at 470 mg
(one pill) on nights 1–3 and the insomniacs could increase
their dose to a maximum of 1,410 mg (three pills) after week
1. Dose escalation occurred if lower doses proved to be insufficient. After 1 week of treatment, 11 of the 20 participants
reported that valerian “moderately” improved their insomnia
at the 940 mg dose (two pills). By week 2, all increased their
dose to 1,410 mg, nine rated their insomnia “moderately to
extremely” improved, and six rated their insomnia “extremely”
improved.25 There was no discussion as to what aspect of their
sleep disturbances was improved.
Chronic insomniacs were given valarian 450 mg for 1 week
and were required to maintain sleep diaries. Valerian was not
shown to be appreciably better than placebo adminstration in
a series of randomized n-of-1 trials.26 Similarly, valerian (6.4
mg) for 28 days did not relieve insomnia or anxiety to a greater
extent than placebo in an Internet-based study. Adverse events
occurred with similar frequency between the treatment group
and the placebo group except that significantly more reports
of diarrhea (18% of 114) occurred in the valerian group compared to those receiving placebo (8%).27
Polysomnography (PSG), the concurrent recording of electroencephalograph (EEG), electromyogram, and electrooculogram, is the standard method of objectively assessing sleep. It
is often combined with computer analyses of EEG frequency
and power (ie, spectral analyses). PSGs and spectra analyses of
sleep EEG showed no significant differences between a 900 mg
valerian dose and placebo administration in healthy volunteers.
No adverse events or side effects were reported.28 Results of
objective assessments of sleep latency have varied. Actigraphy,
recording movements of arms or legs, is a less labor-intensive
and intrusive method of assessing sleep than PSG. Actigraphs,
worn by eight mild insomniacs, showed decreases in sleep
latencies following valerian 450 mg for 4 nonconsecutive
nights. In contrast, 900 mg did not produce a further improvement in sleep latencies and the higher dose had significantly
greater morning sleepiness associated with it.29 In a PSG study,
no significant decrease in sleep latency was demonstrated following 8 consecutive days of valerian (405 mg on day 1 and
1,215 mg on days 2–8) in 14 elderly female insomniacs. On
other sleep measures, this dosing produced selective effects on
non-rapid eye movement (REM) sleep stages. Non-REM is
characterized by slower brain activity, divided into sleep stages
1–4, and is not associated with dreaming. Relative to baseline,
valerian decreased the percentage of stage 1 sleep on night
1 and further decreased it on night 8. No systematic change
occurred in the placebo group. Slow wave sleep (SWS; sum of
sleep stages 3 and 4) significantly increased from baseline to
TABLE 2
SIDE EFFECTS WITH NONPRESCRIPTION SLEEP AIDS
Sleep Aid
Side Effects and Precautions
Antihistamines
Residual daytime sedation, drowsiness, dry mouth, tolerance, may interact with other medications
Valerian
Headache, dizziness, gastrointestinal disturbances, daytime
sleepiness, nervousness, anxiousness, heart palpitations
St. John’s wort
Increase sensitivity to sunlight, anxiety, dry mouth, dizziness, gastrointestinal symptoms, fatigue, may interact
with other antidepressants
Kava
Skin rash, tiredness, gastrointestinal disturbances,
muscle weakness, loss of coordination, vision changes,
drinking alcohol can be contraindicated, liver disease
with excessive use
Melatonin
Headaches, daytime sleepiness, dizziness, nausea, abdominal discomfort, confusion, sleepwalking or nightmares
L-Tryptophan
Drowsiness, dizziness, dry mouth, headache, nausea,
may interact with other antidepressants, avoid excessive exposure to ultraviolet light to reduce the chance of
cataract formation
Alcohol
Dependency, tolerance, negative impact on the sleep quality,
disturbs sleep cycle, can cause snoring, can cause apnea
episodes in those who do not normally have symptoms.
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S. Randall, T.A. Roehrs, T. Roth
night 8. REM sleep (sleep stage characterized by active brain
waves and dreams) was unaltered by valerian.30
Sixteen insomniacs given valerian 600 mg for 14 days
showed significant decreases in SWS latency in comparison
to placebo, and a significant increase in the percentage of
SWS compared to baseline as measured by PSG. Other sleep
parameters were not significantly altered. Only three independent side effects or adverse effects occurred following valerian
administration, which included one episode of gastrointestinal
complaints, migraine, and an accident associated with the
PSG procedures. Subjective measures of sleep and other sleep
parameters were not significantly altered.31 Overall, these
double-blind data suggest that although valerian is safe it does
not improve the symptoms of disturbed sleep.22 It would be
interesting to pursue the question of the increase in slow-wave
sleep, its clinical significance, and the degree to which this is
mediated by GABA.
Valerian is frequently combined with other herbal extracts
such as hops and lemon balm, each purportedly having their
own sedative or tranquilizing effects. A valerian preparation
(valerian 400 mg, hops 375 mg, and lemon balm 160 mg) was
rated better than control following one night of administration. No side effects were reported with this preparation.32 In
contrast, for 3 nonconsecutive nights a commercial preparation
of valerian 120 mg and hops 60 mg produced no significant
change in sleep latency or sleep quality on subjectively rated
sleep measures in healthy normal volunteers. This valerian preparation resulted in significantly greater reports of “more sleepy
than usual” responses in comparison to the placebo group.33
Similar results were reported in mild insomniacs administered
a valerian (374 mg)-hops (83.8 mg) combination for 28 days.
This dosing and duration failed to produce a significant effect
in sleep parameters using sleep diaries and PSG.
analysis of kava in the treatment of anxiety reported adverse
events such as stomach complaints, restlessness, tremor, headache and tiredness (Table 2).35
Stress-induced insomnia was ameliorated after 6 weeks of 120
mg of kava and further improved by 6 weeks of valerian (600 mg)
as measured by sleep questionnaires. There was a 2-week wash-out
period between both treatments and, importantly, sleep during
the washout did not differ from baseline. Side effects of kava
included, diarrhea, gastric disturbances, and dry mouth.36
A frequent symptom associated with anxiety disorder is sleep
disturbances. Kava 300 mg for 28 days did not significantly
relieve anxiety or insomnia symptoms using the Insomnia Severity
Index and State-Trait Anxiety Inventory, respectively.27 In contrast,
significant improvements relative to placebo in sleep quality and
the recuperative effects of sleep as well as decreases in anxiety
were demonstrated in patients with sleep disturbances associated with anxiety of non-psychotic origin following kava 200
mg (WS®1490) for 4 weeks.37 Sleep questionnaires such as the
Hamilton Rating Scale for Anxiety, self-rating scales of well being,
and the Clinical Global Impressions scale showed improvements
in sleep and anxiety. No drug-related adverse events or changes in
clinical or laboratory parameters were noted.
As is the case in many of these products, there are some noncontrolled data suggesting efficacy. However, objective and/or
other placebo controlled trials that further suggest efficacy
for insomnia are limited. Further, the benefit has to balanced
against the risk, and the potential of liver toxicity in the case of
kava cannot be dismissed.
St. John’s Wort
Melatonin
St. John’s wort (hypericum perforatum) is the medicinal herb
used for a variety of ailments including depression, anxiety,
and fatigue. The active components are thought to be hyperforin and hypericin, although different formulations vary in
their level of constituents.34 Most clinical studies focus on the
treatment of depression rather than insomnia. No published
double-blind placebo controlled studies were found using St.
John’s wort to ameliorate primary insomnia.
The pineal gland produces the neurohormone melatonin (Nacetyl-5-methoxytryptamine). Synthesis and secretion occurs
nocturnally by darkness and is inhibited by environmental
light, which suggests that melatonin is involved in modulating
circadian rhythm. Melatonin secretion starts at approximately
9:00pm and peaks between 2AM and 4AM.38 Melatonin
supplements are commonly used to combat jet lag and sleep
disturbances, to protect cells from free-radical damage, and for
enhancement of immune function. The mechanism by which
melatonin affects sleep, beyond its circadian signaling capability (phase shifting), is unknown, but it likely involves stimulation of melatonin receptors.8
The half-life of melatonin ranges from 0.54–2 hours; with
doses ranging from 0.3–5.0 mg, melatonin is less likely to cause
residual daytime drowsiness. Side effects reported in the literature included headache, odd taste in mouth, and poor sleep
quality (Table 2).39 Melatonin supplements are relatively safe
NEUROHORMONES AND TRANSMITTER
PRECURSORS
Kava
Kava (or kava kava) comes from the roots of the Polynesian
plant Piper methysticum is indigenous to the South Pacific.
Supplements containing kava are marketed to alleviate menopausal symptoms, anxiety, and insomnia. Liver damage may
be a risk factor associated with kava, and the FDA issued an
advisory to consumers of this important potential risk. A metaPrimary Psychiatry
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Over-the-Counter Sleep-Aid Medication and Insomnia
when used short term over days or weeks. However, the safety
of melatonin over months has not been studied.
Riemann and colleagues40 showed significant decreases
in nighttime melatonin concentrations in insomniacs, and
others have shown delays in melatonin secretion. However,
several double-blind, placebo-controlled studies have failed
to show the effectiveness of supplemental melatonin in treating primary insomnia. Melatonin in doses that range from
0.3–5 mg showed no significant differences over placebo
in sleep measures such as sleep efficiency; total sleep time;
latency to sleep; number of nocturnal awakenings; average
length of the non-REM-REM cycle; percent of stage 1, 2,
delta sleep, and REM sleep; total minutes of each sleep stage;
and in the latency to REM sleep. The lack of hypnotic activity was evident when measured by self reports or by PSG
measures.39-43 MacFarlane and colleagues44 found a significant
improvement in subjective assessments of sleep and daytime
alertness in insomniacs given a much larger dose, 75mg, in a
single, crossover placebo-controlled study. It is important to
recognize that this dose is dramatically higher than the physiologic doses of melatonin (0.5–1 mg) and hence the safety of
this dose requires study.
Melatonin appears to ameliorate secondary and age-related
insomnia. Increased sleep efficiency was noted in both populations after administration of melatonin.43 Improved sleep efficiency occurred in an elderly population with doses of 0.1–3.0
mg which elevated plasma levels within normal range.45,46
Overall, the present data would suggest that melatonin is not
an effective treatment for the management of primary insomnia. However, it has clear phase shifting properties and hence
it may have efficacy in elderly insomniacs with decreases in
endogenous melatonin and insomnia associated with sleep
circadian rhythm disorder.
L-tryptophan supplements appeared to be effective hypnotic
agents in chronic insomniacs with sleep maintenance disturbances that were characterized by 3–6 discrete awakenings
during the night. Insomniacs self-reported 100% improvement
following 1 g nightly administration for 1 week.48 No consistent significant effects of L-tryptophan on sleep parameters
determined by PSG were found in doses <1 g. Significant
decreases in sleep latencies were observed following 1–3 g of
tryptophan but inconsistent findings were noted on total sleep
time, SWS, and REM sleep.49
In a study by Schneider-Helmert and Spinweber,50 chronic
insomniacs characterized by both sleep onset and sleep maintenance problems showed therapeutic improvement occurring
over time with repeated administration of low doses of L-tryptophan. The hypnotic effects appeared late in the treatment
period or, as shown in some studies, even after discontinuation
of treatment. L-tryptophan is also effective in reducing sleep
onset time on the first night of administration in doses ranging
from 1–15 g in young situational insomniacs.50
The treatment of depression with the selective serotonin
reuptake inhibitor fluoxetine can exacerbate insomnia. The
hypnotic effects of tryptophan in conjunction with an
antidepressant were used to potentiate an improvement
in insomnia. Tryptophan (2–4 g) and fluoxetine (20 mg)
administrated for 8 weeks significantly decreased depression
scores and had a SWS protective effect. A significant decrease
in SWS was noted in the fluoxetine placebo group but not in
the fluoxetine-tryptophan group.51
L-tryptophan administration has not been linked with
impairments in visuomotor, cognitive, or memory performance.50 Some side effects of tryptophan can include drowsiness, tiredness/fatigue, nausea, loss of appetite, dizziness, headache, and dry mouth (Table 2).
Tryptophan
ALCOHOL
L-tryptophan is an essential amino acid that comes from
food. Once absorbed, it can be converted to serotonin and melatonin. In the brain, serotonin is synthesized from tryptophan,
which is the major metabolic route.47 Low levels of serotonin
have been reported to be associated with depression, anxiety,
and insomnia, and L-tryptophan supplements have been used
to treat these disorders despite the absence of convincing data
of its benefit.
The tryptophan-depletion model has been used to
determine the association between tryptophan and sleep.
Tryptophan depletion, following an ingestion of a tryptophan-free amino acid drink, significantly increased stage 1
sleep and decreased stage 2 sleep. However, indices of sleep
induction and sleep efficiency were not affected. Indices of
REM density (the frequency of eye movements per unit of
time during REM sleep) were significantly increased, whereas
REM latency remained unaltered.40
Primary Psychiatry
© MBL Communications
In 2001, approximately 30% of chronic insomniacs in the
general population reported using alcohol to induce sleep and
67% of those reported that alcohol was effective.52 However,
in PSG studies insomniacs who used alcohol had significantly
impaired measures of sleep continuity and had more severe
alcohol dependence and depression.53 Males and those never
married or those separated or divorced/widowed are approximately 1.5 times more likely to use alcohol as a sleep aid than
females or those who are married.10
Alcohol consumed at bedtime may decrease the time
required to fall asleep and increase SWS. Because of alcohol’s
sedating effect, many people with insomnia consume alcohol
to promote sleep. However, alcohol consumed within an hour
of bedtime appears to disrupt the second half of the sleep
period.54,55 Alcohol affects the proportions of the various sleep
stages with dose-dependent suppression of REM sleep. Higher
57
May 2008
S. Randall, T.A. Roehrs, T. Roth
doses of alcohol increased nocturnal awakenings and/or lighter
stages of sleep (stage 1) during the second half of the night.
The second-half disruption of sleep continuity is referred to
as a “rebound effect,” occurring as alcohol is metabolized or
eliminated from the body.54
Overall, the use of alcohol as well as the discontinuation of
alcohol is associated with disturbances of sleep. This is most
clearly seen in alcoholics who exhibit profoundly disturbed
sleep during active drinking and after months of abstinence.
Finally, the relation of alcohol consumption to improve sleep to
the evolution of chronic alcoholism warrants study.
16. Rickels K, Morris RJ, Newman H, Rosenfeld H, Schiller H, Weinstock R. Diphenhydramine in insomniac family
practice patients: A double blind study. J Clin Pharmacol. 1983;23(5-6):234-242.
17. Richardson GS, Roehrs TA, Rosenthal L, Koshorek G, Roth T. Tolerance to daytime sedative effects of H1
antihistamines. J Clin Psychopharmacol. 2002;22(5):511-515.
18. Mumford GK, Silverman K, Griffiths RR. Reinforcing, subjective and performance effects of lorazepam and
diphenhydramine in humans. Exp Clin Psychopharmacol. 1996;4(4): 421-430.
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20. Leybishkis B, Fasseas P, Ryan KF. Doxylamine overdose as a potential cause of rhabdomyolysis. Am J Med
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25. Dominguez RA, Bravo-Valverde RL, Kaplowitz BR, Cott JM. Valerian as a hypnotic for Hispanic patients. Cultur
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38. Chung, KF Melatonin use in sleep disorders HK Pract. 1997;19(12):669-672.
39. Ellis CM, Lemmens G, Parkes JD. Melatonin and insomnia. J Sleep Res. 1996;5(1):61-65.
40. Riemann D, Klein T, Rodenbeck A, et al. Nocturnal cortisol and melatonin secretion in primary insomnia.
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melatonin: a double-blind, placebo-controlled, crossover study. J Psychiatry Neurosci. 2003;28(3):191-196.
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Psychopharmacology (Berl). 1986;89(1):1-7.
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52. Ancoli-Isael, S., Roth, T. Characteristics of insomnia in the United States: results of the 1991 National Sleep
Foundation Survey. I. Sleep. 1999;22(suppl 2):347-353.
53. Brower KJ, Aldrich MS, Robinson EA, Zucker RA, Greden JF. Insomnia, self-medication, and relapse to alcoholism. Am J Psychiatry. 2001;158(3):399-404.
54. Roehrs T, Roth T. Sleep, sleepiness, and alcohol use. Alcohol Res Health. 2001;25(2):101-109.
55. Roehrs T, Papineau K, Rosenthal L, Roth T. Ethanol as a hypnotic in insomniacs: self administration and
effects on sleep and mood. Neuropsychopharmacology. 1999;20(3):279-286.
56. American Academy of Sleep Medicine. Clinical Practice Review Committee. Do drugstores have the cure for
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CONCLUSION
Much of the data on the efficacy and safety of OTC sleep
aids is inconclusive and is associated with problems such as too
few participants in the studies, little demographic and diagnostic information regarding study participants, inconsistency
in demographic and diagnostic information among studies to
allow comparisons, lack of placebo-control groups, subjective
reports with a lack of objective data, and short-term treatment
with study medication which provides little indication about
long-term usage.56
Treatment of insomnia with antihistamine-containing OTC
sleep aids may help occasional mild insomnia. Prolonged use
of some if not all antihistaminic drugs may result in tolerance
and/or dependence and produce daytime sleepiness. The data
on other non-prescription sleep aids is too limited or inconsistent in results to consider their use. While alcohol may have
initial sedative effects, it is associated with rapid tolerance
development and dose escalation (Table 2). PP
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