This work may not be copied, distributed, displayed, published, reproduced, transmitted, modified, posted, sold, licensed, or used for commercial purposes. By downloading this file, you are agreeing to the publisher’s Terms & Conditions.

Articles

Over-the-Counter Agents for the Treatment of Occasional Disturbed Sleep or Transient Insomnia: A Systematic Review of Efficacy and Safety

Over-the-Counter Agents for the Treatment of Occasional Disturbed Sleep or Transient Insomnia:

A Systematic Review of Efficacy and Safety

Vertical divider

ABSTRACT

Objective: To investigate the level of evidence supporting the use of common over-the-counter (OTC) agents (diphenhydramine, doxylamine, melatonin, and valerian) for occasional disturbed sleep or insomnia.

Data sources: A systematic review of the literature was conducted on July 31, 2014, using MEDLINE (PubMed) and the search terms (insomnia OR sleep) AND (over*the*counter OR OTC OR non*prescription OR antihistamine OR doxylamine OR diphenhydramine OR melatonin OR valerian) with the filters English, human, and clinical trials.

Study selection: Identified publications (from 2003 to July 31, 2014, following previous published literature reviews) that met the inclusion criteria were selected. The criteria included randomized placebo-controlled clinical studies that utilized overnight objective (polysomnography) or next-day participant-reported sleep-related endpoints and that were conducted in healthy participants with or without occasional disturbed sleep or diagnosed insomnia.

Results: Measures of efficacy and tolerability were summarized for each study individually and grouped according to OTC agent: H1 antagonists or antihistamines (3 studies, diphenhydramine), melatonin (8), and valerian or valerian/hops (7). Of the 3 sleep agents, studies conducted with melatonin, especially prolonged-release formulations in older individuals with diagnosed insomnia, demonstrated the most consistent beneficial effects (vs placebo) on sleep measures, specifically sleep onset and sleep quality, with favorable tolerability. In contrast, the clinical trial data for diphenhydramine, immediate-release melatonin, and valerian suggested limited beneficial effects.

Conclusions: A review of randomized controlled studies over the past 12 years suggests commonly used OTC sleep-aid agents, especially diphenhydamine and valerian, lack robust clinical evidence supporting efficacy and safety.

Prim Care Companion CNS Disord 2015;17(6):doi:10.4088/PCC.15r01798

aDepartment of Family Medicine, Boston University, Boston, Massachusetts

bPfizer Consumer Healthcare, Pfizer Inc, Madison, New Jersey

*Corresponding author: Larry Culpepper, MD, MPH, Department of Family Medicine, Boston University, 850 Harrison Ave, Boston, MA 02118 (Laculpep@bu.edu).

Occasional disturbed sleep, consisting of difficulty initiating sleep, difficulty maintaining sleep, early morning awakening, and nonrestorative sleep, is frequently reported among individuals in the United States. Approximately one-fifth of the respondents in the 2008 Sleep in America Poll1 experienced at least 1 of these symptoms 2-3 nights a week. Other studies2-5 have likewise reported occasional disturbed sleep in up to one-third of various populations, although an objective definition of occasional disturbed sleep (regarding duration, frequency, and severity) is not available, possibly contributing to variability across studies.

With the transient nature of occasional disturbed sleep, individuals often turn to nonpharmacologic (cognitive-behavioral approaches, sleep hygiene) or over-the-counter (OTC) agents to improve sleep.2,6,7 Nonprescription antihistamine-containing sleep aids (diphenhydramine hydrochloride, diphenhydramine citrate, or doxylamine succinate) as well as herbal and nutritional supplements (eg, valerian, melatonin, kava kava, dogwood, L-tryptophan, St John’s wort) are often used for the treatment of "occasional sleeplessness" but are not indicated for the management of diagnosed insomnia due to the lack of specific safety and efficacy data.8 Although OTC sleep aids claim to provide benefits for adults with occasional sleeplessness, established efficacy and safety in well-designed clinical trials in relevant populations are rare. Moreover, herbal and nutritional supplements (such as melatonin) are not required to undergo the same rigorous clinical testing as prescription medications.

The lack of scientific evidence supporting the efficacy and safety of OTC sleep aids for insomnia symptoms was highlighted in a comprehensive review by Meoli et al.8 The authors conducted a systematic review of oral, nonprescription treatment for insomnia (1980-2002), excluding melatonin (which they stated had already undergone extensive evaluation), to determine the level of evidence regarding the safety and efficacy of nonprescription drugs for insomnia. The authors concluded that although placebo-controlled studies are available for some OTC sleep aids, rigorous scientific evidence supporting the efficacy and safety of nonprescription sleep aids, including herbal, dietary, or nutritional supplements, was not available.8 In a systematic review9 published in 2005 of melatonin in randomized controlled clinical trials of individuals with sleeping disorders (including but not limited to insomnia), it was concluded that melatonin had limited value in individuals with insomnia, but confirmation in large, well-designed clinical trials was needed. These evidence-based reviews are in agreement with clinical guidelines,10,11 which do not recommend OTC sleep agents for the treatment of chronic or primary insomnia due to the lack of well-designed studies and supporting evidence. As a result, health care providers can only recommend sleep aids with caution until further evidence becomes available to support their efficacy and safety. As such, we undertook a review of more recent placebo-controlled randomized studies, including the past 12 years, to reevaluate treatment recommendations. This review was based on a systematic literature search of all published studies (up to July 31, 2014) supporting the efficacy and safety of nonprescription agents for the management of occasional disturbed sleep with a focus on summarizing only those studies conducted after 2002 (given the previous published reviews).

clinical points

  • Commonly used nonprescription sleep aids continue to lack robust clinical evidence supporting efficacy and safety in relevant populations.
  • Further clinical investigations and novel treatments are needed to improve management of occasional disturbed sleep.

Systematic Review of Currently Available OTC Sleep Aids

We focused on common recommended OTC agents that are available in pharmacies in the United States and have been evaluated in controlled clinical studies: those including antihistamines (diphenhydramine, doxylamine) or natural supplements (melatonin, valerian) (Table 1).10,13As a result, we did not include information on other herbal or nutritional supplements. We also did not include combination products comprising pain relievers (eg, ibuprofen) and diphenhydramine because these products are only indicated for use when having difficulty sleeping due to associated pain.

Table 1

Click figure to enlarge

Table 1r

A MEDLINE literature search (PubMed) was conducted using the search terms (insomnia OR sleep) AND (over*the*counter OR OTC OR non*prescription OR antihistamine OR doxylamine OR diphenhydramine OR melatonin OR valerian) and the additional filters English, human, and clinical trials. No date restrictions were imposed other than an end date of July 31, 2014. The resulting 926 articles were screened for relevance (ie, clinical trial that involved the collection of overnight measures of polysomnography [PSG] or next-morning participant-reported sleep assessments). Nonrelevant articles, including studies conducted in populations with underlying serious medical conditions (physical or psychiatric diseases or sleep disorders other than insomnia) and studies exclusively on sedative or cognitive effects following daytime administration (without an intervening period of bedtime), were excluded. A total of 126 articles (H1 antagonists: 25, valerian: 25, melatonin: 78; multiple drugs were included in some articles) were identified as potentially relevant. These articles comprised all publications, including those prior to 2002, up to the end date of July 31, 2014 (Figure 1).

Figure 1

Click figure to enlarge

Bibliographies of identified articles also were reviewed to identify other potentially relevant placebo-controlled randomized studies for inclusion. Given the previous reviews by Meoli et al8 and Buscemi et al,9 we focused on those studies published after 2002. The studies were carefully selected to include only randomized placebo-controlled studies in healthy participants with or without diagnosed insomnia (using established diagnostic classification criteria) or occasional disturbed sleep (generally defined as mild symptoms of insomnia occurring 2-3 times per week) that included objective or subjective (ie, participant-reported) sleep-related endpoints.

Efficacy and Safety Of OTC Drugs and Natural Supplements

Diphenhydramine and Doxylamine

Although numerous OTC formulations are available to aid sleep, the majority contain diphenhydramine, a nonselective histamine H1-receptor antagonist that has significant affinity at other receptor subtypes leading to nonspecific side effects, including anticholinergic effects (sedation, dry mouth, blurred vision). The US Food and Drug Administration (FDA) included diphenhydramine hydrochloride (up to 50 mg) and diphenhydramine citrate (up to 76 mg) as safe and effective nighttime sleep aids as part of the FDA Final Drug Monograph for OTC Use.22 Doxylamine succinate (up to 25 mg) is not yet included in this monograph (on the basis of insufficient evidence), but specific formulations (eg, Unisom) have received FDA approval. Very few published studies have rigorously evaluated the hypnotic effects of H1 antagonists as OTC sleep agents. In the Meoli et al8 review, it was concluded that although short-term efficacy was demonstrated on subjective measures (participant self-reports) in some studies, the evidence should still be considered preliminary, largely owing to small sample sizes and lack of objective sleep measures (ie, PSG-derived parameters).

In the present review, 25 publications on diphenhydramine and other antihistamine products were identified as potentially relevant; this includes all publications, as well as those prior to 2002 (Figure 1). Several of these articles failed to meet the inclusion criteria and were eliminated, mostly owing to no overnight sleep-related endpoints, use of H1 antagonists not available as OTC sleep agents, or the presence of an underlying medical condition in the study population. This elimination resulted in 7 publications meeting the inclusion criteria (randomized placebo-controlled with at least 1 specific sleep endpoint and conducted in healthy adults with or without primary insomnia or occasional disturbed sleep). Of these articles, 323-25 were published after 2002 and are summarized in Table 2.

Table 2

Click figure to enlarge

Table 2r

Each of these studies used diphenhydramine 50 mg (although the specific salt, citrate vs hydrochloride, was provided in only 1 study23) administered either as a single dose or multiple dose over 2 weeks. Together, these studies failed to demonstrate consistent positive improvements on self-reported and objective (PSG-derived) sleep measures. Morin et al,23 the largest of the 3 studies, reported significant improvements relative to placebo on self-reported sleep efficiency and the Insomnia Severity Index, but both Morin et al23 and Katayose et al24 failed to observe significant effects on key PSG-derived parameters (eg, sleep onset latency, sleep efficiency, total sleep time) among healthy individuals with and without occasional sleep disturbances, respectively.

In the third study, Glass et al25 evaluated diphenhydramine 50 mg (over 2 weeks) in a small sample of older individuals (aged 70-89 years) with diagnosed insomnia. Diphenhydramine was associated with a small but significant decrease in participant-reported number of awakenings but with no significant effects on other key self-reported sleep parameters (eg, total sleep time, sleep latency, and sleep quality).25 Together, these studies,23-25 although few in number, indicate limited support of diphenhydramine for sleep efficacy.

In terms of safety, 224,25 of the 3 studies examined next-day residual effects (a safety concern frequently associated with H1 antagonists) using a battery of tests to measure psychomotor/cognitive functioning and sleepiness. Diphenhydramine (50 mg administered at 11:45 PM) was associated with significant psychomotor impairment on the 1-back test (a working memory task) and a decreased level of wakefulness as measured by the α attenuation coefficient during the morning and afternoon test sessions the following day (the effect on wakefulness represented an average across test times).24 Adverse events and measures of withdrawal or rebound effects were collected in 2 studies.23,25 Morin et al23 reported no significant differences in adverse event frequency among the treatment groups (placebo and diphenhydramine 50 mg) and no evidence of rebound insomnia following treatment discontinuation. Likewise, in Glass et al,25 the frequency and type of adverse events were similar among treatment groups, although a somewhat higher frequency of rebound insomnia in the diphenhydramine group was reported: signs of rebound insomnia were detected in 7 of 15 participants who discontinued diphenhydramine treatment versus 5 of 14 following placebo.

Melatonin

Melatonin (N-acetyl-5-methoxy-tryptamine) is a naturally occurring hormone produced by the pineal gland, which acts physiologically to regulate the circadian cycle. Exogenous melatonin is believed to promote sleep and is used as an herbal supplement in the United States. We identified 78 studies in total that referred to melatonin use in insomnia, of which 24 were placebo-controlled clinical studies that met our inclusion criteria (including those published in 2002 or earlier; Figure 1). Many of the excluded studies were conducted in the daytime or in individuals or patient populations with underlying illnesses or sleep disorders other than primary insomnia (eg, delayed sleep-phase disorder or sleep disturbances associated with jet lag or shift work).

Of the studies published after 2002, a total of 826-33 met the inclusion criteria (with 1 study resulting in 2 publications33,34) (Figure 1, Table 3). All but 3 studies used sustained- or prolonged-release melatonin. Of the 8 studies, 226,27 were conducted in healthy volunteers with or without occasional disturbed sleep and 629-34 in individuals with a diagnosis of insomnia (DSM-IV). The 2 studies26,27 conducted in healthy volunteers were small in size (n = 20-26; 1 was a crossover study) and showed little benefit of immediate-release melatonin compared with placebo on a variety of objective and self-reported sleep endpoints. In 1 study,26 using both objective (actigraphy) and subjective sleep measures and considered sufficiently powered, 2 groups of older (aged ≥ 65 years) healthy participants categorized as either normal or problem sleepers treated nightly with immediate-release melatonin (5 mg) for 4 weeks showed no significant benefit on sleep measures, with the exception of reduced actigraphy-derived number of awakenings in normal sleepers. In the second study, which was considered a pilot study, Peck et al27 evaluated the effects of melatonin 1 mg/d immediate-release for 4 weeks in older individuals (aged 64-89 years) and demonstrated significant improvements versus placebo on morning "restedness" and on a cognitive test (verbal recall on the California Verbal Learning Test) performed in the afternoon at week 4. Neither study26,27 included PSG assessments.

Table 3a

Click figure to enlarge

Table 3ar

Table 3b

Click figure to enlarge

Table 3br

In the 6 studies29-34 (Table 3) that included participants with diagnosed insomnia, all but 1 were conducted using a sustained- or prolonged-release formulation. Four29-32 of 6 studies were conducted exclusively in older individuals (aged ≥ 55 years). Overall, significant positive effects of immediate- (5 mg/d for 8 weeks) and prolonged-release formulation (2 mg/d for 3 weeks) were observed on participant-reported sleep quality,29-33 sleep onset,32,33 and morning alertness.29,30 Not all endpoints were evaluated in each study, so consistency of treatment effects is not easily determined; furthermore, 1 small crossover study28 (n = 10, mean age of 50 years) failed to show any significant effects of a "sustained-release" formulation (0.3 or 1.0 mg/d for 7 days) on either sleep quality or sleep onset or on any other participant-reported endpoint included in the study. A secondary analysis34 of a large study (n = 722) suggested that age may be an important factor; a significant effect on sleep-onset latency was observed in the ≥ 55 years cohort but not in the younger cohort. These effects were sustained for up to 26 weeks of treatment.34 Two of the 6 studies included PSG assessment; 132 observed a significant reduction (relative to placebo) in PSG-derived sleep-onset latency following prolonged-release formulation administration (2 mg/d for 3 weeks), whereas a smaller crossover study28 (with 0.3, 1.0 mg/d for 1 week) showed no significant effects on any PSG parameters. A number of methodological differences (eg, dose, formulation, treatment duration, and study population) could account for this discrepancy. Neither study28,32 showed any significant treatment effects on sleep architecture.

Next-day residual effects on psychomotor/cognitive functioning were evaluated in 1 relatively small study32 (n = 40) of older individuals (aged ≥ 55 years) with insomnia. Nightly 3-week administration of prolonged-release formulation (2 mg 2 hours before bedtime) versus placebo resulted in no significant performance impairment (in some cases, significant improvements were observed) on next-day psychomotor tests (reaction time tests and critical flicker fusion were conducted at 9:00 AM).32

Immediate-release melatonin and prolonged-release formulation were well tolerated with a low incidence of mild adverse events, often comparable to placebo.26,27,29-34 Studies29,32,34 with prolonged-release formulation also reported no evidence of withdrawal or rebound effects following discontinuation after 3 or 26 weeks of nightly administration.

Valerian and Valerian/Hops

Valerian is a plant derivative that has long been used to aid sleep and anxiety.35 Valerian can be marketed in powder form or sold as an extract in aqueous or alcoholic media. The method of extraction can influence the active components,36 and, therefore, method of preparation is an important consideration and varies among published reports.

After a systematic review of the literature and subsequent screening (Figure 1), 25 studies of valerian were identified, of which 12 were verified as placebo-controlled randomized studies investigating the efficacy of valerian or valerian/hops. Thirteen studies were eliminated because they included individuals with underlying medical conditions, had study design limitations, or did not include overnight sleep measures, the latter the most common.

Of the 12 studies that met the inclusion criteria, 723,37-42 were published after 2002; all but 2 evaluated multiple doses over 2-4 weeks. Six studies23,37-41 were conducted in healthy volunteers who reported occasional or mild insomnia symptoms and 142 in individuals with a diagnosis of insomnia (ICD-10) (Table 4). In agreement with Meoli et al8 and a subsequent meta-analysis43 published 1 year later, limited evidence is available regarding the efficacy of valerian in occasional disturbed sleep and insomnia. Of the studies reviewed here (Table 4), 3 of 7 met their primary endpoint, which included (1) participant-reported sleep quality (Pittsburgh Sleep Quality Index) in postmenopausal women with "mild insomnia" after 4 weeks of treatment,41 (2) PSG-derived change in "sleep quantity" from baseline following single-dose administration of valerian/hops in participants with occasional disturbed sleep,39 and (3) objectively defined sleep latency (home recorder system) in participants with insomnia treated with valerian/hops (but not valerian alone) for 4 weeks.42

Table 4a

Click figure to enlarge

Table 4ar

Table 4b

Click figure to enlarge

Table 4br

In contrast, 4 studies23,37,38,40 were negative on primary endpoints comprising self-reported (sleep diaries, questionnaires) and PSG-derived sleep parameters. Specifically, Diaper and Hindmarch37 found no significant effects on any PSG parameter after a single dose of valerian versus placebo in a crossover study of 16 participants with mild sleep complaints. Likewise, no sleep-related improvements were found using self-reported and PSG-derived measures following multiple doses (2-4 weeks) of valerian or valerian/hops in individuals with occasional or mild insomnia,23,40 with 1 study40 conducted in older individuals (aged 55-80 years). In a large Web-based study38 that randomized over 400 participants with self-reported insomnia, 14-day treatment with valerian did not result in significant improvement in sleep quality relative to placebo (primary endpoint), although small, yet significant, beneficial effects of valerian versus placebo were demonstrated on mean improvement in night awakenings (0.13 vs 0.03) and global self-assessment of change (9.1% vs 3.7% of valerian vs placebo-treated individuals, respectively, reporting their sleep as "better" or "much better"). Reasons for the inconsistent effects on sleep measures observed across studies may be related to small sample sizes (with some exceptions, including both negative and positive studies23,38,41) and different valerian preparations (with and without hops) and doses, which vary considerably among studies.

Few adverse events (relative to placebo) were reported in the 7 studies,23,37-42 consistent with the conclusion of Meoli et al8 that valerian is associated with a relatively benign side effect profile. Next-day effects were evaluated as secondary outcome measures in 2 studies.23,37 Following 4 weeks of nightly treatment, Morin et al23 reported no next-day residual effects on subjective ratings of sluggishness or drowsiness or rebound insomnia with valerian/hops (374 mg/83.8 mg) versus placebo. Likewise, Diaper and Hindmarch37 observed no effects on next-day psychomotor performance (evaluated at 7:05 AM) following valerian 300 or 600 mg versus placebo (administered as a single dose at 10:00 PM on the evening prior to tests). Although these studies23,37 are not comparable because of differences in valerian preparation, doses, and outcome measures, these observations broadly suggest that valerian may not cause noticeable significant next-day effects in healthy individuals with occasional disturbed sleep; however, neither study demonstrated beneficial effects on sleep.

DISCUSSION

The OTC landscape is evolving alongside research into improving our understanding of occasional disturbed sleep as an unmet clinical need. Our review highlights that over the past 12 years, there have been relatively few published reports of large, randomized placebo-controlled studies evaluating the efficacy (with self-report and PSG measures) and safety of OTC agents in the intended population (individuals with occasional sleep disturbances or mild insomnia), despite their widespread and frequent use2-5 often without input from a health care provider. Studies on melatonin have been the most widely published, followed by valerian and then antihistamines, specifically diphenhydramine.

Three randomized placebo-controlled studies23-25 on single- and multiple-dose (50 mg) diphenhydramine published in the past 12 years were identified. Although few in number, these studies represent progress over the past 12 years in terms of further evaluating the efficacy (by including objective PSG measures) and safety (by examining residual next-day effects and rebound insomnia) of diphenhydramine in randomized placebo-controlled studies. Of particular note is 1 relatively large, well-designed study23 conducted in individuals with occasional disturbed sleep that included both participant-reported and objective (PSG) sleep measures; few significant treatment effects (diphenhydramine vs placebo) were observed and none were related to objective PSG measures, a general pattern consistent with smaller crossover studies.24,25 In terms of safety, next-day residual effects and rebound insomnia were observed,24,25 but not consistently, and adverse events (and discontinuations due to adverse events) following diphenhydramine were slightly higher relative to placebo in 1 study23 but similar in another.25 Together, the scientific evidence suggests limited beneficial effects of diphenhydramine on sleep, an increased risk of next-day performance impairments, and potential rebound insomnia following discontinuation, although additional studies are needed to confirm these safety risks.

Evaluating the efficacy and safety of melatonin in randomized controlled clinical trials also progressed in the past 12 years, with larger, better-designed clinical trials (eg, longer treatment duration up to 26 weeks), although most were limited to the prolonged-release formulation in older individuals (aged ≥ 55 years) with diagnosed insomnia. In general, significant positive effects on sleep-related measures, mostly self-reported sleep latency, sleep quality, and morning alertness, were observed, with the exception of 1 small study28 of a sustained-release formulation that failed to show any effects (perhaps owing to variable ages and lack of statistical power). The novel prolonged-released formulation (Circadin, Neurim Pharmaceuticals Ltd, Tel-Aviv, Israel) used in 4 studies29,30,32,33 is currently approved in Europe and other countries as a prescription drug for the short-term treatment of primary insomnia in individuals aged ≥ 55 years.44 These studies were included in this review because they suggest that OTC sustained or prolonged-release melatonin formulations might provide beneficial effects, although further studies are needed, particularly across a wider age range and in individuals with occasional disturbed sleep (rather than diagnosed insomnia).

In contrast, the evidence remains less conclusive for immediate-release melatonin (versus prolonged-release melatonin). Of the 3 clinical trials26,27,31 identified, isolated positive effects were observed on morning "restedness" and sleep quality, but 1 crossover study,26 considered sufficiently powered (n = 20), failed to demonstrate any significant sleep-related benefits (based on actigraphy and self-reports). Thus, scientific evidence supporting the efficacy of immediate-release melatonin remains inconclusive; this may reflect the fewer number of randomized controlled studies conducted with this formulation (3) since 2002, relatively small sample sizes (n = 20-26), variations in population and study design, absence of objective PSG measures, and the use of concomitant medications in at least 1 study (eg, benzodiazepines in Garzón et al31). Scientific evidence regarding safety is more consistent. Melatonin, including the prolonged-release formulation, was well tolerated, with adverse events generally similar between the placebo and active treatment arms and no evidence of significant next-day impairment or rebound insomnia following treatment discontinuation.

For valerian, 7 randomized controlled studies23,37-42 were conducted since 2002. The evidence supporting valerian’s (or valerian/hops’ ) efficacy is inconsistent. Less than half (3/7) of the studies reported significant effects on primary sleep endpoints, and the specific endpoints were different among the 3 studies.39,41,42 The remaining negative studies, some with a large sample size, failed to show significant beneficial effects on primary sleep measures, including PSG-derived endpoints. These observations are in line with those generated over 10 years ago8 and with a systematic review45 conducted in 2007 and further confirm the paucity of data available to support valerian efficacy despite its widespread use. One important consideration that may account for some of the discrepant results, beyond differences in study design, dosing schedule, and participants, is the method of valerian extraction and preparation and whether it was combined with hops. To this point, 2 of 3 studies39,42 that reported positive effects used a combination product (valerian/hops). Regarding safety, the studies suggest a favorable tolerability profile, with adverse events similar to placebo in most studies, and no evidence (albeit, based on a limited number of studies) suggesting next-day residual impairment or rebound insomnia after discontinuation.

In addition to the considerations summarized here regarding the efficacy and tolerability of OTC sleep agents, other concerns may pose significant risk, namely drug-drug interactions (Table 1). Given that many individuals with occasional sleep disturbance are older and may have significant comorbidities and take concomitant medications, possible drug interactions are an important safety element when considering OTC use. Significant drug interactions are evident for antihistamines based on in vivo and in vitro (metabolism) studies.46-48 Likewise, drug interactions with melatonin and valerian may also present concerns.49,50 Specific studies, comparing combination of OTC agents with alcohol (commonly used to promote sleep) and commonly prescribed therapies for insomnia, such as zolpidem, eszopiclone, and zaleplon, are needed. In addition to drug interaction studies, carefully designed safety studies are critical. This is particularly important for older individuals who are frequently more susceptible to side effects (eg, anticholinergic effects associated with diphenhydramine) and their potentially dangerous consequences (falls resulting from dizziness).

Limitations

Our systematic review of the OTC literature should be interpreted in light of certain caveats. We made the decision not to include agents with very limited clinical trial data. We therefore excluded studies on some herbal remedies such as kava kava, dogwood, and St John’s wort that are used to treat occasional disturbed sleep. The exclusion of these agents should be considered when interpreting the evidence summarized in the present study. Meoli et al8 included a range of herbal products and supplements in their systematic review but concluded that although specifically designed randomized controlled trials have been conducted on certain OTC sleep agents (other than valerian and antihistamines), evidence was in general limited with respect to efficacy. We also did not consider alcohol; although commonly used as an agent to promote sleep onset, potential harmful effects do not support its use. Finally, we focused on the treatment of either occasional disturbed sleep or diagnosed insomnia in otherwise healthy individuals and thereby did not include studies that examined insomnia symptoms that were secondary to other medical or psychiatric disorders (including other sleep disorders/symptoms resulting from jet lag/shift work, delayed sleep phase disorder, restless legs syndrome). The decision was made to review the effects of OTC agents in a generally healthy population (to the extent possible) and to minimize confounds associated with serious underlying medical conditions and concomitant medications.

CONCLUSIONS

Currently available literature suggests that commonly used OTC sleep agents, especially antihistamines and valerian, continue to lack robust clinical evidence supporting efficacy and safety in relevant populations. A prolonged-release formulation of melatonin appears to be efficacious for symptoms associated with sleep onset and shows a favorable tolerability profile, but the effects may be limited to older individuals (aged ≥ 55 years) with insomnia. Further clinical investigations on these and novel compounds are needed to improve management of occasional disturbed sleep. Moreover, continued educational efforts targeting health care providers, pharmacists, and the public to improve communication about sleep issues related to health and quality of life and their treatment with OTC sleep aids are needed.

Submitted: February 5, 2015; accepted June 23, 2015.

Published online: December 31, 2015.

Drug names: buprenorphine (Subutex, Suboxone, and others), doxylamine (Diclegis), eszopiclone (Lunesta), sodium oxybate (Xyrem), temazepam (Restoril and others), zaleplon (Sonata and others), zolpidem (Ambien, Edluar, and others).

Potential conflicts of interest: Dr Culpepper has served as an advisor or consultant for AstraZeneca, Boehringer-Ingelheim, Elsevier Press, Forest, Janssen, Jazz, Lundbeck A/S, Merck, Pfizer, Reckitt Benckiser, Sanofi-Aventis, Shire PLC, Sunovion, and Takeda; has made presentations regarding a federally funded study of methods to reduce hospital readmissions (with no mention of pharmaceutical agents) supported through Merck’s speakers bureau; owns stock in M3 (My Mood Monitor); and receives royalties from UpToDate and Oxford University Press. Dr Wingertzahn was a full-time employee of Pfizer and held stock and/or stock options during manuscript development.

Funding/support: Medical writing and literature search support were funded by Pfizer.

Role of the sponsor: Pfizer provided funding for medical writing and literature search support but had no role in the design and conduct of the systematic review, preparation, or approval of the manuscript.

Acknowledgments: Medical writing and literature search support were funded by Pfizer and provided by Karen Burrows, MPhil, and Diane Hoffman, PhD, Engage Scientific Solutions, Southport, Connecticut. Dr Hoffman and Ms Burrows report no other conflicts of interest related to the subject of this article.

Disclaimer: Dr Culpepper, the journal’s editor in chief, was not involved in the editorial review or decision to publish this article.

REFERENCES

1. 2008 Sleep in American Poll. National Sleep Foundation Web site. http://sleepfoundation.org/sites/default/files/2008%20POLL%20SOF.PDF. Accessed November 6, 2014.

2. Ancoli-Israel S, Roth T. Characteristics of insomnia in the United States: results of the 1991 National Sleep Foundation Survey, I. Sleep. 1999;22(suppl 2):S347-S353. PubMed

3. LeBlanc M, Mérette C, Savard J, et al. Incidence and risk factors of insomnia in a population-based sample. Sleep. 2009;32(8):1027-1037. PubMed

4. Buysse DJ, Angst J, Gamma A, et al. Prevalence, course, and comorbidity of insomnia and depression in young adults. Sleep. 2008;31(4):473-480. PubMed

5. Karlson CW, Gallagher MW, Olson CA, et al. Insomnia symptoms and well-being: longitudinal follow-up. Health Psychol. 2013;32(3):311-319. PubMed doi:10.1037/a0028186

6. Neutel CI, Patten SB. Sleep medication use in Canadian seniors. Can J Clin Pharmacol. 2009;16(3):e443-e452. PubMed

7. Moore TA, Berger AM, Dizona P. Sleep aid use during and following breast cancer adjuvant chemotherapy. Psychooncology. 2011;20(3):321-325. PubMed doi:10.1002/pon.1756

8. Meoli AL, Rosen C, Kristo D, et al; Clinical Practice Review Committee; American Academy of Sleep Medicine. Oral nonprescription treatment for insomnia: an evaluation of products with limited evidence. J Clin Sleep Med. 2005;1(2):173-187. PubMed

9. Buscemi N, Vandermeer B, Hooton N, et al. The efficacy and safety of exogenous melatonin for primary sleep disorders: a meta-analysis. J Gen Intern Med. 2005;20(12):1151-1158. PubMed doi:10.1111/j.1525-1497.2005.0243.x

10. Schutte-Rodin S, Broch L, Buysse D, et al. Clinical guideline for the evaluation and management of chronic insomnia in adults. J Clin Sleep Med. 2008;4(5):487-504. PubMed

11. Guideline summary: clinical guideline for the treatment of primary insomnia in middle-aged and older adults. National Guideline Clearinghouse Web site. http://www.guideline.gov/content.aspx?id=48218&search=hypnotics. Accessed December 12, 2014

12. Know more. Be sure. Drugs.com Web site. http://www.drugs.com/. Updated 2015. Accessed September 22, 2015.

13. Trouble sleeping? over-the-counter sleep aids might help temporarily-but lifestyle changes are usually the best approach for chronic insomnia. Mayo Clinic Web site. http://www.mayoclinic.org/healthy-lifestyle/adult-health/in-depth/sleep-aids/art-20047860?p=1. Updated 2014. Accessed December 3, 2014.

14. Simons KJ, Watson WT, Martin TJ, et al. Diphenhydramine: pharmacokinetics and pharmacodynamics in elderly adults, young adults, and children. J Clin Pharmacol. 1990;30(7):665-671. PubMed doi:10.1002/j.1552-4604.1990.tb01871.x

15. Akutsu T, Kobayashi K, Sakurada K, et al. Identification of human cytochrome P450 isozymes involved in diphenhydramine N-demethylation. Drug Metab Dispos. 2007;35(1):72-78. PubMed doi:10.1124/dmd.106.012088

16. Friedman H, Greenblatt DJ. The pharmacokinetics of doxylamine: use of automated gas chromatography with nitrogen-phosphorus detection. J Clin Pharmacol. 1985;25(6):448-451. PubMed doi:10.1002/j.1552-4604.1985.tb02875.x

17. Friedman H, Greenblatt DJ, Scavone JM, et al. Clearance of the antihistamine doxylamine: reduced in elderly men but not in elderly women. Clin Pharmacokinet. 1989;16(5):312-316. PubMed doi:10.2165/00003088-198916050-00003

18. Videla S, Lahjou M, Guibord P, et al. Food effects on the pharmacokinetics of doxylamine hydrogen succinate 25 mg film-coated tablets: a single-dose, randomized, two-period crossover study in healthy volunteers. Drugs R D. 2012;12(4):217-225. PubMed doi:10.2165/11641640-000000000-00000

19. Aldhous M, Franey C, Wright J, et al. Plasma concentrations of melatonin in man following oral absorption of different preparations. Br J Clin Pharmacol. 1985;19(4):517-521. PubMed doi:10.1111/j.1365-2125.1985.tb02679.x

20. Ma X, Idle JR, Krausz KW, et al. Metabolism of melatonin by human cytochromes p450. Drug Metab Dispos. 2005;33(4):489-494. PubMed doi:10.1124/dmd.104.002410

21. Anderson GD, Elmer GW, Kantor ED, et al. Pharmacokinetics of valerenic acid after administration of valerian in healthy subjects. Phytother Res. 2005;19(9):801-803. PubMed doi:10.1002/ptr.1742

22. Code of Federal Regulations Title 21. Part 338. Nighttime sleep-aid drug products for over-the-counter human use. Food and Drug Administration Web site. http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm?cfrpart=338&showfr=1. Updated 2015. Accessed December 2, 2014.

23. Morin CM, Koetter U, Bastien C, et al. Valerian-hops combination and diphenhydramine for treating insomnia: a randomized placebo-controlled clinical trial. Sleep. 2005;28(11):1465-1471. PubMed

24. Katayose Y, Aritake S, Kitamura S, et al. Carryover effect on next-day sleepiness and psychomotor performance of nighttime administered antihistaminic drugs: a randomized controlled trial. Hum Psychopharmacol. 2012;27(4):428-436. PubMed doi:10.1002/hup.2244

25. Glass JR, Sproule BA, Herrmann N, et al. Effects of 2-week treatment with temazepam and diphenhydramine in elderly insomniacs: a randomized, placebo-controlled trial. J Clin Psychopharmacol. 2008;28(2):182-188. PubMed doi:10.1097/JCP.0b013e31816a9e4f

26. Baskett JJ, Broad JB, Wood PC, et al. Does melatonin improve sleep in older people? a randomized crossover trial. Age Ageing. 2003;32(2):164-170. PubMed doi:10.1093/ageing/32.2.164

27. Peck JS, LeGoff DB, Ahmed I, et al. Cognitive effects of exogenous melatonin administration in elderly persons: a pilot study. Am J Geriatr Psychiatry. 2004;12(4):432-436. PubMed

28. Almeida Montes LG, Ontiveros Uribe MP, Cortés Sotres J, et al. Treatment of primary insomnia with melatonin: a double-blind, placebo-controlled, crossover study. J Psychiatry Neurosci. 2003;28(3):191-196. PubMed

29. Lemoine P, Nir T, Laudon M, et al. Prolonged-release melatonin improves sleep quality and morning alertness in insomnia patients aged 55 years and older and has no withdrawal effects. J Sleep Res. 2007;16(4):372-380. PubMed doi:10.1111/j.1365-2869.2007.00613.x

30. Wade AG, Ford I, Crawford G, et al. Efficacy of prolonged release melatonin in insomnia patients aged 55-80 years: quality of sleep and next-day alertness outcomes. Curr Med Res Opin. 2007;23(10):2597-2605. PubMed doi:10.1185/030079907X233098

31. Garzón C, Guerrero JM, Aramburu O, et al. Effect of melatonin administration on sleep, behavioral disorders and hypnotic drug discontinuation in the elderly: a randomized, double-blind, placebo-controlled study. Aging Clin Exp Res. 2009;21(1):38-42. PubMed doi:10.1007/BF03324897

32. Luthringer R, Muzet M, Zisapel N, et al. The effect of prolonged-release melatonin on sleep measures and psychomotor performance in elderly patients with insomnia. Int Clin Psychopharmacol. 2009;24(5):239-249. PubMed doi:10.1097/YIC.0b013e32832e9b08

33. Wade AG, Ford I, Crawford G, et al. Nightly treatment of primary insomnia with prolonged release melatonin for 6 months: a randomized placebo controlled trial on age and endogenous melatonin as predictors of efficacy and safety. BMC Med. 2010;8(1):51. PubMed doi:10.1186/1741-7015-8-51

34. Wade AG, Crawford G, Ford I, et al. Prolonged release melatonin in the treatment of primary insomnia: evaluation of the age cut-off for short- and long-term response. Curr Med Res Opin. 2011;27(1):87-98. PubMed doi:10.1185/03007995.2010.537317

35. Monograph. Valeriana officinalis. Altern Med Rev. 2004;9(4):438-441. PubMed

36. Houghton PJ. The scientific basis for the reputed activity of Valerian. J Pharm Pharmacol. 1999;51(5):505-512. PubMed doi:10.1211/0022357991772772

37. Diaper A, Hindmarch I. A double-blind, placebo-controlled investigation of the effects of two doses of a valerian preparation on the sleep, cognitive and psychomotor function of sleep-disturbed older adults. Phytother Res. 2004;18(10):831-836. PubMed doi:10.1002/ptr.1574

38. Oxman AD, Flottorp S, Håvelsrud K, et al. A televised, web-based randomised trial of an herbal remedy (valerian) for insomnia. PLoS ONE. 2007;2(10):e1040. PubMed doi:10.1371/journal.pone.0001040

39. Dimpfel W, Suter A. Sleep improving effects of a single dose administration of a valerian/hops fluid extract: a double-blind, randomized, placebo-controlled sleep-EEG study in a parallel design using electrohypnograms. Eur J Med Res. 2008;13(5):200-204. PubMed

40. Taibi DM, Vitiello MV, Barsness S, et al. A randomized clinical trial of valerian fails to improve self-reported, polysomnographic, and actigraphic sleep in older women with insomnia. Sleep Med. 2009;10(3):319-328. PubMed doi:10.1016/j.sleep.2008.02.001

41. Taavoni S, Ekbatani N, Kashaniyan M, et al. Effect of valerian on sleep quality in postmenopausal women: a randomized placebo-controlled clinical trial. Menopause. 2011;18(9):951-955. PubMed doi:10.1097/gme.0b013e31820e9acf

42. Koetter U, Schrader E, Käufeler R, et al. A randomized, double blind, placebo-controlled, prospective clinical study to demonstrate clinical efficacy of a fixed valerian hops extract combination (Ze 91019) in patients suffering from nonorganic sleep disorder. Phytother Res. 2007;21(9):847-851. PubMed doi:10.1002/ptr.2167

43. Bent S, Padula A, Moore D, et al. Valerian for sleep: a systematic review and meta-analysis. Am J Med. 2006;119(12):1005-1012. PubMed doi:10.1016/j.amjmed.2006.02.026

44. Lemoine P, Zisapel N. Prolonged-release formulation of melatonin (Circadin) for the treatment of insomnia. Expert Opin Pharmacother. 2012;13(6):895-905. PubMed doi:10.1517/14656566.2012.667076

45. Taibi DM, Landis CA, Petry H, et al. A systematic review of valerian as a sleep aid: safe but not effective. Sleep Med Rev. 2007;11(3):209-230. PubMed doi:10.1016/j.smrv.2007.03.002

46. Sharma A, Hamelin BA. Classic histamine H1 receptor antagonists: a critical review of their metabolic and pharmacokinetic fate from a bird’s eye view. Curr Drug Metab. 2003;4(2):105-129. PubMed doi:10.2174/1389200033489523

47. Lessard E, Yessine MA, Hamelin BA, et al. Diphenhydramine alters the disposition of venlafaxine through inhibition of CYP2D6 activity in humans. J Clin Psychopharmacol. 2001;21(2):175-184. PubMed doi:10.1097/00004714-200104000-00009

48. Sharma A, Pibarot P, Pilote S, et al. Modulation of metoprolol pharmacokinetics and hemodynamics by diphenhydramine coadministration during exercise testing in healthy premenopausal women. J Pharmacol Exp Ther. 2005;313(3):1172-1181. PubMed doi:10.1124/jpet.104.081109

49. Papagiannidou E, Skene DJ, Ioannides C. Potential drug interactions with melatonin. Physiol Behav. 2014;131:17-24. PubMed doi:10.1016/j.physbeh.2014.04.016

50. Lefebvre T, Foster BC, Drouin CE, et al. In vitro activity of commercial valerian root extracts against human cytochrome P450 3A4. J Pharm Pharm Sci. 2004;7(2):265-273. PubMed

Related Articles

Volume: 17

Quick Links: Sleep-Wake

$40.00

Buy this Article as a PDF