Pharmacotherapeutic Options for Chronic Insomnia

FACULTY:

Courtney I. Jarvis, PharmD
Anna K. Morin, PharmD
Ann M. Lynch, PharmD
Assistant Professors of Pharmacy Practice
Department of Pharmacy Practice
Massachusetts College of Pharmacy and
Health Sciences
Worcester, Massachusetts

FACULTY DISCLOSURE STATEMENTS:

Drs. Jarvis, Morin, and Lynch have no actual or potential conflicts of interest in relation to this program.

U.S. Pharmacist does not view the existence of relationships as an implication of bias or that the value of the material is decreased. The content of the activity was planned to be balanced, objective, and scientifically rigorous. Occasionally, authors may express opinions that represent their own viewpoint. Conclusions drawn by participants should be derived from objective analysis of scientific data.

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DISCLAIMER:

Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patients’ conditions and possible contraindications or dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities.

GOAL:

To provide pharmacists with the most current information regarding the diagnosis and treatment of chronic insomnia in order to prepare them to evaluate and recognize treatment options for adult patients with varying symptoms of chronic insomnia.

OBJECTIVES:  

After reading this article, the participant should be able to:

1. Describe the characteristics, risk factors, potential causes, and diagnosis of chronic insomnia.*
2. Review nonpharmacologic strategies for the treatment of chronic insomnia.*
3. Evaluate the pharmacokinetic and mechanistic properties of traditional and novel pharmacologic agents and their place in the treatment of chronic insomnia.
4. Discuss key counseling and education points for patients with chronic insomnia.

* Also applies to pharmacy technicians.

Affecting at least one third of adults in the United States, insomnia is a highly prevalent and costly health problem that can lead to significant impairment of social and occupational functioning.¹ The American Psychiatric Association defines insomnia as delayed sleep onset (sleep latency), impaired sleep maintenance with numerous or prolonged nocturnal awakenings, inadequate sleep duration with early-morning awakenings, or sleep that is nonrestorative.²

Further categorized based on duration and underlying cause, insomnia can be short term or chronic and primary or secondary.^3,4 Duration of symptoms is classified as transient insomnia (one to three nights), short-term insomnia (less than one month), and chronic insomnia (one month or more).^3,4 Chronic insomnia affects at least 10% of patients experiencing sleep disturbances.¹ Symptoms of sleep disturbance can exist autonomously from other disorders or conditions (primary insomnia) or can be caused by other medical or psychiatric conditions (secondary insomnia).¹ Substance abuse (including alcohol use), sleep-respiratory disorders, movement disorders, circadian rhythm sleep disorders, environmental factors, and some medications (TABLE 1) can cause sleep disturbances.^1,5 Populations at increased risk for insomnia include women, the elderly, and those with medical and psychiatric comorbidities.^1,6 The clinical significance of insomnia is determined by the effects of sleep disturbance on daily cognitive, physical, psychological, and social functioning.²

Sleep is divided into cyclic stages of rapid eye movement (REM) sleep and non-REM sleep.⁷ Non-REM sleep, essential for health maintenance, is divided into four stages that occur in cycles throughout the night. Stage 1 is the transition from drowsy awake to sleep. It is characterized by slow rolling eye movements and disappearance of electroencephalogram (EEG) alpha rhythm. Stage 2 is light or intermediate sleep that is characterized by EEG alpha rapid-wave rhythm, often dominating much of the night. Stages 3 and 4 involve deep sleep characterized by large amounts of slow EEG delta wave rhythm.

REM sleep (Stage 5), essential for learning and mood regulation, is characterized by heightened dream activity and occurs approximately every 90 minutes.⁷ Progression through the five stages of both non-REM and REM sleep in organized and repeating cycles throughout the night is known as the architecture of sleep. Acute disruption of sleep architecture can lead to sleep disturbances and, if left untreated, can eventually lead to chronic insomnia.

Treatment Strategies

Several nonpharmacologic and pharmacologic treatment strategies have shown efficacy in insomnia. Treatment of any underlying physical or psychological disorder should be considered before employing treatment strategies specific to the sleep disorder.

Table 1

Medications Known to Cause Sleep Disturbances

Adrenocorticotropin and cortisone Antibiotics (e.g., quinolones) Antidepressants (e.g., SSRIs, bupropion) Antihypertensives (e.g., alpha-agonists, beta-blockers, central-acting agents) Antineoplastic agents Appetite suppressants Beta-agonists Caffeine Decongestants Diuretics Dopamine agonists Ephedrine and pseudoephedrine Ethanol Ginseng Lipid- and cholesterol-lowering agents Niacin Oral contraceptives Psychostimulants and amphetamines Sedatives/hypnotics Theophylline Thyroid preparations

Source: Reference 5.

Nonpharmacologic Strategies

Behavioral and cognitive strategies (TABLE 2), both as monotherapy and as augmentation to medications, provide safe and effective treatment for insomnia. Behavioral interventions are directed at changing maladaptive sleep habits and reducing autonomic arousal. Examples of behavioral strategies include stimulus control therapy, sleep restriction, relaxation training, paradoxical intention, and sleep hygiene education. Cognitive therapy seeks to alter the faulty beliefs and attitudes of insomniacs about sleep. The goal is to recognize, challenge, and change patient-specific, unrealistic sleep expectations (e.g., the need for eight hours of sleep every night), misconceptions about the causes of insomnia (e.g., insomnia is completely caused by a chemical imbalance), and apprehension or anxiety about bedtime. Once the patient-specific, dysfunctional sleep cognitions have been identified, cognitive therapy aims to replace them with more adaptive substitutes through the use of restructuring techniques such as reattribution training, decatastrophizing, hypothesis testing, reappraisal, and attention shifting.⁸ Many of these strategies require training and daily implementation; improvements in sleep parameters are not immediate and patient motivation and encouragement are necessary.

Table 2
Nonpharmacologic Strategies for Insomnia
Activity	Description
Stimulus- control therapy	Helps reassociate sleep stimuli with falling asleep; encourages the reestablishment of a regular sleep-wake schedule
Sleep restriction	Limits time in bed to actual sleep time; temporary, mild sleep deprivation results in faster sleep onset and better sleep maintenance and quality
Relaxation training	Reduces autonomic (i.e., stress and muscle tension) and cognitive (i.e., intrusive thoughts) arousal that interferes with sleep; methods include progressive muscle relaxation, biofeedback, rhythmic breathing, imagery training, and meditation
Paradoxical intention	Attempts to change unrealistic sleep expectations; patients stay awake as long as possible; leads to decreased concern about falling asleep and the consequences of sleeplessness
Sleep hygiene education	Recommendations regarding sleep behaviors and environmental conditions that may affect quality and quantity of sleep
Cognitive therapy	Addresses patient-specific unrealistic expectations about sleep requirements and misconceptions about causes of sleep disturbances
Source: References 8, 9.

At the very least, sleep hygiene education should be included in the treatment strategy for all patients who present with symptoms of sleep disturbances. While unlikely to impact symptoms of chronic insomnia when used alone, sleep hygiene interventions are relatively simple to employ and can be tailored as an adjunct to pharmacotherapy. Sleep hygiene measures include:^8,9

• Avoiding caffeine and other stimulants, alcohol, and nicotine especially within a few hours of bedtime
• Maintaining a regular sleep-wake cycle and avoid daytime napping
• Exercising regularly, but not too close to bedtime
• Minimizing bedroom noise, light, and temperature extremes
• Going to bed only when sleepy and avoiding excessive wakeful time in bed (more than 20 minutes)
• Using the bedroom for sleep and intimacy only
• Limiting liquids and avoiding heavy meals before bedtime, but eating a light snack if hungry.

Pharmacologic Strategies

Benzodiazepines: Supported by studies confirming safety and efficacy, benzodiazepines (BZs) are first-line agents for the treatment of insomnia.¹⁰ The BZs that are FDA approved for use as sedative hypnotics (estazolam, flurazepam, quazepam, temazepam, and triazolam) are all categorized as schedule C-IV by the Drug Enforcement Agency.¹¹ All BZs enhance the activity of gamma-amino butyric acid (GABA), the primary inhibitory neuro-transmitter in the central nervous system (CNS), by binding at the GABA_A receptor sites.¹¹ The GABA_A receptor contains two sub-types: the BZ₁ or omega₁ receptor (stimulation here plays a role in sleep onset and the sleep cycle) and the BZ₂ or omega₂ receptor (stimulation here may affect memory, learning, and sensory and motor function).¹¹

These GABA_A receptor subtypes are channels, or pores, composed of two alpha, two beta, and one gamma subunit. BZ activation opens these pentameric receptor channels, allowing for enhanced GABA binding to the site and increased chloride influx into the neuronal cell. In general, the result of BZ activity on the GABA_A receptor is modification of the sleep cycle leading to a decrease in sleep latency, a decrease in the number of awakenings during the night and an increase in the total time spent asleep.^6,10,11

Differences among BZs are primarily pharmacokinetic in nature and are summarized in TABLE 3, along with recommended dosage ranges.¹² Differences in onset and duration of action help to determine which BZ is most appropriate based on the presenting sleep disturbance. An agent with rapid onset and short duration would be the most appropriate choice for a patient whose primary sleep disturbance is difficulty falling asleep. In a patient with numerous awakenings or early awakening, an agent with a longer duration of action may be more appropriate.

When used short term (less than two weeks), BZs are considered safe and effective for the treatment of insomnia.^6,10 Common adverse effects associated with the use of BZs include drowsiness, dizziness, and headache.¹¹

Residual daytime sedation (commonly referred to as the �hangover effect�) is often associated with BZs with a long duration of action.¹¹ Patients experiencing this effect report a decrease in mental alertness, headache, and a feeling of slowness upon awakening. Amnesia and memory impairment have been most often reported with triazolam.^10,11 Abrupt discontinuation of a BZ can lead to withdrawal symptoms (i.e., dysphoria, abdominal cramping, vomiting, diaphoresis, tremor, and, rarely, seizures) and rebound insomnia.¹¹ Therefore, patients taking a BZ for more than two weeks should slowly taper the dose before discontinuation.¹¹ BZs should be used with caution in individuals with a history of substance abuse.

Nonbenzodiazepines: Nonbenzodiazepine (non-BZ) compounds have been developed in an attempt to minimize the adverse effects associated with the use of BZs for the treatment of insomnia. In contrast to the BZs, non-BZ hypnotics are more selective for the alpha₁ subunit of the GABA receptor and thus may be more specific for sedation with fewer adverse effects.¹³

Zolpidem, zaleplon, and eszopiclone possess distinct pharmacologic profiles, mechanisms of action, and clinical activity (TABLE 3).³ The use of BZs has steadily declined since the introduction of zolpidem in 1993.³

Zolpidem: Zolpidem is an imidazopyridine-derivative, sedative-hypnotic agent indicated for the short-term treatment of insomnia. It has highly selective effects on sleep induction and few anticonvulsant and myorelaxant activities. Due to its longer duration of action than other agents, zolpidem reduces sleep latency and increases total sleep time.¹⁴ Exhibiting a bioavailability of 70%, it is rapidly absorbed within 20 to 40 minutes, is distributed throughout the body, and binds to albumin and alpha₁-acid glycoprotein without accumulation.^13,15

Zolpidem has been extensively evaluated in patients with primary insomnia in controlled trials.^16-19 Studies using objective and/or subjective measures demonstrate that nightly zolpidem improves sleep latency and sleep duration in patients with chronic insomnia.^16,20 However, some objective parameters such as waking after sleep onset and number of awakenings were not significantly different compared with placebo.^16,18 Some studies with objective and subjective measures show that the effects of zolpidem may diminish during the treatment period.¹⁸ Such findings, however, are not consistently reported. Several studies have demonstrated improved sleep latency and total sleep time with nightly administered zolpidem for up to three months with no rebound insomnia or withdrawal symptoms seen after zolpidem discontinuation.^13,17 Alternatively, withdrawal symptoms and rebound insomnia after discontinuation of zolpidem have been seen in other studies.²¹

Table 3
Characteristics of FDA-Approved Sleep Agents
Generic Name	Brand Name	Class	Duration of Action	Elimination Half-Life(h)*	Onset of Action (min)	Dosage (mg)*	Insomnia Indication
Estazolam	ProSom	BZ	Intermediate	8-24	15-30	1-2	Sleep onset and maintenance
Flurazepam	Dalmane	BZ	Long	48-120	60-120	15-30	Sleep maintenance
Quazepam	Doral	BZ	Long	48-120	20-45	7.5-15	Sleep maintenance
Temazepam	Restoril	BZ	Intermediate	3-25	45-60	7.5-30	Sleep maintenance
Triazolam	Halcion	BZ	Short	1.5-5	15-30	0.125-0.25	Sleep onset
Eszopiclone	Lunesta	Non-BZ	Short	6	30	2-3	Sleep onset and maintenance
Ramelteon	Rozerem	Non-BZ	Short	2-5	30	8	Sleep onset
Zaleplon	Sonata	Non-BZ	Short	0.5-1	20	10-20	Sleep onset
Zolpidem	Ambien	Non-BZ	Short	1.5-4.5	30	5-10	Sleep onset and maintenance
Zolpidem controlled- release	Ambien CR	Non-BZ	Short	1.5-4.5	30	6.25-12.5	Sleep onset and maintenance
* In healthy adults. BZ: benzodiazepine. Source: Reference 12.

In an attempt to overcome the development of tolerance and dependence in patients who require long-term pharmacotherapy, the continuous use of zolpidem has been compared with intermittent administration (i.e., five consecutive nights of zolpidem followed by two nights of placebo per week). Comparable improvements in sleep latency, total sleep time, overall quality of life, and tolerability were seen with both dosing strategies.^19,20

The recommended dosage of zolpidem is 10 mg in healthy adults and 5 mg in the elderly, debilitated patients, and those with hepatic dysfunction, to be taken immediately before bed.¹⁵ Common adverse effects are headache (especially during the discontinuation phase), drowsiness, fatigue, dizziness, and residual daytime sedation. Confusion, disorientation, obsessive ideas, delirium, and psychosis have also been reported.¹⁶ Non-CNS related adverse effects include gastrointestinal symptoms and skin rash.¹⁹ At recommended dosages, zolpidem does not appear to negatively affect next-day psychomotor or cognitive function, and the potential for dependence, tolerance, or rebound insomnia upon discontinuation appears minimal.

Zolpidem Extended-Release: Extended-release zolpidem, the first ever extended-release sleep aid, was approved by the FDA in September 2005 for the treatment of insomnia characterized by difficulties with sleep onset and/or sleep maintenance.²² Extended-release zolpidem is delivered in two stages through the use of a bilayered tablet; the first layer dissolves quickly to induce sleep, while the second layer is released more gradually to improve sleep maintenance. Despite differences in the dosing formulations, the pharmacokinetics of both zolpidem products are similar.²² No studies to date have compared the efficacy of extended-release zolpidem to the immediate-release formulation.

The recommended dosage of extended-release zolpidem is 12.5 mg immediately before bed for healthy adult patients. The dosage should be reduced to 6.25 mg for patients over 65 years of age, debilitated patients, or patients with hepatic dysfunction. Extended-release zolpidem tablets should be swallowed whole, not divided, chewed, or crushed.²²

All adverse events seen with the extended-release formulation are similar to those seen with immediate-release zolpidem. Due to its rapid onset of action, extended-release zolpidem should only be ingested immediately prior to bedtime.²²

Zaleplon: Zaleplon is a pyrazolopyrimidine non-BZ hypnotic agent that, like zolpidem, binds selectively to the alpha₁ subunit of the GABA receptor complex. It exerts sedative, anxiolytic, muscle relaxant, and anticonvulsant effects.¹³ Zaleplon is approved for immediate use at bedtime or later in the night (up to four hours prior to the anticipated wake time) when difficulty falling asleep is experienced.²³ High fat meals can interfere with absorption, delaying the time to peak plasma concentration and reducing the maximum plasma concentration.¹³

Improvements in sleep onset have been observed, but zaleplon fails to show improvements in sleep maintenance or sleep duration at the recommended 10-mg dosage, indicating that zaleplon is effective for patients unable to fall asleep, but not at keeping them asleep.²¹

The recommended dosage of zaleplon is 10 mg in adults and 5 mg in the elderly.^12,23 Zaleplon has a favorable safety profile and is well tolerated. Headache, which appears to be dose dependent, is the most commonly reported adverse event. Less commonly, CNS-related effects such as drowsiness, paresthesias, incoordination, dizziness, hallucinations, and ataxia have been reported.^13,23

Zaleplon can be dosed in the middle of the night without producing residual sedation and next-morning memory impairment in patients with sleep-maintenance insomnia.^24,25 Whether administered during the day, at bedtime, or during the night, zaleplon is associated with less psychomotor and memory impairment and more rapid resolution of adverse effects than zolpidem.^24,25

Eszopiclone: Eszopiclone is a novel, single isomer, non-BZ belonging to the family of cyclopyrrolones.^13,26 Eszopiclone is the S-isomer of the well-studied hypnotic agent zopiclone, which has been available in countries other than the U.S. for almost 20 years.²⁷ The degree of selectivity for the alpha₁ subunit of the GABA receptor is between the low level of benzodiazepines and the high levels of zolpidem and zaleplon. Eszopiclone induces hypnotic, anticonvulsant, and sedative effects.^13,27

Eszopiclone produces significant and sustained improvements in patient-assessed sleep onset, sleep maintenance, sleep quality, and total sleep time.²⁸ Significant improvements in next-day effects, including daytime alertness, ability to function or concentrate, and sense of physical well-being, are also benefits of eszopiclone. Tolerance has not been observed after as much as 12 months of nightly treatment with eszopiclone, nor is withdrawal seen upon discontinuation.²⁸

The recommended starting dosage of eszopiclone is 2 mg at bedtime for patients who can remain in bed for at least eight hours; this may be increased to 3 mg based on patient response.²⁶ The starting dosage should be reduced to 1 mg for patients with severe liver disease, those taking potent CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin, and nelfinavir) and patients older than 65 years of age.²⁶ Ingestion of eszopiclone with or shortly after a high-fat meal may delay the time to sleep induction by up to one hour.²⁶ Eszopiclone is well tolerated, with the most commonly reported adverse event being an unpleasant taste.²⁸ Headache and dizziness have also been reported.²⁶

Melatonin Receptor Agonists (Ramelteon): Unlike the other non-BZ agents, ramelteon is a selective melatonin receptor agonist. Melatonin, an endogenous hormone responsible for modulating the circadian rhythm, is released from the pineal gland into the circulation in response to environmental light/dark signals.²⁹ The exact mechanism of action of melatonin on sleep is unknown, but likely involves stimulation of melatonin (MT) receptors. The MT₁ and MT₂ receptor subtypes appear to contribute to regulation of the 24-hour sleep-wake cycle, whereas the MT₃ receptors do not appear to play a role in sleep. Exogenous supplemental melatonin has a short half-life and lacks selectivity for the MT₁ and MT₂ receptors.²⁹ In comparison, ramelteon has a high affinity for MT₁ and MT₂ receptors, suggesting more specific action on the sleep-onset process than melatonin.³⁰

Ramelteon is rapidly and extensively absorbed after oral administration; however, the absolute bioavailability is less than 2%. Ramelteon undergoes extensive first-pass metabolism to four main metabolites, all of which are more active than the parent compound.³⁰ Renal clearance of ramelteon is reduced in elderly patients; however, dosage adjustment is not required in patients with renal insufficiency.

Ramelteon significantly reduces sleep latency and increases total sleep time with no next-day residual effects.³¹ Rebound insomnia and withdrawal effects do not occur upon discontinuation.³¹

The recommended dosage of ramelteon for all patients is 8 mg orally within 30 minutes of going to bed.¹⁷ It is recommended that ramelteon not be given with or immediately after a high-fat meal due to delays in oral absorption.³⁰ Ramelteon is generally well tolerated; the most common adverse events include headache, somnolence, dizziness, nausea, fatigue, and exacerbated insomnia.³¹

Trazodone: A significant percentage of those with sleep disturbances have depressive symptoms. Depressive symptoms can precede, occur independently of, cause, or result from insomnia. Chronic insomnia has been linked to the development of depressive symptoms. As a result, despite the lack of FDA approval, sedating antidepressants are often used to treat insomnia.⁶ Trazodone, a triazolopyridine antidepressant with sedating properties, is commonly used to treat insomnia at nightly dosages of 100 mg or less.⁶ Commonly reported adverse effects associated with trazodone 75 to 500 mg/day include blurred vision, constipation, dizziness, drowsiness, dry mouth, headache, hypotension, nausea, and vomiting.³² Rare, yet more serious adverse effects include cardiac events (i.e., syncope, exacerbation of ischemic attacks, torsade de pointes, other arrhythmias) and priapism.³² Due to the fact that little data exist evaluating its use in non-depressed patients with insomnia, trazodone should be used with caution, particularly in the elderly and in patients with preexisting cardiovascular disease.^6,32

Nonprescription/OTC Treatments

The availability of nonprescription products for the treatment of insomnia, including antihistamines, dietary supplements, and herbal products, allows for increased treatment access to those experiencing symptoms of insomnia. Growing popularity of these OTC sleep aids indicates the propensity for patients to self-medicate and the level of patient satisfaction with the performance of these agents, despite the lack of concrete efficacy data. Like all medications, these products are not devoid of risk and do pose the potential for toxicity through inappropriate dosing, drug interactions, or not being taken properly. Premarket evaluation and approval by the FDA are not required for OTC products, dietary supplements, or herbal products. Instead, they are considered �generally regarded as safe� (GRAS), unless claims are made for specific disease prevention or treatment.³³ Furthermore, dietary supplements sold in the U.S. must comply only with Good Manufacturing Practice regulations, which are primarily concerned with sanitation rather than manufacturing consistency or quality.³³ The widespread availability, perceived safety, and low cost of these products can encourage experimentation and potentially delay medical attention and effective treatment.

Antihistamines: Diphenhydramine and doxylamine are first-generation, centrally acting histamine (H₁)-receptor antagonists commonly used, alone or in combination with an analgesic, in nonprescription products marketed for the relief of insomnia. Of the two agents, diphenhydramine is the most widely used.^6,34,35 While other available first-generation antihistamines (i.e., chlorpheniramine, brompheniramine, and pyrilamine) are sedating and could induce sleep, they have not proven to have an effect on sleep duration or efficiency and may cause additional side effects.³⁵ Loratadine, a second-generation antihistamine available OTC, possesses limited ability to cross the blood-brain barrier and is thus not a suitable option for use as treatment of insomnia. Due to many potential side effects and drug interactions, antihistamines are not recommended for use in the elderly. Before recommending an OTC antihistamine for the treatment of insomnia, it is imperative to identify current medications (prescription and nonprescription) and medical conditions to avoid undesirable synergistic, antagonistic, or adverse effects.

Although they are commonly used as sleep aids, there are limited data to support the use of OTC anti-histamines such as diphenhydramine for the treatment of insomnia. A limited number of randomized controlled trials of H₁-receptor antagonists have suggested subjective improvement in overall sleep, but these trials included only a small number of participants, reported a comparatively short duration of sleep, and lacked objective data.³⁶ Although there is substantial evidence that first-generation antihistamines cause sedation, there are little clinical data to support sustained improvement in sleep when these agents are administered at night.

Lipophilic properties allow diphenhydramine to readily cross the blood-brain barrier, causing sedation.¹¹ In addition to the primary H₁-receptor activity, antihistamines also act at serotonergic, cholinergic, and central alpha-adrenergic receptors to varying degrees, causing significant side effects.⁶

The recommended dosage of diphenhydramine is 25 to 75 mg at bedtime.³⁶ An increase in dosage does not produce a linear increase in response. Dose-related residual morning sedation (hangover effect) occurs commonly due to a long elimination half-life.^6,11,35 Muscarinic-receptor antagonism induces anticholinergic effects (e.g., dry mouth, dry eyes, urinary retention, constipation, blurred vision, and delirium) and should be considered, particularly in the elderly.³⁵ Antihistamines also commonly cause dizziness and can affect driving performance and the lower seizure threshold in patients with epilepsy. There is some indication that tolerance to the intended sedation effect can develop by the fourth day of treatment, rendering the treatment ineffective to induce sleep but still capable of producing unwanted side effects.³⁶

Herbal/Natural/Alternative Options: Patients often perceive dietary supplements and herbal products as more natural and safer alternatives to prescription and other nonprescription drugs. Data supporting safety and efficacy of such products are weak due to studies of few subjects, short duration of treatment, and varying dosages and product formulations. Furthermore, because these products are marketed as dietary/herbal supplements, their manufacturing is not regulated by the FDA for quality or consistency, and variances in potency across manufacturers, formulations, and product lots can result.³³

Melatonin and valerian are commonly used as mild hypnotics, and evidence supports their use for insomnia symptoms in certain populations.³⁷ Kava (kava kava, Piper methysticum) is best known for its use as an anxiolytic but is also often used for its sedative properties in insomnia despite lacking evidence of efficacy.³⁷ Furthermore, kava is considered unsafe due to reports of hepatotoxicity with recommended daily doses (70 to 280 mg at bedtime), and its use should be discouraged.³⁷ L-tryptophan, an amino acid precursor to melatonin and serotonin, was removed from the U.S. market in 1990 due to numerous case reports of eosinophil-myalgia syndrome (EMS).³⁷ However, its by-product, 5-HTP, is still available. Neither product has been proven through reliable evidence to be effective for insomnia and should not be recommended because of possible contamination leading to EMS.³⁷ There is not enough evidence to support the efficacy and safety of other natural products promoted to have sedative effects (i.e., chamomile, passion flower, coenzyme Q10, hops, lemon balm, lavender, and skullcap) for the treatment of sleep disturbances.³⁷

Melatonin: As previously discussed, melatonin exhibits effects on the circadian rhythm. However, the use of melatonin for the treatment of insomnia is not supported by rigorous data.³⁷ Many of the reported studies are of poor quality and design and have produced inconsistent and conflicting results.³⁸ Improvement in sleep duration and sleep latency, but not in sleep quality, have been documented by some trials. When changing time zones, taking melatonin one hour prior to the desired sleep time can be effective for insomnia associated with jet lag.^29,37

Melatonin is considered GRAS in recommended doses (0.3 to 5 mg administered 30 to 120 minutes before bedtime) for short-term use and is likely safe when used orally for up to two years.³⁷ Next-morning residual effects are uncommon with the use of melatonin.³⁷ Due to limited studies, safety has not been established in children less than 18 years of age; thus, the use of melatonin in this population is not recommended.³⁷

Commonly reported side effects of melatonin include fatigue, dizziness, headache, irritability, and drowsiness.²⁹ Less common side effects may include mood changes, hypotension, atherosclerotic plaque build-up, hyperglycemia, mild gastrointestinal distress, increased intraocular pressure, and fluctuations in reproductive and thyroid hormones.^29,37 Caution is advised in patients with vascular disorders and in those taking immunosuppressive therapy, as melatonin may cause vasoconstriction and enhance immune functioning.³⁷ High dosages (75 to 300 mg/day) can inhibit ovulation and contribute to infertility in women.²⁹ Case reports raise concerns about increased risk of bleeding, seizures, psychotic symptoms, and disorientation with melatonin overdose.³⁷ Caution should be exercised in patients taking warfarin or other agents that affect coagulation and platelet activity.

Valerian (Valeriana officinalis): Valerian, or valerian root, is commonly used to treat insomnia and anxiety. The parent drug may contain as many as 150 individual compounds.³⁷ The valepotriates and valerenic acid components are believed to contribute to the sedative effects of valerian.³⁹ Its effects on sleep are unclear, but GABA-ergic activity at both pre-and postsynaptic sites has been suggested.⁴⁰ A characteristic unpleasant odor associated with valerian is due to its isovaleric acid component.³⁹

The FDA recognizes valerian as GRAS, and the German Commission E has approved valerian as a nonprescription agent to treat sleeping disorders and nervous restlessness. A systematic review of randomized clinical trials evaluating the effectiveness of valerian for insomnia found that short-term use reduces sleep latency, improves subjective sleep, and promotes sleep maintenance.^39,40 Clinical trials have not evaluated tolerance, dependence, withdrawal, and rebound symptoms upon discontinuation.³⁹

Studied adult dosages for insomnia range from 1.5 to 3 g of actual herb/root, corresponding to 400 to 900 mg of an aqueous extract, taken 30 to 60 minutes before bedtime. More recent available studies have reported success with 600 mg daily, taken one hour before bedtime.^37,39 Valerian can also be used one hour before bedtime in the form of a tea, prepared by steeping 1.5 to 3 g of the root for 5 to 10 minutes in 150 mL of boiling water.³⁹ There are insufficient data to recommend valerian therapy in children younger than 18 years of age.^39,40 Valerian is well tolerated for up to four to six weeks and is likely safe when taken orally at recommended doses. Mild side effects of dizziness, hangover, headache, insomnia, excitability, ataxia, uneasiness, and hypothermia have been reported but were not greater than placebo.³⁹

The possibility of withdrawal tachycardia should be considered in patients with a history of cardiac disease on long-term valerian therapy. Hepatotoxicity has been reported with some combination products containing valerian.^37,39 While it is unclear whether valerian itself is hepatotoxic, its use in patients with liver dysfunction is contraindicated. Due to the risk of additive effects, concomitant use of valerian with other sedating agents should be avoided.³⁷

Valerian is considered a dietary/herbal supplement and is not required to be standardized in the U.S. Thus, preparations may differ, depending on where and when the plant was harvested.³⁷

Conclusion

Insomnia is a prevalent condition associated with significant morbidity.^1,2 The inability to sustain nighttime sleep has been linked with patient reports of excessive daytime sleepiness, as well as negative psychosocial and quality-of-life consequences.^1,3,6 In addition, substantial economic and medical consequences are associated with untreated insomnia.^1,34 Improving both sleep onset and sleep maintenance disturbances without negative effects on measures of daytime function is an important therapeutic goal in the treatment of insomnia.

Treatment of sleep disturbances involves both nonpharmacologic and pharmacologic approaches. Nonpharmacologic strategies for the treatment of insomnia may improve insomnia, but treatment response can vary, and these strategies remain underutilized.^3,8,9,34 BZs have been well studied and are commonly used in the pharmacologic treatment of insomnia, but are associated with significant limitations.^6,11 Non-BZs offer hypnotic efficacy similar to that of the BZs but may offer decreased risk of tolerance long term and a lower risk of next-day hangover effects.^6,34 Eszopiclone is the only non-BZ agent evaluated in trials lasting six to 12 months.^13,26,27

In addition, trazodone and OTC products offer an alternative. However, despite their widespread use, a dearth of information exists regarding the safety and efficacy of these agents in the treatment of insomnia, and they should be used with caution. Ramelteon, a melatonin-receptor agonist, provides an additional option for the treatment of insomnia, but whether this agent offers any significant advantages over the non-BZs requires further clinical experience.²⁹ In general, nonpharmacotherapy and pharmacotherapy used by individuals with sleep disturbances should address particular underlying causes. Pharmacotherapy should be used with appropriate caution, at minimal effective dosages, and for the minimal duration required.⁶

REFERENCES

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