Behavioral Objectives

After completing this continuing education article, the pharmacist should be able to:

1. Review the primary causes of insomnia.
2. Identify the different types of insomnia (eg, trouble with sleep onset, early awakenings).
3. Review the medications currently available for the treatment of insomnia and understand relevant patient information that the medical professional should solicit to guide treatment, including the primary cause of the insomnia, the presence of concurrent medications, and parameters such as latency to persistent sleep, total sleep time, sleep architecture, and sleep efficiency.
4. Discuss dosing considerations for insomnia medications and appropriate initiation and titration of therapy.
5. Identify special patient population concerns.
6. Discuss the safety profiles of commonly prescribed insomnia medications.
7. Identify nonpharmacologic sleep hygiene measures insomnia patients should employ.

Sleep problems are common complaints of individuals worldwide. In a global survey across 10 countries and 4 continents, almost a third of subjects were currently experiencing insomnia, according to self-assessment measures.¹ A recent US study found an 11% prevalence rate for insomnia in 13-to 16-year-olds with a median age at onset of 11 years.² Insomnia is not only a burden to the individual, producing extreme daytime fatigue,^1,3,4 functional disability,^5,6 restricted activity,⁵ and cognitive impairment,^3,4,6 but it has broader repercussions as well. Use of health care resources is increased,⁷ accident rates are higher,^8,9 and work productivity^8,9 is decreased in insomniac patients. The costs associated with lost productivity are substantial and considerably higher than those reported for workers with bipolar disorder.¹⁰

Despite the high prevalence, impact, and cost of insomnia, it remains substantially underreported and undertreated.^4,7 Even among severe insomniacs, only 55% ever discussed sleep complaints with a doctor, and only 27% reported use of a sedative or hypnotic medication.⁷ Given the range of efficacious medications and nonpharmacologic interventions that are available, increased diagnosis and treatment of insomnia could significantly reduce both the personal and societal burden of the condition. All patients with insomnia are not alike, however, nor are the treatments. The source, severity, and symptoms of the insomnia must be understood in order to determine appropriate treatment. Additionally, a patient's comorbid medical disorders and concurrent medications should be considered in order to avoid adverse events and drug interactions with insomnia medications.

As a part of the health care team, pharmacists need to be aware of optimal practices in the management of insomnia to improve treatment of this pervasive, burdensome, and complex disorder.

Understanding the Patient with Insomnia

Pinpointing the Source

According to DSM-IV-TR criteria,¹¹ primary insomnia is defined as a sleep disorder characterized by difficulty falling asleep or maintaining sleep, or feeling unrestored by sleep. Additionally, it must cause the patient significant distress or functional impairment to meet criteria. In patients with primary insomnia, a clinical cause is not identifiable.¹² Although the precise pathogenesis of primary insomnia is unknown, research suggests that patients may experience a constant state of hyperarousability.¹³ Conversely, secondary insomnia may arise from several recognizable sources:¹³

• Poor sleep habits
• Medical conditions that interfere with sleep such as pain, cough, d i f f iculty breathing, or restless legs syndrome
• Substance use (ie, caffeine, alcohol, nicotine, or drugs)
• Psychosocial stressors
• Psychiatric disorders such as anxiety or depression

Most insomnia is secondary in origin,¹³ and stress, anxiety, and depression are prominent underlying factors.^14-17 Stressors known to promote insomnia include bereavement, change in sleep schedule or environment, loneliness, and work-or family-related stress.^14,15 Anxiety disorders are the most common psychiatric disorders associated with insomnia, with 24% to 36% of insomniacs reporting them.^18,19 The prevalence of depression is also high and is reported in 14% to 31% of those with insomnia.^18,19 Although insomnia is typically viewed as a symptom of anxiety or depression, longitudinal studies show that it often predates the emergence of these disorders, suggesting that insomnia treatment could possibly prevent psychiatric morbidity.^18,19

Insomnia may also occur as a side effect of a medication for any number of acute or chronic medical disorders. Clinicians should be careful to elicit information from patients on current drugs they are taking to determine if any of them may be interfering with sleep (Table 1).

Characterizing the Insomnia

The profile of insomnia differs from patient to patient and may even change over time within a given patient.¹⁰ It is important to carefully characterize the particular sleep difficulties so that treatment can be individualized. Sleep diaries may be kept for a period of weeks to collect information on bedtime and time of arising, duration and quality of sleep, timing and quantity of meals and exercise, and ingestion of alcohol, drugs, caffeine, etc.²⁰ Several characteristics should be considered for optimal management:

• Type of insomnia (primary or secondary)
  • If secondary, underlying cause(s) are identified
• Duration of insomnia (transient, short-term, or chronic)
• Symptoms of insomnia
  • Difficulty falling asleep
  • Frequent nocturnal awakenings
  • Early morning awakening with inability to return to sleep
  • Poor quality of sleep (easily awakened, excessive dreaming, feeling unrestored after sleep)

Primary insomnia is a diagnosis of exclusion after all secondary sources of insomnia are ruled out.¹³ If the insomnia appears to be secondary, then in most situations, the secondary causes should be treated first, keeping in mind that there may be more than one cause.²⁰ If this treatment is unsuccessful, then the insomnia should be treated as primary.¹³

Most insomnia is transient or short-term in duration. In a large US survey, 75% of respondents with insomnia reported that it was occasional, lasting only about 5 days (on average) for a single bout of insomnia. These individuals had been experiencing episodes of short-term insomnia for a mean duration of 9.3 years, however.¹⁴ Chronic insomnia was reported by 9% overall (25% of insomniacs), although the incidence was much greater in the elderly (>65 years old), with 20% reporting chronic insomnia.¹⁴

Review of medical and psychiatric history, sleep history, and sleep diary information will facilitate characterization of insomnia and determination of the source of difficulties. Difficulties in maintaining sleep are very common and have been reported by >66% of insomniacs, whereas sleep initiation problems are reported by a somewhat lower proportion overall (~60%).^4,14 The type and duration of sleep complaints have been associated with demographic variables. Chronic insomnia is more common in the elderly¹⁴ and patients with psychiatric¹⁹ or medical disorders.²¹ Sleep maintenance difficulties (versus sleep initiation difficulties) predominate in anxious,²² depressed, and elderly patients.¹⁰

Management of Insomnia: Nonpharmacologic Interventions

Nonpharmacologic therapies for insomnia are usually cognitive-behavioral in nature, and they have proven effective in clinical trials when delivered by well-trained therapists. Table 2 describes the nonpharmacologic therapies that met the American Psychological Association ( APA) criteria for efficacious treatments, based on a thorough review of clinical trials data.²³ Additionally, although sleep hygiene education has not proven effective when used alone, it is often employed in combination with other therapies and may be useful as an adjunct.²³ The basic rules of sleep hygiene recommend the following:¹²

• Maintain a consistent bedtime and awakening time every day
• Exercise regularly, but no vigorous exercise within 2 to 4 hours of bedtime
• Avoid caffeine and nicotine at least 6 hours before bedtime; moderate use of alcohol is acceptable but none within 4 hours of bedtime
• Keep bedroom quiet and temperature moderate
• Avoid naps during the day
• Relax before bedtime, and do not watch the clock during the night

The use of nondrug therapies is attractive from a side-effect perspective but can be impractical. Sessions are time-consuming and require trained personnel to administer.¹⁰ Insurance may not cover the cost, and patients may not be adequately motivated to follow through without close supervision.¹² Moreover, these interventions are not well-tested in a primary care setting or in patients with insomnia secondary to comorbid disorders. More research is needed to develop a nondrug therapy that is applicable to primary care and effective in insomnia associated with medical and psychiatric illness.²³

Pharmacologic Management of Insomnia

Benzodiazepine-receptor agonists (BZRAs) are considered drugs of choice for pharmacologic management of insomnia. They are recommended for treatment of primary insomnia and transient or short-term insomnia due to acute illness, stress, and travel (eg, jet lag). Ideally, treatment of secondary chronic insomnia should be directed at the underlying cause (eg, depression, anxiety, arthritis pain). Resolution of these disorders takes time, however, and concurrent treatment of insomnia may be desirable. Furthermore, treatment of an underlying disorder does not always lead to remission of insomnia.²⁴ Historically, BZRAs have been recommended for short-term use. Recently, however, sleep specialists have begun to question the need to limit therapy duration, given the positive efficacy and safety profiles of available BZRAs.²⁵ Although most of the hypnotics are indicated for short-term use, the 2 newest entries into the market—eszopiclone (a BZRA) and ramelteon (a melatonin receptor agonist)—are not restricted to short-term use in the package labeling.

Drugs that are FDA-approved for insomnia include the BZRAs (benzodiazepines and nonbenzodiazepines) and the recently approved melatonin agonist ramelteon. Table 3 lists the individual drugs by class along with their marketed dosage strengths, dose range, half-life, and the receptors believed to be responsible for their therapeutic action. The obvious pharmacologic differences among these hypnotics are their half-lives and receptor pharmacology. Benzodiazepines differ from nonbenzodiazepines in receptor selectivity. The nonbenzodiazepines, zolpidem and zaleplon, are selective for GABA^A receptors containing the α¹ subunit, whereas benzodiazepines are nonselective with comparable affinity for GABA^A receptors containing either α¹, α², α³, or α⁵ subunits.²⁶ The precise binding site of eszopiclone (the S-isomer of racemic zopiclone) on the GABA^A receptor complex is unknown.²⁷ Ramelteon is a melatonin agonist with selectivity for the melatonin MT¹ and MT² receptors.²⁸

Several products aimed at improving sleep are available without a prescription. Herbal products said to improve insomnia include valerian root and kava kava.^29,30 Valerian may work best for mild insomnia when taken continuously rather than as an acute sleep aid.³¹ Kava kava is no longer recommended for use by the FDA as it may cause severe liver toxicity.³⁰ Melatonin, a naturally occurring hormone, is also marketed as a sleep aid, but its performance in treating insomnia appears inconsistent.^32-34 A few antihistamines, including diphenhydramine and doxylamine, are also used as sleep aids due to their sedating properties. Anticholinergic side effects and excessive next-day sedation limit their chronic use, however.

Individualizing Therapy Based on Efficacy Parameters

Differences in receptor pharmacology among hypnotics can potentially be exploited when tailoring therapy to patients' needs. GABA^A receptors containing α¹ subunits are believed to mediate the sedative, anticonvulsant, and amnestic effects of BZRAs, whereas those containing α² subunits mediate anxiolytic action. (GABA^A receptors containing α³ and α⁵ subunits constitute a small minority of GABA^A receptors, and their functions have not yet been defined.²⁶) Theoretically, patients with an underlying anxiety disorder or whose insomnia is definitely stress-induced may garner additional efficacy benefits from a benzodiazepine hypnotic. Unfortunately there are no head-to-head comparator studies evaluating nonbenzodiazepine BZRAs (α¹ selective) versus benzodiazepines in anxiety-induced insomnia to properly test this hypothesis. Additionally, it should be noted that triazolam, a short-acting benzodiazepine, has been associated with rebound daytime anxiety and may therefore be less appropriate in anxiety-induced insomnia.³⁵

Ramelteon is the only FDA-approved hypnotic that does not exert its effects via benzodiazepine receptors. Instead, ramelteon is a selective agonist at melatonin MT¹ and MT² receptors, receptors believed to participate in regulation of the circadian rhythm that underlies the sleep-wake cycle.²⁸ Patients suffering from insomnia related to dysregulation of circadian rhythm could potentially receive additional benefit from this agent. This theory has not been specifically tested, however. Interestingly, studies of melatonin as a hypnotic have shown inconsistent efficacy across a variety of experimental paradigms,³⁶ but efficacy in patients with disturbances of sleep-wake cycle has been more promising.³⁷ These patients include shift workers, travelers with jet lag, blind patients, and patients with delayed sleep phase syndrome. Elderly individuals are also more likely to suffer from insomnia as a result of an underlying circadian dysregulation.³⁸

Sedating antidepressants such as trazodone, nefazodone, and mirtazapine are not indicated for insomnia but are frequently employed in this regard.²⁵ Inhibition of serotonin (5HT²) receptors by these agents may mediate hypnotic effects, at least in part.³⁹ Despite their popularity, their evidence of effectiveness in nondepressed patients with insomnia is scant, and they are associated with next-day sedative effects and other tolerability problems.^13,24 For depressed patients with insomnia, however, sedating antidepressants may be a reasonable alternative because they have shown better efficacy results in this population and have the benefit of also treating the underlying depression.³⁹

Individualizing drug therapy to patient needs is a complex process and should involve consideration of other medication factors in addition to receptor pharmacology. The pharmacokinetic profile, particularly half-life, also impacts efficacy and safety and differentiates hypnotics where receptor pharmacology may not. In the context of efficacy, pharmacokinetic profile may dictate whether an agent is effective for sleep-onset problems, sleep maintenance problems, or both. Table 4 lists FDA-approved hypnotics and the type of sleep symptom for which they have proven efficacy. Not surprisingly, agents with shorter half-lives tend to be less effective for sleep maintenance-related difficulties. Neither zaleplon nor ramelteon has proven efficacy for sleep maintenance (when taken before retiring), and they are indicated for patients with sleep-onset difficulties only.^28,40 In clinical practice, zaleplon is often used in the early morning hours for patients who wake up too early and have difficulty falling back to sleep.²⁴ Estazolam has shown inconsistent efficacy in improving sleep-onset time^41,42 and may therefore be less suitable for sleep induction than the other hypnotics listed in Table 4. This may be a result of slower absorption and/or lower lipophilicity as compared with most of the other hypnotics listed.^42,43

Insomnia in elderly populations is characterized by complaints of both poor quality and reduced quantity of sleep. Early morning awakening is one of the most common specific complaints in this age group.⁴⁴ Hypnotics with sustained efficacy throughout the night would be most appropriate in patients with this problem. Although the efficacy of hypnotics has not been well-tested for this parameter, several studies objectively evaluated wake time at the end of the night using polysomnography. Triazolam (0.25 mg),⁴⁵ zolpidem (10 mg),⁴⁶ and zaleplon (5 or 10 mg),⁴⁷ the agents with the shortest half-lives, were no more effective than placebo in reducing wake time in the latter portion of the night (last third or quarter). Temazepam (an intermediate- acting hypnotic) significantly reduced wake time in the last third of the night during short-term use in elderly insomniacs, however (7.5-mg dose).⁴⁸ Studies of estazolam, eszopiclone, or ramelteon that measured polysomnographic sleep parameters related to early morning awakening could not be identified.

Poor sleep quality is also a frequent complaint, particularly among elderly insomniacs.⁴⁴ Both benzodiazepines and nonbenzodiazepine hypnotics have been shown to improve subjective measures of sleep quality (ie, patients report sleeping more deeply or feeling more refreshed after sleep). However, sleep architecture is an objective parameter that may reflect sleep quality and has been differentially affected by hypnotic treatment. Sleep architecture is determined by the proportion of time spent in each of the sleep stages using polysomnography. A patient who spends more time in the lighter stages of sleep or in REM (rapid eye movement stage of sleep associated with dreaming) may feel less refreshed by sleep in the morning. Stages 3 and 4 are called slow wave sleep and are the deepest levels of sleep.⁴⁹ Slow wave sleep may be reduced by benzodiazepines but tends to be preserved by nonbenzodiazepines.^49,50 Effects of hypnotics on slow wave sleep appear dose-dependent as well. Suppression of slow wave sleep has been reported with high doses of temazepam (30 mg)^51,52 and zolpidem⁴⁹ but not with lower doses.

Tolerance to Long-term Use of Hypnotic Therapy

The efficacy of hypnotics has sometimes been reported to decrease after repeated use, particularly with benzodiazepines. A meta-analysis of short-acting agents found that triazolam was associated with the most severe tolerance, but tolerance was mild with zolpidem.⁵³ Temazepam,⁵¹ estazolam,⁵⁴ zaleplon,⁵⁵ zolpidem,⁵⁶ and ramelteon²⁸ have shown continued efficacy over a period of several weeks with nightly use. Intermittent use of zolpidem over a period of 8 weeks was also effective.⁵⁷ Eszopiclone has shown the most sustained efficacy with sleep improvements demonstrated for up to 6 months.⁵⁸

Safety and Tolerability Issues Affecting Drug Selection

Safety and tolerability issues associated with hypnotic use vary widely. Table 5 lists some of the prominent issues and summarizes information on each of these for various hypnotics. These issues as well as the issues specific to special patient populations must be taken into account for optimal management of insomnia.

Rebound Insomnia. Rebound insomnia (a worsening of sleep difficulties as compared with baseline) after abrupt withdrawal of therapy has been reported for both benzodiazepines and nonbenzodiazepines. This phenomenon is related to the dose and half-life of BZRA hypnotics—a shorter half-life and higher dose increase the risk for rebound insomnia.⁵⁹ It tends to be mild and of short duration (1 night) for the nonbenzodiazepines^27,40,60 and has not been reported for ramelteon²⁸ or temazepam 7.5 mg.^48,61 A study directly comparing zolpidem 10 mg with temazepam 20 mg (~equivalent doses) detected no differences in incidence of rebound insomnia.⁶² In head-to-head comparisons of zolpidem and zaleplon, zolpidem 10 mg but not zaleplon (5-20 mg) produced a higher rate of rebound insomnia (subjectively reported) as compared with placebo on the first withdrawal night.^55,63 Rebound insomnia is most severe with triazolam, the shortest-acting benzodiazepine.^53,64 Tapering of hypnotic medications rather than abrupt withdrawal has been shown to ameliorate rebound insomnia.⁶⁵ Additionally, using the lowest effective dose of a hypnotic may prevent rebound, as studies have shown that rebound insomnia is dose-specific—ie, it appears at dose levels that show no additional efficacy as compared with a lower dose.⁶⁶

Residual Effects. Residual effects reported the day after hypnotic use (or later) consist primarily of sedation, psychomotor impairment, and cognitive problems. They can affect next-day performance and are quite common with long-acting benzodiazepines that accumulate in the circulation after repeated administration.²⁴ Residual effects such as ataxia and impaired coordination have been particularly concerning in elderly patients, because they raise the risk for falls and hip fracture.⁶⁷ In adult patients of all ages, the risk for car accidents is increased, particularly with high-dose or long-half-life benzodiazepines.⁶⁷ Short-half-life nonbenzodiazepine hypnotics can also cause problems. A recent report in The New York Times indicates that zolpidem is one of the top 10 drugs detected in impaired drivers in 10 of 24 states that routinely test for it.⁶⁸

Although flurazepam and quazepam carry indications for insomnia, they are not generally recommended because next-day residual effects are common with these agents.¹³ These benzodiazepines have long half-lives and produce active metabolites during biotransformation. The accumulation of their final metabolite is believed to underlie the next-day sedative effects. The final metabolite of both flurazepam and quazepam is desalkylflurazepam and has an elimination half-life of 48 to 120 hours.⁴³

The residual effects of shorter-acting benzodiazepines and the nonbenzodiazepines are much less severe and, at lower doses, may be undetectable within 8 hours of administration. Comparing among these agents is difficult, however, because of the paucity of head-to-head trials that evaluated residual effects. A recent comprehensive review of hypnotic residual effects was based on expert ratings, meta-analyses, and results from a standardized driving test and compared findings for zolpidem, zaleplon, temazepam, and triazolam, among other agents.⁶⁷ The probability of residual effects (sleepiness, psychomotor or cognitive impairment) 8 to 12 hours after hypnotic administration was considered unlikely for temazepam (20 mg), triazolam (0.125 mg), zaleplon (10-20 mg), and zolpidem (10 mg). The risk increased but was still considered "minor" for triazolam 0.25, and temazepam 30 mg; the risk with triazolam 0.5 mg was moderate. (Note that the hypnotics included in the review may have been reformulated in currently marketed drugs, and effects of current formulations could be different.)

Lower doses of zolpidem (5 mg) and temazepam (7.5 or 15 mg) and any dose of estazolam were not included in the review, nor were the 2 newest hypnotics—eszopiclone and ramelteon, likely because data were minimal or nonexistent at the time of the review (published in 2004). Because residual effects are clearly dose-related, it can be assumed that the lowest doses of zolpidem and temazepam would be even less likely to produce residual effects than the higher doses. Little evidence is available for estazolam, but a double-blind crossover study designed to evaluate next-day effects found significant deficits in psychomotor and cognitive performance at 10 hours after dosing as compared with placebo.⁶⁹ Considering these findings, the side-effect profile (dominated by sedation-related events),⁷⁰ and the longer half-life of estazolam, it seems likely that next-day residual effects would be more probable for this agent as compared with others listed in Table 5.

Based on data available for eszopiclone (residual effects as reported in package labeling and 1 comparator trial⁷¹), residual effects 8 hours or more after administration would be unlikely, similar to the other nonbenzodiazepines and the shorter-half-life benzodiazepines. In the only comparator trial available, no differences were detected between eszopiclone 1 mg to 3 mg and zolpidem 10 mg on subjective measures of morning sleepiness, daytime alertness, or daytime function.⁷¹ Data on ramelteon are even more lacking but suggest next-day effects would be unlikely with this hypnotic as well.²⁸ Additional direct comparator studies between hypnotics are needed to sort out any potential differences among low-dose temazepam, low-dose triazolam, ramelteon, and the nonbenzodiazepine BZRAs. Zaleplon appears to have some advantage among hypnotics included in the comprehensive review, because it was the only hypnotic rated as unlikely to have residual effects as early as 4 to 8 hours after dosing,⁶⁷ thus reflecting its ultrashort half-life.

Drug Interactions. All the FDA-approved hypnotics, with the exception of temazepam, are metabolized via CYP3A4 enzymes to a degree capable of allowing their involvement in clinically significant pharmacokinetic interactions with some CYP3A4 inhibitors or inducers. Estazolam and triazolam are contraindicated with potent inhibitors of CYP3A4 such as ketoconazole and itraconazole. Triazolam is also contraindicated with nefazodone. Cautious use with possible dosage reduction of the benzodiazepine is recommended with less potent CYP3A4 inhibitors (eg, fluvoxamine, cimetidine, diltiazem, isoniazid, and some macrolide antibiotics).^42,72

The nonbenzodiazepines have shown clinically significant interactions with strong CYP3A4 inhibitors (eg, ketoconazole, erythromycin) and inducers (eg, rifampicin).^27,40,60,73 Efficacy of the nonbenzodiazepines may be reduced by CYP3A4 inducers. Cautious use with strong inhibitors of CYP3A4 may be necessary, although dosage reductions are not specifically recommended in package labeling. Zaleplon is also metabolized via aldehyde oxidase, and dosage reduction to 5 mg is recommended when it is coadministered with cimetidine (a CYP3A4 and aldehyde oxidase inhibitor).⁴⁰

Ramelteon is metabolized primarily through CYP1A2, but CYP3A4 and the CYP2C subfamily also participate. Ramelteon should not be administered with the strong CYP1A2 inhibitor, fluvoxamine, which raises the area under the curve for ramelteon ~190-fold. Ramelteon should be administered with caution in patients taking less potent CYP1A2 inhibitors, strong CYP3A4 inhibitors (ketoconazole), or strong CYP2C9 inhibitors (fluconazole). The efficacy of ramelteon may be reduced if used in combination with strong CYP inducers (rifampin).²⁸

All hypnotics have the potential for pharmacodynamic interactions when administered with other drugs capable of producing CNS depression such as psychotropics, anticonvulsants, antihistamines, narcotic analgesics, and alcohol. Dosage adjustment of the hypnotic may be necessary to reduce additive CNS-depressant effects.

Abuse Liability

All the benzodiazepine and nonbenzodiazepine BZRAs are Schedule IV controlled substances. Ramelteon is not a controlled substance and showed no potential for abuse at doses up to 20 times the recommended therapeutic dose.²⁸

The relative abuse potential of 19 sedative-hypnotics has been ranked based on 3 sources of information: (1) data from studies of reinforcing effects in human and animal models of drug self-administration; (2) data from studies of human drug liking; (3) actual abuse rates estimated from epidemiology studies and case reports.⁷⁴ Interestingly, abuse potential did not appear to be linked with GABA^A receptor selectivity. Among the FDA-approved hypnotics, temazepam, triazolam, zaleplon, and eszopiclone were ranked similarly and received moderate abuse liability scores (about halfway between the hypnotics most and least likely to be abused). The relative abuse potential of zolpidem and estazolam was estimated to be somewhat lower (at the top of the bottom third). Rankings were not differentiated by dose, however, and the authors recommend that when prescribing hypnotics in potentially vulnerable patients they should be restricted to the lowest effective dose and limited quantities.⁷⁴

Special Issue with Ramelteon

Data with ramelteon are limited given its recent entry into the hypnotic market, but thus far its safety profile appears relatively benign based on package insert content and results from 1 published study.⁷⁵ A potential concern exists, however, that is specific to this hypnotic and that involves its effects on prolactin levels. A 6-month study with a daily 16-mg dose (twice the recommended dose) found a 34% increase in mean prolactin levels for ramelteon-treated women as compared with a 4% decrease in placebo-treated women. For both men and women, the incidence of elevated prolactin levels among ramelteon-treated patients was increased (32% versus 19% for placebo).²⁸ A 4-week study did not detect clinically significant changes in prolactin levels, however.²⁸ Increases in prolactin level have been associated with sexual dysfunction and reproductive abnormalities in both men and women.⁷⁶ Whether long-term, daily, or intermittent use of ramelteon 8 mg would affect prolactin or produce hyperprolactinemiainduced adverse events remains to be determined.

Use of Hypnotics in Special Populations

The clearance of many of the FDA-approved hypnotics is reduced in elderly patients, and initiation of therapy is recommended at the lowest available dose for all of them. Additionally, a half tablet (0.5 mg) is recommended with estazolam for small elderly patients. Increased dose-related adverse events have been reported in the elderly during triazolam use.⁷² Elderly patients may be more sensitive to the effects of hypnotics in general, even when plasma drug levels are not increased, and these agents should be used with caution in geriatric populations.⁷⁷

Exposure to eszopiclone, zaleplon, zolpidem, and ramelteon is increased in patients with hepatic impairment.^27,28,40,60 Dosage adjustments may be necessary with eszopiclone, zaleplon, and zolpidem. Zaleplon and ramelteon should not be used in patients with severe hepatic impairment. Renally impaired patients do not require dose adjustments. The package inserts for estazolam, temazepam, and triazolam do not report problems with hepatic or renal impairment, and no specific dosing recommendations are given.

Benzodiazepines are labeled pregnancy category X and are contraindicated in pregnancy. Zaleplon, eszopiclone, zolpidem, and ramelteon carry a category C rating and are not generally recommended but can be used if the potential benefit outweighs the risk.

The package labeling should be consulted for further information on the use of hypnotics in patients with concurrent medical conditions.

Role of the Pharmacist

Pharmacists can be particularly helpful to patients experiencing insomnia. Medication lists and refill data along with OTC purchases may provide clues about problems with sleep. Consider the following ideas when supporting patients with sleep difficulty:

• Understand the patient's type of sleep problem. Inquire if the patient has trouble falling asleep, sleeping through the entire night, waking up earlier than desired, or feeling tired upon awakening.
• Learn if the insomnia is secondary to another medical condition. Ensure that the underlying cause of insomnia is being properly treated, and be watchful for undiagnosed depression or anxiety. Report any clinical observations to the prescribing physician.
• If an underlying condition is documented, consider if the prescribed treatment addresses both the insomnia and the primary condition. If not, determine if an alternative product could meet both needs.
• Evaluate if the pharmacokinetic and pharmacodynamic properties of the prescribed medication match the patient's need based on the primary sleep-related issue.
• Ensure that the prescribed medication for insomnia could not make any underlying health conditions worse.
• Get a complete list of medications used by the patient, including prescription, nonprescription, and herbal remedies. OTC products that can interfere with sleep include cough and cold or pain medications that contain pseudoephedrine, caffeine, or other ingredients. Prescription medications known to potentially cause sleep problems include some diuretics, hormones including oral contraceptives, steroids, beta-agonists, diet pills, drugs used to improve attention control, and some antidepressant medications.
• Inquire about the use of OTC or herbal products as a self-treatment of insomnia to avoid drug duplication. In older persons, ensure that the physician adjusts drug doses to accommodate potential changes in metabolism or loss of functional reserve. Encourage physicians to start patients at risk for a drug-related problem at the lowest possible dose. Counsel the patient on avoiding alcohol and nicotine before bedtime, as both chemicals can disturb sleep.
• Gather information on the patient's lifestyle and habits. Will the prescribed agent interfere with day-today routines or lifestyle preferences? If so, consider recommending an alternative agent to the prescribing physician.
• Provide patients with explicit information about how the medicine will work, when to take the medicine, potential side effects, and how to assess the drug's effectiveness. Reinforce that insomnia medications are intended for short-term use and that the underlying cause of insomnia must be treated.
• Give patients a written list of nonpharmacologic interventions known to improve sleep. Encourage the patient to implement as many as possible in addition to the medication.
• Review possible residual effects of the medication with the patient. Encourage the patient to follow up with the physician if residual effects occur that interfere with daily activities.
• Discuss the potential for rebound insomnia upon drug discontinuation, especially with long-term medication use.

Conclusion

The recognition and management of insomnia need to be improved in order to reduce its tremendous burden on patients as well as society as a whole. Therapy should be chosen to best meet the needs of each individual patient. If drug treatment is deemed necessary, patients' specific sleep complaints and medical history should be carefully profiled and matched to the hypnotic with the most compatible efficacy and safety profile. In all cases, treatment with the lowest effective dose is key to an optimal outcome.

Deborah L. Due, PhD, Scientific Information Specialist, Raleigh, NC & Lynn S. Fitzgerald, BSPharm, PharmD, President, Bullhorn Communications Inc, Apex, NC

For a list of references, send a stamped, self-addressed envelope to: References Department, Attn. A. Stahl, Pharmacy Times, 241 Forsgate Drive, Jamesburg, NJ 08831; or send an e-mail request to: astahl@ascendmedia.com.

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CEReview Questions

1.Which one of the following is not a potential source of secondary insomnia?

1. Anxiety or depression
2. Being in a state of hyperarousability
3. Poor sleep habits
4. Alcohol use

2.Which of the following statements about chronic insomnia is false?

1. It is more common than short-term insomnia.
2. It may have more than one cause.
3. It occurs more frequently in the elderly.
4. It may be caused by diuretic use.

3. In the treatment of secondary insomnia, it is always important to:

1. Determine the underlying cause, if possible.
2. Treat the underlying cause until it is completely resolved, before treating the insomnia.
3. Treat the underlying cause with a medication that has sedative properties.
4. Use a nonpharmacologic therapy for insomnia.

4. The rules of sleep hygiene suggest that insomnia will be improved by:

1. Keeping the bedroom very warm.
2. Relaxing during the day.
3. Sleeping in late when possible (eg, on weekends).
4. Regular exercise (performed at least 4 hours before bedtime).

5. According to American Psychological Association criteria, which of the following nonpharmacologic techniques has (have) well-established efficacy for treating insomnia?

1. Stimulus control
2. Good sleep hygiene
3. Biofeedback
4. All of the above

6. The primary goal of one of the nonpharmacologic interventions for insomnia is to decrease the patient's worries about not being able to fall asleep. This therapy is called:

1. Stimulus control.
2. Paradoxical intention.
3. Progressive muscle relaxation.
4. Sleep restriction.

7. Benzodiazepines are distinguished from BZRAs based on:

1. Drug half-life.
2. Lipophilicity.
3. Receptor selectivity.
4. All of the above

8.Which of the following is true of ramelteon?

1. It is a melatonin antagonist.
2. It acts at melatonin MT¹ and MT² receptors.
3. It is indicated for sleep maintenance insomnia.
4. It is indicated for short-term use only.

9.Which of the following statements is true for all the FDA-approved hypnotics?

1. They improve sleep maintenance.
2. They are controlled substances.
3. They are FDA-approved for short-term use only.
4. None of the above

10. Poor sleep quality:

1. May be improved by BZRAs.
2. Is commonly reported in elderly insomniacs.
3. May appear as a decrease in slow wave sleep during polysomnography recordings.
4. All of the above

11.Which of the hypnotics has (have) demonstrated efficacy in a long-term ( 6-month) controlled trial?

1. Ramelteon
2. Eszopiclone
3. All the nonbenzodiazepine BZRAs
4. Triazolam

12. Rebound insomnia may be less likely to occur:

1. When using a hypnotic with a short half-life.
2. If the hypnotic medication is tapered rather than discontinued abruptly.
3. When a higher dose of a hypnotic is used.
4. All of the above

13. Factors that may increase the risk of residual or next-day sedative effects include:

1. Using a sedating antidepressant as a hypnotic.
2. Using a BZRA in combination with an opioid analgesic.
3. Using a hypnotic with active metabolites.
4. All of the above

14. Residual effects of hypnotics:

1. May increase the risk of car accidents.
2. Are unlikely with quazepam and flurazepam.
3. May be increased in the elderly.
4. A and C

15.Which hypnotic(s) is (are) metabolized via CYP3A4 enzymes and may participate in clinically significant drug interactions with CYP3A4 inhibitors?

1. Estazolam, triazolam, zaleplon, eszopiclone, and ramelteon
2. Ramelteon only
3. All FDA-approved hypnotics
4. Estazolam, triazolam, and temazepam

16. The following combinations of medications are contraindicated or not recommended:

1. Ramelteon with fluvoxamine
2. Triazolam with nefazodone
3. Estazolam or triazolam with itraconazole
4. All of the above

17. Pharmacodynamic drug interactions may occur between:

1. Benzodiazepines and alcohol.
2. Benzodiazepines and nonbenzodiazepine BZRAs.
3. Zaleplon and cimetidine.
4. A and B

18.Which of the following statements is (are) true?

1. Abuse liability is lowest with nonbenzodiazepine BZRAs.
2. Ramelteon has a high abuse potential.
3. Limited quantities of hypnotics should be prescribed in patients prone to drug abuse.
4. A and C

19. The use of hypnotics in elderly patients:

1. Should be initiated at the lowest available dose.
2. May be associated with an increased incidence of adverse events.
3. Should be limited to patients in whom nonpharmacologic interventions are impractical or unsuccessful.
4. All of the above

20. Hepatically impaired patients:

1. Should not use nonbenzodiazepine BZRAs.
2. Should not use ramelteon or zaleplon if their impairment is severe.
3. Should use only the lowest available dose of eszopiclone or zolpidem.
4. Should not use benzodiazepines.