The Journal for Nurse Practitioners
Volume 2, Issue 9 , Pages S621-S632, October 2006

Long-Term Pharmacotherapy in the Management of Chronic Insomnia

  • Andrew D. Krystal

      Affiliations

    • Andrew D. Krystal, MD, MS, is associate professor with tenure in the Department of Psychiatry at Duke University Medical Center. He directs the Sleep Research Laboratory and Insomnia Program. He is board certified in psychiatry, sleep medicine, and clinical neurophysiology and works primarily in the areas of sleep and mood disorders. He has research grant support from NIH, Sepracor, Pfizer, Merck, Somaxon, Neurocrine, GlaxoSmithKline, Sanofi-Aventis, Cephalon, and Respironics. He serves as a consultant for Sepracor, Somaxon, Neurocrine GlaxoSmithKline, Pfizer, Sanofi-Aventis, Cephalon, Respironics, Neurogen, Transoral, Takeda, Johnson & Johnson, Lilly, King, and Organon and is a speaker for Sepracor and Sanofi-Aventis.
    • ,
  • Shari Rogers

      Affiliations

    • Shari Rogers, MSN, CRNP, ACNP-BC, is a board-certified acute care nurse practitioner with the Sleep Medicine Center at the University of Pittsburgh Medical Center. She also serves as adjunct faculty for the Acute Care Nurse Practitioner Program at the University of Pittsburgh School of Nursing.
    • ,
  • Margaret A. Fitzgerald

      Affiliations

    • Margaret A. Fitzgerald, MS, APRN, BC, NP-C, FAANP, CSP, is the president of Fitzgerald Health Education Associates, Inc. in North Andover, Mass, and a board-certified family nurse practitioner and Certified Speaking Professional. She is a family practice provider at the Greater Lawrence (Mass) Family Health Center where she also serves as adjunct faculty to the Health Center's Family Practice Residency Program. She has relationships with Sepracor, GlaxoSmithKline, Janssen Ortho-McNeil, and Schwarz Pharma.

Article Outline

Abstract 

Chronic insomnia is common among primary care patients and often necessitates long-term management. The available treatment options for the clinical care of such patients are limited. Medication management is the most common therapy for this condition; however, this practice was hindered until recently by clinical guidelines that discouraged the prescription of the medications approved by the Food and Drug Administration for longer than 4 weeks. Further, few research studies have been conducted on the longer-term medication management of insomnia that might allow clinicians to assess the expected risks and benefits of longer-term therapy. Recent research, however, indicates that longer-term treatment with some agents may be safe and effective. This article reviews these studies and discusses them in the context of the diagnostic steps to consider when deciding whether to initiate or continue pharmacotherapy for insomnia.

Keywords:  Benzodiazepine , chronic insomnia , cognitive-behavioral therapy , nonbenzodiazepine

 

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Introduction 

The prevalence of chronic insomnia in the adult population has been estimated to be 10% to 15%,1 and more than half of the participants in community studies reported at least one chronic sleep complaint.2 Among primary care clinic patients chronic insomnia is found in between 10% and 50%,3, 4, 5 and it often coexists with other medical and psychiatric conditions.6, 7 The duration of sleep complaints is frequently quite long. Of the 50% of persons who report difficulties sleeping, 20% to 36% experience insomnia symptoms for longer than 1 year.8, 9, 10, 11, 12, 13, 14, 15

Although pharmacotherapy is the most common treatment for chronic insomnia, few studies have examined the efficacy and safety of long-term usage of many of the agents currently prescribed.16 Adding to the clinical challenge for advanced practice nurses and other clinicians, until recently, all insomnia medications approved by the US Food and Drug Administration (FDA) were indicated only for short-term treatment,17 and clinical guidelines discouraged the administration of these agents for longer than 3 to 4 weeks.18 Recent research, however, indicates that longer-term treatment of insomnia with certain agents may be safe and effective. This article reviews the research about long-term pharmacotherapy for chronic insomnia in the context of the diagnostic steps to consider when deciding whether to initiate or continue pharmacotherapy for insomnia.

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Assessing the Need for Pharmacotherapy 

Although a means of establishing how long a patient may experience insomnia does not currently exist, evidence suggests that patients with severe insomnia15 or concomitant psychiatric disorders19 such as depression and anxiety are more likely to have longer-lasting difficulties and require longer-term treatment. Although preliminary, evidence suggests that treating insomnia may alleviate the burden of other diseases,20, 21 such as rheumatoid arthritis and osteoarthritis, that symptoms of insomnia often persist despite remission of depressive symptoms in response to antidepressant therapy,22 and that the residual insomnia may predispose patients to recurrence of depression.23 Therefore, treatment of insomnia, particularly long-term insomnia, may be seen as part of a program to promote the total well-being of the patient.

Determination of whether a patient with chronic insomnia will benefit from medication and duration of pharmacotherapy rests on decisions made through a series of diagnostic steps, as follows (Figure 1).

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Establishing a Diagnosis of Chronic Insomnia 

Overview 

Primary care providers usually see patients for an acute or specific condition, for a follow-up visit for a chronic condition, or for a routine annual checkup, all of which present an opportunity for assessment of a sleep disorder.24 Insomnia is the most frequent sleep complaint reported.25 Insomnia is defined as difficulty falling asleep, staying asleep, or waking up too early or a report of nonrefreshing sleep.26 Insomnia can be classified as primary or comorbid, historically referred to as “secondary.” Primary insomnia is insomnia not associated with any medical, psychiatric, or substance use disorder. Most cases of insomnia are comorbid, or existing with other conditions.25 Several conditions are associated with increased rates of insomnia: increasing age,27 female sex,28 and comorbid psychiatric (especially anxiety or depression)7 or medical conditions. The extent to which the insomnia negatively affects the patient's daytime function guides the clinician in terms of treatment.

Determine Functional Impairment 

Insomniacs most commonly complain of daytime fatigue, irritability, and concentration difficulties. Evaluating the degree of functional impairment is an important step in determining the need for treatment and whether pharmacotherapy is an option. The greater the degree of functional impairment, the greater is the need for instituting therapy. The consequences of untreated insomnia may be a substantial burden for persons, their families, and society at large. The perception of impaired cognitive function,29 work absenteeism,30, 31, 32 an increased risk of accidents,32, 33 an association with risk of medical and psychiatric disease,4, 30, 32, 34, 35, 36 and a reduced quality of life in general31, 37 are among the consequences of untreated insomnia. The severity of these consequences should be considered when deciding to recommend treatment.

To determine functional impairment, the clinician must first perform a thorough history and physical examination, including a sleep history.26 A key question for the practitioner to ask is whether the patient has adequate opportunity to sleep, as patients who intentionally truncate their sleep cycle will often experience daytime consequences. Ask questions to help characterize the sleep complaint such as does the patient have difficulty initiating or maintaining sleep or awakening too early. Ascertain how long the problem has been present, and how frequent the insomnia occurs. A thorough sleep history includes assessing the patient's sleep habits. Identify the time of sleep onset and of awakening, including the number and duration of nocturnal awakenings. Discuss the patient's bedtime rituals and sleep environment. Does the patient go to bed at the same time every night? Discuss the patient's daytime function in terms of condition on awakening, cognitive problems (memory, etc), need for naps, and degree of daytime symptoms.

It is important to distinguish between complaints of daytime fatigue and sleepiness because the latter should prompt the clinician to consider other sleep disorders such as obstructive sleep apnea or narcolepsy.38 A sleep diary in which the patient records such things as bedtime, time of awakenings (including variation in sleep patterns from day to day and week to week, out-of-bed time), caffeine intake, and naps can be helpful for the clinician. Other tools that may help in the evaluation of insomnia are rating scales such as the Insomnia Severity Index (ISI)39 or Pittsburgh Sleep Quality Index,40 and a sleep log. Other rating scales are discussed in the companion article in this issue. A sample sleep log (recommended to be kept by the patient for 1 to 2 weeks) can be found in the booklet, Insomnia: Assessment and Management in Primary Care,26 from the National Institutes of Health.

Identify Comorbid Conditions 

A thorough medical and psychiatric history is crucial to help identify whether the insomnia is related to a concomitant medical or mental disorder.

As previously stated, chronic insomnia may be associated with other psychiatric, medical, or substance abuse disorders, or other sleep disorders (sleep apnea, restless leg syndrome, periodic limb movement disorder, etc) or it may be a primary disorder that is not related to other conditions. Circadian rhythm disturbances such as jet lag, delayed or advanced sleep phase syndrome, and shift work disorder are considered primary sleep disorders and not causes of secondary insomnia (see companion manuscript on insomnia classifications by Edinger and Epstein; a discussion and additional references can be found in Doghramji41). In delayed sleep phase syndrome, patients go to sleep later and wake later than usual, usually interfering with daily activities. This condition is often self-perpetuating and does not usually respond to attempts to reestablish normal bedtime hours. Treatment such as bright-light phototherapy may help. In advanced sleep phase syndrome the converse is seen: going to sleep earlier than usual and waking earlier. This syndrome is often seen in elderly patients and may result in daytime sleepiness. Light therapy may also be used to reset the circadian clock. Working night shifts can affect the circadian clock with resulting sleep deprivation and increased safety hazards for these workers. Light therapy may also help persons with this disorder although education and safety programs for employers and employees should be included.

Katz et al5 examined the association between specific chronic conditions and insomnia in a sample of 3445 patients. Clinical risk factors associated with mild and severe insomnia at baseline (derived from analyses examining the association between clinician-identified conditions and patient-reported comorbidities and insomnia) include myocardial infarction, congestive heart failure, angina pectoris, chronic obstructive pulmonary disease, back problems, hip impairment, osteoarthritis, rheumatoid arthritis, peptic ulcer disease, and fibromyalgia.5, 19, 42

Because chronic insomnia can occur with other conditions, such as major depression, anxiety disorder, or chronic pain, it is important for the clinician to determine whether one of these disorders is present and, if so, whether therapy for that disorder is indicated. Although it is always important to treat such conditions, it is not the case that this uniformly alleviates the insomnia as had long been believed. As a result, it is recommended that specific therapy for both the insomnia and associated condition be considered.22, 23

Determine Need for Referral 

Most cases of insomnia should not require referral to a sleep specialist or to a sleep laboratory for polysomnography (PSG). Referral, however, is strongly recommended for patients who exhibit signs and symptoms of obstructive sleep apnea (OSA), including snoring, witnessed apneas, and excessive daytime sleepiness.43 Other symptoms that may point to OSA are a history of morning headaches, nocturnal choking or gasping, nocturnal esophageal reflux, nocturia, erectile dysfunction, and the presence of systemic hypertension or otherwise unexplained pulmonary hypertension44 and, in particular, difficult-to-treat hypertension.43

Referral to a sleep specialist should also be considered for those patients who manifest unusual or abnormal behaviors or movements during sleep such as periodic leg movements of sleep (PLMS) or parasomnias such as sleep walking. Whereas PSG is indicated when OSA or PLMS are suspected, it is not indicated for the evaluation of insomnia.46

Patients with restless leg syndrome (RLS) often experience difficulty falling or staying asleep because of the unpleasant sensations in the legs and urge to move them.45 Evaluation of RLS does not require a PSG and most cases can be effectively treated in the primary care setting, with referral to a sleep specialist reserved for refractory cases.

Bed partners often observe the snoring or arrests in breathing that signal sleep apnea, the leg movements that characterize periodic movements of sleep, and the various nocturnal behaviors seen in patients with parasomnias. As a result, taking a history from a bed partner can be crucial in helping clinicians identify these conditions.

Consider Nonpharmacologic Treatments 

Cognitive-behavioral therapy (CBT) is the mainstay of insomnia therapy and is usually used with pharmacotherapy. CBT identifies and addresses dysfunctional beliefs and attitudes about sleep and maladaptive behaviors that may cause or perpetuate insomnia. One benefit to CBT is that it may have long-lasting benefits if effective.47, 48

One limitation to CBT is that it requires provider time and training to implement and relies on the patient making a behavioral or lifestyle change. Clinicians may view CBT as less cost-effective than pharmacotherapy because of the time needed to learn and implement this modality.49 Patients may also incur expense because CBT is not always covered by medical insurance. In terms of the time and training requirements, however, effective shorter-term and “primary care friendly” methods of implementing cognitive behavioral therapy are being developed.49

Whether pharmacotherapy is instituted, some form of CBT should always be considered. If behavioral targets are identified, such as sleep hygiene problems (Table 1), spending excessive time in bed, planning or worrying in bed, focusing on the adverse consequences of sleep loss, they should be addressed. Other nonpharmacologic methods of treating insomnia include stimulus control, progressive muscle relaxation, and paradoxical intention (having the patient try to stay awake which is thought to alleviate performance anxiety and facilitate sleep), all of which have met the American Psychological Association's criteria for empirically supported psychological treatments for insomnia.50 Stimulus control therapy seeks to remove the conditioned responses to bedtimes and bed or bedroom environmental cues that are associated with the sleep of the patients with insomnia. Patients are trained to reassociate the bed and bedroom with rapid sleep onset. They are told that the bed and bedroom are to be used only for sleep; when unable to fall asleep within a reasonable time the patient should get out of bed and return only when sleepy again. Relaxation therapies aim for a reversal of arousal (physiologic and cognitive) during both day and night. Methods include muscle relaxation, biofeedback, visualization techniques, meditation, and breathing exercises. Additional examples of sleep hygiene and examples of other therapies can be found in Morin et al.49

Table 1. Sleep Hygiene Principles
•Go to bed at the same time every night

•Wake up at the same time every day

•Exercise regularly, preferably in the late afternoon but not close to bedtime

•Make it a habit to engage in relaxing activities before bedtime

•Keep your bedroom quiet and cool

•Avoid caffeine and nicotine for at least 6 hours before bedtime and limit total daily consumption

•Drink alcohol only in moderation and avoid it starting at least 4 hours before bedtime

•Position the clock at night so that it is not visible

•Avoid napping

•Remove possible disturbances from the bedroom such as pets, bright lights

•Do not stay in bed if awake for more than 15 minutes

•Do not use bedroom for anything other than sleep or sex

Source: Insomnia: assessment and management in primary care. Bethesda, Md: National Institutes of Health, National Heart, Lung, and Blood Institute; 1998. (NIH publ no. 98-4088.)

Assess Risks and Benefits of Long-Term Pharmacotherapy 

The 4 major classes of medications commonly used to treat insomnia are benzodiazepines, nonbenzodiazepines (defined below), antidepressants, and antihistamines. Recently, a fifth class of medications was added to the treatment options for insomnia. Ramelteon, a melatonin receptor agonist, was recently approved for treatment of sleep-onset insomnia.

The risks and benefits of any medication being considered for longer-term therapy can be ascertained best from longer-term studies with that agent. However, assessing medication options is made difficult because very little data are available on the long-term treatment of chronic insomnia with hypnotics51 and a near total absence of studies of the long- or short-term treatment of insomnia with antidepressant, antipsychotics, and antihistamines. Studies that are available to date will be discussed later.

Benzodiazepines 

Benzodiazepines exert their effect by binding to part of the benzodiazepine-specific site of the GABA (γ-aminobutyric acid) complex. GABA is the primary inhibitory neurotransmitter of the central nervous system. By binding to this receptor, these medications potentiate the inhibitory effects of GABA, resulting in their therapeutic effects as sedatives, anxiolytics, and muscle relaxants. The medications in this class that have been marketed as sedative-hypnotics include temazepam, triazolam, quazepam, flurazepam, and estazolam.52

Until recently, and since their advent in the 1960s, benzodiazepines have been the main prescription medications for the treatment of insomnia. Benzodiazepines are an effective therapy for short-term insomnia.37 However, only one study has application to the risks and benefits of longer-term pharmacotherapy. In a randomized, controlled, double-blind study comparing temazepam at doses of 7.5 to 30 mg with CBT and placebo, patients reported an improved ability to stay asleep after 2 months of nightly treatment in a small group of individuals (n = 20 per group) with chronic insomnia.53 Follow-up results in this study showed that CBT was the most durable of the treatments in terms of improvements in sleep patterns; initial gains produced by CBT and temazepam were maintained short term (3-month follow-up), but at 12- and 24-month follow-up only CBT produced durable changes. Temazepam gradually lost clinical benefits, and by 24 months patients had returned to their baseline sleep difficulties.

In another randomized controlled trial, 50 patients receiving lormetazepam had significantly shorter sleep latency (time to onset of sleep; from “lights out” to the start of sleep) compared with placebo after 6 months of nightly treatment. Another 25 patients in that study took nitrazepam without benefit for sleep latency. Although both medications improved sleep quality compared with placebo, the difference was not evident at 6-month follow-up. In addition, on withdrawal a rebound in subjective quality of sleep and sleep latency was observed that took 2 to 3 weeks to abate.54 It is important to consider the possible adverse effects of this medication class, including residual daytime sedation, impairment of motor skills and cognition, dependence, and rebound insomnia.25

Nonbenzodiazepines 

Nonbenzodiazepines act at the same site in the brain as benzodiazepines (the GABAA receptor site, involved in enhancing the inhibitory response to GABA). However, their structural and chemical properties differ from the benzodiazepines resulting in receptor binding that produces different clinical profiles than the benzodiazepines. The nonbenzodiazepines approved for treatment of insomnia are zolpidem, zaleplon, and eszopiclone.

Zolpidem, a commonly prescribed hypnotic, has a short half-life that most likely contributes to its efficacy in improving sleep onset and its relatively low incidence of next-day residual effects.55 However, the short half-life may also limit the ability of zolpidem to maintain sleep throughout the night. Studies using objective PSG or subjective measures showed that 2 to 5 weeks of nightly zolpidem improves sleep latency and sleep duration in patients with chronic insomnia.56, 57

A meta-analysis of efficacy data from randomized, placebo-controlled, double-blind trials with zolpidem and benzodiazepines reported similar results.51 In contrast, studies evaluating PSG-recorded sleep maintenance indicators, including wake time after sleep onset (WASO) and number of awakenings (NAW), were not significantly different57, 58 compared with placebo. In two 4-week studies comparing zolpidem 10 mg with zaleplon 10 mg, zaleplon 20 mg, and placebo, zaleplon-treated subjects had a greater rate of rebound insomnia (defined as a worsening in sleep compared with baseline) and significantly more benzodiazepine withdrawal symptoms compared with placebo subjects on the first night after discontinuation.59, 60

Zolpidem extended-release formulation was recently approved for the treatment of insomnia, based on two 3-week placebo controlled studies of nightly administration. The FDA also included an indication for improvement of sleep maintenance.61

Zaleplon studies show improved measures of sleep latency59, 60 but not improvements in total sleep time (TST) or number of awakenings relating to placebo, likely because of its short half-life.42, 60

Because the longest randomized, double-blind, placebo-controlled studies of nightly use of zolpidem and zaleplon are 5 weeks in duration, the ability of these agents to provide sustained efficacy beyond this period remains unknown. Although the longer-term safety of zolpidem remains unknown, an open-label study of the treatment of elderly insomnia patients with zaleplon 5 mg and 10 mg did not identify significant safety or withdrawal problems in up to 12 months of nightly treatment.60

Although nonbenzodiazepine hypnotics appear to have a low rate of abuse, few community-based epidemiologic studies are available. Dependence and abuse is often higher for patients who were former drug or alcohol abusers, a phenomenon consistent with that seen with benzodiazepines.62More rigorous studies are required to fully quantify the prevalence of dependence and abuse associated with zolpidem and other nonbenzodiazepine hypnotics63 (see side box).

Rebound insomnia has been noted in some short-term studies of zaleplon64 but not other studies.60, 65

Eszopiclone, a recent addition to the nonbenzodiazepine receptor agonist class, was the first sedative-hypnotic approved for long-term use for treatment of insomnia. In a 6-month, multicenter, double-blind, placebo-controlled trial,67 eszopiclone 3 mg was associated with significantly better outcomes on self-report measures of sleep latency, sleep maintenance, TST, and sleep quality at every month of the study. Self-report measures of next-day function, sense of physical well-being, and daytime alertness were also significantly better with eszopiclone than with placebo throughout the 6-month study period. The sustained efficacy was demonstrated for an entire year of nightly dosing (6-month double-blind followed by 6-month open label trial68 and in short-term studies69, 70, 71). None of the studies found significant withdrawal difficulties.

Dependence and Abuse

When discussing abuse and dependence several terms may overlap and therefore need to be defined. Tolerance refers to reduced efficacy of a given drug dose over time, or, conversely, the need for increased amounts of the drug to achieve the same clinical effect. Rebound insomnia is a posttreatment deterioration in efficacy measures (eg, TST, sleep latency) to levels worse than baseline levels. The onset is rapid, but the effect typically resolves in 1 to 3 days. Withdrawal occurs when blood or tissue concentrations of the substance decline in a person who has used the substance for a long time. Withdrawal symptoms include unpleasant physiologic and cognitive symptoms that may induce the user to continue taking the substance to avoid these unpleasant effects.

For the benzodiazepine receptor agonists (includes benzodiazepines and nonbenzodiazepine hypnotics) withdrawal is defined by the presence of at least 2 of the following: insomnia, autonomic hyperactivity, hand tremor, nausea or vomiting, hallucinations, psychomotor agitation, anxiety, or grand mal seizures. Unlike rebound insomnia, recurrent insomnia is defined as the return to baseline of the target symptoms; it has a gradual onset and persists over time. Substance abuse and substance dependence are both defined in DSM-IV,66 and the criteria for each are distinct (Table 2).

Table 2. DSM-IV Criteria for Diagnosis of Substance Dependence and Substance Abuse
Substance dependence: a maladaptive pattern of substance use, leading to clinically significant impairment or distress, as manifested by 3 or more of the following, occurring at any time in the same 12-month period:
•Tolerance

•Withdrawal

•Substance taken in larger amounts or over a longer period than was intended

•Persistent desire or unsuccessful efforts to cut down or control substance use

•Great deal of time spent in activities necessary to obtain the substance, use the substance, or recover from its effects

•Important social, occupational, or recreational activities given up or reduced because of substance use

•Continued use despite knowledge that substance causes or exacerbates a physical or psychological problem

Substance abuse: a maladaptive pattern of substance use, leading to clinically significant impairment or distress, as manifested by 1 or more of the following, occurring within a 12-month period:
•Recurrent substance use resulting in failure to fulfill major role obligations at work, school, or home (eg, absences, poor work performance, child neglect)

•Recurrent substance use in physically hazardous situations (eg, driving, machine operation)

•Recurrent substance-related legal problems (eg, arrests)

•Continued substance use despite having persistent or recurrent social or interpersonal problems caused or exacerbated by the effects of the substance (eg, arguments, physical fights)

Source: American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders DSM-IV-TR. Washington, DC, American Psychiatric Publishing, Inc; 2000. p. 197-199.

Substance abuse generally indicates a maladaptive pattern of use that is associated with frankly obvious harmful consequences to oneself or others. Substance dependence is defined by the presence of 3 of 7 criteria. These 7 criteria include tolerance, withdrawal, and several behaviors that show a pattern of compulsive behavior. Thus, the presence of tolerance and withdrawal, in the absence of at least one additional criterion, do not in themselves constitute substance dependence, nor are they directly related to substance abuse, rebound insomnia, or recurrent insomnia (Table 2).

As with prescription of any drug, there are certain patients who require special consideration when prescribing medications, especially sedative-hypnotics. These include the following:

•Sleep apnea patients. Symptoms may be exacerbated by treatment with a sedating medication.

•Dementia patients. Hypnotics may increase the risk of “sundowning” (periods of increased confusion or agitation that tend to occur in the evening or early night).

•Liver or renal impairment patients. Elimination of medications may be slowed, leading to an increase in side effects and duration of action.

•Elderly patients. Slower metabolism may slow elimination of medications.

•Pregnant or breast-feeding women. Avoid medication, if possible. Data are lacking for most medications, including the nonbenzodiazepines. There have been reports of some benzodiazepines causing fetal damage.

•Pediatric patients. The assessment of sleep disorders in children is very different than that of adults. Although prescribing sedatives and hypnotics for this patient group is common among community-based pediatricians, an empirically based approach to the use of these medications is needed.72 Effective behavioral and cognitive or behavioral methods for treating pediatric insomnia have also been developed.73

Antidepressants 

Studies of the off-label use of antidepressants in patients with insomnia are limited to those of short duration and to patients with depression56, 74; however, clinicians often prescribe them,75 possibly because of a perception that they are safer and carry less risk of abuse. Trazodone is the most frequently prescribed antidepressant for treatment of insomnia despite a paucity of data.75 No long-term studies of the use of trazodone to treat insomnia are available. Walsh et al56 conducted a 2-week placebo-controlled trial in which trazodone 50 mg and zolpidem 10 mg were studied in 308 patients with primary insomnia. Relative to placebo, trazodone had modest efficacy for the first week but did not differentiate from placebo during the second week.

Tricyclic antidepressants such as amitriptyline have also been used to treat insomnia as well, but with little supporting data. Each classification of antidepressants has its own adverse effects, with some potentially severe cardiovascular effects. The clinician should consider the possible adverse effects of these medications when weighing the risks and benefits of therapy outside of treating depression.

Antihistamines 

Many over-the-counter medications for insomnia treatment contain antihistamines. The two antihistamines most commonly used as over-the-counter sleep aids in the United States are diphenhydramine and doxylamine. In short-term (2 week), double-blind, placebo-controlled studies diphenhydramine has been associated with improved self-reported measures of sleep quantity, quality, and maintenance.76, 77, 78 No controlled studies show the long-term (>3 week) efficacy of diphenhydramine for objectively determined measures of sleep onset and sleep maintenance in patients with chronic insomnia.

A recent randomized, double-blind, crossover trial (n = 15) study of diphenhydramine in insomnia showed that a tolerance to sedative effects developed within 3 days of therapy.79 They therefore do not appear to be appropriate for longer-term treatment of insomnia.

Melatonin receptor agonists 

This class of medications represents the newest pharmacologic therapy for the management of insomnia. Ramelteon, a melatonin receptor agonist, was recently approved for the treatment of insomnia characterized by difficulty with sleep onset.80 Endogenous melatonin is a hormone secreted by the pineal gland largely during nighttime hours and is implicated in the regulation of the sleep-wake cycle. Melatonin has a hypnotic effect, but the exact mechanism of melatonin's sleep-promoting properties is not clearly understood. Melatonin appears to act on specific receptors, named MT1 and MT2, in the suprachiasmatic nuclei of the anterior hypothalamus, the location of the body's master clock.

Ramelteon is structurally different from melatonin but acts on both the MT1 and MT2 receptors which is believed to be the mechanism of its sleep-promoting properties.80 The half-life of ramelteon is 1 to 2.6 hours, and it is therefore indicated for use in those patients with a primary complaint of difficulty falling asleep. Because it has no affinity for the GABA receptor, it is not associated with central nervous system depression as are the benzodiazepines. In a randomized, double-blind study reported in the ramelteon New Drug Application, ramelteon was shown to reduce sleep latency in chronic insomnia when compared with placebo.81 However, the duration of the study was only 5 weeks. Ramelteon appears to have little risk of dependence, abuse, withdrawal, or rebound insomnia, and it is not limited to short-term use.

Assess Risk of Abuse and Tolerance 

Abuse of insomnia agents seems to be infrequent and limited to patients with a history of substance abuse.82 However, it has been observed that persons with insomnia tend to increase their dosages only if a medication fails to work or loses its effect over time.83 It is therefore important to distinguish between the pursuit of an effective therapy (therapy seeking) and the tendency to abuse medications (drug seeking) in patients with insomnia. Patients must be assessed for other causes for a loss of efficacy aside from pharmacologic tolerance. Such possibilities include development of a new condition or worsening of a preexisting condition, a stressful event, addition of a new medication or a change in existing medication, noncompliance, side effects, or a change in sleep-wake behaviors.

Choose a Medication 

Because data are few on insomnia medications, especially for long-term use, and comparisons between drugs are lacking, the choice of pharmacotherapy may depend on the clinical problem. Choosing to administer the most-effective agent with the shortest half-life84 (Table 3) may minimize the risks of next-day medication effects, but this may not always be an optimal strategy in longer-term management. This is because the type of symptom experienced, such as difficulty falling asleep, staying asleep, early morning awakening, or some combination, may change for many patients with insomnia over time.11 In such cases, longer half-life agents may be more effective in ensuring that the patient is able to fall asleep and stay asleep. This variability of symptoms also points to the need for periodic reevaluation to determine whether symptoms have changed.

Table 3. Comparison of Insomnia Treatments
Generic Name (Brand Name)Dose Range (mg) Adults*Peak plasma Level (hr)Half-life (hr)Comments
Nonprescription Drugs
Diphenhydramine (Benadryl®, Nytol®, Sominex®)25-50 mg1-32.4-9.3Anticholinergic side effects
Doxylamine (Unisom® Nighttime Sleep Aid)25-50 mg2-310Anticholinergic side effects
Prescription Drugs Term of use/comments
Trazodone (Desyrel®; nonproprietaries)None approved for insomnia1-2Biphasic: 3-6 and 5-9Not approved by FDA for insomnia treatment
Estazolam (ProSom®, nonproprietaries)1-21-310-2412 weeks/benzodiazepine precautions: withdrawal symptoms and rebound insomnia with abrupt discontinuation
Flurazepam (Dalmane®)15-30.5-147-10028 nights/benzodiazepine precautions
Lorazepam (Ativan®)2-4212-182-4 weeks/benzodiazepine precautions
Oxazepam (Serax®; nonproprietaries) 5.7-10.93Not approved by FDA for insomnia treatment
Quazepam (Doral®)7.5-151-339-190 (active metabolites)Up to 4 weeks/benzodiazepine precautions
Temazepam (Restoril®; nonproprietaries)7.5-151.2-1.60.4-6; 3.5-18.4Up to 5 weeks/benzodiazepine precautions
Triazolam (Halcion®).125-.2521.5-5.57-10 days/earlier tolerance than other benzodiazepines
Non-benzodiazepines and others
Eszopiclone (Lunesta®)2-316FDA approved for long term use/no tolerance seen over 6 months of continuous use
Zolpidem (Ambien®)5-101.62.5Short term use/tolerance not observed up to 35 days of continuous use
Zolpidem controlled-release (Ambien CR®)12.51.52.8Not limited to short-term use/first night rebound after abrupt discontinuation
Zaleplon (Sonata®)5-1011Short-term use/no tolerance or rebound up to 35 days continuous use
Ramelteon (Rozerem®)80.5-1.5

References: Medscape Drug Information. Available at www.medscape.com. Accessed 7/27/06; RxList. Available at www.rxlist.com. Accessed 7/27/06; Physicians' Desk Reference, 60th edition, 2006. Thomson PDR, Montvale, NJ. (and online at pdr.net).

* Dosage may be individualized by prescriber, especially for the elderly.

Although there is empirical support for the safety and efficacy of pharmacotherapy with some agents dosed both nightly and intermittently, no data exist currently to guide the clinician in determining which regimen is appropriate for a given patient. Patients with intermittent insomnia who may have an idea that they will have trouble sleeping before going to bed, or who experience relatively infrequent sleep problems and can tolerate the stress related to a sleepless night, are the best candidates for intermittent dosing regimens. Other patients with insomnia are most likely candidates for nightly dosing.

Agree on a Follow-up Plan 

The lack of data to provide guidance about regularity of follow-up means that clinicians should assess the needs of each individual case and should take into account the following possibilities: the patient's symptoms may change over time, the medication may not be effective initially or over time, the patient may not comply, new conditions may arise, the patient's sleep-wake habits may change, and side effects may develop.

The severity of the insomnia and associated conditions should determine the interval between visits. At each visit it is important to reevaluate the risk-to-benefit ratio of the current treatment and possible alternatives (including no treatment). On the basis of this assessment, a treatment plan for the interval until the next visit should be formulated.

Because we also lack guidelines on when medications should be stopped, it is useful to make a plan at the initial visit about when to attempt medication discontinuation to see whether the medication is still needed. The plan should include discussion of behavioral strategies to change maladaptive behaviors. It is reasonable to assume that the patient whose insomnia is improved with medication will be more receptive to CBT.38

When considering medication discontinuation, plan to taper the dosage and possibly lessen the frequency, and explain to the patient that his or her sleep may worsen initially after medication discontinuation. He or she should expect to have a period of readjustment after discontinuing medication before assessing whether there is a need for further medication.

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Conclusions 

The amount of data presently available makes decisions about pharmacotherapy for patients with chronic insomnia a challenge. To date, the risks and benefits of insomnia medications have not been adequately assessed. Further studies are needed to fill the gaps in the knowledge on insomnia and its treatment. However, we are in an environment today in which therapeutic options are increasing and the body of knowledge is expanding. An effective therapeutic program can be developed after a thorough assessment and considering the particular situation of each individual patient. CBT, pharmacotherapy, or a combination of both may be called for, depending on the type and severity of the insomnia. The advanced practice nurse, often the first clinician to assess the patient, can play a key role in optimizing the treatment of insomnia for each patient.

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 A.D.K. and M.A.F. received compensation from Sepracor Inc. for the services they provided in support of the development of this manuscript. (S.R. opted not to receive compensation.)

PII: S1555-4155(06)00577-0

doi:10.1016/j.nurpra.2006.08.003

The Journal for Nurse Practitioners
Volume 2, Issue 9 , Pages S621-S632, October 2006

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