Treatment of Insomnia

By | April 8, 2015

Several classes of medications are used in the treatment of insomnia. They include the benzodiazepines, non-benzodiazepine hypnotics, antidepressants, and over-the-counter medications. There are six benzodiazepines that are specifically marketed as hypnotics in the United States or in Canada: flurazepam, temazepam, triazolam, estazolam, quazepam, and (in Canada only) nitrazepam. Several other benzodiazepines (e.g., lorazepam, clonazepam, oxazepam), which are primarily marketed as anxiolytics, are frequently used for insomnia as well. In addition, there are three newer hypnotics (zolpidem, zaleplon, and zopiclone) which, although non-benzodiazepine agents, act primarily on the same benzodiazepine and GABA (Gamma Amino Butyric Acid) receptors. Unlike the true benzodiazepines, which all have hypnotic, anxiolytic, and anticonvulsant properties, these newer drugs may have more selective/specific hypnotic effects. In Table Benzodiazepine-Receptor Agents Commonly Prescribed for Insomnia are presented a list of benzodiazepine-receptor agents commonly used in the management of insomnia.

Table Benzodiazepine-Receptor Agents Commonly Prescribed for Insomnia

Benzodiazepines Equivalent dosage
Usual dosage
Bromazepam b (Lectopam®) 3 1.5-6 8-19
Clonazepam (Klonopin®) 0.25 0.5-2 20-60
Estazolam (ProSom®) 1 1.0-2.0 8-24
Flurazepam (Dalmane®) 15 15-30 48-100
Lorazepam (Ativan®) 1 0.5-2 10-20
Nitrazepam b (Mogadon®) 10 5-10 16-18
Oxazepam (Serax®) 15 10-30 5-10
Temazepam (Restoril®) 15 7.5-30 8-17
Triazolam (Halcion®) 0.25 0.125-0.25 2-4
Quazepam (Doral®) 15 7.5-30 40-120
Zaleplon (Sonata®) 5 5-10 1
Zopiclone b (Imovane®) 3.75 3.75-7.5 4-6
Zolpidem (Ambien®) 5 5-10 1.5-5

a May be longer in older adults. b Not available in the United States.

Antidepressants with sedating properties (e.g., trazodone, amitriptyline, doxepin) are often used in the treatment of insomnia. These agents are used in much smaller doses for treating primary insomnia (e.g., 10—20 mg of amitriptyline) than are those prescribed for depression. Although numerous studies have documented the effects of antidepressants on the sleep of individuals with major depression, few studies have examined the efficacy and safety of those agents when used as hypnotics with nondepressed insomniacs. For this reason, antidepressants are usually not recommended as the first line of treatment for primary insomnia. Antihistamine (e.g., diphenhydramine) is the active ingredient of most over-the-counter medicines that are advertised and sold to promote sleep (e.g., Sominex, Nytol, Sleep-Eze, Unisom). Most of those agents produce drowsiness, but there is limited evidence that they are efficacious in the treatment of insomnia. Melatonin is another popular agent that is increasingly used as a sleep aid. It is a naturally occurring hormone produced by the pineal gland at night. Although it may be promising for some forms of circadian sleep disturbances associated with shift work and jet lag, the benefits of melatonin for insomnia are equivocal, and the adverse effects with long-term usage are unknown. Thus, although it is widely available in over-the-counter preparations, the clinical use of melatonin for insomnia is premature at this time. There are several other natural health products (e.g., St. John’s Wort, Valerian) that are promoted as sleep aids but for which there is little empirical support.

Most sleep experts agree that, when a sleep medication is indicated for insomnia, it should be a benzodiazepine-receptor agent (BRAs, i.e., benzodiazepines, zaleplon, zopiclone, and zolpidem). The remaining discussion will focus on those agents. Hypnotic medications, such as the benzodiazepines and the newer non-benzodiazepine agents, present a lower risk of physical dependence and lethal overdose than older drugs, such as chloral hydrate and the barbiturates (American Psychiatric Association). Their therapeutic, abuse-potential, and side-effect profiles are comparable, although hypnotics with rapid onset and short-to-intermediate duration of actions may present the highest ratio of benefits to residual effects. The main differences among the benzodiazepine-receptor agents are their pharmacokinetic properties: absorption, distribution, and elimination. The rate of absorption and rate of distribution determine the speed of onset of the drug effect; elimination half-life and rate of distribution determine the length of time during which the drug effects persist. Combined with the dosage, these properties mediate the effects of the drugs on sleep and on daytime functioning.

Evidence for Efficacy

Controlled clinical trials have shown that all benzodiazepine-receptor agents are more effective than placebo in the acute and short-term phases of insomnia treatment. Hypnotic medications improve sleep continuity and efficiency through a reduction of sleep onset latency and time awake after sleep onset. These agents also reduce the number of awakenings and stage shifts through the night. Their effects on sleep stages vary with the specific class of medications. All hypnotic drugs increase Stage 1 and Stage 2 sleep. benzodiazepines tend to reduce the proportion of slow-wave (Stages 3—4) sleep and, to a lesser extent, REM sleep. These last changes are less pronounced with zolpidem and zopiclone.

In a recent meta-analysis of 22 placebo-controlled trials (n = 1,894), benzodiazepines and zolpidem were found to produce reliable improvements of sleep onset latency (mean effect size = .56), number of awakenings (.65), total sleep time (.71), and sleep quality (.62). Another metaanalysis showed that benzodiazepines reduced sleep latency by a modest 10 minutes and increased total sleep duration by about 1 hour. Thus, hypnotic medications are efficacious for the acute and short-term management of insomnia. In addition, there is high level of satisfaction with benzodiazepine treatment among patients who are willing to take such medications. However, because the median treatment duration in controlled studies is only 1 week (range: 4—35 days), and follow-ups are virtually absent, the long-term efficacy of hypnotic medications remains unknown.

Treatment of Insomnia: Risks and Limitations. Clinical Indications and Contraindications

Risks and Limitations

The main limitations of hypnotic medications are their residual effects the next day and their associated risks of tolerance and dependence. The most common residual effects are daytime drowsiness; dizziness or lightheadedness; and impairments of cognitive and psychomotor functions, including memory impairments and slower reaction times. In general, hypnotic medications have relatively few side effects, when used at the appropriate doses. Also, short-acting agents have less residual effects the next day than long-acting ones. Long-acting benzodiazepines (e.g., flurazepam and quazepam) are more likely to produce next-day residual effects, such as drowsiness and impairments of psychomotor and cognitive functions. These residual effects are more pronounced in elderly people because of slower drug metabolism as a consequence of aging. Long-acting benzodiazepines result in an increased rate of falls and hip fractures and motor vehicle accidents in the elderly population. benzodiazepines can cause respiratory depression, a problem that is more likely to occur in people who already have severe sleep apnea or chronic obstructive pulmonary disease. Another potential residual effect is anterograde amnesia, a problem that is more likely with shorter acting agents. When used on a prolonged basis, hypnotics may lead to tolerance, and it may be necessary to increase the dosage to maintain therapeutic effects. This tolerance effect, however, varies across agents and individuals, and some people may remain on the same dosage for prolonged periods of time. Whether this prolonged usage is a sign of continued effectiveness or of fear of discontinuing the medication is unclear. Rebound insomnia is a common problem associated with discontinuation of benzodiazepine hypnotics; it is more pronounced with short-acting drugs and can be attenuated with a gradual tapering regimen. Zolpidem and zopiclone may produce less rebound insomnia on discontinuation. Finally, all sleep-promoting medications, prescribed or over-the-counter, carry some risk of dependence (American Psychiatric Association), which is often more psychological than physical.

Clinical Indications and Contraindications

The main indication for using hypnotic medications is situational insomnia, usually arising from acute stress, medical illness or hospitalization, and changes in the sleep environment or sleep schedules (jet lag, shift work; National Institutes of Health). For chronic insomnia, a short-term trial of sleep medications may be indicated during the initial treatment phase in order to break the cycle of sleeplessness and emotional distress. For individuals who are unresponsive to psychological interventions, hypnotic medications may prove a useful alternative. Sleep medications may also be a useful adjunct for insomnia secondary to psychopathology (e.g., major depression and generalized anxiety disorders), although the main focus of treatment should be on the underlying condition. The same principle applies to the management of insomnia associated with another sleep disorder (e.g., restless legs/periodic limb movements) or with a medical condition (e.g., pain).

Hypnotic medications are contraindicated among patients who are actively abusing alcohol or drugs. benzodiazepines should be avoided in patients with severe sleep apnea because it may worsen the breathing problem and its associated cardiovascular complications. Sleep medications are also contraindicated in pregnant women and in individuals who are on call (e.g., nurses, fireman, etc.) and might need to awake rapidly and go to work during their usual sleep period. Hypnotics would then interfere with alertness and cognitive functions. Use of sleep medications should be monitored carefully among older adults (National Institutes of Health) and patients with hepatic, renal, or pulmonary diseases and among patients with severe psychiatric conditions, such as psychoses and borderline personality disorders.

Treatment of Insomnia: Prescribing Guidelines

Selection of a hypnotic medication is partly dependent on the nature of the insomnia complaint, the individual’s age, and the presence of any associated medical or psychological condition. The best hypnotic drug will promote sleep at night and will have no or minimal residual effects the next day. As such, speed of onset of action and duration of effects are two important considerations in selecting a sleep medication. Drugs with a rapid absorption rate and a short half-life (e.g., zolpidem, zalephon, triazolam) are better suited for sleep-onset insomnia, whereas those with an intermediate half-life (temazepam, lorazepam, oxazepam) are more effective for sleep-maintenance problems. Drugs with a long duration of action (e.g., flurazepam) should be avoided in older adults because they take longer to metabolize drugs that affect the central nervous system and are more likely to experience daytime residual effects. On the other hand, this residual sedation may be therapeutic for a younger person with significant daytime anxiety. In this latter case, a long-acting agent may promote sleep at night and produce residual anxiolytic effects the next day.

A general principle that applies to all hypnotic medications is to use the lowest effective dosage for the shortest period of time. Recommended dosages for the various hypnotic drugs are provided in Table Benzodiazepine-Receptor Agents Commonly Prescribed for Insomnia. It is always best to start with the smallest dosage and to increase it only if necessary. Higher dosages will prolong the duration of action and are more likely to produce adverse effects. A drug that is available in different dosages may be easier to taper at the end of treatment. The standard recommendation is to use sleep medications only as needed (prn schedule) and not to exceed two or three times per week (National Institutes of Health). Although this pattern of intermittent usage may prevent tolerance, it may also promote dependency through a negative conditioning process. For example, after being awake for more than an hour (an aversive stimulus), the individual who takes a sleeping pill only occasionally is likely to associate this behavior with a quick relief from sleeplessness. As such, the pill-taking behavior is negatively reinforced and is likely to recur in the near future. For this reason, some clinicians have suggested to patients to take sleep medications every night, over a limited period time, in order to avoid reinforcing this conditioning between sleeplessness and the pill-taking behavior. For the same reason, it may be preferable to use sleep medication at a predetermined time (i.e., bedtime) rather than simply waiting 1 or 2 hours of wakefulness to get back up to take the medication.

Duration of treatment is also dependent on the course of insomnia. For acute insomnia, sleep medications may be used for several consecutive nights. Treatment duration ideally should not exceed 4 weeks, to avoid tolerance and minimize the risk of dependency. If insomnia is a recurring problem and is predictable (e.g., when traveling), it may be necessary to repeat this treatment regimen periodically. For chronic insomnia, sleep medications may be used for a few nights (up to 2—3 weeks) to break the cycle of performance anxiety, but the main focus of therapy should be non-pharmacological. Because insomnia is often a recurrent problem, it may be necessary to develop new treatment maintenance models, such as intermittent-dosing strategies. Although this treatment maintenance model has yielded interesting results with antidepressant medications for major depression, it remains to be validated for insomnia treated with benzodiazepine hypnotics.

In summary, hypnotic medications are effective for the acute and short-term management of insomnia; they have a quick onset of action, often producing significant therapeutic benefits on the very first night of usage. These benefits last several nights and, in some cases, up to a few weeks. There is currently little evidence of sustained sleep benefits on drug discontinuation or of continued efficacy with prolonged usage. No single agent can achieve complete control of insomnia. In addition, all benzodiazepine hypnotics carry some risk of dependence, particularly with prolonged usage. As several panels of insomnia experts have already concluded, the primary indication for hypnotic medications is for situational sleep difficulties; their role in the clinical management of chronic insomnia should be as an adjunct to behavioral interventions (National Institutes of Health).

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Treatment of Insomnia: Integrated Psychopharmacological Approaches

Despite the extensive literature reporting on the separate effects of behavioral and pharmacological therapies, only a handful of studies have directly evaluated the combined or differential effects of those treatment modalities. Three of those studies compared triazolam with relaxation or sleep hygiene, and the other one compared cognitive—behavior therapy (CBT) with temazepam. The data from those studies collectively indicate that both treatment modalities are effective in the short term. Drug therapy produces quicker and slightly better results in the acute phase (first week) of treatment, whereas behavioral and drug therapies are equally effective in the short-term interval (4—8 weeks). Combined interventions appear to have a slight advantage over a single-treatment modality during the initial course of treatment. Furthermore, long-term effects have been fairly consistent for the single-treatment modalities but more equivocal for the combined approach. For instance, sleep improvements are well sustained after behavioral treatment, and those obtained with hypnotic drugs are quickly lost after discontinuation of the medication. Combined biobehavioral interventions may yield a slightly better outcome during initial treatment, but long-term effects are more equivocal. Studies with short-term follow-ups (<1 month) indicate that a combined intervention (i.e., triazolam plus relaxation) produces more sustained benefits than drug therapy alone, whereas the only two investigations with follow-ups exceeding 6 months in duration reported more variable long-term outcomes among patients receiving a combined intervention relative to those treated with behavioral treatment alone. It appears that some of those patients retain their initial sleep improvements, whereas others return to their baseline values. Thus, despite the intuitive appeal in combining drug and nondrug interventions, it is not entirely clear when, how, and for whom it is indicated to combine behavioral and drug treatments for insomnia.

An integrated biobehavioral intervention should theoretically optimize treatment outcome by capitalizing on the more immediate and potent effects of drug therapy and the more sustained effects of psychological interventions. In practice, however, the limited evidence available is not entirely clear as to whether a combined intervention has an additive or subtractive effect on long-term outcome. In light of the mediating role of psychological factors in chronic insomnia, behavioral and attitudinal changes may be essential to sustain improvements in sleep patterns. When combining behavioral and drug therapies, patients’ attributions of the initial benefits may be critical in determining long-term outcomes. Attribution of therapeutic benefits to the drug alone, without integration of self-management skills, may place a patient at significantly greater risk for relapse once the drug is discontinued. Additional research is needed to evaluate the effects of single and combined drug and nondrug treatments for insomnia and to examine potential mechanisms of changes mediating short- and long-term outcomes. Likewise, clinical strategies to facilitate discontinuation of hypnotic medications are currently under evaluation.

Clinical Guidelines for Selecting Single Versus Combined Interventions

Despite the limited empirical evidence available on the integration of behavioral and pharmacological approaches for insomnia, some general principles can guide practitioners in selecting optimal treatment strategies. These guidelines are functions of several factors, including the nature (primary vs. secondary), duration, and course of insomnia; the presence of comorbid psychological or medical conditions; prior usage of hypnotic medications and, importantly, consumer’s preference.

For acute and situational insomnia, treatment should focus on alleviating the precipitating factors (i.e., stress, medical illness) when possible. In some instances (e.g., bereavement, divorce, jet lag) a hypnotic medication may be necessary and very useful to alleviate sleep difficulties. For chronic and primary insomnia, behavioral treatment should represent the main intervention, with hypnotic medications serving as an adjunct.

The presence of comorbid medical or psychological disorders is another factor to consider in selecting the most appropriate treatment for insomnia. Several contraindications (e.g., renal and hepatic diseases) to using hypnotic medications were discussed earlier in this chapter. When insomnia is associated with another psychopathology or with another medical condition, the general principle is to treat the underlying condition first. However, this is not always possible; neither does this approach always resolve the concurrent sleep difficulties. For example, treatment of chronic pain or major depression does not always alleviate the often-associated sleep disturbances. In such instances, it may be necessary to introduce a treatment, behavioral or pharmacological, that focuses directly on sleep disturbances.

Prior usage of hypnotic drugs is another important consideration in selecting the most appropriate treatment for insomnia. Two different scenarios are likely to arise in clinical practice. The first one, most commonly encountered by psychologists, involves a patient who has already been on hypnotic medications for a prolonged period and is unable to discontinue his or her sleeping pills. In such an instance of hypnotic-dependent insomnia, the most appropriate intervention would involve a gradual tapering from hypnotic medications, accompanied by CBT. In the second scenario, a patient may have used hypnotic medications only infrequently or not at all in the past. In such instance, a short-term trial on hypnotic medications could be very useful during the initial period of treatment in order to provide some immediate relief and reduce performance anxiety. CBT would be initiated simultaneously and maintained on drug withdrawal.

Patient preference is another important factor for selecting psychological and pharmacological therapy. Regardless of how effective a treatment is, if a patient fails to comply with the clinician’s recommendation its clinical utility will be rather limited. Thus, if a patient is unwilling to use a sleep medication, behavioral interventions may be the only alternative left. Likewise, if a patient is unwilling to invest time and efforts in the behavioral approach, medication may be a better choice of treatment. Although behavioral approaches are generally more acceptable than drug treatments to patients with insomnia, this issue of treatment preference needs to be addressed systematically when discussing the various treatment options with a patient.

Data are still limited on how to best integrate sleep medications and behavioral interventions. The few studies available on this issue have initiated and discontinued drug and nondrug approaches at the same time. To take full advantages of the quicker results from drug therapy and the more sustained effects of behavioral intervention, a sequential approach might be preferable to a combined (concurrent) approach. Unlike with a combined method, in which both treatments are initiated and discontinued at the same time, in a sequential approach drug treatment is initiated first and gradually discontinued while the behavioral intervention is implemented concurrently. This method would ensure that patients are still in treatment after drug tapering; it would provide them with the opportunity to fully integrate newly learned self-management skills, especially at a time when rebound insomnia is likely to reinforce the belief that medication is needed indefinitely.

Criteria for Outcome Evaluation

There is currently no consensus as to how treatment effectiveness should be measured and what the optimal outcome should be when treating insomnia. Clinical studies have focused almost exclusively on symptom reductions, that is, reduction of the time required to fall asleep or the frequency and duration of nocturnal awakenings and increase in the amount of total sleep time. Although these sleep indexes are important in evaluating outcome, insomnia is more than just a complaint about poor sleep. It is often the emotional distress about sleep loss and the fear of its consequences (e.g., fatigue, impaired daytime functioning), rather than insomnia per se, that prompt individuals to seek treatment. Thus, an important marker of progress should be the perception of control over sleep. Likewise, measures of functional impairments, mood disturbances, psychological well-being, and quality of life, and even use of health-care services and hypnotic medications, would provide more clinically meaningful indexes to capture the impact of treatment.

Treatment of Insomnia: Summary and Conclusion

Psychological and pharmacological therapies produce reliable changes in several sleep parameters, but each treatment modality has its own advantages and limitations, and neither approach is effective for all patients and all subtypes of insomnia. Some patients fail to respond to treatment, regardless of its nature, and the majority of responders do not necessarily become “good sleepers.” In terms of trajectory of changes, drug therapy produces acute changes in sleep patterns, but these benefits are typically not maintained after discontinuation of the medication. Given that insomnia is often a recurrent condition, short-term drug treatment is unlikely to be sufficient for the clinical management of this condition. Behavioral interventions are more time consuming and take longer to produce therapeutic benefits. However, these gains are well sustained over time. Combined approaches have yielded short-term outcomes that are either equivalent to or slightly better than either form of therapy alone. Long-term effects have been mixed. Although integrated approaches are preferable to drug therapy alone, it is yet unclear whether the addition of sleep medications to behavioral treatment enhances outcome. Additional research is needed to design and evaluate more efficient models for integrating bio-behavioral approaches, using multifaceted and sequential therapies.

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