Management of Chronic Sleep-Maintenance Insomnia

Introduction

Middle-of-the-night (MOTN) awakening is the most common complaint in patients with chronic insomnia.^[1] It frequently coexists with sleep-onset difficulties.

The key to effective management of MOTN awakening is an adequate history that identifies potential etiologies of the disturbance, comorbid factors, and associated phenomena. MOTN awakening may present in varied fashion. For example, a distinction between prolonged midcycle awakenings (> 15-20 minutes) and multiple, transient awakenings may be clinically useful; although there are no absolutes, the latter complaint may be more likely a function of an ongoing or repetitive physiologic disturbance during sleep, such as obstructive breathing events or periodic movement. A comprehensive review of the sleep history is beyond the scope of this article; however, several key factors should be considered:

• Are there any identifiable precipitants to awakenings?
  
• What comorbid factors may contribute to the sleep continuity problem?
  
• What does the patient do in response to an awakening?
  
• What cognitive and emotional responses are associated with awakening?

Sleep-maintenance problems may be primary (eg, psychophysiologic insomnia) or comorbid with other conditions. Historically, insomnia complaints associated with comorbid conditions such as depression or medical disorders were relegated to secondary status and often left untreated with the expectation that treatment of the primary condition would resolve the insomnia. That assumption is no longer considered valid,^[2] and combined treatment of both the comorbid condition and the sleep disturbance is indicated.

Assessment and Management of Comorbid Conditions

Effective therapy begins with identifying and addressing related conditions. Among psychiatric comorbidities, mood disorders, anxiety disorders, and substance abuse problems are most common. Depression has long been associated with sleep-maintenance problems. Some patients with MOTN or early-morning awakening may misattribute mood disturbance to the sleep problem itself. Symptom overlap between insomnia and depression, including fatigue and diminished concentration, can make accurate diagnosis a challenge. Evidence of other neurovegetative and psychological symptoms of depression usually warrants a trial of antidepressant medication. For most patients, a selective serotonin reuptake inhibitor or serotonin-norepinephrine reuptake inhibitor is appropriate, although a more sedating antidepressant such as mirtazapine may address both mood and sleep problems in select patients. Current evidence suggests that combining an antidepressant with insomnia-specific treatment, whether pharmacologic or cognitive-behavioral, results in improved outcomes for both depression and sleep disturbance.^[3]

Posttraumatic stress disorder (PTSD) may be associated with both sleep-onset and sleep-maintenance disturbance. Recurrent nightmares are a somewhat unique factor that fuels MOTN awakening in this population. In addition to standard therapies for the anxiety disorder and insomnia, more specific treatment directed at the nightmares may be a necessary component of managing MOTN awakening in those with PTSD. Two newer approaches to posttraumatic nightmares have emerged in recent years. These are the alpha₁-adrenergic blocker, prazosin,^[4] and the cognitive-desensitization procedure, imagery rehearsal therapy.^[5]

Among the numerous medical conditions that may contribute to sleep-continuity disorders, several are commonly encountered. A large epidemiologic survey found that more than 40% of patients with chronic insomnia who had MOTN or early awakenings had chronic painful conditions, primarily musculoskeletal pain or headache.^[6] Adequate attention to pain management, including consideration of longer-acting analgesics at bedtime, are helpful in these patients, in tandem with direct insomnia treatment. Gastroesophageal reflux disease is a common and often undetected cause of sleep disturbance,^[7] and should be managed with standard therapies. Similarly, cough or hypoxemia in chronic lung disease, nocturia, or gastrointestinal symptoms caused by irritable bowel syndrome can contribute to awakenings.

Substance abuse, especially with alcohol, is a common condition that gives rise to recurrent awakening as the substance is metabolized and sedating effects diminish. Abuse may develop as a complication of self-medication with alcohol for an insomnia problem.

Other primary sleep disorders are common sources of MOTN awakening. Arousals caused by obstructive sleep apnea may give rise to repetitive, full awakenings.^[8] Evidence of snoring, observed pauses, or daytime sleepiness should prompt further assessment. Central sleep apnea, most commonly seen in congestive heart failure (Cheyne-Stokes respirations) or with opioid use, may also lead to awakenings.^[9] Restless legs syndrome and associated periodic limb movement in sleep should also be considered in the differential diagnosis. Effective therapy for these disorders will typically reduce or eliminate sleep-continuity problems.

Cognitive-Behavioral and Pharmacologic Therapies

When comorbid factors have been identified and addressed, therapeutic attention should turn to the insomnia complaint itself. Approaches to sleep-maintenance problems include both pharmacologic and psychological/behavioral therapies. A clear, evidence-based set of treatment guidelines for application of pharmacologic and cognitive-behavioral treatments for insomnia (CBT-I) has not yet been derived. However, there are several sound principles that should be adhered to in the management of MOTN awakenings. Consensus-based guidelines from the American Academy of Sleep Medicine^[10] indicate that all patients with chronic insomnia should receive a course of CBT-I whenever available. There is sound evidence to indicate that a time-limited course of CBT-I (typically 3-8 visits) produces sustained sleep improvement over periods of up to 24 months.^[11] This is in contrast to a time-limited course of hypnotic therapy, in which the improvement in sleep achieved during active medication treatment often reverts to baseline disturbance following discontinuation of the drug.^[12] There is some debate regarding the utility of co-administering medication with CBT-I, with mixed outcome results for CBT-I alone vs combined therapy.

It is important to recognize that CBTs for insomnia are specific modalities that require detailed knowledge and practice experience on the part of the therapist. Currently, a paucity of cognitive therapists is a significant logistic hurdle in treating these patients. Sleep hygiene is an oft-cited set of "healthy sleep principles" that include recommendations such as maintaining a regular sleep-wake schedule, using the bed for sleep only, avoiding stimulating substances (most notable, caffeine) in excess or close to bedtime, exercise, and general stress management approaches. For patients with sleep-maintenance problems, other hygiene issues such as avoiding excessive amounts of fluid in the evening or foods that might aggravate gastroesophageal reflux disease are advisable. Clock-watching upon awakening is almost universal and generally provokes increased arousal levels.

The efficacy of specific CBTs for continuity disturbance has been evaluated in several meta-analyses.^[13,14] Stimulus control (SC) therapy^[15] is designed to break the association between bed and waking/arousal that typically arises in patients with chronic insomnia and replace this with the desired association between bed and sleep/relaxation. The core instruction is to remove oneself from the bed within 20 minutes or so when unable to sleep. For MOTN awakening, this applies to an inability to return to sleep within the 20-minute time frame. Sleep restriction (SR)^[16] applies this same principle, further aided by increased homeostatic sleep drive from deprivation, to accomplish similar goals. Patients are permitted time in bed equivalent to estimated baseline time asleep as derived from sleep logs. Time in bed is increased gradually as sleep efficiency (percentage of time in bed spent asleep) improves. Effect sizes derived from these meta-analyses for reductions in number of awakenings and wake time after sleep onset are slightly less robust than those for sleep-onset problems, but nevertheless range between 0.7 and 0.8, which suggests very significant improvement. Comparable degrees of improvement in sleep continuity have been reported for SC and SR. In practice, most CBT-I includes multiple components such as SC and SR as well as cognitive therapy to address distortions and misattributions common to the condition. Relaxation therapy may or may not be included as well. These multimodal treatments produce quite significant improvement for patients with primary MOTN awakening disturbance.

Pharmacotherapy may be used in conjunction with CBT-I, or when such treatment is unavailable, as a primary therapy. The decision to prescribe hypnotic mediation should be a joint decision of patient and physician. Certainly patient preference to use, or to avoid, such mediation is a driving factor. Other considerations in this decision include the outcome of any previous medication trials, potential side effects or drug-drug interactions, history of medication abuse, other comorbid conditions, and cost. Consensus guidelines indicate that the first-line pharmacotherapy for chronic insomnia should be a short- to intermediate-acting benzodiazepine receptor agonist (BzRA) or melatonin agonist.^[10,17,18] The single most important consideration in choosing a specific BzRA is the duration of action. Very short-acting agents such as zaleplon and the melatonin-agonist ramelteon are not suitable choices for sleep-maintenance disturbances as their half-lives are no more than 1 to 2 hours. Zolpidem has a slightly longer half-life (mean elimination half-life ~ 2.6 hours) and may be suitable for some individuals with MOTN awakening, although in most cases, agents with somewhat longer duration, such as eszopiclone (mean elimination half-life ~ 6 hours) or zolpidem controlled-release are most suitable. Temazepam is a standard benzodiazepine with a half-life (8-15 hours) that is comparable to these agents and is a suitable (and less expensive) alternative to newer-generation BzRAs. Hypnotic agents have historically been recommended primarily for short-term use, and all but eszopiclone, zolpidem controlled-release, and ramelteon carry short-term use restrictions from the US Food and Drug Administration. Many patients have been treated with hypnotic medications over long periods without apparent adverse effects. Evidence that has emerged in recent years indicates that, at least for newer BzRAs such as zolpidem controlled-release and eszopiclone, these agents may be used in well-controlled settings over extended periods on a nightly or near nightly basis with maintenance of efficacy and minimal adverse effects or complications such as dosage escalation or withdrawal problems.^[17,18] However, before any patient is treated with long-term hypnotic therapy, a comprehensive evaluation must be made and effective CBT-I should have been pursued without adequate resolution of the problem. Long-term treatment also requires ongoing follow-up, intermittent reassessment of medication effectiveness and complications, and monitoring for emergence of other comorbidities.

Other prescribed agents for treatment of sleep-maintenance insomnia have been subjected to far less analysis than the BzRA group and ramelteon, which are the only medications approved for treatment of insomnia. Sedating antidepressants, particularly trazodone, have been evaluated in a limited number of trials, many uncontrolled, involving patients with depression and insomnia complaints.^[19,20] These trials suggest that trazodone may be helpful in promoting sleep maintenance in this specific population, but its use should generally be considered second line. Other sedating psychotropic medications such as the increasingly prescribed quetiapine have very little empiric evidence to support their use for chronic insomnia and they have significant side effects. These agents are best reserved for patients who have failed other hypnotic trials and who have other psychiatric indications for the use of antipsychotic medication. Widely used home remedies such as alcohol or over-the-counter medications such as antihistamines and herbal supplements are not recommended in the management of persistent MOTN awakenings. A number of new pharmacologic therapies, many with novel mechanisms, can be expected to emerge in the coming years. Several of these may be especially suitable for sleep maintenance and will be discussed in another article of this series.

Conclusion

Chronic sleep-maintenance disorders are common and have significant impact on health, function, and quality of life. Effective management requires careful assessment of the sleep disorder, as well as investigation of contributing comorbidities. Current thinking suggests that maximum therapeutic benefit is achieved when both the insomnia and related conditions are the targets of intervention. Treatment of the insomnia may be 2-pronged, using CBT for insomnia as a first-line approach whenever possible, and employing an effective, intermediate-duration hypnotic medication as patient preference and other conditions dictate.

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