Chronic Insomnia

Etiology

Individuals who have difficulty to cope with a stressful situation or those who report being habitual light sleepers have an elevated propensity to develop chronic insomnia. There is a high rate of association between insomnia and psychiatric disorders like depression, anxiety, and post-traumatic stress disorder.[1] Comorbid medical issues like restless legs syndrome, chronic pain, gastroesophageal reflux disease (GERD), respiratory issues, and immobility are associated with risk of chronic insomnia. Developmental issues during childhood, for example, separation anxiety, may predispose a child to develop sleep problems. People with certain personality traits like perfectionism, ambitiousness, neuroticism, low extraversion, and susceptibility to depression and worry are more likely to develop insomnia over time. Insomnia is also more commonly seen in individuals with psychosocial stress like disrupted family life, divorce, the death of a spouse, and alcohol or substance abuse.

Epidemiology

Insomnia is prevalent in 10% to 15% of the general population. Roughly 5.5 million office visits related to sleep disturbances were reported in the United States in 2010. Though it affects all age groups, it is more prevalent in women of peri-menopausal and post-menopausal transitions and older adults.

Pathophysiology

The genetic factors responsible for sleep deprivation were isolated from "insomnia-like Drosophila flies" (ins-l flies), which had traits similar to human insomnia. The genes associated with insomnia are Apolipoprotein (Apo) E4, PER3 4/4, HLA-DQB1*0602, homozygous Clock gene 3111C/C Clock and short (s-) allele of the 5-HTTLPR.

The molecular factors responsible for the sleep-wake regulation include the wake-promoting chemicals like orexin, catecholamine, and histamine and sleep promoting chemicals like GABA, serotonin, adenosine, melatonin, and prostaglandin D2. The orexin mediated increased neuronal firing in the wake-promoting area and inhibition of the sleep-promoting area (ventrolateral preoptic nucleus and median preoptic nucleus) is one of the possible mechanisms contributing to insomnia (sleep switch model).[2]

History and Physical

The management plan for chronic insomnia should involve comprehensive evaluation that includes a history of sleep-related disturbances, associated underlying medical and/or psychiatric problems, medications or other sleep-related disorders.

A detailed sleep history is essential for the evaluation of insomnia. The clinician should be able to identify if the sleep disturbances are from difficulty in initiating sleep or maintaining sleep or both. Patients with underlying depression may have symptoms of waking up too early in the morning (early morning insomnia) and should be screened for the same. Inquiring about the sleep hygiene practices (activities performed just before bedtime including nighttime consumption of alcohol and caffeinated beverages, use of electronic gadgets at bedtime and frequency of daytime naps) can also be helpful to determine the ways to mitigate the sleep disturbances. Other sleep-related disorders like restless leg syndrome (RLS), sleep apnea, periodic limb movements, nocturnal leg cramps can contribute to seep fragmentation and should be evaluated during the clinical encounter.

Evaluation

Laboratory Workup

The laboratory test can provide a supportive data to evaluate the underlying medical conditions that can be associated with insomnia. The initial laboratory workup should include thyroid function tests, glycosylated hemoglobin, complete blood count, serum iron studies, liver function tests, and renal function tests. 

Questionnaires

Self-evaluating questionnaires and assessment scales are helpful to document sleep disturbances and the quality of sleep. The most widely used ones are Epworth Sleepiness Scale (from 0 to 24 with a score of more than 15 indicating severe daytime sleepiness) and Pittsburgh Sleep Quality Index (poor sleep score of greater than 5). [3],[4]

Sleep Logs/Diary

Sleep logs/diaries are reliable and cost-effective ways to assess the sleep-wake cycle in an individual. Sleep logs are maintained for 2 to 4 weeks and also include documentation of alcohol and caffeine consumption, bedtime activities, and daytime napping. Sleep logs are used to determine the total sleep time (TST), wakefulness after sleep onset (WASO), sleep efficiency (SE), and circadian rhythm disturbances. The only major limitation associated with the sleep log is the reliability and validity of its documentation.[5]

Actigraphy

Wrist actigraph is a noninvasive device used to record the gross motor activity during the daytime and sleep. The various sleep parameters assessed by actigraphy are total sleep duration, wakefulness after sleep onset (WASO), sleep latency and daytime naps. One of the limitations associated with this device is that it cannot access the periodic limb movements (PLM) or abnormal breathing pattern in insomnia in which case polysomnography is indicated to assess the other sleep disorders associated with insomnia.[6]

Polysomnography

Polysomnography is the preferred method in the diagnosis of a variety of sleep disorders including sleep apnea, sleep-related hypoventilation, and parasomnias. However, it is not indicated in the initial assessment of primary insomnia[7] unless a co-existing sleep disorder is suspected.

Treatment / Management

Non-Pharmacological Management[8](A1)

Sleep Hygiene

Sleep hygiene includes educating the patients about lifestyle modifications like limiting the daytime naps, avoiding late night dinner or evening intake of alcohol, caffeine, or smoking. It also involves encouraging them to adopt a healthy diet, exercise regime and maintain a regular sleep and wake time schedules. The sleep hygiene index and the sleep hygiene awareness and practice scales can be used to assess the sleep hygiene. However, sleep hygiene alone is ineffective in managing the patients with chronic insomnia and should be used with other aspects of cognitive behavior therapy.

Sleep Restriction Therapy

This therapy depends on limiting the number of sleep hours with the idea that a reduced sleep time might improve the sleep drive and result in a consolidated sleep. This therapy might increase the chances of daytime sleepiness due to the sleep loss associated with the therapy. Based on the results, the total nighttime sleep can be gradually extended later.

Stimulus Control Therapy

The patient should be advised to restrict the maladaptive behaviors like eating or reading in bed, late night use of digital devices in the bed and go to bed to sleep only when feeling extremely sleepy.

Relaxation Therapy

Regular practice of breathing exercise, meditation or yoga can help to improve the sleeping pattern and reduce underlying anxiety and stress.

Cognitive Behavioral Therapy for insomnia (CBTi)

Cognitive behavioral therapy is an excellent therapeutic option in the management of insomnia. Effective CBTi can show significant improvement in sleep onset latency (SOL), wakefulness after sleep onset (WASO) and total sleep time (TST). Studies have shown CBTi is superior to pharmacotherapy in the management of insomnia. It is typically delivered in 6 sessions over 6 to 8 week period by either health care nurse, sleep therapist, physician assistant, or even a social worker. The sessions include sleep education, relaxation techniques, sleep restriction therapy, stimulus control therapy, cognitive and behavioral therapy. The CBTi can be delivered even in group sessions in which people with similar complaints are grouped. It can also be provided through the telehealth (video conferencing) or internet-based versions that are beneficial for those who are hesitant to visit a therapist in person. "SHUTi" is an online internet based CBTi program proven for insomnia. "Sleep Ninja" is a smartphone app, that delivers CBTi over the phone.[9]. However, the major limitation of these web-based versions is that a lot of self-encouragement is required to follow through the entire length of the programs regularly. Another limitation of the CBTi program is a shortage of efficient therapists to deliver the therapy effectively along with limited financial support which further restricts the patients from the benefits of the program.[10](A1)

Pharmacological Management

Drugs acting on GABA-A receptors

The benzodiazepines (BZD) and benzodiazepine receptor agonists (BzRA or non-BZD) both act on the GABA receptor sites thereby exerting sedative, anxiolytic, muscle relaxant, and hypnotic effects. One significant difference between the 2 groups is the receptor affinity towards different subtypes of GABA alpha subunit. While all the BZD have similar affinity to various subtypes of alpha subunits, BzRA have varying affinity to different subtypes of alpha subunits. For example, zolpidem, zopiclone, and zaleplon have higher affinity to alpha-1 subunit and lower affinity to alpha-2 and alpha-3 subunit; whereas, eszopiclone has higher affinity to alpha-2 and alpha-3 subunit of GABA receptor. The adverse effects associated with BZD like rapid development of tolerance, the risk of abuse or dependence, the occurrence of rebound insomnia after drug discontinuation, and cognitive impairment further limit the use of BZD over BzRA.

The benzodiazepine receptor agonist (non-BZD or BzRA) became available in the United States in 1992 and since then have been used for the management of insomnia. The benzodiazepine receptor agonists are rapidly absorbed,  relatively short-acting (as compared to benzodiazepines) and have relatively better side effect profiles. They are effective in treating sleep onset insomnia, sleep maintenance insomnia or both.[11],[12](A1)

Zolpidem binds selectively to alpha one subtype of GABA-A receptor. It has a short half-life of 2.2 hours and is available in immediate-release (IR) formulation of 5-mg and 10-mg doses, which are effective for the treatment of short-term insomnia. The controlled-release (CR) form is available in 6.25-mg and 12.5-mg dosage for sleep onset and sleep maintenance insomnia. A sublingual form (doses in male 3.5 mg and female 1.75 mg) is available for the treatment of middle of night awakenings (MOTN) and difficulty in returning to sleep and should be used if there is a minimum of 4 more hours of intended sleep time. The adverse effects associated with zolpidem are a headache, falls, somnolence, and antegrade amnesia.

Zaleplon has the shortest duration of action with the half-life of one hour and is available at the doses of 5 mg, 10 mg, 20 mg for the treatment of insomnia. The adverse effects associated with it are a headache, drowsiness, nausea, and worsening of depressive symptoms in patients with the comorbid depressive disorder.

Eszopiclone helps to improve the sleep efficiency, daytime functioning along with a reduction in sleep onset latency with wakefulness after sleep onset. It is used for management of sleep onset insomnia (2 mg) and sleep maintenance (3 mg) insomnia. It acts on the alpha-2, and alpha-3 receptors subtype of the GABA-A receptors, thereby exerting anxiolytic and antidepressant effect respectively, and hence, is effective in the management of insomnia with comorbid depression or generalized anxiety disorder. Common adverse effects associated with eszopiclone are unpleasant metallic taste, headache, dizziness, and somnolence.

Drugs Acting on Melatonin Receptors

Melatonin is a natural hormone produced by the pineal gland. The circadian system in the hypothalamus and the suprachiasmatic nucleus regulates the levels of this hormone throughout the day and night. Melatonin is available over the counter and is approved by Food and Drug Administration (FDA) for treatment of insomnia, especially in older adults. A dose range of 2 to 8 mg is effective in treating circadian rhythm sleep-wake disorders. However, food can delay the absorption of melatonin, and a gap should be maintained between the last meal of the day and the intake of melatonin.

Ramelteon decreases the sleep latency by acting on the melatonin MT1 and MT2 receptors in the suprachiasmatic nucleus with higher affinity than melatonin itself. A dosage of 8 mg is recommended by the Food and Drug Administration (FDA) for the management of sleep onset insomnia. It exerts minimal adverse effects including somnolence, fatigue, and dizziness.

Tasimelteon is another melatonin receptor agonist effective in improving sleep initiation and maintenance particularly in blind patients with non-24-hour sleep-wake disorders.

Drugs acting as Orexin Receptor Antagonist:

Suvorexant is a dual orexin receptor antagonist (OX1 and OX2 receptor) which counteracts the orexin/hypocretin mediated nighttime awakening. It is effective in doses of 5 mg, 10 mg, 15 mg, and 20 mg for the management of sleep onset and sleep maintenance insomnia. A dose of 15 mg and 20 mg has shown improvement in total sleep time and a reduction in sleep onset latency. However, the FDA does not recommend a higher dose of 30 mg or 40 mg of suvorexant because of safety concerns, with an increased risk of next day driving difficulty, increased daytime somnolence and narcolepsy-like symptoms (hypnogogic-hypnopompic hallucinations, cataplexy, and vivid dreams). Also, suvorexant is contraindicated in patients with narcolepsy because of possible underlying mechanisms of orexin antagonism.

Drugs Acting as Histamine-1 Receptor Antagonist

Doxepin is a tricyclic antidepressant, but at a low dose of 3 mg and 6 mg, it is effective in the management of sleep maintenance insomnia. It causes improvement in total sleep time, wakefulness after sleep onset and sleep efficiency. At low doses (3 mg and 6 mg), Doxepin acts as pure H-1 receptor antagonist being 800 times more potent than diphenhydramine for H-1 receptors, and at high doses of 25 mg to 300 mg daily (antidepressant dosage), it exerts antihistaminic, antiserotonergic, anticholinergic and antiadrenergic activity. The adverse effects associated with doxepin at low doses are headache and somnolence.

Off-Label Drugs

Antidepressants: Trazodone, mirtazapine, and amitriptyline are most commonly used antidepressants for the management of insomnia at low doses mainly because of their antihistaminic effect. Studies have shown a 50 mg once a day dose of trazodone has proved to be effective in improving sleep latency, wakefulness after sleep onset and duration of sleep.

Atypical antipsychotics: Olanzapine and quetiapine can be useful in the treatment of insomnia with comorbid psychotic conditions. They exert a sedative effect at low doses by their antihistaminic and antiserotonergic activity.

Anticonvulsants: Gabapentin has shown to improve the sleep efficiency and decrease the wakefulness after sleep onset. It can be effective in managing insomnia in patients with alcohol dependence. Pregabalin increases the total sleep time, stage N3, sleep efficiency and decreases the sleep onset latency and REM sleep. It is helpful in improving sleep in patients with generalized anxiety disorder and fibromyalgia.[13]

Differential Diagnosis

• Central sleep apnea

• Cheyne-Stokes breathing pattern

• Depression

• High altitude periodic breathing

• Jet-lag disorder

• Medication-related insomnia

• Obstructive sleep apnea (OSA)

• Periodic limb movement disorder

• Restless legs syndrome

• Sleeplessness and circadian rhythm disorder