Insomnia

Insomnia (or sleeplessness) is most often defined by an individual's report of sleeping difficulties.^[1] While the term is sometimes used in sleep literature to describe a disorder demonstrated by polysomnographic evidence of disturbed sleep, insomnia is often defined as a positive response to either of two questions: "Do you experience difficulty sleeping?" or "Do you have difficulty falling or staying asleep?"^[1]

Thus, insomnia is most often thought of as both a sign and a symptom^[1][2] that can accompany several sleep, medical, and psychiatric disorders, characterized by persistent difficulty falling asleep and/or staying asleep or sleep of poor quality. Insomnia is typically followed by functional impairment while awake. One definition of insomnia is difficulties initiating and/or maintaining sleep, or nonrestorative sleep, associated with impairments of daytime functioning or marked distress for more than 1 month."^[3]

Insomnia can be grouped into primary and secondary, or comorbid, insomnia.^[4][5][6] Primary insomnia is a sleep disorder not attributable to a medical, psychiatric, or environmental cause.^[7] A complete diagnosis will differentiate between:

• insomnia as secondary to another condition,
• primary insomnia co-morbid with one or more conditions, or
• free-standing primary insomnia.

Classification

Types of insomnia

Insomnia can be classified as transient, acute, or chronic.

1. Transient insomnia lasts for less than a week. It can be caused by another disorder, by changes in the sleep environment, by the timing of sleep, severe depression, or by stress. Its consequences – sleepiness and impaired psychomotor performance – are similar to those of sleep deprivation.^[8]
2. Acute insomnia is the inability to consistently sleep well for a period of less than a month. Insomnia is present when there is difficulty initiating or maintaining sleep or when the sleep that is obtained is non-refreshing or of poor quality. These problems occur despite adequate opportunity and circumstances for sleep and they must result in problems with daytime function. ^[9][10]
3. Chronic insomnia lasts for longer than a month. It can be caused by another disorder, or it can be a primary disorder. People with high levels of stress hormones or shifts in the levels of cytokines are more likely to have Chronic insomnia.^[11] Its effects can vary according to its causes. They might include muscular fatigue, hallucinations, and/or mental fatigue. Some people that live with this disorder see things as if they are happening in slow motion, wherein moving objects seem to blend together. Chronic insomnia can cause double vision.^[8]

Patterns of insomnia

Sleep-onset insomnia is difficulty falling asleep at the beginning of the night, often a symptom of anxiety disorders or the delayed sleep phase disorder.

Nocturnal awakenings are characterized by difficulty returning to sleep after awakening in the middle of the night or waking too early in the morning: middle-of-the-night insomnia and terminal insomnia. The former may be a symptom of pain disorders or illness; the latter is often a characteristic of clinical depression.

Poor sleep quality

Poor sleep quality can occur as a result of, for example, restless legs, sleep apnea or major depression. Poor sleep quality is caused by the individual not reaching stage 3 or delta sleep which has restorative properties.

Major depression leads to alterations in the function of the hypothalamic-pituitary-adrenal axis, causing excessive release of cortisol which can lead to poor sleep quality.

Nocturnal polyuria, excessive nighttime urination, can be very disturbing to sleep.^[12]

Subjective insomnia

Some cases of insomnia are not really insomnia in the traditional sense. People experiencing sleep state misperception often sleep for normal durations, yet severely overestimate the time taken to fall asleep. They may believe they slept for only four hours while they, in fact, slept a full eight hours.

Causes and co-morbidities

Symptoms of insomnia can be caused by or can be co-morbid with:

• Use of psychoactive drugs (such as stimulants), including certain medications, herbs, caffeine, nicotine, cocaine, amphetamines, methylphenidate, aripiprazole, MDMA, modafinil, or excessive alcohol intake.
• Use of fluoroquinolone antibiotic drugs, see fluoroquinolone toxicity, associated with more severe and chronic types of insomnia^[13]
• Restless Legs Syndrome, which can cause sleep onset insomnia due to the discomforting sensations felt and the need to move the legs or other body parts to relieve these sensations.
• Periodic limb movement disorder (PLMD), which occurs during sleep and can cause arousals that the sleeper is unaware of.
• Pain^[14] An injury or condition that causes pain can preclude an individual from finding a comfortable position in which to fall asleep, and can in addition cause awakening.
• Hormone shifts such as those that precede menstruation and those during menopause
• Life events such as fear, stress, anxiety, emotional or mental tension, work problems, financial stress, birth of a child and bereavement.
• Mental disorders such as bipolar disorder, clinical depression, generalized anxiety disorder, post traumatic stress disorder, schizophrenia, obsessive compulsive disorder, or dementia.^[15]
• Disturbances of the circadian rhythm, such as shift work and jet lag, can cause an inability to sleep at some times of the day and excessive sleepiness at other times of the day. Chronic circadian rhythm disorders are characterized by similar symptoms.
• Certain neurological disorders, brain lesions, or a history of traumatic brain injury
• Medical conditions such as hyperthyroidism and rheumatoid arthritis^[16]
• Abuse of over-the counter or prescription sleep aids (sedative or depressant drugs) can produce rebound insomnia
• Poor sleep hygiene, e.g., noise
• Parasomnias, which include such disruptive sleep events as nightmares, sleepwalking, night terrors, violent behavior while sleeping, and REM behavior disorder, in which the physical body moves in response to events within dreams
• A rare genetic condition can cause a prion-based, permanent and eventually fatal form of insomnia called fatal familial insomnia.^[17]
• Physical exercise. Exercise-induced insomnia is common in athletes, causing prolonged sleep onset latency.^[18]

Sleep studies using polysomnography have suggested that people who have sleep disruption have elevated nighttime levels of circulating cortisol and adrenocorticotropic hormone They also have an elevated metabolic rate, which does not occur in people who do not have insomnia but whose sleep is intentionally disrupted during a sleep study. Studies of brain metabolism using positron emission tomography (PET) scans indicate that people with insomnia have higher metabolic rates by night and by day. The question remains whether these changes are the causes or consequences of long-term insomnia.^[16]

A common misperception is that the amount of sleep required decreases as a person ages. The ability to sleep for long periods, rather than the need for sleep, appears to be lost as people get older. Some elderly insomniacs toss and turn in bed and occasionally fall off the bed at night, diminishing the amount of sleep they receive.^[19]

Diagnosis

Specialists in sleep medicine are qualified to diagnose the many different sleep disorders. Patients with various disorders including delayed sleep phase syndrome are often mis-diagnosed with primary insomnia. When a person has trouble getting to sleep, but has a normal sleep pattern once asleep, a circadian rhythm disorder is a likely cause.

In many cases, insomnia is co-morbid with another disease, side-effects from medications, or a psychological problem. Approximately half of all diagnosed insomnia is related to psychiatric disorders.^[21] In depression in many cases "insomnia should be regarded as a co-morbid condition, rather than as a secondary one;" insomnia typically predates psychiatric symptoms.^[21] "In fact, it is possible that insomnia represents a significant risk for the development of a subsequent psychiatric disorder."^[1]

Knowledge of causation is not necessary for a diagnosis.^[21]

Treatment

It is important to identify or rule out medical and psychological causes before deciding on the treatment for insomnia.^[22] Attention to sleep hygiene is an important first line treatment strategy and should be tried before any pharmacological approach is considered.^[23] Pharmacological treatments have been used mainly to reduce symptoms in acute insomnia; their role in the management of chronic insomnia remains unclear.^[4]

Non-pharmacological

Non-pharmacological strategies are superior to hypnotic medication for insomnia because tolerance develops to the hypnotic effects. In addition, dependence can develop with rebound withdrawal effects developing upon discontinuation. Hypnotic medication is therefore only recommended for short-term use, especially in acute or chronic insomnia.^[24] Non pharmacological strategies however, have long lasting improvements to insomnia and are recommended as a first line and long term strategy of managing insomnia. The strategies include attention to sleep hygiene, stimulus control, behavioral interventions, sleep-restriction therapy, paradoxical intention, patient education and relaxation therapy.^[25] Reducing the temperature of blood flowing to the brain slows the brain's metabolic rate thereby reducing insomnia. ^[26]

EEG biofeedback has demonstrated effectiveness in the treatment of insomnia with improvements in duration as well as quality of sleep.^[27]

Stimulus control therapy is a treatment for patients who have conditioned themselves to associate the bed, or sleep in general, with a negative response. As stimulus control therapy involves taking steps to control the sleep environment, it is sometimes referred interchangeably with the concept of sleep hygiene. Examples of such environmental modifications include using the bed for sleep or sex only, not for activities such as reading or watching television; waking up at the same time every morning, including on weekends; going to bed only when sleepy and when there is a high likelihood that sleep will occur; leaving the bed and beginning an activity in another location if sleep does not result in a reasonably brief period of time after getting into bed (commonly ~20 min); reducing the subjective effort and energy expended trying to fall asleep; avoiding exposure to bright light during nighttime hours, and eliminating daytime naps.

A component of stimulus control therapy is sleep restriction, a technique that aims to match the time spent in bed with actual time spent asleep. This technique involves maintaining a strict sleep-wake schedule, sleeping only at certain times of the day and for specific amounts of time to induce mild sleep deprivation. Complete treatment usually lasts up to 3 weeks and involves making oneself sleep for only a minimum amount of time that they are actually capable of on average, and then, if capable (i.e. when sleep efficiency improves), slowly increasing this amount (~15 min) by going to bed earlier as the body attempts to reset its internal sleep clock. Bright light therapy, which is often used to help early morning wakers reset their natural sleep cycle, can also be used with sleep restriction therapy to reinforce a new wake schedule. Although applying this technique with consistency is difficult, it can have a positive effect on insomnia in motivated patients.

Paradoxical intention is a cognitive reframing technique where the insomniac, instead of attempting to fall asleep at night, makes every effort to stay awake (i.e. essentially stops trying to fall asleep). One theory that may explain the effectiveness of this method is that by not voluntarily making oneself go to sleep, it relieves the performance anxiety that arises from the need or requirement to fall asleep, which is meant to be a passive act. This technique has been shown to reduce sleep effort and performance anxiety and also lower subjective assessment of sleep-onset latency and overestimation of the sleep deficit (a quality found in many insomniacs).^[28]

Meditation has been recommended for the treatment of insomnia. The meditation teacher Siddhārtha Gautama, 'The Buddha', is recorded as having recommended the practice of 'loving-kindness' meditation, or mettā bhāvanā as a way to produce relaxation and thereby, sound sleep – putting it first in a list of the benefits of that meditation.^[29] More recently, studies have concluded that: a mindfulness practice reduced mental and bodily restlessness before sleep and the subjective symptoms of insomnia;^[30] and that mindfulness-based cognitive behavioural therapy reduced restlessness, sleep effort and dysfunctional sleep-related thoughts^[31] including worry.^[32]

Cognitive Behavioral Therapy for Insomnia

A recent study found that Cognitive Behavioral Therapy for Insomnia (CBT-I) is more effective than hypnotic medications in controlling insomnia.^[33] In this therapy, patients are taught improved sleep habits and relieved of counter-productive assumptions about sleep. Common misconceptions and expectations that can be modified include: (1) unrealistic sleep expectations (e.g., I need to have 8 hours of sleep each night), (2) misconceptions about insomnia causes (e.g., I have a chemical imbalance causing my insomnia), (3) amplifying the consequences of insomnia (e.g., I cannot do anything after a bad night's sleep), and (4) performance anxiety after trying for so long to have a good night's sleep by controlling the sleep process. Numerous studies have reported positive outcomes of combining cognitive behavioral therapy for insomnia treatment with treatments such as stimulus control and the relaxation therapies. Hypnotic medications are equally effective in the short-term treatment of insomnia but their effects wear off over time due to tolerance. The effects of CBT-I have sustained and lasting effects on treating insomnia long after therapy has been discontinued.^[34][35] The addition of hypnotic medications with CBT-I adds no benefit in insomnia. The long lasting benefits of a course of CBT-I shows superiority over pharmacological hypnotic drugs. Even in the short term when compared to short-term hypnotic medication such as zolpidem (Ambien), CBT-I still shows significant superiority. Thus CBT-I is recommended as a first line treatment for insomnia.^[36]

Medications

Many insomniacs rely on sleeping tablets and other sedatives to get rest, with research showing that medications are prescribed to over 95% of insomniac cases.^[37][38] Certain classes of sedatives such as benzodiazepines and newer nonbenzodiazepine drugs can also cause physical dependence, which manifests in withdrawal symptoms if the drug is not carefully tapered down. The benzodiazepine and nonbenzodiazepine hypnotic medications also have a number of side-effects such as day time fatigue, motor vehicle crashes, cognitive impairments and falls and fractures. Elderly people are more sensitive to these side-effects.^[39] The non-benzodiazepines zolpidem and zaleplon have not adequately demonstrated effectiveness in sleep maintenance. Some benzodiazepines have demonstrated effectiveness in sleep maintenance in the short term but in the longer term are associated with tolerance and dependence. Drugs that may prove more effective and safer than existing drugs for insomnia are in development.^[40]

In comparing the options, a systematic review found that benzodiazepines and nonbenzodiazepines have similar efficacy that is not significantly more than for antidepressants.^[41] Benzodiazepines did not have a significant tendency for more adverse drug reactions.^[41] Chronic users of hypnotic medications for insomnia do not have better sleep than chronic insomniacs not taking medications. In fact, chronic users of hypnotic medications have more regular nighttime awakenings than insomniacs not taking hypnotic medications.^[42] A further review of the literature regarding benzodiazepine hypnotic as well as the nonbenzodiazepines concluded that these drugs cause an unjustifiable risk to the individual and to public health and lack evidence of long-term effectiveness. The risks include dependence, accidents, and other adverse effects. Gradual discontinuation of hypnotics in long-term users leads to improved health without worsening of sleep. It is preferred that hypnotics be prescribed for only a few days at the lowest effective dose and avoided altogether wherever possible in the elderly.^[43]

Benzodiazepines

The most commonly used class of hypnotics prescribed for insomnia are the benzodiazepines. Benzodiazepines all bind unselectively to the GABA_A receptor.^[41] But certain benzodiazepines (hypnotic benzodiazepines) have significantly higher activity at the α₁ subunit of the GABA_A receptor compared to other benzodiazepines (for example, triazolam and temazepam have significantly higher activity at the α₁ subunit compared to alprazolam and diazepam, making them superior sedative-hypnotics – alprazolam and diazepam in turn have higher activity at the α₂ subunit compared to triazolam and temazepam, making them superior anxiolytic agents). Modulation of the α₁ subunit is associated with sedation, motor-impairment, respiratory depression, amnesia, ataxia, and reinforcing behavior (drug-seeking behavior). Modulation of the α₂ subunit is associated with anxiolytic activity and disinhibition. For this reason, certain benzodiazepines are better suited to treat insomnia than others. Hypnotic benzodiazepines include drugs such as temazepam, flunitrazepam, triazolam, flurazepam, midazolam, nitrazepam, and quazepam. These drugs can lead to tolerance, physical dependence, and the benzodiazepine withdrawal syndrome upon discontinuation, especially after consistent usage over long periods of time. Benzodiazepines, while inducing unconsciousness, actually worsen sleep as they promote light sleep while decreasing time spent in deep sleep.^[45] A further problem is, with regular use of short-acting sleep aids for insomnia, daytime rebound anxiety can emerge.^[46] Benzodiazepines can help to initiate sleep and increase sleep time, but they also decrease deep sleep and increase light sleep. Although there is little evidence for benefit of benzodiazepines in insomnia and evidence of major harm, prescriptions have continued to increase.^[47] There is a general awareness that long-term use of benzodiazepines for insomnia in most people is inappropriate and that a gradual withdrawal is usually beneficial due to the adverse effects associated with the long-term use of benzodiazepines and is recommended whenever possible.^[48][49]

Non-benzodiazepines

Nonbenzodiazepine sedative-hypnotic drugs, such as zolpidem, zaleplon, zopiclone, and eszopiclone, are a newer classification of hypnotic medications indicated for mild to moderate insomnia. They work on the benzodiazepine site on the GABA_A receptor complex similarly to the benzodiazepine class of drugs. Some but not all of the nonbenzodiazepines are selective for the α₁ subunit on GABA_A receptors, which is responsible for inducing sleep and may therefore have a cleaner side-effect profile than the older benzodiazepines. Zopiclone and eszopiclone like benzodiazepine drugs bind unselectively to α₁, α₂, α₃ and α₅ GABA_A benzodiazepine receptors.^[50] Zolpidem is more selective and zaleplon is highly selective for the α₁ subunit, thus giving them an advantage over benzodiazepines in terms of sleep architecture and a reduction in side-effects. The nonbenzodiazepine sedative-hypnotic drugs have milder activity at the α₁ subunit on GABA_A receptors compared to most benzodiazepines, rendering them ineffective for moderately severe to severe insomnia.^[51][52] However, there are controversies over whether these non-benzodiazepine drugs are superior to benzodiazepines. These drugs appear to cause both psychological dependence and physical dependence, though less than traditional benzodiazepines and can also cause the same memory and cognitive disturbances along with morning sedation.

Alcohol

Alcohol is often used as a form of self-treatment of insomnia to induce sleep. However, alcohol use to induce sleep can be a cause of insomnia. Long-term use of alcohol is associated with a decrease in NREM stage 3 and 4 sleep as well as suppression of REM sleep and REM sleep fragmentation. Frequent moving between sleep stages occurs, with awakenings due to headaches, the need to urinate, dehydration, and excessive sweating. Glutamine rebound also plays a role as when someone is drinking; alcohol inhibits glutamine, one of the body's natural stimulants. When the person stops drinking, the body tries to make up for lost time by producing more glutamine than it needs. The increase in glutamine levels stimulates the brain while the drinker is trying to sleep, keeping him/her from reaching the deepest levels of sleep.^[53] Stopping chronic alcohol use can also lead to severe insomnia with vivid dreams. During withdrawal REM sleep is typically exaggerated as part of a rebound effect.^[54]

Opioids

Opioid medications such as hydrocodone, oxycodone, and morphine are used for insomnia that is associated with pain due to their analgesic properties and hypnotic effects. Opioids can fragment sleep and decrease REM and stage 2 sleep. By producing analgesia and sedation, opioids may be appropriate in carefully selected patients with pain-associated insomnia.^[14]Though, dependence on opium can lead to suffering from long time disturbance in sleep^[55] .

Antidepressants

Some antidepressants such as amitriptyline, doxepin, mirtazapine, and trazodone can often have a very strong sedative effect, and are prescribed off label to treat insomnia.^[56] The major drawback of these drugs is that they have properties that can lead to many side-effects; for example, amitriptyline and doxepin both have antihistaminergic, anticholinergic, and antiadrenergic properties, which contribute to their side-effect profile, while mirtazapines side-effects are primarily antihistaminergic, and trazadones side-effects are primarily antiadrenergic. Some also alter sleep architecture. As with benzodiazepines, the use of antidepressants in the treatment of insomnia can lead to withdrawal effects; withdrawal may induce rebound insomnia.

Mirtazapine is known to decrease sleep latency, promoting sleep efficiency and increasing the total amount of sleeping time in patients suffering from both depression and insomnia.^[57][58]

Melatonin and melatonin agonists

The hormone melatonin, sold as a "dietary supplement" in some countries or as a slow-release prescription drug (Circadin) in Europe, is effective in several types of insomnia. Melatonin has demonstrated effectiveness equivalent to the prescription sleeping tablet zopiclone in inducing sleep and regulating the sleep/waking cycle.^[59] One particular benefit of melatonin is that it can treat insomnia without altering the sleep pattern, which is altered by many prescription sleeping tablets. Another benefit is it does not impair performance related skills.^[60][61]

Melatonin agonists, including ramelteon (Rozerem) and tasimelteon, seem to lack the potential for dependence.^[62] This class of drugs has a relatively mild side-effect profile and low likelihood of causing morning sedation. While these drugs show good effect for the treatment of insomnia due to jet lag^[63] and the chronic circadian rhythm disorders, the results for other forms of insomnia are less promising.^[64]

Antihistamines

The antihistamine diphenhydramine is widely used in nonprescription sleep aids such as Benadryl. The antihistamine doxylamine is used in nonprescription sleep aids such as Unisom (USA) and Unisom 2 (Canada). In some countries, including Australia, it is marketed under the names Restavit and Dozile. It is the most effective over-the-counter sedative currently available in the United States, and is more sedating than some prescription hypnotics.^[65]

While the two drugs mentioned above are available over the counter in most countries, the effectiveness of these agents may decrease over time, and the incidence of next-day sedation is higher than for most of the newer prescription drugs. Anticholinergic side-effects may also be a draw back of these particular drugs. Dependence does not seem to be an issue with this class of drugs.

Cyproheptadine is a useful alternative to benzodiazepine hypnotics in the treatment of insomnia. Cyproheptadine may be superior to benzodiazepines in the treatment of insomnia because cyproheptadine enhances sleep quality and quantity, whereas benzodiazepines tend to decrease sleep quality.^[66]

Atypical antipsychotics

Low doses of certain atypical antipsychotics such as quetiapine, olanzapine, and risperidone are also prescribed for their sedative effect, but the danger of neurological, metabolic, and cognitive side-effects makes these drugs a poor choice to treat insomnia. Over time, quetiapine may lose its effectiveness as a sedative. The ability of quetiapine to produce sedation is determined by the dosage. Higher doses are usually taken for its use as an antipsychotic, while lower doses have a marked sedative effect.

Eplivanserin is an investigational drug with a mechanism similar to antipsychotics.^[62]

Other substances

Some insomniacs use herbs such as medical marijuana, valerian, chamomile, lavender, hops, and passion-flower. Valerian has undergone multiple studies and appears to be modestly effective.^[67][68][69]

Insomnia may be a symptom of magnesium deficiency, or low magnesium levels, but this has not yet been proven. A healthy diet containing magnesium can help to improve sleep in individuals without an adequate intake of magnesium.^[70]

L-Arginine L-aspartate, S-adenosyl-L-homocysteine, and Delta sleep-inducing peptide (DSIP) may be also helpful in alleviating insomnia.^[71] There is some evidence showing that 3 grams of L-Glycine before bedtime improves sleep quality.^[72]

Almorexant was an orexin antagonist undergoing clinical trials as a novel drug, but was dropped in January 2011 due to a poor side effect profile.^[73]

Epidemiology

A survey of 1.1 million residents in the United States conducted by the American Cancer Society found that those that reported sleeping about 7 hours per night had the lowest rates of mortality, whereas those that slept for fewer than 6 hours or more than 8 hours had higher mortality rates. Getting 8.5 or more hours of sleep per night increased the mortality rate by 15%. Severe insomnia – sleeping less than 3.5 hours in women and 4.5 hours in men – also led to a 15% increase in mortality. However, most of the increase in mortality from severe insomnia was discounted after controlling for co-morbid disorders. After controlling for sleep duration and insomnia, use of sleeping pills was also found to be associated with an increased mortality rate.^[74]

The lowest mortality was seen in individuals who slept between six and a half and seven and a half hours per night. Even sleeping only 4.5 hours per night is associated with very little increase in mortality. Thus, mild to moderate insomnia for most people is associated with increased longevity and severe insomnia is associated only with a very small effect on mortality.^[74]

As long as a patient refrains from using sleeping pills, there is little to no increase in mortality associated with insomnia, but there does appear to be an increase in longevity. This is reassuring for patients with insomnia in that, despite the sometimes-unpleasantness of insomnia, insomnia itself appears to be associated with increased longevity.^[74] It is unclear why sleeping longer than 7.5 hours is associated with excess mortality.^[74]

Insomnia is 40% more common in women than in men.^[75]

Prevalence

The National Sleep Foundation's 2002 Sleep in America poll showed that 58% of adults in the U.S. experienced symptoms of insomnia a few nights a week or more.^[76] Although insomnia was the most common sleep problem among about one half of older adults (48%), they were less likely to experience frequent symptoms of insomnia than their younger counterparts (45% vs. 62%), and their symptoms were more likely to be associated with medical conditions, according to the poll of adults between the ages of 55 and 84.^[76]

As explained by Thomas Roth,^[1] estimates of the prevalence of insomnia depend on the criteria used as well as the population studied. About 30% of adults report at least one of the symptoms of insomnia. When daytime impairment is added as a criterion, the prevalence is about 10%. Primary insomnia persisting for at least one month yields estimates of 6%.

See also

• Somniphobia
• Sleep deprivation
• Actigraphy
• Thai Ngoc, Vietnamese insomniac, claimed to be awake for 38 years
• Al Herpin, American insomniac, known as the "Man Who Never Slept"

References

Further reading

• Summers-Bremner, Eluned. Insomnia: A Cultural History (University of Chicago Press, 2008) 176 pp. ISBN 978-1-86189-317-8 excerpt and text search