Insomnia: General Considerations

More than one-third of adults experience transient insomnia at some point in their life. In up to 40% of cases, insomnia can develop into a more chronic and persistent condition.

The diagnosis of insomnia is made when the patient reports dissatisfaction with sleep (sleep-onset or sleep-maintenance insomnia) as well as other daytime symptoms (e.g., sleepiness, impaired attention, mood disturbances). To be considered chronic, this condition occurs for at least three nights per week and last for more than 3 months. Although several insomnia subtypes have been delineated, diagnosis and treatment are similar.

The precise pathophysiologic mechanisms underlying insomnia have not been identified yet, but neurobiological and psychological models have been proposed. Known contributing factors may include emotional, behavioral, cognitive, and genetic factors. These are often conceptually classified into predisposing (genetic etc.), precipitating (often stress or illness), and perpetuating (maladaptive behaviors that lead to chronicity) factors.

Available treatments for insomnia include pharmacologic and nonpharmacologic therapies. The treatment plan should consider any comorbidities that could lead to sleep disruption. These include any primary sleep disorders (e.g., sleep apnea and periodic limb movement in sleep), medications, other comorbidities, and behavioral factors. Initial counseling and education about good sleep practices are usually helpful and are often sufficient to reduce insomnia symptoms. It is typically helpful to start by explaining, in comprehensible terms, the rationale and the concept that the duration of wakefulness and circadian rhythms both affect sleep onset independently and that specific substances (e.g., caffeine, medications, recreational compounds) as well as perpetual sleep-related stressors (e.g., activities performed in bed that do not involve intimacy or sleep) can affect sleep is a negative way. Thereafter, recommendation can be given to keep regular wake times, limiting time in bed to sleep time, use of bed for sleep and intimacy only, avoiding afternoon caffeine and limiting alcohol intake, and limiting daytime napping (otherwise, naps should be very brief, <30 minutes, and taken in the early afternoon at the latest). In cases of persistent insomnia, formal cognitive behavioral therapy programs may prove very helpful. In some reports, cognitive behavioral therapy for insomnia may have equal or better effect compared to pharmacologic treatment, and the effect may be longer lasting. However, use is often limited by insurance coverage, the availability of psychologists, and the necessary time commitments.

Pharmacologic therapy may be appropriate when treatment is anticipated to be short (e.g., insomnia in the setting of stress) or in addition to behavioral treatments. The choice of agent should consider (1) predominant type of complaints, whether sleep initiation or sleep maintenance; (2) frequency of insomnia symptoms (nightly versus intermittent); (3) length of treatment anticipated; and (4) age and comorbidities of the patient. Sleep initiation insomnia may respond well to short-acting medications, and these can be used as needed if the condition is intermittent; in this case the choice of hypnotics should depend on comorbidities. Nightly sleep maintenance insomnia may need nightly longer-acting medications, such as eszopiclone or suvorexant. Patients with comorbid anxiety or depressive symptoms may benefit from antidepressant treatment, such as mirtazapine or trazodone. A history of sleepwalking as a child should be considered a caution in using zolpidem and, to some extent eszopiclone, as they may increase the risk for complex behaviors in sleep. Other factors, such as the patient’s age and gender, should also be considered before starting pharmacologic treatment for insomnia. In 2013 the FDA issued a warning, recommending that a lower dose of hypnotics be used to prevent next-morning impairment due to residual effects. Females appear to be more susceptible to this risk ( Box 26.1 ). Orexin antagonists are a novel group of medications that have a favorable side effect profile. Their common mechanism is inhibition of the orexin A and B receptors in the lateral and posterior hypothalamus, which is responsible for the maintenance of wakefulness. The lack of direct action on GABA makes them attractive for treatment of individuals who are at risk of falls or those with concerns for any cognitive impairment.

Overall, the medications that are used most frequently in the treatment of insomnia include benzodiazepines, which have the advantages of being cheap and ubiquitous. However, they are associated with various problems, such as excessive sedation, high frequency of falls (due to nonselective GABA effects), hypotension, tendency to lose efficacy after longer use, muscle relaxant effect, and significant cognitive effects. Other treatments include hypnotic such as zolpidem, zolpidem XR, Intermezzo (zolpidem ultra-short-acting, 1.75–3 mg), zaleplon, and eszopiclone. The advantages of these hypnotics are that some are very short acting (Intermezzo, zaleplon) or are FDA approved for chronic insomnia treatment (eszopiclone, zolpidem CR). However, frequent problems include common side effects such as parasomnia and oversedation, and some also have a potential to lose efficacy. Other options for insomnia treatment include melatonin agonists (ramelteon), orexin antagonists (suvorexant, lemborexant, and daridorexant), antidepressants (mirtazapine, trazodone, amitriptilyne), antihistamines, and other substances (herbal, etc.).

Circadian Rhythm Sleep Disorders

The timing of sleep and wakefulness is maintained on one end by homeostatic factors and on another by the endogenous circadian system. Normally, the sleep phase of the circadian rhythm occurs about 1–2 hours after the onset of melatonin secretion. It may occur later or earlier than society-driven scheduled sleep time, resulting in a delayed or advanced sleep-wake phase disorder.

Circadian rhythm sleep-wake disorders are common. In delayed sleep-wake phase disorder, sleep occurs systematically later than needed, whereas in advanced sleep-wake phase disorder, sleep occurs systematically earlier than needed. In both cases, sleep length is similar to that of healthy individuals, and patients feel refreshed when sleeping according to their naturally desired clock time. Delayed sleep-wake phase disorder is thought to account for 10% of patients with chronic insomnia and is particularly common in adolescents and young adults, occurring in 7%–16%. Advanced sleep-wake phase disorder is estimated to occur in 1% of middle-aged adults and even more commonly in older populations. Non–24-hour circadian rhythm disorder is thought to occur in >50% of blind individuals, and up to 80% of this population complains of sleep disturbances. Twenty percent of the workforce engages in shift work, and 10%–38% of this population is estimated to suffer from shift work circadian rhythm disorder.

The diagnosis and treatment of circadian rhythm sleep-wake disorders are sometimes difficult without an accurate assessment of the patient’s circadian phase. In research conditions, plasma measurements of melatonin and core body temperature are commonly used. However, these are labor intensive and expensive, require special settings, and are therefore impractical for routine clinic use. More feasible assessment parameters include salivary and urine melatonin measures.

The evaluation of circadian sleep-wake disorders usually starts with a sleep log to assess typical sleep patterns. An objective measure, such as actigraphy, may provide supportive information about the pattern of rest and activity, though it does not necessarily coincide with the circadian phase for sleep. Knowledge of the circadian phase is important because light can have opposite effects on the circadian sleep phase depending on the time of exposure; bright/blue light in the “biological morning” can advance the sleep phase, while late light exposure delays it. Salivary measurement of dim light melatonin onset time (DLMO) may be feasible and convenient in regular clinical practice.

Despite their high prevalence, circadian rhythm sleep-wake disorders are commonly misdiagnosed as insomnia or, in some situations, hypersomnia. A recent study of patients diagnosed with primary insomnia demonstrated that 10%–22% had a bedtime that was out of phase with their circadian sleep time, suggesting a circadian etiology for their sleep problems. This misdiagnosis may lead to unsuccessful, expensive, and sometimes harmful consequences.

Treatment of circadian rhythm sleep disorders is based on timed bright or blue light (morning for delayed phase disorders and afternoon for advanced phase disorders) and melatonin (1 hour prior to required bedtime in delayed phase disorder). For non–24-hour sleep-wake phase disorders in blind individuals, tasimelteon has been recently found effective, but its side effects include elevated live enzymes. It is helpful to counsel patients that the accuracy of the timing of any interventions for delayed sleep-wake phase disorder may be crucial for successful treatment. As has been mentioned, the effect of light depends on the light spectrum/wavelength, intensity, prior light exposure, and, most important, timing. The same light intensity may delay the sleep phase of the circadian cycle if it is administered prior to the core body temperature minimum or advance it if administered after it. For the same reasons, administration of exogenous melatonin should also be timed by circadian phase. According to a recent study of exogenous melatonin in individuals with delayed sleep-wake phase disorder who also had a delayed DLMO, 0.5 mg melatonin administered 1 hour before the required sleep onset time (time the individual needs to be asleep to obtain a sufficient amount of sleep at the time they have to awaken for morning obligations) can be a safe and effective treatment option.

Sleep-Disordered Breathing: Obstructive Sleep Apnea and Central Sleep Apnea

Sleep apnea is a primary sleep disorder characterized by pauses of breathing during sleep. There are three main types of sleep apnea: obstructive sleep apnea, central sleep apnea, and complex sleep apnea. An obstructive apnea is defined as a cessation of airflow for at least 10 seconds and results from collapse of the upper airway during sleep. By contrast, during a central apnea, the interruption of airflow occurs when there is a lack of effort to breathe, usually arising from the brain respiratory centers to the muscles that control breathing. Some patients may have both obstructive and central apnea.

Sleep apnea can be diagnosed during polysomnography, in which the severity of sleep apnea is quantified by the number of respiratory events per hour of sleep. Along with clinical symptoms, at least five events per hour (Apnea-Hypopnea Index ≥5) are required for a diagnosis of sleep apnea. According to prevalent criteria, an Apnea-Hypopnea Index between 5 and 14 is considered mild sleep apnea, an Index between 15 and 29 is considered moderate sleep apnea, and in Index of more than 30 events per hour is considered severe sleep apnea. Several screening scales for sleep apnea have been developed to identify at-risk patients. One of the most frequently used in clinic is the STOP-BANG questionnaire, which contains four yes-or-no questions that relate to clinical signs of sleep apnea (S: snoring; T: tiredness during daytime; O: observed apnea; P: high blood pressure) as well as four items related to the well-known sleep apnea risk factors (B: body mass index > 35; A: Age > 50 years; N: Neck circumference > 40 cm; G: male gender). A patient is at high risk of sleep apnea if three or more questions are answered positively.

In the general middle-aged population, moderate to severe sleep apnea can be found in about 30%–50% of males and 11%–23% of females. Clinical symptoms most often include loud snoring, choking and gasping, apneas witnessed by the bed partner, excessive sleepiness and fatigue, and morning headache. Sleep apnea has debilitating effects on the patient and their family’s quality of life. When left untreated, sleep apnea can also have major negative health consequences; it increases the risk of hypertension, type 2 diabetes, and cardiovascular diseases. In a large cohort study, risk of stroke in males with moderate to severe obstructive sleep apnea increased incrementally with each unit of increased severity. Sleep apnea is also a well-known risk factor for cognitive deficits. The negative consequences of sleep apnea can be at least partially reversed by consistent and accurate treatment.

Several treatment options are available for sleep apnea. For mild cases of obstructive sleep apnea, conservative therapies such as weight loss and avoiding a supine position (for positional sleep apnea) can be helpful. The most widely used and currently first-line treatment for obstructive sleep apnea is positive airway pressure therapy. Continuous positive airway pressure is typically the initial treatment and consists of a continuous flow of air into the nose, while bilevel therapy provides a higher pressure on inspiration and a lower pressure on expiration. The latter is sometimes more comfortable with higher pressures. Autotitrating machines have been very helpful to expedite treatment. Adaptive servoventilation can also be used to treat complex sleep apnea. Continuous positive airway pressure therapy in individuals with obstructive sleep apnea has been found to reduce subjective daytime sleepiness and improve cognitive functioning, as well as mood and quality of life. It also can improve blood pressure and glucose control. Oral appliances such as mandibular advancement devices may also help to improve mild to moderate cases of obstructive sleep apnea that are not associated with any significant risk factors or for patients who are intolerant to positive airway pressure therapy. Surgical treatment methods include most commonly soft palate surgery, nasal surgery, and maxillomandibular surgery. These may diminish sleep apnea severity, although they generally do not cure sleep apnea. In some situations, hypoglossal nerve stimulation can be considered in patients who cannot tolerate PAP therapy. Typically, individuals who are considered for this therapy undergo evaluation with endoscopy under anesthesia with direct visualization of the type of collapse of the upper airway. Those with concentric collapse or with pronounced anatomic abnormalities of the upper airway may not be ideal candidates, as the stimulation is not sufficiently helpful.

Hypersomnia Disorders, Narcolepsy, and Idiopathic Hypersomnia

In evaluating hypersomnia, the following issues should be considered:

1. Is there enough sleep opportunity? In adults, typical sleep need is more than 7 hours, with adequate, consistent timing.

2. Are there factors that impair sleep quality and, as a result, lead to insufficient or poor-quality sleep? These include medications, environmental factors, and primary sleep disorders, such as sleep apnea and sleep-related movement disorders.

3. Does the hypersomnia recur more than three times per week for more than 3 months?

Disorders causing central hypersomnia are rare. They include narcolepsy type 1 (with cataplexy), narcolepsy type 2 (no cataplexy), idiopathic hypersomnia (with long sleep time or without long sleep time), and recurrent hypersomnia (e.g., Kleine-Levin syndrome). Narcolepsy is a disorder of rapid eye movement (REM) sleep regulation. Classic symptoms include sleepiness, sleep paralysis, and hypnagogic hallucinations. Cataplexy in narcolepsy type 1 consists of a loss of muscle tone, provoked typically by positive emotions (classically, laughing or telling a joke). Occasionally, surprise or anger can be a trigger. For narcolepsy patients, all daytime naps are short (15–40 minutes) and refreshing. There is a common genetic association (DQB1*0602 haplotype), and patients with narcolepsy type 1 may also have lower orexin measured in cerebrospinal fluid.

The diagnosis is made first clinically; however, an objective documentation using the multiple sleep latency test is needed to confirm the sleepiness. This test is typically performed on the day after a polysomnography and consists of five nap opportunities. Most narcolepsy patients fall asleep within minutes if given the opportunity; therefore a short sleep latency (average of <8 minutes over the five nap opportunities) as well as REM sleep during these naps would be supportive of narcolepsy. Current criteria require that REM sleep is seen in two or more naps or that REM sleep is seen in one nap along with a REM latency of less than 15 minutes on the preceding polysomnogram. Cerebrospinal fluid measurements of hypocretin may help to establish the diagnosis of narcolepsy type 1 (with cataplexy); it became available in the United States in 2019.

The treatment of sleepiness often starts with wake-promoting medications. These can be modafinil or armodafinil. If these are not tolerated or are ineffective, stimulants (methylphenidate or amphetamine/dextroamphetamine) can be used. Cautions should include monitoring blood pressure and evaluating for arrhythmias, which can be worsened by these medications. Other medications that may be considered include solriamfetol, pitolisant, and oxybate (sodium oxybate or calcium, magnesium, potassium sodium oxybate). None of these have been approved for use in pregnancy. Cataplexy responds to antidepressants, typically selective serotonin reuptake inhibitors (SSRIs); sodium oxybate or calcium, magnesium, potassium, sodium oxybate; or pitolisant. Common comorbidities of narcolepsy include REM behavior disorder, which is present in as many as 10% of narcolepsy patients, as well as periodic limb movement of sleep. Both may be worsened by SSRIs, including the medications that are used for cataplexy treatment.

Hypersomnia can sometimes be seen after head trauma; in some reports, hypersomnia affects as many as half of patients with traumatic brain injury, and a quarter of these patients may have sleep-disordered breathing. Treatment of sleep-disordered breathing may be helpful, and use of any sedating medications should be judicious.

In rare conditions, hypersomnia can be idiopathic. Idiopathic hypersomnia condition typically presents with long, nonrefreshing naps as well as sleep inertia. Two types exist: (1) with a long sleep time and (2) without long sleep time. The criteria for diagnosis include the clinical presentation as well as supportive evidence from the multiple sleep latency test: a sleep latency <8 minutes and no sleep-onset REM. Treatment is often challenging. Modafinil or armodifinil at higher doses can be used, and sometimes other stimulants can be helpful. In another rare condition, Kleine-Levin syndrome, hypersomnia is recurrent. Kleine-Levin syndrome typically presents in adolescence or in the early 20s. It consists of periods that last for approximately 2 weeks, during which patients exhibit very long sleep (often 12–21 hours per day), and during the waking periods individuals exhibit cognitive abnormalities (i.e., major apathy, confusion, slowness, amnesia), dream-like behavior, hyperphagia, or hypersexuality. Between episodes, individuals have a normal level of functioning. Treatment with lithium may decrease the frequency of episodes, while stimulants have a marginal effect during the events.

Non–Rapid Eye Movement Parasomnias

Parasomnias can be grouped by the type of behavior that is seen or may be based on the sleep stage in which they occur. The most common non-REM parasomnias include somnambulism, confusional arousals, and night terrors. These parasomnias are characterized by a wide variety of behaviors, but they mostly occur from slow-wave sleep, and as such, they typically arise in the first half of the night. They most commonly manifest with directed behaviors. They are not stereotypical and may have a variable duration. Upon awakening, the patient does not have any vivid dream recall. If any dream mentation is recalled, it is very brief. The pathophysiology of non-REM parasomnias is not well understood, although the hypothesis of dysregulated slow-wave sleep has been proposed.

Important steps in the diagnosis include (1) evaluation for comorbid sleep fragmenting disorders and (2) distinction from nocturnal seizures. A laboratory based polysomnogram is indicated in most cases to assess for comorbid sleep disorders, such as sleep apnea or REM behavior disorder. Consideration should be given to evaluation with an EEG, especially in adults. A routine EEG may be helpful to assess for any interictal epileptiform discharges, and if capturing events is needed, a 24- to 72-hour assessment may provide further information. If extended 10–20 EEG montage can be added during the polysomnogram, this may expedite evaluation.

Treatment of REM parasomnias may involve benzodiazepines or, in some cases, tricyclic antidepressants. Clinicians should be aware that some medications may induce somnambulism; according to a recent review, the strongest evidence for medication-induced sleepwalking was found for zolpidem and sodium oxybate. Counseling about safety of the sleep environment and treatment of comorbid sleep disorders provide relief for many patients.

Rapid Eye Movement Behavior Disorder

REM behavior disorder (RBD) is characterized by abnormal physical behaviors that emerge from REM sleep and can lead to injury and disturbed sleep. Most patients have frequent events—typically more than once per week. Abnormalities can be seen almost nightly and consist of intermittent loss of the normal atonia of REM sleep. This phenomenon is considered supportive of the diagnosis. Clinical screening for RBD includes clinical history and validated RBD questionnaires.

RBD has serious consequences for the health of the patient. Besides the risk of sometimes severe injury, a direct consequence of a violent nocturnal movement, it often leads to sleep disruption. Furthermore, it is commonly seen in association with Parkinson disease, and many experts in the field consider it a prodrome of neurodegenerative conditions. Other comorbidities may include a higher risk of cerebral hemorrhage as well as stroke. Multiple factors may contribute to the risk of RBD. Aside from neurodegenerative conditions, RBD is seen in association with disorders of REM sleep regulations, including narcolepsy, posttraumatic stress disorder, and the use of SSRIs. Though RBD prevalence is not known exactly, a few studies have estimated it to be approximately 0.5%–1.06% in the general population, with higher numbers among the elderly.

In healthy individuals, REM sleep is closely linked to circadian phase, with a peak a little after the nadir of the core body temperature; thus, it is also around the time when melatonin secretion is maximal. Studies using a forced desynchrony protocol suggest that the circadian system has a primary effect of REM sleep regulation with a modifying effect from the homeostatic factors. Various other factors affect REM sleep, including complex interactions with the serotonergic system, primarily from the raphe nuclei in the medulla, which inhibit the REM-generating pontine tegmentum nuclei. Clinically, patients treated with antidepressants, particularly with serotonergic properties such as SSRIs, tend to suppress REM sleep; antidepressant use may also lead to REM sleep without atonia and/or trigger dream enactment events.

The melatonin MT ₁ and MT ₂ receptors likely both affect the NREM/REM ratio, with activation of the MT ₂ leading to earlier and more abundant NREM sleep, while MT ₁ receptor activation favors REM sleep. As was mentioned previously, RBD is common in patients with Parkinson’s disease, and a reduced number of melatonin receptors have been found in the areas involved in neurodegeneration. A recent study found a depleted MT ₁ receptor expression in the striatum and amygdala and depleted MT ₂ receptor expression in the substantia nigra and amygdala. In addition to circadian phase shift, activation of MT ₁ and MT ₂ receptors has been implicated as a potential protective mechanism against multiple other progressive neurodegenerative disorders, while MT ₂ receptors have been implicated in neurogenesis. Thus, REM suppression and/or disruption, as a result of the neurodegenerative process, that also involves impaired MT ₁ and MT ₂ receptor function may be a key mechanism for RBD pathophysiology and potential therapeutic target.

Treatment options for RBD are limited. The most commonly used agent is clonazepam, which must be used with caution in patients with dementia symptoms and has many potentially serious side effects. Due to the strong association with neurodegenerative conditions, RBD patients are likely to have contraindications for benzodiazepine treatment. Since the mechanism for RBD includes REM sleep disruption, much thought has been given to the question of whether improved REM sleep regulation can be a pathway to treat RBD.

Melatonin is the most common therapeutic alternative to clonazepam for RBD. Initial studies may have been partially prompted by its high clinical convenience, a very favorable side effect profile, and availability in the United States. It was first reported as effective in a case report in 1997 of a 64-year-old male who experienced improvement of his RBD symptoms after treatment with 3 mg melatonin, without any change in his REM proportion on polysomnography. Further studies have included open label case series. In one recent study, melatonin was found to be as effective as clonazepam for RBD treatment. However, studies have often been small, open label, and sometimes retrospective, and generally the timing of melatonin is not consistently reported.

The use of melatonin has several clinical challenges, since the medication is over the counter, not regulated, and dose and bioavailability can vary widely. It has therefore been proposed to also use melatonin agonists, which have a higher affinity to melatonin receptors, for treatment. Ramelteon has been reported to be successful in some cases. In 2013 Nomura et al. used 8 mg ramelteon in two patients who had polysomnography (PSG) confirmed RBD in association with parkinsonian syndromes. One of the patients had multisystem atrophy and could not tolerate clonazepam due to the lability of her blood pressure; the other had persistent symptoms despite clonazepam treatment. Both individuals experienced improvement in their RBD symptoms, including in the RBD severity scale, which is based on PSG recordings. Later, Esaki et al. treated 12 consecutive patients with idiopathic RBD in an open label trial, using 8 mg ramelteon given 30 minutes before bedtime, and reported a trend toward improvement. Another study examined the effect of ramelteon on motor and nonmotor symptoms in patients with Parkinson’s disease, with or without RBD, and reported improvement in a variety of measures after treatment, including a statistically significant RBD improvement. Novel data (some in presentations at conferences) have recently emerged regarding the chronotherapeutic aspects of RBD, suggesting that there may be not only a potential for improved symptom control but also long-term benefit in terms of decreasing neurodegeneration. However, due to a large first-pass effect, the absolute bioavailability of ramelteon following an oral dose is less than 2%, and there is a large degree of intersubject variability in plasma concentration after exposure.

Other therapeutic targets may include sleep consolidation. Recent smaller-scale studies have explored treatment with sodium oxybate. A study of 12 participants with treatment-resistant RBD and 12 controls found some improvement of symptoms.

Restless Legs Syndrome and Periodic Limb Movements of Sleep

Restless legs syndrome is characterized by an uncomfortable sensation leading to an urge to move the limbs that occurs or worsens while at rest, has consistent evening predominance, is associated with dysesthesia, and is partially relieved by physical activity. Patients often describe the sensation as “creeping, crawling tingling” or shock-like feelings or simply as indescribable discomfort. Over the course of the disease, the sensations can spread to the arms or trunk. One of the major characteristics of restless legs syndrome is its worsening in the evening and at night, which results in difficulty initiating sleep, as patients often get up and pace around the room to relieve the discomfort. In turn, poor sleep often leads to fatigue and daytime sleepiness.

Restless legs syndrome is one of the most common sleep-related movement disorders, affecting about 15% of adults. Generally, it affects females more than males, and prevalence is higher with old age. The cause can be idiopathic or secondary. In its idiopathic form, there is no known cause, but most patients will have a family history of the syndrome. Secondary restless legs syndrome most often has a later onset course and is associated with various neurologic disorders (i.e., multiple sclerosis, Parkinson disease) iron deficiency (low ferritin level), or pregnancy.

The diagnosis is made by clinical review of the patient’s medical history. Restless legs syndrome and periodic limb movement of sleep frequently cooccur; the latter is present in 80%–90% of patients diagnosed with restless legs syndrome. The presence of periodic limb movement of sleep is also supportive for the diagnosis of restless legs syndrome. Periodic limb movement of sleep can be diagnosed by clinical history, but a polysomnography may be useful to confirm the diagnosis, particularly in patients with unexplained symptoms of insomnia or hypersomnia.

Multiple studies highlight an important role of brain iron levels in the pathology of restless legs syndrome and periodic limb movement of sleep, but these are lower in patients with restless legs syndrome. Dysfunction of the dopaminergic system has also been demonstrated as a potential pathophysiologic mechanism for restless legs syndrome. Evaluation of the serum ferritin level is recommended. If the ferritin level is below 50 μg/L, replacement of iron should be considered via oral or intravenous supplementation. Otherwise, pharmacologic treatment of restless legs syndrome may start with either dopamine agonists or gabapentin or gabapentin enacarbil. Levodopa, ropinirole, pramipexole, cabergoline, and pergolide are all considered effective. The doses of dopamine agonists should be kept as low as possible to decrease the possibility of worsening symptoms over time (termed augmentation). Other effective medications include pregabalin and rotigotine. In more advanced disease, when other medications are no longer effective or in the setting of severe augmentation, opiates can be considered. Intravenous ferric carboxymaltose and pneumatic compression devices were reported to be likely effective in idiopathic restless legs syndrome. Clonidine and bupropion appear to have insufficient evidence for efficacy at this time.

A challenging long-term complication of restless legs syndrome is the development of augmentation. This phenomenon consists of earlier occurrence and worsening of the symptoms. For example, a patient who presented with typical symptom onset around bedtime (10:00–11:00 p.m.) and now reports that symptoms begin to occur in the early evening or afternoon likely suffers from augmentation. To decrease the likelihood of augmentation, initial treatment may consider gabapentin or gabapentin enacarbil instead of any dopamine agonists.

The occurrence of restless legs syndrome is notably higher in pregnant people compared to nonpregnant individuals, with prevalence reaching up to 16% during the third trimester. Pregnancy-associated restless legs syndrome is a transient condition. Risk factors include lower hemoglobin levels, iron and vitamin deficiencies, genetic factors, and smoking. Pregnant individuals who are affected by restless legs syndrome exhibit an elevated risk of preterm birth, poor quality of sleep, and depression during pregnancy. In considering treatment, nonpharmacologic approaches such as moderate exercise and yoga are recommended as initial steps. Iron replacement may be helpful as well. Other pharmacologic interventions remain controversial at this time.