eMedicine Specialties > Neurology > Sleep-Related Diseases
Sleeplessness and Circadian Rhythm Disorder: Treatment & Medication
Updated: Aug 22, 2008
- Overview
- Differential Diagnoses & Workup
- Treatment & Medication
- Follow-up
Treatment
Medical Care
Behavioral and light therapy are the mainstays of treatment of circadian rhythm disturbances. Emphasize good sleep hygiene and discourage maladaptive behaviors.
- Bright light therapy: Circadian rhythm disturbances respond very well to light therapy, especially bright light (>600 lux). For entrainment purposes, bright room light over time may be sufficient; however, a higher intensity of light (>6000 lux over 30-60 min) is often necessary to accomplish acute phase shifts. The timing of light therapy is also important because it affects the degree and direction of the rhythm shift. For example, light therapy applied in the early evening and nighttime hours delays the cycle (in patients with advanced sleep-phase syndrome [ASPS]), whereas therapy given in the early morning stimulates morning alertness and an earlier bedtime (in patients with delayed sleep-phase syndrome [DSPS]).
- Chronotherapy: This behavioral treatment consists of a gradual shift in sleep time in accordance with the patient's tendency. Thus, in DSPS, a progressive delay of 3 h/d is prescribed, followed by strict maintenance of a regular bedtime hour once the desired schedule is achieved. In ASPS, chronotherapy focuses on advancing bedtime by 2-3 hours per night over 1 week until a desired schedule is achieved.
- Enhancing environmental cues: This is an important part of the treatment of circadian rhythm disorders. Patients are encouraged to keep a dark quiet room during sleep and a well-lit room upon awakening. Avoid bright light exposure in the evening. Enforce regular hours of eating and other activities.
- Lifestyle: Patients may respond to shifts in their active phases by exhibiting signs of sleep deprivation. For example, teenagers may have difficulty keeping late hours and getting up for an early morning class. Shift workers may have difficulty if shifts are changed too rapidly before they have had a chance to adjust.
Surgical Care
Sleep disturbances associated with obstructive sleep apnea (OSA) syndrome may be amenable to surgical intervention. See Obstructive Sleep Apnea and Sleep Dysfunction in Women.
Consultations
- Sleep medicine specialist
- Neurologist
- Psychiatrist
- Pulmonologist
Diet
- Nocturnal eating disorder is an entity distinct from circadian rhythm disorders and is characterized by an inability to maintain sleep over the night. Sleep is interrupted and patients are unable to return to sleep without eating or drinking.
- Dietary advice includes the following:
- Limit large meals.
- Avoid intake of excessive fluids before bedtime. This is an element that is generally emphasized when attempting to improve sleep hygiene.
- Discourage obesity.
Activity
- In patients with irregular sleep-wake cycles, behavioral modification has been shown to be helpful. This includes encouraging structured daytime activity, even in the presence of fatigue. Attendants in nursing homes can help elderly patients remain awake by involving them in activities and restricting sleep to conventional time periods. Encourage afternoon naps scheduled daily at a regular time. This helps to avoid multiple brief daytime naps and to consolidate sleep to the desired time.
- Emphasizing a program of regular morning exercise is a component of promoting sleep hygiene. Advise patients to avoid strenuous exercise before bedtime.
Medication
Therapy for circadian rhythm disturbances is largely behavioral. Light therapy has been shown to be an effective modifier of circadian cycles. Mixed modalities may be effective in elderly patients with dementia who have irregular sleep-wake rhythms. Combination of planned sleep scheduling, timed light exposure, or timed melatonin administration can be helpful.
Benzodiazepines
These agents are recommended in preference to barbiturates because of their low toxicity and clinical efficacy. They have a rapid onset of action. Concerns remain with regard to rebound insomnia, residual daytime effects, and addictive potential. Short-acting benzodiazepines are often chosen in the early treatment of sleep-onset insomnia and are used in conjunction with behavioral therapy. Long-standing insomnia with sleep maintenance as well as sleep-onset insomnia often requires long-acting agents.
Triazolam (Halcion)
Frequently chosen as short-term adjunct to behavioral therapy. This short-acting agent is effective in helping patients fall asleep. Not effective in those with sleep maintenance problems. For patients with sleep maintenance insomnia, a benzodiazepine with intermediate (eg, estazolam [ProSom]) or long half-life (eg, quazepam) may be considered. Information given here is for triazolam. For longer-acting agents, please consult PDR.
Adult
Initial dose: 0.25 mg PO qhs
Elderly patients: 0.125-0.25 mg PO qhs
Pediatric
Not established
Phenothiazines, barbiturates, alcohols, and MAOIs increase toxicity of benzodiazepines in CNS
Documented hypersensitivity; pregnancy
Pregnancy
X - Contraindicated; benefit does not outweigh risk
Precautions
Caution and close monitoring needed in hepatic disease, low albumin levels, or renal or pulmonary disease; causes residual daytime sedation, impairs cognition, and increases risk of falls, especially in older people; caution with other CNS depressants
Nonbenzodiazepine hypnotics
These agents are gaining popularity because they do not have significant effect on sleep architecture and are not associated with the rebound phenomenon seen with the benzodiazepines.
Zolpidem (Ambien, Ambien CR)
Nonbenzodiazepine hypnotic of imidazopyridine class. Rapidly absorbed, has elimination half-life of 2.5 h, and is good short-term option for patients with sleep-onset insomnia who require pharmacologic support. The extended-release product (Ambien CR) consists of a coated 2-layer tablet and is useful for insomnia characterized by difficulties with sleep onset and/or sleep maintenance. The first layer releases drug content immediately to induce sleep; the second layer gradually releases additional drug to provide continuous sleep.
Adult
10 mg PO qhs
Extended-release: 12.5 mg PO hs
Extended-release in elderly patients: 6.25 mg PO hs
Pediatric
Not established
Increases toxicity of alcohol and CNS depressants; effect may be delayed if taken with food or shortly after a meal
Documented hypersensitivity; lactation
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Monitor elderly patients for impaired cognitive or motor performance; adverse effects include drowsiness, dizziness, lightheadedness, and impaired coordination; patients should be cautioned about operating heavy machinery and driving; extended-release dosage form must be swallowed whole (do not divide, chew, or crush)
Eszopiclone (Lunesta)
Nonbenzodiazepine hypnotic pyrrolopyrazine derivative of the cyclopyrrolone class. The precise mechanism of action is unknown but is believed to interact with GABA-receptor at binding domains close to or allosterically coupled to benzodiazepine receptors. Indicated for insomnia to decrease sleep latency and improve sleep maintenance. Short half-life of 6 h. Higher doses (ie, 2 mg for elderly adults and 3 mg for nonelderly adults) are more effective for sleep maintenance, whereas lower doses (ie, 1 mg for elderly adults and 2 mg for nonelderly adults) are suitable for difficulty in falling asleep.
Adult
Nonelderly adults: 2 mg PO hs; may increase to 3 mg PO hs prn
Elderly adults: 1 mg PO hs initially; not to exceed 2 mg PO hs
Severe hepatic impairment: Do not exceed 2 mg PO hs
Pediatric
<18 years: Not established
>18 years: Administer as in adults
CYP3A4 and CYP2E1 substrate; potent CYP3A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin, nefazodone, ritonavir, nelfinavir) increases AUC, Cmax, and t1/2 and therefore potential toxicity (decrease dose); potent CYP3A4 inducers (eg, rifampicin) increase clearance; coadministration with alcohol or other CNS depressants may increase effect and toxicity (decrease dose); coadministration with olanzapine may decrease DSST scores; sleep onset may be delayed if taken with or immediately after a high-fat or heavy meal
Documented hypersensitivity
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
May cause dysgeusia, headache, or coldlike symptoms; rare adverse effects associated with hypnotics include short-term amnesia, confusion, agitation, hallucinations, worsened depression, or suicidal thoughts; high doses (ie, 6-12 mg) produce euphoric effects similar to those of diazepam 20 mg; anxiety, abnormal dreams, nausea, and upset stomach may occur within 48 h after discontinuing; alertness may be affected the following day, use caution while operating machinery or driving a car
Zaleplon
Nonbenzodiazepine hypnotic from the pyrazolopyrimidine class. Has a chemical structure unrelated to benzodiazepines, barbiturates, or other hypnotic drugs but interacts with the GABA-BZ receptor complex. Binds selectively to the omega-1 receptor situated on the alpha subunit of the GABAA receptor complex in the brain. Potentiates t-butyl-bicyclophosphorothionate (TBPS) binding. Has preferential binding to the omega-1 receptor of the GABA receptor family.
Adult
10 mg PO hs; may increase to 20 mg prn if tolerated
Start with 5 mg PO hs in elderly and debilitated patients; doses >10 mg are not recommended in these populations
Pediatric
Not established
Cimetidine significantly increases effect of zaleplon; contraindicated in patients receiving Sodium oxybate
Documented hypersensitivity; anaphylaxis may occur with first dose
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Failure of insomnia to remit after 7-10 d of treatment may indicate need for evaluation of a primary psychiatric or medical illness; limit treatment to 7-10 d of use and reevaluate patient if to be taken for >2-3 wk (do not prescribe zaleplon in quantities exceeding a 1-mo supply); in hepatic function impairment, reduce dose to 5 mg PO hs; caution in patients exhibiting signs or symptoms of depression; 5-mg and 10-mg cap contain tartrazine and may trigger bronchospasm in susceptible individuals particularly those with aspirin sensitivity.
Pineal gland hormones
Melatonin has been reported to be useful in the treatment of jet lag and in the treatment of sleep-onset insomnia in elderly patients who are melatonin deficient. Recommendations regarding melatonin are based on the extensive literature review from the Cochrane Library.6 However, because of the phenomenon of publication bias, studies showing efficacy are more likely to be available for review than those that do not show efficacy. Furthermore, potential users of these agents should be cautioned that variations in quality, purity, and quantity of active ingredient in natural pharmaceuticals make interpretation of studies difficult and raises concerns about interactions and contaminants.
Melatonin
Available as OTC preparation. Used to enhance natural sleep process and for resetting body's internal time clock when traveling through different time zones. Has also been used for treatment of circadian rhythm sleep disorders in blind people with no light perception. No RDA of melatonin has been approved by the FDA, nor is FDA-approved prescribing information available for any of the doses discussed here. Individual patients may or may not experience the reported benefits of melatonin.
Physicians and patients should consider risks and benefits of each therapeutic option. Slow-release products are reported to be less effective. Melatonin is believed to be effective when crossing 5 or more time zones and is less effective when traveling in westward direction.
Adult
Jet lag: 0.5-5 mg PO qhs with improved efficacy suggested at higher doses; may be initiated several nights prior to travel
Elderly melatonin-deficient patients with sleep-onset insomnia: 1-2 mg PO qhs
Pediatric
Not established
Fluvoxamine increases levels, thus increasing drowsiness; nifedipine increases HR and BP
Documented hypersensitivity
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Adverse effects include suppression of male libido, hypothermia, retinal damage, headache, nightmares, and worsening of depression; caution in patients who have epilepsy, are taking warfarin, have autoimmune or endocrine disorders, or are pregnant or lactating (such individuals should consult a physician before using melatonin, as should individuals taking other medications)
Melatonin agonists
These agents are indicated for insomnia characterized by difficulty with sleep onset.
Ramelteon (Rozerem)
Melatonin receptor agonist with high selectivity for human melatonin MT1 and MT2 receptors. MT1 and MT2 are thought to promote sleep and be involved in maintenance of circadian rhythm and normal sleep-wake cycle.
Adult
8 mg PO 30 min before bedtime on empty stomach
Pediatric
Not established
Major substrate of cytochrome P450 CYP1A2 and minor substrate of CYP2C and CYP3A4; strong CYP1A2 inhibitors (eg, fluvoxamine) increase AUC up to 190-fold and Cmax 70-fold; strong CYP inducers (eg, rifampin) decrease total exposure by mean of 80%; strong CYP3A4 inhibitors (eg, ketoconazole) and strong CYP2C9 inhibitors (eg, fluconazole) may increase serum levels
Documented hypersensitivity; strong cytochrome P450 CYP1A2 inhibitors (eg, fluvoxamine); severe hepatic impairment
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Caution with mild hepatic impairment; adverse effects leading to discontinuation in clinical trials included dizziness, nausea, fatigue, headache, and worsening insomnia
More on Sleeplessness and Circadian Rhythm Disorder |
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| Differential Diagnoses & Workup: Sleeplessness and Circadian Rhythm Disorder |
 Treatment & Medication: Sleeplessness and Circadian Rhythm Disorder |
| Follow-up: Sleeplessness and Circadian Rhythm Disorder |
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Further Reading
Keywords
sleeplessness, circadian rhythms, ultradian rhythm, entrainment, free-running clock, zeitgeber, insomnia, biological clock, jet lag, sleep disorders, sleep deprivation, daytime sleepiness, biological rhythms, delayed sleep-phase syndrome, DSPS, advanced sleep-phase syndrome, ASPS, irregular sleep-wake cycle, suprachiasmatic nuclei, SCN, suprachiasmatic nuclei lesions, SCN lesions, Alzheimer disease, Alzheimer's disease, shift work syndrome, circadian rhythm disorder, motor vehicle accidents, heavy machinery accidents, obstructive sleep apnea, OSA, excessive daytime sleepiness, EDS, upper airway resistance syndrome, congestive heart failure, chronic obstructive pulmonary disease, neurodegenerative disease, chronic lung disease
