Posted by: Indonesian Children | September 13, 2009

Medication in Sleep disorders

Many of the medications described below are not approved by the Food and Drug Administration (FDA) for adolescents and children.

The common classes of drugs used for the treatment of parasomnias are benzodiazepines and anticonvulsants. The general aim of drug treatment is to prevent arousal out of sleep or to suppress REM sleep.

Benzodiazepines 

Benzodiazepines help suppress REM sleep and limit arousal. They include the following drugs:

  • Diazepam (Valium) is most frequently used in children, especially children with night terrors.
  • Alprazolam (Xanax) is the second choice in this category for parasomnias. It has a brief duration of action; therefore, the likelihood of morning effects, such as grogginess, is decreased. However, it has a potential for exacerbating symptoms at lower doses when effects attenuate, owing to possible rebound.
  • Clonazepam (Klonopin) is similar to alprazolam; it is a good alternative option to diazepam.

Anticonvulsants 

Anticonvulsants inhibit arousal. They include the following drugs:

  • Carbamazepine (Tegretol, Carbatrol) is the most commonly used drug for parasomnias.
  • Valproate (Depakene, Depakote) has been reported to be effective in treating parasomnias, in both a once nightly dosage schedule and a standard dosage schedule.
  • Gabapentin (Neurontin) has not been used as frequently as the other 2 anticonvulsants. As with carbamazepine and valproate, no information is available and no consensus has been reached regarding the use of a once nightly dosage versus a standard antiepileptic dosage.

Antiparkinsonian 

Antiparkinsonian drugs are very effective for the treatment of persons with restless legs syndrome and periodic limb movement disorder.

  • Levodopa is the most commonly used drug for the treatment of restless legs syndrome and periodic limb movement disorder. An oral dose of 50-100 mg, controlled-release formulation, is prescribed as initial therapy for restless legs syndrome.
  • For periodic limb movement disorder, a controlled-release preparation of levodopa combined with a decarboxylase inhibitor (carbidopa) at a dose of 50-100 mg is started.
  • A dose increase not to exceed 200 mg may be required to completely suppress restless legs syndrome and periodic limb movement disorder.
  • The major adverse effects of levodopa therapy are (1) rebound of symptoms during the daytime and (2) tardive dyskinesia (difficulty in performing voluntary movements), which is extremely uncommon.
  • Ropinirole (Requip), pergolide (Permax), and pramipexole (Mirapex) cause fewer side effects compared with levodopa and have become first-line drugs in the treatment of restless legs syndrome and periodic limb movement disorder. Pramipexole is started at a lowest dose of one half tablet of 0.25 mg once a day for 5 days and then increased to 0.25 mg per day. The dose may be increased to a maximum of 0.5 mg per day. Ropinirole is started at 0.25 mg at bedtime for individuals with primarily nighttime symptoms. For those with symptoms throughout the day, it may be given 2 times per day. The dose may be gradually increased each week. Average doses are 2.5 mg per day.

Opiates
 
Opiates, such as codeine, propoxyphene, and dihydromorphone, have been used in persons who have severe restless legs syndrome and who do not benefit from other therapy. One should be closely observed for development of tolerance and dependency 

Medications

The common classes of drugs used for the treatment of parasomnias are benzodiazepines and anticonvulsants. The general aim of drug treatment is to prevent arousal out of sleep or to suppress REM sleep.

Benzodiazepines 

Benzodiazepines help suppress REM sleep and limit arousal. They include the following drugs:

  • Diazepam (Valium) is most frequently used in children, especially children with night terrors.
  • Alprazolam (Xanax) is the second choice in this category for parasomnias. It has a brief duration of action; therefore, the likelihood of morning effects, such as grogginess, is decreased. However, it has a potential for exacerbating symptoms at lower doses when effects attenuate, owing to possible rebound.
  • Clonazepam (Klonopin) is similar to alprazolam; it is a good alternative option to diazepam.

Anticonvulsants 

Anticonvulsants inhibit arousal. They include the following drugs:

  • Carbamazepine (Tegretol, Carbatrol) is the most commonly used drug for parasomnias.
  • Valproate (Depakene, Depakote) has been reported to be effective in treating parasomnias, in both a once nightly dosage schedule and a standard dosage schedule.
  • Gabapentin (Neurontin) has not been used as frequently as the other 2 anticonvulsants. As with carbamazepine and valproate, no information is available and no consensus has been reached regarding the use of a once nightly dosage versus a standard antiepileptic dosage.

Antiparkinsonian 

Antiparkinsonian drugs are very effective for the treatment of persons with restless legs syndrome and periodic limb movement disorder.

  • Levodopa is the most commonly used drug for the treatment of restless legs syndrome and periodic limb movement disorder. An oral dose of 50-100 mg, controlled-release formulation, is prescribed as initial therapy for restless legs syndrome.
  • For periodic limb movement disorder, a controlled-release preparation of levodopa combined with a decarboxylase inhibitor (carbidopa) at a dose of 50-100 mg is started.
  • A dose increase not to exceed 200 mg may be required to completely suppress restless legs syndrome and periodic limb movement disorder.
  • The major adverse effects of levodopa therapy are (1) rebound of symptoms during the daytime and (2) tardive dyskinesia (difficulty in performing voluntary movements), which is extremely uncommon.
  • Ropinirole (Requip), pergolide (Permax), and pramipexole (Mirapex) cause fewer side effects compared with levodopa and have become first-line drugs in the treatment of restless legs syndrome and periodic limb movement disorder. Pramipexole is started at a lowest dose of one half tablet of 0.25 mg once a day for 5 days and then increased to 0.25 mg per day. The dose may be increased to a maximum of 0.5 mg per day. Ropinirole is started at 0.25 mg at bedtime for individuals with primarily nighttime symptoms. For those with symptoms throughout the day, it may be given 2 times per day. The dose may be gradually increased each week. Average doses are 2.5 mg per day.

Opiates
 
Opiates, such as codeine, propoxyphene, and dihydromorphone, have been used in persons who have severe restless legs syndrome and who do not benefit from other therapy. One should be closely observed for development of tolerance and dependency

Vasopressin analogs

Desmopressin is a synthetic antidiuretic hormone with actions mimicking vasopressin. It is used for treating enuresis.

 

Desmopressin (DDAVP)

For use in primary nocturnal enuresis in children > 6 y. Increases cellular permeability of collecting ducts, resulting in reabsorption of water by kidneys.

Adult

0.2-0.6 mg PO qhs

Pediatric

Nasal spray: 20 mcg (0.2 mL) intranasally qhs
Tablets: 0.1-0.4 mg PO qhs

Coadministration with demeclocycline and lithium decrease effects; fludrocortisone and chlorpropamide increase effects of desmopressin

Documented hypersensitivity; platelet-type von Willebrand disease; any potential for water intoxication

Pregnancy

B – Usually safe but benefits must outweigh the risks.

Precautions

Renal abnormalities; history of electrolyte imbalance

Dopamine agonists

Preliminary efficacious results for treatment using these agents have been noted in youths with RLS and PLMS. Findings are based on nonrandomized non – placebo-controlled study. Pergolide was withdrawn from the US market March 29, 2007, because of heart valve damage resulting in cardiac valve regurgitation. Do not abruptly stop pergolide. Health care professionals should assess patients’ need for dopamine agonist (DA) therapy and consider alternative treatment. If continued treatment with a DA is needed, another DA should be substituted for pergolide. For more information, see FDA MedWatch Product Safety Alert and Medscape Alerts: Pergolide Withdrawn From US Market.

 

Pergolide (Permax)

Pergolide withdrawn from US market. Not FDA-approved for RLS or PLMS. Potent and long-acting dopamine agonist. Reduces tonic stimulation of dopaminergic D-2 receptors located on intrastriatal cholinergic neurons.

Adult

0.05 mg PO hs for first 2 d initially; gradually increase by 0.05 mg/d q3d over next 12 d, followed by increments of 0.25 mg/d q3d until optimal therapeutic dosage is achieved, generally 0.25-0.5 mg is effective

Pediatric

Not established, limited data exist: 0.4-1 mg/d PO divided qid

Dopamine antagonists (eg, phenothiazines, butyrophenones, thioxanthenes, metoclopramide) may diminish effect; because pergolide mesylate is more than 90% bound to plasma proteins, exercise caution if pergolide is coadministered with other drugs known to affect protein binding

Documented hypersensitivity

Pregnancy

C – Safety for use during pregnancy has not been established.

Precautions

May cause valvular heart disease (yearly echocardiograms recommended for patients on chronic therapy); inhibits secretion of prolactin; causes transient rise in serum concentrations of growth hormone and decrease in serum concentrations of luteinizing hormone; adverse effects include nausea, hypotension, hallucinations, and somnolence; use caution in patients who have been treated for cardiac dysrhythmias; may cause or exacerbate preexisting states of confusion and hallucinations or dyskinesia

Tricyclic antidepressants

These agents are used for treating narcolepsy and enuresis. Please note that scant data exist for use in childhood narcolepsy. Sudden death has been reported in 8 children, possibly related to use of imipramine and desipramine; findings have been inconclusive about the causes of these deaths. No FDA indication exists for use in children with narcolepsy and enuresis.

 

Imipramine (Tofranil)

Inhibits the reuptake of norepinephrine or serotonin (5-hydroxytryptamine, 5-HT) at presynaptic neuron. May be useful in pediatric ADHD as well as enuresis and possibly pediatric-onset narcolepsy.

Adult

Not established

Pediatric

10 mg PO qd initially and, if tolerated but not effective, increase dose to 25 mg PO qd; titrate upward slowly by 25 mg/wk to effectiveness or intolerable adverse effects

Increases toxicity of sympathomimetic agents (eg, isoproterenol, epinephrine) by potentiating effects; inhibits antihypertensive effects of clonidine

Documented hypersensitivity; narrow-angle glaucoma; acute recovery phase following myocardial infarction; concurrent use of MAOIs or fluoxetine or coadministration in the previous 2 wk (avoid)

Pregnancy

D – Unsafe in pregnancy

Precautions

Overdose may be lethal; may impair mental or physical abilities required for performance of potentially hazardous tasks; cardiovascular disease; conduction disturbances; seizure disorders; urinary retention; hyperthyroidism; patients receiving thyroid replacement; frequent ECG monitoring advised

Anticonvulsants

Valproic acid was efficacious in small case series for adults with RLS and PLMS.

 

Valproic acid (Depakene, Depakote)

It is likely that all forms of valproic acid have similar efficacy. The following preparations can be used: 250-mg tab, 125-mg sprinkle caps, or 250 mg/5-mL liquid (US preparations).

Adult

125-600 mg PO qhs when used in investigational studies for RLS and PLMS

Pediatric

Not established

Coadministration with cimetidine, salicylates, felbamate, and erythromycin may increase toxicity; rifampin may significantly reduce valproate levels; in pediatric patients, protein binding and metabolism of valproate decrease when taken concomitantly with salicylates; coadministration with carbamazepine may result in variable changes of carbamazepine concentrations with possible loss of seizure control; valproate may increase diazepam and ethosuximide toxicity (monitor closely); valproate may increase phenobarbital and phenytoin levels while either one may decrease valproate levels; valproate may displace warfarin from protein-binding sites (monitor coagulation test results); may increase zidovudine levels in HIV seropositive patients

Documented hypersensitivity; hepatic disease/dysfunction; history of thrombocytopenia due to valproic acid

Pregnancy

D – Unsafe in pregnancy

Precautions

Thrombocytopenia and abnormal coagulation parameters have occurred; the risk of thrombocytopenia increases significantly at total trough valproate plasma concentrations >110 mcg/mL in females and 135 mcg/mL in males; carefully monitor patients early in treatment; monitor periodically while the patient is stable; adolescent women may experience substantial weight gain and irregular menses and can develop polycystic ovaries; thrombocytopenic effect, particularly at higher doses and during intercurrent illnesses, may cause bruising/bleeding; mitochondrial syndromes may be worsened by valproic acid, thus use with extreme caution; do not use in pregnant adolescents or sexually active adolescents not taking adequate birth control

Hormones

These agents are used for treating circadian rhythm disturbances.

 

Melatonin

Used to treat circadian rhythm disturbances in blind patients without light perception.

Adult

1-10 mg PO qhs

Pediatric

Administer as in adults

Coadministration with other CNS depressants may result in excessive somnolence; fluvoxamine increases melatonin levels; may increase blood pressure and heart rate of patients on nifedipine

Documented hypersensitivity

Pregnancy

C – Safety for use during pregnancy has not been established.

Precautions

May cause dysphoria, headache, nausea, pruritus, and elevated alkaline phosphatase; caution with liver impairment, cardiovascular disease, neurologic disorders, or depression

Sedative/hypnotic agents

Studies for these drugs are limited to adults, and no FDA indications are approved for children younger than 18 years.

 

Eszopiclone (Lunesta)

Nonbenzodiazepine hypnotic pyrrolopyrazine derivative of the cyclopyrrolone class. The precise mechanism of action is unknown, but believed to interact with GABA-receptor at binding domains close to, or allosterically coupled to, benzodiazepine receptors. Indicated for insomnia in adults to decrease sleep latency and improve sleep maintenance. Short half-life of 6 h. Higher doses (ie, 2 mg for elderly and 3 mg for nonelderly adults) are more effective for sleep maintenance, whereas lower doses are (ie, 1 mg for elderly 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 persons: 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

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) increases 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

Pregnancy

C – Safety for use during pregnancy has not been established.

Precautions

May cause dysgeusia, headache, or cold-like 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 operating machinery or driving a car; caution with severe COPD or hepatic disease

 

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 maintaining circadian rhythm and normal sleep-wake cycle. Indicated for insomnia in adults characterized by difficulty with sleep onset.

 

Medical Treatment

The treatment of parasomnias is aimed at lessening the frequency and/or intensity of the events.

Sleepwalking and sleep terror disorder 

In children, sleepwalking and sleep terrors usually do not need to be treated. However, risk factors should be identified and minimized. 

In adults, especially in cases involving sleep-related injury, drugs may be required and can be lifesaving. Benzodiazepines, which are used for insomnia situations where an individual awakens after falling asleep, such as estazolam (ProSom), have been found to be safe and remarkably effective in adults with sleepwalking and sleep terrors.

REM sleep behavior disorder 

Treatment for REM sleep behavior disorder is initiated with clonazepam (Klonopin) at 0.5-1.5 mg taken at bedtime. Clonazepam is remarkably effective in controlling both the behavioral and the dream-disordered components of REM sleep behavior disorder. This drug has been shown to be beneficial in the long term. Drug discontinuation often results in prompt relapse.

Tricyclic antidepressants are occasionally used in the treatment of REM sleep behavior disorder. Imipramine has been used, but the effects are unpredictable. 

Several reports of levodopa/carbidopa, gabapentin, pramipexole, and clonidine have been published, but the benefit of these drugs has not been systemically evaluated.

Restless legs syndrome and periodic limb movement disorder 

Restless legs syndrome and periodic limb movement disorder are treated with 3 classes of medications. Treatment guidelines are as follows:

  • Anti-parkinsonian drugs, such as levodopa/carbidopa, bromocriptine, ropinirole (Requip), pergolide (Permax), and pramipexole (Mirapex), have been used.
  • Benzodiazepines, especially clonazepam have been effective. Other benzodiazepines used have included diazepamtemazepam, and lorazepam.
  • Opiates, such as codeine, oxycodone, methadone, and propoxyphene, are other drugs that have been used.
  • Dopamine agonists, such as levodopa or pergolide, may be effective, but the effectiveness may not last, and some individuals are unable to tolerate side effects. 
  • Other drugs that have shown effectiveness include clonidine or anticonvulsants, such as carbamazepine, valproate, and gabapentin. 
  • Several studies have reported efficacy of different medications belonging to the aforementioned groups, but comparative studies between various classes of drugs or even individual drugs do not exist. Therefore, persons should receive one drug, and, if no response is noted, they should be placed on another drug of the same class or a different class.
  • A combination of drugs may be required in more severe cases. Some persons who do not respond to benzodiazepines alone, levodopa alone, or a combination of both may be treated with opiates.
  • One should receive the smallest possible dose and should be closely observed for the development of dependency. Experience reveals that the incidence of abuse, tolerance, or addiction to opiates or benzodiazepines in persons with severe restless legs syndrome appears to be insignificant. The disabling condition of severe restless legs syndrome must be treated aggressively.
  • Restless legs syndrome and periodic limb movement disorder are chronic conditions that require long-term drug therapy. Some persons may develop symptoms of restless legs during the daytime, and this may be treated with controlled release of levodopa/carbidopa administered in the evening and morning.
  • Avoidance of certain drugs, such as tricyclic antidepressants, fluoxetine, or lithium, may be helpful because these drugs generally worsen the symptoms of restless legs syndrome and periodic limb movement disorder.
  • A decrease in body iron stores, as indicated by serum ferritin (an iron-protein complex) levels less than 50 mcg/L, should be corrected with iron supplementation. Oral iron is preferred but takes a long time to provide improvement, because gastrointestinal absorption is low. However, replenishment is an effective treatment strategy for iron-deficiency anemia and may also relieve symptoms of restless legs syndrome and periodic limb movement disorder (if present).

 

Supported  by

CHILDREN SLEEP CLINIC

Yudhasmara Foundation

Office ; JL Taman Bendungan Asahan 5 Jakarta Indonesia 10210

phone : 62(021) 70081995 – 5703646

email : judarwanto@gmail.com,

https://sleepclinic.wordpress.com/

 

 

 

Clinic and Editor in Chief :

Widodo Judarwanto, pediatrician

email : judarwanto@gmail.com

curriculum vitae

 

 

Copyright © 2009, Children Sleep Clinic  Information Education Network. All rights reserved


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