narcolepsy
NARCOLEPSY

Narcolepsy is a chronic neurologic sleep disorder wherein the patient have excessive daytime sleepiness and rapid eye movement sleep is dysregulated.

It affects 1 in 1000 individuals, with prevalence of about 0.04% of general population.
The exact cause remains unclear.
Studies suggest a combination of genetic predisposition, abnormal neurotransmitter functioning and abnormal immune modulation.
Symptoms include excessive daytime sleepiness, cataplexy, sleep paralysis, sleep-related hallucinations, automatic behavior, fragmented nocturnal sleep and insomnia.

Principles of Therapy

There is no cure for narcolepsy

  • Its disabling symptoms can be controlled with appropriate & targeted therapy
  • The goal is to produce the fullest possible return of normal function at home, school, work, & socially with minimal side effects

Considerations for Choice of Agent

  • Benefit-to-risk ratio (eg efficacy & adverse effects)
  • Convenience of administration
  • Cost

Effective Agents For Daytime Sleepiness

  • If patient has failed adequate doses of stimulant medications, other sleep disorders may be contributing to sleepiness
  • Patient may benefit from combination of long- & short-acting stimulants

Pharmacotherapy

Amphetamine & Amphetamine-like Central Nervous System Stimulants

  • Indirect sympathomimetics that increase monoamine levels within the synaptic cleft by enhancing the release of norepinephrine, dopamine, & serotonin, while blocking their reuptake
  • Effective in managing daytime sleepiness
    • Studies show objective improvement in somnolence in 65-85% of patients
    • Low risk of addiction but the risk is greater in patients who are taking high dosages of stimulants, on long-term therapy, & with an underlying psychiatric disorder
  • Amphetamines are most likely to result in the development of tolerance when used in high doses
  • Methylphenidate is usually considered as 1st-line therapy in patients with severe narcolepsy & in those who fail in Modafinil
    • Improves sleep tendency
    • Similar efficacy with Dextroamphetamine but has a better therapeutic index & lower risk of adverse effects
  • Modafinil
    • Indirectly increases wakefulness through inhibition of GABA release via serotonergic mechanism or indirectly on dopaminergic stimulation
      • Stimulates norepinephrine inhibition of the ventrolateral preoptic nucleus which is responsible for promoting sleep
    • 1st-line medication in the treatment of excessive daytime sleepiness & irresistible episodes of sleep
    • May be the 1st-line agent in newly diagnosed patients with mild-moderate narcolepsy
    • Effects:
      • Improves wakefulness in patients with excessive sleepiness
      • Does not generally normalize sleep, thus, may be less effective than other stimulants
      • Risk/benefit ratio has been established in a number of studies
      • Has low abuse potential & not associated with rebound hypersomnolence
  • Armodafinil is the longer half-life enantiomer of Modafinil that has been assessed for treatment of excessive sleepiness in patients with narcolepsy
    • A study have shown that it improves sleepiness as measured by the maintenance of wakefulness test mean sleep latency, & in the Clinical Global Impression of Change

Selegiline

  • Monoamine oxidase B inhibitor
  • May be an effective treatment for daytime sleepiness & cataplexy
    • Improves narcoleptic symptoms, sleep cycles & polysomnographic measurements
    • Decreases occurrence of cataplexy
    • High doses needed; diet-induced hypertension is a risk at effective doses
    • Potential drug & diet-induced interactions limit its use
      • Avoid tyramine or maintain a diet low in tyramine

Sodium oxybate

  • Action: Inhibits the release of GABA, glutamate, & dopamine
  • Effective for the treatment of excessive daytime sleepiness & cataplexy & improvement in the quality of sleep by preventing nocturnal fragmentation
    • Reduces nocturnal awakenings, increases stage non-REM 3 (delta or slow wave) sleep, decreases light sleep & consolidates REM sleep periods
    • Needs high doses of 6-9 g to reach its therapeutic effect
    • Has moderate risk for abuse
    • Better tolerated because it lacks anticholinergic side effects
  • Treatment of choice for narcolepsy with cataplexy
    • Improvement in cataplexy is much more rapid than effect on daytime sleepiness

Effective Agents For Other Narcoleptic Symptoms

  • Stimulant therapy alone, by decreasing drowsiness, often improves cataplexy
  • Sleep paralysis & hypnagogic hallucinations seldom need treatment

Benzodiazepines & Non-benzodiazepines

  • Triazolam showed improved sleep efficiency & overall sleep quality
  • Eszopiclone & Clonazepam have been used with varying success in the treatment of fragmented nocturnal sleep

Norepinephrine Reuptake Inhibitor

  • Effective for the treatment of cataplexy & excessive daytime sleepiness
  • Recommended drug in patients with resistant cataplexy after failure of Venlafaxine, Fluoxetine, & older serotonin reuptake inhibitors
  • Less effective than Modafinil & Sodium oxybate in teenagers & adults
  • Atomoxetine is a highly specific noradrenergic reuptake inhibitor
  • Viloxazine significantly reduces cataplexy, helps treat hallucinations & has few adverse effects
  • Robexitine exerts anticataplectic effects & improve excessive daytime sleepiness

Selective Norepinephrine/Serotonin Reuptake Inhibitors

  • Effective treatment for cataplexy, sleep paralysis, & hypnagogic/hypnopompic hallucinations
  • Recommended drugs due to their greater efficacy & improved side-effect profile
  • Venlafaxine is the most commonly used drug in this class
    • Potent inhibitor of norepinephrine & serotonin
    • Improves excessive daytime sleepiness & cataplexy
    • Helpful in the treatment of hallucinations
    • Easily obtainable & can be taken during wakefulness
  • Action: Block the presynaptic reuptake of catecholamines, thereby increasing their activity; however, they are more selective for serotonin
  • Effective in decreasing cataplexy & inhibiting nocturnal rapid eye movement sleep
  • Selective serotonin reuptake inhibitors are less effective compared to tricyclic antidepressants
    • However, selective serotonin reuptake inhibitors are safer & better tolerated than other antidepressants
  • Not recommended as 1st-line agents for cataplexy because of the availability & better efficacy of newer medications
  • Fluoxetine is the most commonly used selective serotonin reuptake inhibitors for the treatment of cataplexy
  • Femoxitine, Fluvoxamine, Paroxetine & Zimeldine have also shown efficacy

Tricyclic Antidepressants (TCAs)

  • Action: Block the presynaptic reuptake of catecholamines, thus enhancing their postsynaptic activity
  • Have anticataplectic activity
    • Increase muscle tone & suppress rapid eye movement
    • Effective in treating sleep paralysis & hallucinations
  • Clomipramine is the most efficacious & widely used for cataplexy
    • Has the most REM-suppressing activity because of its greater ability to block serotonin reuptake
  • Imipramine has shown efficacy in decreasing hallucinations
  • Rebound cataplexy phenomenon may occur on abrupt discontinuation of tricyclic antidepressants
    • May lead to status cataplecticus when severe
  • Some studies recommend tricyclic antidepressants as last resort due to adverse effects
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