Narcolepsy Treatment

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

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