Narcolepsy Treatment
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
- Indirectly increases wakefulness through inhibition of GABA release via serotonergic mechanism or indirectly on dopaminergic stimulation
- 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