Hypocretin Deficiency And Pharmacologic Correlates

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The current treatment of narcolepsy is symptomatically based. In the past, cataplexy was treated using tricyclic medications (such as protriptyline and cloimpramine) or higher dose serotonin-reuptake inhibitors (such as fluoxetine). Adrenergic reuptake inhibition has been shown to be most effective in reducing cataplexy in animal models16 and clinical experience with selective noradrenergic reuptake inhibitors such as reboxetine suggest very positive anticataplectic effects. More recently dual serotonergic-adrenergic reuptake inhibitors such as venlafaxine have been more commonly used as first-line therapy for cataplexy. Experience with newer medications such atomoxetine, a selective adrenergic reuptake inhibitor similar to reboxetine, is more limited but promising effects have been observed in clinical practice. As serotonin reuptake inhibitors also reduce REM sleep, this may suggest a preferential adrenergic control of REM atonia.

Sleepiness is commonly treated using amphetamine-like stimulants (L- or D-amphetamine, methylphenidate or modafinil). These compounds produce wakefulness by presynaptic augmentation of dopaminergic neurotransmission, either via enhancement of dopamine release (amphetamine) or reuptake inhibition (methylphenidate).17,94 However, the mode of action of modafinil remains controversial.

GHB (gamma-hydroxybutyrate) was approved by the FDA in 2002 for treatment of cataplexy (Schedule III controlled substance).95 GHB is administered at night and consolidates nocturnal sleep by increasing slow wave sleep while also decreasing REM sleep. Chronic use also decreases daytime cataplexy and possibly sleepiness, usually within 1-3 months after initiation of therapy. However, this compound has a very short half-life and must be administered twice during the night. Current experience suggests a favorable side effect/efficacy profile, but the margin of safety for the compound is small and approval for GHB was complicated by its popularity as a drug of abuse. Pharmacological studies are being performed to evaluate efficacy on EDS.

Anecdotal information is available on the treatment of hypnagogic hallucinations, sleep paralysis, and disturbed nocturnal sleep. The first two symptoms partially respond to antidepressants, while disturbed nocturnal sleep can be treated using GHB or benzodiazepine hypnotics but the latter of these does not improve daytime sleepiness.

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