What is the treatment for narcolepsy and cataplexy?

Treatment of Narcolepsy and Cataplexy

Sodium oxybate is the first-line treatment for cataplexy and should be strongly considered for managing both cataplexy and excessive daytime sleepiness in adults with narcolepsy, based on moderate-quality evidence from multiple randomized controlled trials. 1, 2, 3

First-Line Pharmacological Treatment for Cataplexy

Sodium oxybate is the primary treatment for cataplexy in adults with narcolepsy, demonstrating clinically significant improvements in cataplexy attacks, excessive daytime sleepiness, and overall disease severity. 1, 3, 4

• Administer as a liquid in two equally divided doses at night: the first dose at bedtime and the second dose 2.5-4 hours later. 1, 3, 5
• In clinical trials, 90% of patients received equal divided doses, while 10% received unequal doses. 5
• Patients previously on Xyrem can be switched gram-for-gram to XYWAV (lower-sodium formulation), with 69% requiring no dose adjustment. 5
• Patients not previously on sodium oxybate should start at 4.5 g/night and titrate by 1-1.5 g/night/week to achieve a tolerable and effective dose. 5

Critical Safety Warnings for Sodium Oxybate:

• FDA black box warning: This is a central nervous system depressant that may cause respiratory depression; use with extreme caution in patients with any respiratory conditions. 1, 3
• This is an FDA Schedule III controlled substance (sodium salt of gamma-hydroxybutyrate/GHB) and is only available through the Risk Evaluation Mitigation Strategy (REMS) program using certified pharmacies. 1
• Common adverse events include nausea, dizziness, nocturnal enuresis, headache, chest discomfort, sleep disturbances, and confusion. 1, 3
• Co-administration with divalproex sodium increases GHB exposure by approximately 25% and causes greater impairment on attention and working memory tests than either drug alone. 5

Alternative First-Line Option for Cataplexy

Pitolisant (histamine-3-receptor inverse agonist) is effective for cataplexy management and offers a significant advantage: it is not a controlled substance. 6, 1, 2, 3

• Currently approved for treatment of narcolepsy and cataplexy in adults. 6
• In adolescents with Prader-Willi syndrome (who have a narcolepsy-like phenotype), pitolisant decreased daytime sleepiness and improved processing speed and mental clarity. 6
• This is the first and only treatment approved for adult patients with narcolepsy with cataplexy that is not scheduled as a controlled substance by the US Drug Enforcement Administration. 6

Second-Line Treatment for Cataplexy

Antidepressants are effective for cataplexy control, particularly those affecting norepinephrine and serotonin systems. 3, 7, 8, 4

• Tricyclic antidepressants (such as imipramine) have traditionally been used as anticataplectics. 7, 9, 10
• Newer selective serotonergic/adrenergic reuptake inhibitors are increasingly used despite limited randomized placebo-controlled trials, as they are better tolerated than tricyclics. 7, 8, 4
• The pathophysiology involves loss of hypocretin-producing neurons, suggesting adrenergic systems are downstream mediators of cataplexy. 2, 3

Treatment of Excessive Daytime Sleepiness (Does NOT Treat Cataplexy)

Modafinil is the first-line treatment for excessive daytime sleepiness in narcolepsy when used in combination with behavioral measures. 4

• In patients with Prader-Willi syndrome and narcolepsy-like phenotype, modafinil 100-200 mg in the morning improved Epworth Sleepiness Scale scores from 14 (mild EDS) to 4 (no EDS), and also improved behavioral and attention concerns. 6
• Modafinil is a US Drug Enforcement Administration Schedule IV controlled substance; abuse may lead to limited physical and psychological dependence. 6
• Not approved for use in individuals less than 17 years of age, and should be monitored with caution due to reports of serious side effects including Stevens-Johnson syndrome. 6
• Important: Modafinil, armodafinil, solriamfetol, dextroamphetamine, and methylphenidate are recommended for excessive daytime sleepiness but do NOT directly treat cataplexy. 1

Non-Pharmacological Management

• Maintain good sleep hygiene and regular sleep-wake schedules to help control cataplexy. 1, 3
• Avoid shift work and on-call schedules. 1, 3
• Frequent scheduled napping can be beneficial. 10
• Patient and family counseling is essential given the chronic, life-long nature of this illness. 10

Monitoring and Follow-Up

• Regularly assess cataplexy frequency and severity to evaluate treatment efficacy. 1, 3
• Monitor for medication side effects, particularly respiratory depression, enuresis, nausea, and headache with sodium oxybate. 1, 3
• Watch for cataplexy exacerbation if any medication affecting adrenergic systems is initiated, as adrenergic systems are downstream mediators of cataplexy pathology. 1, 2, 3
• For elderly patients on sodium oxybate, initiate dosing at lower levels and titrate more gradually. 3

Referral Considerations

• Primary care physicians should refer patients to a sleep specialist when narcolepsy with cataplexy is suspected for proper diagnosis and treatment initiation. 1, 3

Common Pitfalls to Avoid

• Failure to recognize cataplexy as distinct from seizures: In children, cataplexy may resemble clonic, atonic, or myoclonic seizures, but loss of consciousness is absent with cataplexy. 6, 3
• Pediatric presentation differences: Children with cataplexy may have prominent facial involvement including active tongue and perioral muscle movements, and may experience cataplexy without clear emotional triggers (unlike adults). 6
• Inadequate treatment of both components: Treating only excessive daytime sleepiness without addressing cataplexy (or vice versa) worsens overall symptom burden. 3
• Misdiagnosis in children: Young children with narcolepsy may be misdiagnosed as hyperactive or psychotic. 9
• Overlooking obesity: More than half of children who first present with narcolepsy are obese, and approximately one-third have symptoms of attention-deficit/hyperactivity disorder. 6