Treatment for Narcolepsy
For adults with narcolepsy, initiate treatment with modafinil 200-400 mg daily taken in the morning as first-line therapy for excessive daytime sleepiness, and add sodium oxybate (administered as two divided doses at night) when cataplexy is present or when sleepiness remains inadequately controlled. 1, 2, 3
First-Line Pharmacologic Treatments for Adults
For Excessive Daytime Sleepiness
Modafinil is the strongly recommended first-line agent, with typical dosing of 200-400 mg daily taken upon awakening in the morning. 1, 2, 3
Modafinil demonstrates clinically significant improvements in excessive daytime sleepiness, disease severity, and quality of life with moderate quality evidence. 1
Pitolisant is also strongly recommended as first-line therapy and provides clinically significant improvements in excessive daytime sleepiness, cataplexy, and disease severity through its action as a histamine H3-receptor antagonist/inverse agonist. 3, 4
Sodium oxybate is strongly recommended and uniquely treats both excessive daytime sleepiness and cataplexy effectively, though it carries warnings for CNS depression and respiratory depression. 1, 3, 5
For Cataplexy
Sodium oxybate is the first-line treatment for cataplexy, administered as a liquid in two equally divided doses at night (90% of patients) or occasionally as unequal doses (10% of patients). 2, 3, 5
Antidepressants that inhibit reuptake of serotonin and/or norepinephrine serve as alternative treatments for cataplexy, including tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), and serotonin-norepinephrine reuptake inhibitors (SNRIs). 2, 3, 4
Pediatric Treatment Approach
Modafinil is conditionally recommended for pediatric narcolepsy, starting at 100 mg once upon awakening, but carries significant warnings for Stevens-Johnson syndrome and psychosis. 3, 6
Sodium oxybate is conditionally recommended for pediatric patients, providing clinically significant improvements in cataplexy, disease severity, and excessive daytime sleepiness. 1, 3
Serious skin rashes including erythema multiforme major and Stevens-Johnson Syndrome have been associated with modafinil use in pediatric patients aged 5-17 years. 6
Critical Safety Considerations
Modafinil Warnings
Modafinil is a Schedule IV federally controlled substance with potential for abuse or dependency. 1, 6
May cause fetal harm based on animal data, with a 2018 pregnancy registry showing higher rates of major congenital anomalies in children exposed in utero. 1, 6
Reduces effectiveness of oral contraception, requiring alternative contraceptive methods. 1
Common adverse events include insomnia, nausea, diarrhea, headache, and dry mouth. 1
Sodium Oxybate Warnings
Carries black box warnings for CNS depression and respiratory depression. 3, 5
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
Most patients switching from Xyrem to XYWAV (69%) required no dosage change, with 27% requiring increases and only 3% requiring decreases. 5
Monitoring and Follow-Up Protocol
Use the Epworth Sleepiness Scale (ESS) at each visit to quantify sleepiness and monitor treatment response objectively. 2, 3
Increase follow-up frequency when initiating medications or adjusting doses, with specific monitoring for adverse effects of stimulants at each encounter. 2, 3
Avoid inadequate dosing or premature discontinuation due to initial side effects, as narcolepsy requires lifelong management. 3
Special Population Considerations
Elderly Patients
Start medications at lower doses and titrate more gradually in elderly patients due to reduced elimination of modafinil and its metabolites with aging. 2, 6
Elderly narcoleptic patients are generally less sleepy and less likely to exhibit REM sleep dyscontrol despite age-related decrements in sleep quality. 7
Monitor more carefully for obstructive sleep apnoea and periodic leg movements, which are more common in older narcolepsy patients and can worsen previously well-controlled symptoms. 7
Hepatic Impairment
- Reduce modafinil dose to one-half the standard dose in patients with severe hepatic impairment. 6
Pregnancy and Nursing
Modafinil should only be used during pregnancy if potential benefit justifies potential risk to the fetus, given demonstrated developmental toxicity in animal studies at clinically relevant exposures. 6
Unknown whether modafinil or its metabolites are excreted in human milk; exercise caution when administering to nursing women. 6
Combination Therapy Approach
Approximately 59% of patients require continuation of CNS stimulants alongside sodium oxybate for optimal symptom control. 5
No pharmacokinetic interactions exist between sodium oxybate and modafinil, protriptyline, or zolpidem, though pharmacodynamic interactions cannot be ruled out. 5
In many patients, combination treatment with medications acting via different neural pathways is necessary for optimal symptom management. 4
Diagnostic Requirements Before Treatment
Overnight polysomnography (PSG) followed by multiple sleep latency test (MSLT) is required for diagnosis, with MSLT criteria including mean sleep latency ≤8 minutes and presence of REM sleep on ≥2 naps. 2
Assess for key symptoms including excessive daytime sleepiness, sleep paralysis, and hypnagogic/hypnopompic hallucinations. 2
Establish onset, frequency, duration of sleepiness, and any episodes of remission. 2
Common Pitfalls to Avoid
Do not discontinue treatment prematurely due to initial side effects, as narcolepsy is a lifelong disorder requiring ongoing management. 3
Do not overlook comorbid sleep disorders (sleep apnoea, periodic leg movements) that can worsen narcolepsy symptoms, particularly in older patients. 7
Do not forget to counsel patients about alternative contraception when prescribing modafinil to women of reproductive age. 1
Refer to a sleep specialist when narcolepsy is suspected or the cause of sleepiness remains unknown. 2