What causes excessive somnolence in a patient with narcolepsy (National Sleep Foundation defined disorder)?

From the Guidelines

Excessive lethargy in a patient with narcolepsy should be managed with modafinil as the first-line treatment, given its strong recommendation and moderate quality of evidence for improving excessive daytime sleepiness, disease severity, and quality of life 1.

Treatment Approach

When managing excessive lethargy in patients with narcolepsy, it's crucial to consider the underlying condition and potential contributing factors. The treatment approach should include:

• Optimizing wake-promoting agents such as modafinil (200-400 mg daily) or armodafinil (150-250 mg daily)
• Considering stimulants like methylphenidate (10-60 mg daily in divided doses) or amphetamine salts (5-60 mg daily in divided doses) for some patients
• Evaluating the use of sodium oxybate (4.5-9 g nightly in two divided doses) for patients with narcolepsy and cataplexy, as it may improve both nighttime sleep and daytime alertness 1

Assessment and Evaluation

It's essential to assess for:

• Medication side effects, tolerance, or inadequate dosing
• Comorbid conditions that could worsen lethargy, including depression, sleep apnea, insufficient sleep syndrome, medication side effects, or other medical conditions like hypothyroidism or anemia
• Encourage good sleep hygiene with regular sleep-wake schedules, planned short daytime naps (15-20 minutes), and avoidance of alcohol and sedatives

Quality of Evidence

The overall quality of evidence for modafinil is moderate, downgraded due to imprecision 1. However, the benefits of modafinil use in patients outweigh the risks and adverse events, and the balance between the desirable and undesirable effects is strongly in favor of modafinil.

Key Considerations

• Modafinil is an FDA Schedule IV federally controlled substance due to its potential for abuse or dependency
• Sodium oxybate has an FDA black box warning stating that it is a central nervous system depressant and may cause respiratory depression
• The balance of risks and harms is likely different for pregnant and breastfeeding women, and the medication should be used with caution in these populations 1

From the FDA Drug Label

The effectiveness of modafinil tablets in improving wakefulness in adult patients with excessive sleepiness associated with narcolepsy was established in two US 9-week, multi-center, placebo-controlled, parallel-group, double-blind studies of outpatients who met the criteria for narcolepsy The criteria for narcolepsy include either: 1) recurrent daytime naps or lapses into sleep that occur almost daily for at least three months, plus sudden bilateral loss of postural muscle tone in association with intense emotion (cataplexy); or 2) a complaint of excessive sleepiness or sudden muscle weakness with associated features: sleep paralysis, hypnagogic hallucinations, automatic behaviors, disrupted major sleep episode; Both studies demonstrated improvement in objective and subjective measures of excessive daytime sleepiness for both the 200 mg and 400 mg doses compared to placebo

Excessive lethargy in a patient with narcolepsy can be managed with modafinil tablets, as it has been shown to improve wakefulness in adult patients with excessive sleepiness associated with narcolepsy 2.

• The medication has been proven to enhance the ability to remain awake, as measured by the Maintenance of Wakefulness Test (MWT).
• It also improves overall clinical condition, as rated by the Clinical Global Impression of Change (CGI-C) scale.
• Modafinil tablets at doses of 200 mg and 400 mg per day have been shown to be effective in reducing excessive daytime sleepiness in patients with narcolepsy.

From the Research

Excessive Lethargy in Narcolepsy Patients

Excessive lethargy, also known as excessive daytime sleepiness (EDS), is a common symptom in patients with narcolepsy. The treatment of EDS in narcolepsy patients includes the use of wake-promoting compounds such as:

• Modafinil and its R-enantiomer, armodafinil 3, 4, 5
• Amphetamine-like CNS stimulants (such as dextroamphetamine and methylphenidate) 3, 4, 6
• Sodium oxybate, which improves both EDS and cataplexy 3, 4, 6, 7
• Pitolisant, a histamine 3 (H3)-receptor antagonist/inverse agonist, approved by the European Medicines Agency for the treatment of narcolepsy with or without cataplexy in adults 4, 6, 7
• Solriamfetol, a dopamine and norepinephrine reuptake inhibitor, approved by the Food and Drug Administration for the treatment of EDS in adult narcolepsy patients 4, 6, 7

Treatment Options

The choice of treatment for excessive lethargy in narcolepsy patients depends on the severity of symptoms and the presence of other symptoms such as cataplexy. Treatment options may include:

• Monotherapy with a wake-promoting compound such as modafinil or sodium oxybate
• Combination therapy with multiple wake-promoting compounds or with antidepressants to manage cataplexy 6
• Novel treatments such as pitolisant and solriamfetol, which have been recently approved for the treatment of EDS in narcolepsy patients 4, 6, 7

Mechanisms of Action

The mechanisms of action of these treatments vary, but they generally work by:

• Increasing the release of neurotransmitters such as dopamine and norepinephrine, which promote wakefulness 6, 7
• Inhibiting the reuptake of neurotransmitters such as serotonin and norepinephrine, which can help manage cataplexy 6, 7
• Modulating the activity of receptors such as histamine H3 receptors and GABAB receptors, which can help regulate sleep and wakefulness 6, 7