What is Modafinil
Modafinil is a wakefulness-promoting medication that is pharmacologically distinct from traditional stimulants like amphetamine and methylphenidate, FDA-approved for treating excessive daytime sleepiness in narcolepsy, obstructive sleep apnea (as adjunct to CPAP), and shift work sleep disorder. 1, 2
Drug Classification and Mechanism
- Modafinil is classified as a federally controlled substance (C-IV) due to potential for abuse, though this risk is significantly lower than with traditional stimulants 3
- The precise mechanism is not fully understood but likely involves enhancing activity in the hypothalamic wakefulness center, activating tuberomammillary nucleus neurons that release histamine, and activating hypothalamic neurons that release orexin/hypocretin 3
- Unlike classical psychostimulants, modafinil does not typically disturb nighttime sleep patterns and is not associated with tolerance or sensitization 4, 3
Pharmacokinetics
- Modafinil has a half-life of approximately 15 hours, with steady state reached after 2-4 days of dosing 3
- The chemical name is 2-[(diphenylmethyl)sulfinyl]acetamide, with molecular formula C15H15NO2S and molecular weight 273.4 1
- It is a white to off-white crystalline powder that is practically insoluble in water 1
FDA-Approved Indications
- Narcolepsy: Modafinil significantly reduces excessive daytime sleepiness and improves level of illness, with efficacy maintained for up to 40 weeks without development of tolerance 5
- Obstructive sleep apnea/hypopnoea syndrome (OSA/HS): Effective as adjunctive therapy in patients with residual excessive sleepiness despite optimal nasal continuous positive airway pressure (nCPAP) therapy 2, 6
- Shift work sleep disorder (SWSD): Improves night-time wakefulness without disrupting daytime sleep 2
Dosing Guidelines
- The maximum total daily dose is 400 mg per day, typically administered as a single dose in the morning or divided into two doses 3
- For sleepiness: 200-400 mg/day is more effective 3
- For concentration problems and fatigue: 50-200 mg/day may be more appropriate 3
- For elderly patients: Start with 100 mg once upon awakening, with potential increases at weekly intervals as necessary 3
Common Off-Label Uses
- Cancer-related fatigue: The National Comprehensive Cancer Network recommends modafinil for adjunctive treatment, with dose escalation from 100 mg daily (weeks 1-2) to 200 mg daily (weeks 3-4) demonstrating 75% improvement rates at 4 weeks 3
- Adjunct to antidepressants: Used for persistent fatigue and sleepiness despite antidepressant treatment in major depressive disorder, with the strongest evidence among off-label psychiatric uses 3
- Note: Modafinil is NOT FDA-approved for ADHD, despite showing efficacy in trials, partly due to serious dermatological toxicity concerns 7, 8
Safety Profile and Side Effects
- Most common adverse effects (≥5%) include headache (34% vs 23% placebo), nausea (11% vs 3% placebo), nervousness, rhinitis, diarrhea, back pain, anxiety, insomnia, dizziness, and dyspepsia 3, 6
- Modafinil is generally well tolerated across different patient populations with excessive sleepiness 6
- Clinically significant increases in blood pressure or heart rate are infrequent (<1% of patients) 6
- Does not affect sleep architecture according to polysomnography 6
- Decreased appetite, weight loss, and serious dermatological reactions have been reported with greater frequency in children and adolescents, likely due to higher weight-based doses 8
Drug Interactions
- Modafinil induces and inhibits several cytochrome P450 isoenzymes and has the potential for interacting with drugs from all classes 8
- Dose reduction is needed in elderly patients and those with hepatic disease 8
- Caution is required in patients with severe renal insufficiency due to substantial increases in levels of modafinil acid 8
Related Medications
- Armodafinil (Nuvigil): The longer-lasting R-isomer of modafinil, also FDA-approved for excessive sleepiness associated with narcolepsy, obstructive sleep apnea, and shift work sleep disorder 3