Modafinil

• Narcolepsy
• Obstructive Sleep Apnea
• Shift Work Disorder
• Excessive Daytime Sleepiness

Modafinil is a wakefulness-promoting agent used to treat excessive sleepiness associated with narcolepsy, obstructive sleep apnea, and shift work disorder. Unlike traditional stimulants, modafinil has a unique mechanism of action and lower abuse potential.

Mechanism of Action

The exact mechanism is not fully understood, but modafinil appears to work through multiple pathways:

• Dopamine reuptake inhibition: Binds to dopamine transporters, increasing extracellular dopamine
• Norepinephrine modulation: Increases norepinephrine in the hypothalamus and prefrontal cortex
• Histamine enhancement: Activates histaminergic neurons in the tuberomammillary nucleus
• Orexin/hypocretin activation: May enhance orexin neuron activity
• GABA modulation: Reduces GABA release in sleep-promoting regions

Unlike amphetamines, modafinil does not significantly affect peripheral catecholamine release.

Available Formulations

Modafinil is available as oral tablets:

• 100 mg tablets
• 200 mg tablets

A longer-acting isomer, armodafinil (Nuvigil), is also available and contains only the R-enantiomer.

Medical Uses

FDA-Approved Indications:

• Narcolepsy: To improve wakefulness in patients with excessive sleepiness
• Obstructive sleep apnea (OSA): Adjunct to standard treatment (CPAP) for residual excessive sleepiness
• Shift work disorder: To improve wakefulness in patients with excessive sleepiness associated with shift work

Modafinil does not treat the underlying obstruction in OSA; CPAP remains first-line therapy.

Dosing Guidelines

Narcolepsy and OSA:

• 200 mg once daily in the morning
• Some patients may benefit from 400 mg daily
• Dose can be split in some cases

Shift Work Disorder:

• 200 mg approximately 1 hour before the start of work shift

Hepatic Impairment:

• Reduce dose by half in severe hepatic impairment

Important Safety Information

Serious Skin Reactions:

• Rare but serious: Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS)
• Discontinue at first sign of rash unless clearly not drug-related

Psychiatric Symptoms:

• May cause anxiety, depression, mania, psychosis, and suicidal ideation
• Use with caution in patients with psychiatric history

Cardiovascular Effects:

• Not recommended for patients with significant cardiovascular disease
• Can increase heart rate and blood pressure

Contraindications:

• Known hypersensitivity to modafinil or armodafinil

Controlled Substance:

• Schedule IV controlled substance (lower abuse potential than amphetamines)
• Psychological dependence can occur

Drug Interactions

CYP3A4 Induction:

• Steroidal contraceptives: Reduced effectiveness; use alternative or additional contraception
• Cyclosporine: May decrease blood levels

CYP2C19 Inhibition:

• Phenytoin, diazepam: Monitor for increased levels
• Omeprazole: May increase levels

Other Interactions:

• Warfarin: Monitor INR more frequently
• MAOIs: Use with caution
• CNS stimulants: May cause additive effects

Special Populations

• Pregnancy: Category C; avoid unless benefit outweighs risk
• Lactation: Unknown if excreted in breast milk; use with caution
• Elderly: Consider lower doses; elimination may be reduced
• Renal Impairment: No specific adjustment needed
• Pediatric: Not approved for children; serious skin reactions reported in clinical trials