What are the uses and effects of modafinil (provigil)?

Modafinil: Clinical Uses and Effects

FDA-Approved Indications

Modafinil is FDA-approved for treating excessive daytime sleepiness in three specific conditions: narcolepsy, obstructive sleep apnea/hypopnea syndrome (as adjunctive therapy with CPAP), and shift work sleep disorder. 1

• The drug promotes wakefulness through mechanisms that are not fully understood but likely involve enhancing activity in the hypothalamic wakefulness center, activating tuberomammillary nucleus neurons that release histamine, and activating neurons that release orexin/hypocretin 2
• Unlike traditional stimulants, modafinil binds to the dopamine transporter and inhibits dopamine reuptake, though it is not a direct dopamine receptor agonist 1
• The medication has wake-promoting actions similar to sympathomimetic agents like amphetamine and methylphenidate, but with a distinct pharmacologic profile 1

Dosing and Administration

The maximum total daily dose is 400 mg per day, typically administered as a single morning dose or divided into morning and midday doses. 2, 3

• Higher doses (200-400 mg/day) are more effective for treating sleepiness 2, 3
• Lower doses (50-200 mg/day) may be more appropriate for concentration problems and fatigue 2, 3
• The last dose should be taken no later than 2:00 PM to avoid insomnia 3
• For elderly patients, start with 100 mg once upon awakening, with potential weekly increases as necessary 2, 3
• Modafinil has a half-life of approximately 15 hours, with steady state reached after 2-4 days of dosing 2, 3

Off-Label Clinical Applications

The National Comprehensive Cancer Network recommends modafinil as an option for cancer-related fatigue with refractory daytime sedation when methylphenidate or dextroamphetamine are insufficient 3

• However, neither modafinil nor armodafinil demonstrated significant benefit over placebo for cancer-related fatigue in post-treatment survivors in a phase III trial (N=328) in glioma patients 4
• Modafinil is also used off-label for multiple sclerosis-related fatigue 2
• Evidence exists for potential use in attention-deficit disorder, postanesthetic sedation, and as an adjunct to antidepressants for depression, though these remain off-label 5

Common Adverse Effects

The most common adverse effects (≥5%) include headache, nausea, nervousness, rhinitis, diarrhea, back pain, anxiety, insomnia, dizziness, and dyspepsia. 2, 4

• Modafinil may cause increases in blood pressure and heart rate 6
• In overdose situations, symptoms include insomnia, CNS symptoms (restlessness, disorientation, confusion, agitation, anxiety, excitation, hallucination), digestive changes (nausea, diarrhea), and cardiovascular changes (tachycardia, bradycardia, hypertension, chest pain) 1

Serious Safety Warnings

Stop modafinil immediately and seek emergency care if serious rash, serious allergic reaction, or multi-organ hypersensitivity reactions occur. 1

• The American Academy of Sleep Medicine reports that modafinil can cause Stevens-Johnson syndrome, a rare but life-threatening condition, particularly in pediatric patients 3
• Serious dermatologic effects in children include maculopapular and morbilliform rash, erythema multiforme, and Stevens-Johnson Syndrome 6
• Watch for skin rash, hives, sores in mouth, skin blistering and peeling, swelling of face/eyes/lips/tongue/throat, trouble swallowing or breathing, fever, shortness of breath, leg swelling, yellowing of skin or whites of eyes, or dark urine 1
• Both modafinil and armodafinil carry identical warnings for serious rash (including DRESS syndrome), multi-organ hypersensitivity reactions, angioedema, and psychiatric symptoms 4

Abuse Potential and Controlled Substance Status

Modafinil is classified as a federally controlled substance (C-IV) due to potential for abuse, though this risk is substantially lower than with traditional stimulants. 2, 1

• The drug has reinforcing properties, as evidenced by self-administration in monkeys previously trained to self-administer cocaine 1
• Modafinil produces psychoactive and euphoric effects, alterations in mood, perception, thinking, and feelings typical of other CNS stimulants 1
• The American Academy of Sleep Medicine notes that modafinil has lower abuse potential than traditional stimulants like amphetamines, with limited physical and psychological dependence risk 3
• Intoxication and dependence associated with modafinil are uncommon 6

Pediatric Considerations

Modafinil is not FDA-approved for patients under 17 years of age, and use in pediatric populations should be approached with extreme caution due to Stevens-Johnson syndrome risk. 3, 1

• The drug was efficacious in fairly large studies of ADHD in children and adolescents but has not been approved by the FDA, in part because of serious dermatological toxicity 7
• Decreased appetite, weight loss, and serious dermatological effects have been reported with greater frequency in children and adolescents, likely due to higher doses (based on bodyweight) used 7

Pharmacokinetic Considerations

• Modafinil is readily absorbed after oral administration, with peak plasma concentrations occurring at 2-4 hours 1
• Food has no effect on overall bioavailability but may delay time to peak concentration by approximately one hour 1
• The drug is moderately bound to plasma protein (approximately 60%), mainly to albumin 1
• Metabolism occurs primarily in the liver through hydrolytic deamidation, S-oxidation, aromatic ring hydroxylation, and glucuronide conjugation 1
• Less than 10% of an administered dose is excreted as the parent compound 1
• Modafinil induces and inhibits several cytochrome P450 isoenzymes and has potential for drug interactions across all classes 7
• Dose reduction is needed in elderly patients and those with hepatic disease 7
• Caution is needed in patients with severe renal insufficiency due to substantial increases in levels of modafinil acid 7

Important Clinical Caveats

• Modafinil does not cure sleep disorders; it only helps manage excessive sleepiness 1
• The drug does not replace the need for adequate sleep or other prescribed treatments for underlying conditions 1
• In obstructive sleep apnea, continued use of CPAP is essential even when taking modafinil 3, 1
• Unlike traditional stimulants, modafinil typically does not disturb nighttime sleep patterns when dosed appropriately 2
• Modafinil does not benefit cataplexy in narcolepsy patients 7