Modafinil
Modafinil
Generic Name
Modafinil
Brand Names
*Provigil*, *Modalert*, *Modvigil*) is a wakefulness‑promoting agent used primarily for narcolepsy, shift‑work sleep disorder, and obstructive sleep apnea.
Mechanism
- Dopamine reuptake inhibition: Modafinil blocks the dopamine transporter (DAT), increasing extracellular dopamine in the limbic system and cortex.
- Stimulation of orexinergic neurons: Modafinil enhances wake‑promoting orexin (hypocretin) signaling, thereby sustaining alertness.
- Modulation of histamine, norepinephrine, and glutamate: Secondary effects on histaminergic, noradrenergic, and glutamatergic pathways further contribute to its wake‑promoting action.
- Low abuse potential: Unlike methamphetamine, modafinil has a moderate affinity for DAT and lacks significant reinforcing properties.
Pharmacokinetics
- Absorption: Oral bioavailability ~75 %; peak plasma concentrations (Tmax) at 2–4 h post‑dose.
- Distribution: Protein binding ~58–77 %; large volume of distribution (Vd ≈ 44 L).
- Metabolism: Primarily hepatic via cytochrome P450 3A4 (CYP3A4) to sulfated metabolites; minor CYP2C19 involvement.
- Elimination: Renal excretion of metabolites; half‑life ~12–15 h (continuous therapy ≈ 15 h).
- Drug interactions: Induces CYP3A4; may lower levels of oral contraceptives, warfarin, and other CYP3A4 substrates.
- Special populations: No dose adjustment in mild–moderate hepatic or renal impairment; higher exposure in severe renal disease but clinically not significant.
Indications
- Narcolepsy (with or without cataplexy).
- Shift‑work sleep disorder (abnormal daytime sleepiness).
- Obstructive sleep apnea‑related excessive daytime sleepiness (when CPAP use is inadequate).
- Off‑label uses include: ADHD, psychiatric fatigue, and cognitive enhancement in certain neurologic conditions, but evidence remains limited.
Contraindications
- Contraindicated: Patients with a history of severe hypersensitivity to modafinil or sulfonamide derivatives; severe cardiac disease (e.g., uncontrolled arrhythmias).
- Warnings:
- Cardiovascular: May increase heart rate and blood pressure; caution in those with hypertension or ischemic heart disease.
- Psychiatric: Potential for anxiety, agitation, and, rarely, psychosis or mania; monitor patients with a history of mood disorders.
- Pregnancy/Breastfeeding: Limited data; generally not recommended unless benefits outweigh risks.
- Precautions: Use with caution in elderly, liver disease, and patients on enzyme inducers (e.g., phenytoin) or inhibitors (e.g., ketoconazole).
Dosing
| Condition | Typical dose | Titration | Administration notes |
| Narcolepsy | 200 mg PO daily (preferred) | Can be increased to 400 mg daily if inadequate response | Take in the morning; avoid late dosing to prevent insomnia |
| Shift‑work | 200 mg PO 1–2 h before scheduled wakeful period | Same max 400 mg | Avoid during night shifts to prevent sleep dysregulation |
| Obstructive sleep apnea | 200 mg PO | May titrate to 400 mg if necessary | Take in the morning; monitor BP/HR |
| Off‑label | 100–200 mg PO | Tailor to response | Monitor for adverse psychiatric or cardiovascular events |
> Key tip: Administer the lowest effective dose; avoid >400 mg/day to limit cardiovascular side effects.
Adverse Effects
Common (≤ 5 % incidence)
• Headache
• Nausea
• Diarrhea
• Anxiety or jitteriness
• Dizziness
• Insomnia (if taken late)
Serious (≤ 1 % incidence)
• Severe hypersensitivity reactions (rash, angioedema, Stevens–Johnson syndrome)
• Psychosis, mania, or severe mood changes
• Significant hypertension or tachycardia
• Severe skin reactions (e.g., toxic epidermal necrolysis)
Uncommon
• Palpitations
• Visual disturbances
• Liver enzyme elevations (rare)
Monitoring
- BP and HR: Baseline and periodically, especially with chronic use.
- Mental status: Check for anxiety, mood swings, or psychosis, particularly in susceptible individuals.
- Liver function: ALT/AST baseline; monitor if hepatic disease is present.
- Drug levels: Not routinely required but may be considered when interacting with CYP3A4 inducers or inhibitors.
- Pregnancy tests: For women of childbearing potential, ensure effective contraception.
Clinical Pearls
- Wakefulness “on a schedule”: Modafinil’s modest half‑life allows daily dosing without accumulation; patients typically experience increased alertness 2–6 h after ingestion, lasting through the day.
- Drug‑interaction “check‑point”: Since modafinil induces CYP3A4, concomitant use of benzodiazepines may reduce their efficacy; clinicians should adjust doses accordingly.
- Cardiovascular “watchful eye”: A randomized trial showed a mean systolic BP rise of ~5 mmHg; patients with pre‑existing hypertension should be monitored with ambulatory BP monitoring if possible.
- Cognitive enhancer caveats: Although modest improvements in executive function have been reported, evidence is inconsistent; high‑dose regimens may increase adverse psychiatric events.
- Pregnancy “risk‑benefit”: Modafinil crosses the placenta; if prescribed during pregnancy, the obstetrician‑gynecologist should weigh sleep‑disorder risks against fetal exposure.
- Formulary navigation: Some insurance plans require prior authorization for narcolepsy and may limit outpatient claims to 30‑day refills; electronic health record alerts can prompt early completion of forms.
- Off‑label caution: Use for ADHD or chronic fatigue syndrome should be reserved for research settings, as FDA labeling is not supportive and safety data are limited.
--
• *For further in‑depth pharmacology, consult primary literature (e.g., JAMA Neurology, NEJM) or the latest prescribing information from the FDA.*