Modafinil is a synthetic central nervous system stimulant with wakefulness-promoting activity. Modafinil appears to inhibit dopamine reuptake, resulting in an increase in extracellular dopamine. This agent exhibits pronounced wakefulness-promoting activity (without sympathomimetic activity) and may improve cognitive function in certain clinical settings. (NCI04)
Mechanism of Action of Modafinil
Indications of Modafinil
- To improve wakefulness in patients with excessive daytime sleepiness (EDS) associated with narcolepsy.
- Treatment of sleepiness associated with narcolepsy
Modafinil and its R-enantiomer armodafinil[Rx] are central nervous system stimulants used to improve wakefulness in patients with excessive sleepiness. Both modafinil and armodafinil[Rx] are associated with a low rate of serum aminotransferase elevations during therapy, but they have not been implicated in cases of clinically apparent acute liver injury.
Therapeutic Uses of Modafinil
- Modafinil is indicated to improve wakefulness in patients with excessive daytime sleepiness associated with narcolepsy, obstructive sleep apnea/hypopnea (OSAHS), or shift work sleep disorder (SWSD). In OSAHS, modafinil is indicated as an adjunct to standard treatment. Continuing efficacy beyond 9 weeks has not been evaluated in placebo-controlled trials.
- Treatment of fatigue associated with multiple sclerosis.
- Modafinil is a wake-promoting agent shown to improve wakefulness in patients with excessive sleepiness (hypersomnolence) associated with shift work sleep disorder, obstructive sleep apnea, or narcolepsy. Safety and tolerability data from 6 randomized, double-blind, placebo-controlled studies were combined to evaluate modafinil across these different patient populations.
- One thousand five hundred twenty-nine outpatients received modafinil 200, 300, or 400 mg or placebo once daily for up to 12 weeks. Assessments included recording of adverse events and effects of modafinil on blood pressure/heart rate, electrocardiogram intervals, polysomnography, and clinical laboratory parameters. Two hundred seventy-three patients with shift work sleep disorder, 292 with obstructive sleep apnea, and 369 with narcolepsy received modafinil; 567 received placebo.
- Modafinil was well tolerated versus placebo, with headache (34% vs 23%, respectively), nausea (11% vs 3%), and infection (10% vs 12%) the most common adverse events. Adverse events were similar across all patient groups. Twenty-seven serious adverse events were reported (modafinil, n = 18; placebo, n = 9). In modafinil-treated patients, clinically significant increases in diastolic or systolic blood pressure were infrequent (n = 9 and n = 1, respectively, < 1% of patients). In the studies, 1 patient in the modafinil group and 1 in the placebo group had a clinically significant increase in heart rate. New clinically meaningful electrocardiogram abnormalities were rare with modafinil (n = 2) and placebo (n = 4).
- Clinically significant abnormalities in mean laboratory parameters were observed in fewer than 1% of modafinil-treated patients at final visit. Modafinil did not affect sleep architecture in any patient population according to polysomnography. Modafinil is well tolerated in the treatment of excessive sleepiness associated with disorders of sleep and wakefulness and does not affect cardiovascular or sleep parameters.
- Intervention with modafinil (400 mg/day) and placebo occurred over 6-week periods. Primary endpoint (fatigue) was assessed using the Fatigue Severity Scale as the main outcome measure. Other measures included the Visual Analog Scale for Fatigue and the Fatigue Impact Scale. Secondary endpoint (health-related quality of life) was assessed using the 36-Item Short-Form. Analysis of variance for repeated measures was applied to assess treatment, period, and carryover effects. Thirty-six patients were randomized, 33 of whom (mean age: 61 years) completed the required interventions. Treatment with modafinil was safe and well-tolerated. After adjusting for periods and order effects, no difference was observed between treatments. Based on the utilized measures of outcome modafinil was not superior to placebo in alleviating fatigue or improving quality of life in the studied post-polio syndrome population.
- The first-line treatment for patients with troublesome obstructive sleep apnea syndrome is night-time nasal continuous positive airway pressure, which reduces daytime drowsiness and improves cognitive performance. Modafinil, a non amphetamine psychostimulant already marketed for idiopathic narcolepsy and hypersomnia, is the first drug to be approved in France for the treatment of patients with residual daytime drowsiness despite nasal continuous positive airway pressure treatment. Clinical evaluation of modafinil for this indication consists of two short-term double-blind placebo-controlled trials, lasting 4 and 12 weeks, and including a total of about 500 patients.
- At a dose of 400 mg/day, 68% of patients experienced an improvement in their daytime drowsiness (usually partial), compared to 37% of patients on placebo. It is not known how many patients no longer had any daytime drowsiness. A major improvement occurred in about 14% of patients (7% on placebo). The main adverse effects of modafinil are neuropsychological (a headache, nervousness, insomnia, anxiety, nausea). In short, modafinil is an option to consider when continuous positive airway pressure is not sufficiently effective and when drowsiness continues to significantly interfere with daily activities. However, it only appears to provide a major benefit to about 10% of patients. The only important improvement is in daytime drowsiness, and this is often offset by adverse effects such as a headache. Effects of long-term treatment are not known.
Contra-Indications of Modafinil
- Behaving with Excessive Cheerfulness and Activity
- psychotic disorder
- having thoughts of suicide
- aggressive behavior
- high blood pressure
- heart attack
- Unpredictable Severe Constricting Chest Pain
- Disease of Inadequate Blood Flow to the Heart Muscle
- Mitral Valve Prolapse Syndrome
- Left Ventricular Hypertrophy
- severe liver disease
- severe renal impairment
Dosage of Modafinil
Strengths: 100 mg; 200 mg ; 400 mg/day
Obstructive Sleep Apnea/Hypopnea Syndrome
- 200 mg orally once a day in the morning
- 200 mg orally once a day, approximately 1 hour prior to the start of the work shift
- 200 mg orally once a day in the morning
Side Effects of Modafinil
The most common
- a headache
- sleepiness or unusual drowsiness
- clumsiness or unsteadiness
- dry mouth
- false sense of well-being
- increased watering of mouth
- vision changes;
- breast swelling (in men or women); or
- decreased sex drive, impotence, or difficulty having an orgasm.
- blurred vision, tunnel vision, eye pain or swelling, or seeing halos around lights;
- restless muscle movements in your eyes, tongue, jaw, or neck;
- a light-headed feeling, like you, might pass out;
- Drowsiness and lightheadedness the day after taking the medicine.
- Numbed emotions.
- Visual disturbances such as blurred vision or double vision.
- Shaky movements and unsteady walk (ataxia).
- Loss of memory (amnesia).
- Muscle weakness.
- A headache.
- Skin rashes.
- Disturbances of the gut such as diarrhea, constipation, nausea, vomiting or abdominal pain.
- Difficulty in passing urine (urinary retention).
- Changes in sex drive.
- Low blood pressure (hypotension).
- Blood disorders.
- Unexpected aggression, restlessness or irritability (tell your doctor if you experience this).
- Nightmares or hallucinations (tell your doctor if you experience this).
- behavioral changes, including aggressiveness, angry outbursts, bizarre behavior, or decreased inhibitions
- increased trouble sleeping
- memory problems
- muscle spasms
- shortness of breath
- signs of depression (e.g., poor concentration, changes in weight, changes in sleep, decreased interest in activities, thoughts of suicide)
Drug Interactions of Modafinil
Modafinil may interact with following drugs, supplements & may change the efficacy of drugs
- general anesthetics
- antihistamines (e.g., cetirizine, doxylamine, diphenhydramine, hydroxyzine, loratadine)
- antipsychotics (e.g., chlorpromazine, clozapine, haloperidol, olanzapine, quetiapine, risperidone)
- barbiturates (e.g., butalbital, pentobarbital, phenobarbital)
- benzodiazepines (e.g., alprazolam, diazepam, lorazepam)
- diabetes medications (e.g., chlorpropamide, metformin, nateglinide, rosiglitazone)
- estrogens (e.g., conjugated estrogen, )
- low molecular weight heparins
- monoamine oxidase inhibitors (MAOIs; e.g. rasagiline, selegiline, )
- muscle relaxants
- non-steroidal anti-inflammatory medications (NSAIDs; e.g., diclofenac, ibuprofen, naproxen)
- omega-3 fatty acids
- quinolone antibiotics (e.g., ciprofloxacin, norfloxacin, ofloxacin)
- seizure medications ( phenobarbital, phenytoin, valproic acid, )
- selective serotonin reuptake inhibitors (SSRIs; e.g., citalopram, duloxetine, fluoxetine, paroxetine, sertraline)
- serotonin antagonists (anti-emetic medications; e.g., granisetron, ondansetron)
- theophyllines (e.g., aminophylline, oxtriphylline, theophylline)
- thiazide diuretics (water pills; e.g., hydrochlorothiazide, )
- thyroid replacements (e.g., desiccated thyroid, levothyroxine)
- tricyclic antidepressants (e.g., desipramine, nortriptyline)
- triptans (e.g., sumatriptan, rizatriptan)
This medication may interfere with certain medical/laboratory tests (including a brain scan for Parkinson’s disease), possibly causing false test results. Make sure laboratory personnel and all your doctors know you use this drug.
Pregnancy & Lactation of Modafinil
FDA Pregnancy Category C
This medication should not be used during pregnancy unless the benefits outweigh the risks. If you become pregnant while taking this medication, contact your doctor immediately.
It is not known if modafinil passes into breast milk. If you are a breast-feeding mother and are taking this medication, it may affect your baby. Talk to your doctor about whether you should continue breast feeding. Serious reactions have been associated with the use of modafinil by children. The risks and benefits of modafinil have not been established for children. It is not recommended that children be given modafinil.