Modafinil; Uses, Dosage, Side Effects, Interactions

Modafinil; Uses, Dosage, Side Effects, Interactions

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)

Modafinil and its R-enantiomer armodafinil are central nervous system stimulants used to improve wakefulness in patients with excessive sleepiness. Both modafinil and armodafinil 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.

Mechanism of Action of Modafinil

The exact mechanism of action is unclear, although in vitro studies have shown it to inhibit the reuptake of dopamine[Rx] by binding to the dopamine[Rx] reuptake pump, and lead to an increase in extracellular dopamine. Modafinil activates glutamatergic circuits while inhibiting GABA[Rx]. Modafinil is thought to have less potential for abuse than other stimulants due to the absence of any significant euphoric or pleasurable effects. It is possible that modafinil acts by a synergistic combination of mechanisms including direct inhibition of dopamine reuptake, indirect inhibition of noradrenalin[Rx] reuptake in the VLPO and orexin activation. Modafinil has partial alpha 1B-adrenergic agonist effects by directly stimulating the receptors.
The precise mechanism(s) through which modafinil promotes wakefulness is unknown. Modafinil has wake-promoting actions similar to sympathomimetic agents like amphetamine[Rx] and methylphenidate[Rx], although the pharmacologic profile is not identical to that of sympathomimetic amines. Modafinil has weak to negligible interactions with receptors for norepinephrine, serotonin, dopamine, GABA[Rx]adenosine[Rx]histamine[Rx]-3, melatonin, and benzodiazepines. Modafinil also does not inhibit the activities of MAO-B or phosphodiesterases II-V. Modafinil-induced wakefulness can be attenuated by the á1-adrenergic receptor antagonist prazosin[Rx]; however, modafinil is inactive in other in vitro assay systems known to be responsive to á-adrenergic agonists, such as the rat vas deferens preparation. Modafinil is not a director indirect-acting dopamine receptor agonist. However, in vitro, modafinil binds to the dopamine[Rx] transporter and inhibits dopamine[Rx] reuptake. This activity has been associated in vivo with increased extracellular dopamine levels in some brain regions of animals. In genetically engineered mice lacking the dopamine transporter (DAT), modafinil lacked wake-promoting activity, suggesting that this activity was DAT-dependent. However, the wake-promoting effects of modafinil, unlike those of amphetamine[Rx], were not antagonized by the dopamine receptor antagonist haloperidol[Rx] in rats. In addition, alpha-methyl-p-tyrosine[Rx], a dopamine synthesis inhibitor, blocks the action of amphetamine but does not block locomotor activity induced by 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.
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Contra-Indications of Modafinil

  • Behaving with Excessive Cheerfulness and Activity
  • psychotic disorder
  • having thoughts of suicide
  • depression
  • 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

Sleep Disorder

  • 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


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Drug Interactions of Modafinil

Modafinil may interact with following drugs, supplements & may change the efficacy of drugs

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.

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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.



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