Pharmacology

Pharmacodynamics. Modafinil is thought to act selectively in areas of the brain believed to regulate normal wakefulness. This selective CNS activity is distinct from the action of amphetamine and methylphenidate. In vivo, modafinil does not bind to most relevant receptors for sleep-wake regulation, including those for norepinephrine, serotonin, dopamine, GABA, adenosine, melatonin, or benzodiazepines. Functional MRI (fMRI) studies have shown that low cortical activation levels in both normal and narcoleptic subjects are increased following the administration of modafinil. A study of the effects of modafinil on the functional connectivity of insular subregions of the brain has revealed resting state fMRI findings that are consistent with the cognitive enhancing properties of the drug (03). The mechanism of action of modafinil is considered to involve hypocretin, histamine, gamma-aminobutyric acid, and glutamate. Non-noradrenergic, dopamine-dependent adrenergic signaling has also been implicated in the wake-promoting mechanism of modafinil. Modafinil increases daytime wakefulness but does not interfere with the integrity or architecture of nighttime sleep. It significantly improves patients' ability to remain awake when engaged in daily activities. In healthy subjects, modafinil has been shown to increase wakefulness and regional cerebral blood flow in the arousal-related systems.

In a pilot study on human volunteers, modafinil blocked dopamine transporters and increased dopamine in the human brain, including the nucleus accumbens, indicating the potential for development of drug abuse and drug dependence in vulnerable persons.

In a double-blinded placebo-controlled trial of low-dose (100 mg daily) modafinil on human volunteers, fMRI was used to study the effect of modafinil on neural circuits underlying affective processing and cognitive functions (15). Modafinil was found to enhance the efficiency of prefrontal cortical cognitive information processing while dampening reactivity to threatening stimuli in the amygdala, a region that is implicated in anxiety. Enhancement of cognition by modafinil might be the result of increased activation of glutamatergic neurons in the hippocampus and dopaminergic neurons in the prefrontal cortex (18). A study in healthy elderly volunteers using functional MRI has shown that modafinil can modulate the corticocerebellar connectivity of the aging brain, indicating its potential as a cognitive enhancing drug (14).

Pharmacokinetics. Important points are as follows:

Clinical trials

Efficacy and safety of modafinil was established by clinical trials more than 2 decades ago. More recent studies are shown in Table 1.

Table 1. Clinical Trials of Modafinil

In secondary analysis of data from patients with obstructive sleep apnea and excessive sleepiness despite continuous positive airway pressure use, modafinil use was shown to improve functional outcomes of patients (20).

Indications

Modafinil is indicated for the management of excessive daytime sleepiness associated with narcolepsy. The FDA has approved its use to improve wakefulness in patients with excessive sleepiness associated with obstructive sleep apnea/hypopnea syndrome and shift-work sleep disorder.

Off-label uses

Contraindications

Modafinil is contraindicated in patients with known hypersensitivity to the drug.

Goals and duration of treatment

The goal is to counteract excessive daytime sleepiness associated with narcolepsy without interfering with nocturnal sleep. Although modafinil improves measures of sleepiness, it does not normalize them, because it does not correct the basic underlying cause. Therefore, treatment may be required for an indefinite period. Use has been studied for up to 40 weeks in an open-label extension of a clinical trial, and no development of tolerance was seen; however, for long-term use, effectiveness for the individual patient should be periodically evaluated. Although modafinil can maintain wakefulness, memory, and executive functions in sleep-deprived individuals as compared to placebo in various studies, repeated doses cannot prevent deterioration of cognitive performance over a longer period of sleep deprivation.

Patients who receive modafinil as the initial treatment tolerate it well. Difficulties may be encountered in the clinical practice of switching patients from other drugs to modafinil. Subjects withdrawn from amphetamine have the most problems. A gradual withdrawal may ease the difficulties. Other stimulants, such as caffeine, also prescription substances such as methylphenidate and modafinil, are being used by healthy individuals to enhance cognitive performance, but there is a lack of knowledge on the effects of prescription stimulants when taken by healthy individuals as compared with patients (16). Research to investigate the effects of stimulants should be directed to specific cognitive domains that seem most promising, possibly by using tasks that are more demanding.

Dosing

The dose of modafinil is 200 mg daily, given as a single oral dose in the morning.

Special considerations

The dose of modafinil should be reduced in patients with severe hepatic impairment as the drug clearance is reduced as serum levels rise.

Pediatric. Safety and effectiveness in individuals younger than 16 years of age have not been established.

Geriatric. Safety and effectiveness in individuals older than 65 years of age have not been established. Elimination of modafinil and its metabolites may be reduced in elderly patients; therefore, a lower dose should be used in this population.

Pregnancy. Animal studies to assess the effects of modafinil on reproduction and the developing fetus have not been conducted. Due to drug interaction, an increased risk of pregnancy exists when using steroidal contraceptives (including depot or implantable contraceptives) with modafinil tablets. This increased risk continues for 1 month after discontinuation of modafinil therapy.

Results of the analysis of a prospective cohort study using the US Provigil/Nuvigil Pregnancy Registry from 2010 to 2019 demonstrate that there is a potential increased risk of major congenital malformations following in utero exposure to modafinil and/or armodafinil compared with the general population (12). This potential risk is not likely due to the underlying condition of narcolepsy, because previous data suggest that narcolepsy does not increase the risk of abnormal pregnancy outcomes. These findings are consistent with a previously published Danish retrospective database study reporting an absolute risk of 12% for major congenital malformations in first-trimester pregnancy exposure to modafinil (06). Because no specific organ malformation pattern was identified, a clear causal association between use of modafinil and/or armodafinil and major congenital malformations cannot be established.

No adequate and well-controlled trials have been administered with modafinil in pregnant women, and this drug should be used during pregnancy only if the potential benefit outweighs the potential risk.

It is not known whether modafinil or its metabolites are excreted in human milk. Caution should be exercised when modafinil tablets are administered to a nursing woman.

Anesthesia. Because of its effect on neural pathways that activate consciousness, modafinil can cause resistance to induction of anesthesia by propofol, but the concentration of sevoflurane required to induce or maintain anesthesia remained unaltered (09). Modafinil reduces fatigue and improves feelings of alertness in postoperative patients recovering from general anesthesia.

Interactions

Modafinil may interact with drugs that inhibit, induce, or are metabolized by cytochrome P450 isoenzymes. Circulating levels of oral contraceptives, cyclosporine A, and theophylline may be decreased, and those of diazepam, phenytoin, propranolol, and warfarin may be increased. If a patient is already stabilized on drugs metabolized by these enzymes, then the patient’s dosage may need to be adjusted when modafinil is added. Modafinil has no clinically important interactions with methylphenidate, clomipramine, or triazolam.

Adverse effects

Frequently reported adverse events in clinical trials were headache, nausea, nervousness, anxiety, and insomnia. These events declined over time with no evidence of drug dependency. No treatment was needed for the adverse effects. However, there are increasing case reports of modafinil-induced psychosis (07).