Modafinil …

K K Jain MD†

Neuropharmacology & Neurotherapeutics

Updated 10.06.2021
Released 07.06.1999
Expires For CME 10.06.2024

Modafinil

Author: K K Jain MD†

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Modafinil

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Introduction

Historical note and terminology

In 1998 the United States Food and Drug Administration approved modafinil as a wake-promoting agent (to improve wakefulness in patients with excessive daytime sleepiness associated with narcolepsy). This was the first time in over 40 years such a drug was approved. In 2010 the European Medicines Agency withdrew the indication of modafinil for the treatment of obstructive sleep apnea, shift-work sleep disorder, and idiopathic hypersomnia.

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:

	• Absorption of modafinil tablets is rapid, with peak plasma concentrations occurring at 2 to 4 hours.
	• The enantiomers of modafinil exhibit linear kinetics, and steady state is reached after 2 to 4 days of daily dosing.
	• Pharmacokinetics of modafinil are dose independent between 200 and 600 mg/day.
	• Elimination half-life is 15 hours for a multiple dose regimen.
	• Modafinil is moderately bound (approximately 60%) to plasma protein, mainly to albumin.
	• Modafinil is metabolized by the liver through hydrolytic deamidation, S-oxidation, aromatic ring hydroxylation, and glucuronide conjugation. Less than 10% of an administered dose is excreted as the parent compound.
	• Modafinil may interact with drugs that inhibit, induce, or are metabolized by cytochrome P450 isoenzymes.

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

	• Modafinil has been found to augment actions of antidepressants, especially in patients with residual tiredness or fatigue. A metaanalysis of randomized, controlled trials showed that modafinil is an effective adjunctive therapy for acute depressive episodes including symptoms of fatigue (08).
	• Based on neuroprotective effects in experimental animals, modafinil may have a therapeutic potential in neurodegenerative diseases such as Parkinson disease.
	• Efficacy of modafinil in attention deficit hyperactivity disorder has been shown in several controlled clinical trials. Modafinil may have advantages over current therapies for attention deficit hyperactivity disorder in that it can be administered once daily and has fewer reinforcing properties than traditional stimulants. However, the use of modafinil for attention deficit hyperactivity disorder in adolescents and children has not been approved by the FDA.
	• Modafinil reduces excessive daytime sleepiness in patients with Parkinson disease treated with dopaminergic drugs and enables increase in dose of these drugs without worsening the parkinsonian symptoms.
	• Modafinil does not appear to offer advantages over caffeine for improving performance and alertness during sleep loss in otherwise normal, healthy adults.
	• For excessive daytime sleepiness in patients with myotonic dystrophy.
	• Modafinil may be an effective adjunct treatment that improves cognitive function and reduces fatigue in patients with schizophrenia.
	• Chronic fatigue syndrome.
	• For improving cognitive performance and promoting wakefulness in shift workers.
	• A placebo-controlled, randomized trial has shown that modafinil may be a promising intervention for fatigue in amyotrophic lateral sclerosis.
	• Patients with traumatic brain injury show improvement in excessive daytime sleepiness but not in posttraumatic fatigue following use of modafinil.
	• Motion sickness. Treatment with modafinil led to more than 50% improvement in a patient with moderate to severe depressive symptoms, anxiety, and cognitive deficits following traumatic brain injury (19).
	• Modafinil normalizes sleep architecture and decreases daytime sleepiness in abstinent cocaine users.
	• Modafinil may be particularly useful in methamphetamine-dependent subjects who use the drug frequently.
	• Modafinil is effective in children and adolescents with Prader-Willi syndrome.
	• Modafinil has been shown to improve working memory high-dose cocaine users (11).
	• A randomized, placebo-controlled study has shown that modafinil is an effective and safe medication in the treatment of idiopathic hypersomnia (13).
	• In a randomized, double-blind, placebo-controlled, crossover design trial, stroke survivors with nonresolving fatigue reported reduced fatigue and improved quality of life after daily treatment with modafinil (01).
	• Modafinil improves attentional performance in healthy, non-sleep deprived humans at usually prescribed doses that do not induce hyperarousal (05).
	• Modafinil exerts a synergistic effect on the orexin system, controls energy expenditure, and strengthens the ability of the individual to exercise, which has raised the medico-legal question of it as a performance enhancing drug (17).
	• Results of a double blind, randomized, placebo-controlled pilot study suggest that use of single-dose preoperative modafinil may not improve functional recovery after general anesthesia in patients with the diagnosis of obstructive sleep apnea (02).

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.

References

01: Bivard A, Lillicrap T, Krishnamurthy V, et al. MIDAS (Modafinil in Debilitating Fatigue After Stroke): a randomized, double-blind, placebo-controlled, cross-over trial. Stroke 2017;48(5):1293-98. PMID 28404841
02: Carr ZJ, Vells B, Wood BR, et al. A double blind randomized placebo controlled pilot study of single-dose preoperative modafinil for functional recovery after general anesthesia in patients with obstructive sleep apnea. Medicine (Baltimore) 2018;97(39):e12585. PMID 30278569
03: Cera N, Tartaro A, Sensi SL. Modafinil alters intrinsic functional connectivity of the right posterior insula: a pharmacological resting state fMRI study. PLoS One 2014;9(9):e107145. PMID 25237810
04: Chapman JL, Kempler L, Chang CL, et al. Modafinil improves daytime sleepiness in patients with mild to moderate obstructive sleep apnoea not using standard treatments: a randomised placebo-controlled crossover trial. Thorax 2014;69(3):274-9. PMID 24287166
05: Cope ZA, Minassian A, Kreitner D, et al. Modafinil improves attentional performance in healthy, non-sleep deprived humans at doses not inducing hyperarousal across species. Neuropharmacology 2017;125:254-62. PMID 28774856
06: Damkier P, Broe A. First-trimester pregnancy exposure to modafinil and risk of congenital malformations. JAMA 2020;323(4):374-6.** PMID 31990303
07: Flavell J. Modafinil-induced psychosis in a patient with attention deficit hyperactivity disorder. Australas Psychiatry 2021;29(3):366-367. PMID 32713188
08: Goss AJ, Kaser M, Costafreda SG, Sahakian BJ, Fu CH. Modafinil augmentation therapy in unipolar and bipolar depression: a systematic review and meta-analysis of randomized controlled trials. J Clin Psychiatry 2013;74(11):1101-7. PMID 24330897
09: Harwood TN. Resistance to propofol induction in a patient taking modafinil: a case report. A A Case Rep 2017;9(11):322-3.** PMID 28767479
10: Inoue Y, Takasaki Y, Yamashiro Y. Efficacy and safety of adjunctive modafinil treatment on residual excessive daytime sleepiness among nasal continuous positive airway pressure-treated Japanese patients with obstructive sleep apnea syndrome: a double-blind placebo-controlled study. J Clin Sleep Med 2013;9(8):751-7. PMID 23946704
11: Kalechstein AD, Mahoney JJ 3rd, Yoon JH, Bennett R, De la Garza R 2nd. Modafinil, but not escitalopram, improves working memory and sustained attention in long-term, high-dose cocaine users. Neuropharmacology 2013;64:472-8. PMID 22796108
12: Kaplan S, Braverman DL, Frishman I, Bartov N. Pregnancy and fetal outcomes following exposure to modafinil and armodafinil during pregnancy. JAMA Intern Med 2020;e204009. PMID 33074297
13: Mayer G, Benes H, Young P, Bitterlich M, Rodenbeck A. Modafinil in the treatment of idiopathic hypersomnia without long sleep time--a randomized, double-blind, placebo-controlled study. J Sleep Res 2015;24(1):74-81. PMID 25196321
14: Punzi M, Gili T, Petrosini L, Caltagirone C, Spalletta G, Sensi SL. Modafinil-induced changes in functional connectivity in the cortex and cerebellum of healthy elderly subjects. Front Aging Neurosci 2017;9:85. PMID 28424611
15: Rasetti R, Mattay VS, Stankevich B, et al. Modulatory effects of modafinil on neural circuits regulating emotion and cognition. Neuropsychopharmacology 2010;35(10):2101-9. PMID 20555311
16: Repantis D, Bovy L, Ohla K, Kühn S, Dresler M. Cognitive enhancement effects of stimulants: a randomized controlled trial testing methylphenidate, modafinil, and caffeine. Psychopharmacology (Berl) 2021;238(2):441-51. PMID 33201262
17: Salerno M, Villano I, Nicolosi D, et al. Modafinil and orexin system: interactions and medico-legal considerations. Front Biosci (Landmark Ed) 2019;24:564-75.** PMID 30468674
18: Scoriels L, Jones PB, Sahakian BJ. Modafinil effects on cognition and emotion in schizophrenia and its neurochemical modulation in the brain. Neuropharmacology 2013;64:168-84. PMID 22820555
19: Tcheremissine OV, Rachal JC. Modafinil augmentation therapy in patient with traumatic brain injury. Innov Clin Neurosci 2017;14(3-4):11. PMID 28584691
20: Weaver TE, Chasens ER, Arora S. Modafinil improves functional outcomes in patients with residual excessive sleepiness associated with CPAP treatment. J Clin Sleep Med 2009;5(6):499-505. PMID 20465014

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Modafinil

Other Pertinent Drugs

Amphetamine
methylamphetamine
methylphenidate

Also Relevant

Attention deficit hyperactivity disorder
Fatigue in multiple sclerosis
Hypersomnolence
Idiopathic hypersomnia
Narcolepsy
- Neuropharmacology
- Parkinson disease
- Sleep and depression
- Sleep and neuromuscular and spinal cord disorders
- Sleep and multiple sclerosis
- Sleep and parkinsonism
- Shift work disorder
- Stimulant-dependent sleep disorder

Trial design	Results
A randomized, placebo-controlled crossover trial of modafinil for daytime sleepiness due to untreated obstructive sleep apnea.	Modafinil significantly improved subjective sleepiness in patients with mild to moderate obstructive sleep apnea (04).
A double-blind, placebo-controlled trial for evaluation of modafinil for treatment of residual daytime sleepiness in Japanese patients with obstructive sleep apnea on continuous positive airway pressure therapy.	Once-daily modafinil was effective and well tolerated for residual daytime sleepiness that occurred despite optimal positive airway pressure therapy (10).

Modafinil …

Modafinil

Introduction

Historical note and terminology

Pharmacology

Clinical trials

Table 1. Clinical Trials of Modafinil

Indications

Off-label uses

Contraindications

Goals and duration of treatment

Dosing

Special considerations

Interactions

Adverse effects

References

Contributors

Author

This is an article preview.
Start a Free Account
to access the full version.

Questions or Comment?

Also in This Category

Hypersomnolence

Fatal familial insomnia

Sleep and mental disorders

Sleep paralysis

Acupuncture

Sleep and epilepsy

Narcolepsy

Confusional arousal

Modafinil

Introduction

Historical note and terminology

Pharmacology

Clinical trials

Table 1. Clinical Trials of Modafinil

Indications

Off-label uses

Contraindications

Goals and duration of treatment

Dosing

Special considerations

Interactions

Adverse effects

References

Contributors

Author

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Hypersomnolence

Fatal familial insomnia

Sleep and mental disorders

Sleep paralysis

Acupuncture

Sleep and epilepsy

Narcolepsy

Confusional arousal

This is an article preview.
Start a Free Account
to access the full version.