Sleep Disorders
Posttraumatic sleep disturbance
Sep. 01, 2023
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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.
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. |
Efficacy and safety of modafinil was established by clinical trials more than 2 decades ago. More recent studies are shown in Table 1.
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). |
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).
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.
• 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). |
Modafinil is contraindicated in patients with known hypersensitivity to the drug.
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.
The dose of modafinil is 200 mg daily, given as a single oral dose in the morning.
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.
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.
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).
All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
K K Jain MD†
Dr. Jain was a consultant in neurology and had no relevant financial relationships to disclose.
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ISSN: 2831-9125
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