Evidence-Based Reviews

Modafinil: Not just for sleep disorders?

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Off-label use of this stimulant might improve mood disorders, ADHD, and other conditions.


 

References

Ms. B, a middle-aged mother of 3, is being monitored for bipolar disorder. She has a history of stimulant abuse but has been in remission for 5 years. She complains of excessive daytime sleepiness. Most days she wakes at 7 AM, but sleeps on several occasions during the day. She also complains of fatigue and lack of motivation.

She is being treated with lithium, venlafaxine, and zolpidem and reports good adherence. Basic laboratory work and serum lithium levels are within acceptable ranges. Her symptoms do not improve when venlafaxine is titrated from 225 mg/d to 300 mg/d. She also reports previously failed trials with bupropion and fluoxetine.

We decide to try a psychostimulant as an augmenting agent. Because of her past stimulant abuse, we add modafinil, 100 mg/d and increase to 200 mg/d. Ms. B reports improvement in her daytime sleepiness and fatigue and—except for a mild headache—tolerates the medication well.

Modafinil is being investigated for potential roles in managing inattention, excess sleepiness, fatigue, and cognitive dysfunction associated with:

  • mood disorders (major depression and bipolar depression)
  • attention-deficit/hyperactivity disorder (ADHD)
  • schizophrenia
  • cocaine dependence.

This article discusses how the drug promotes wakefulness, how it might improve cognitive function, and what the evidence reveals about off-label indications.

How it works

Although modafinil’s precise mechanism of action is unknown, it is believed to promote wakefulness more selectively than conventional stimulants such as amphetamine and methylphenidate. Modafinil does not bind to norepinephrine, serotonin, dopamine, or benzodiazepine receptors.1,2 It might target specific hypothalamic regions such as the tuberomammillary nucleus and orexin neurons, which are peptide neurotransmitters that promote wakefulness.3,4

Preclinical studies found that modafinil increases neuronal activation in the hypothalamus.2,3 Because several cell groups in the hypothalamus project diffusely to the cerebral cortex and mediate arousal and attention, it has been suggested that modafinil might improve cognitive function.

Clinical trials found that modafinil has beneficial effects on:

  • working memory, recognition memory, and sustained attention in healthy humans
  • prefrontal-dependent cognitive functions in schizophrenia, major depression, and adult ADHD.5

Evidence for approved indications

Modafinil is indicated to improve wakefulness in patients who have excessive sleepiness associated with narcolepsy, obstructive sleep apnea, or shift work sleep disorder. It was approved for reducing excessive sleepiness in narcoleptic patients after two 9-week placebo-controlled clinical trials. The drug significantly reduced sleepiness and improved overall disease status as measured by the Clinical Global Impression of Change (CGI-C) scale.6,7

Modafinil also significantly improved sleep latency and CGI-C scores in 2 clinical trials of patients with obstructive sleep apnea/hypopnea.8,9 Approximately 80% of patients in these studies were using their continuous positive airway pressure devices.

In patients with shift work sleep disorder, a 12-week placebo-controlled clinical trial found that modafinil significantly improved sleep latency and CGI-C scores.10

Dosage and side effects. For patients with narcolepsy or obstructive sleep apnea, the recommended dose is 200 mg given in the morning.11 For patients prescribed modafinil for work-time wakefulness, the dose is 200 mg 1 hour before their work shift. Lower doses are recommended for patients who are elderly or have hepatic impairment. Those with severe hepatic impairment typically are prescribed 100 mg/d.11 Modafinil is rapidly absorbed and is metabolized primarily by the liver (Table 1). A summary of potential drug-drug interactions appears in Table 2.11

In pivotal trials, adverse events that occurred more frequently with modafinil than with placebo and in >5% of the study population included headache, nausea, nervousness, rhinitis, diarrhea, back pain, insomnia, dizziness, and dyspepsia. Headache was most commonly reported; in most patients, it resolved soon after they started taking modafinil. Post-marketing reports have included cases of psychosis, mania, and suspected serious skin reactions, including Stevens-Johnson syndrome.11 Modafinil lacks euphorigenic properties and has minimal potential for abuse.12

Table 1

Modafinil’s pharmacokinetics

Absorbed rapidly, with peak plasma concentrations at 2 to 4 hours
Apparent steady states reached after 2 to 4 days of dosing
Half-life: 15 hours
Major route of elimination (~90%) is metabolism, primarily by the liver
Table 2

Selected drug-drug interactions with modafinil

Action of modafinilPotential drug interactions
Increases elimination of CYP 3A4 substratesCarbamazepine, phenytoin may decrease modafinil levels
Azole antifungals, protease inhibitors, and erythromycin may increase modafinil levels
Inhibits CYP 2C19 enzymeModafinil may increase levels of citalopram, diazepam, and sertraline
Decreases absorption of ethinyl estradiolModafinil can decrease effectiveness of oral contraceptives
CYP: cytochrome P-450
Source: Reference 11

Evidence for off-label uses

Major depressive disorder (MDD). The fatigue and excessive sleepiness often seen with MDD often persist after other depressive symptoms have remitted with antidepressant treatment.13 Patients with these symptoms might benefit from modafinil’s stimulating properties. Conventional stimulants such as methylphenidate have been used to improve neurovegetative symptoms of depression, but modafinil offers several advantages:

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