Modafinil


Article Author:
Karl Greenblatt


Article Editor:
Ninos Adams


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Scott Klenzak
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Brian Farah


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Phillip Hynes
Tehmina Warsi


Updated:
10/27/2018 12:32:08 PM

Indications

Modafinil is a non-amphetamine central nervous system (CNS) stimulant with wakefulness-promoting properties. It is used in the treatment of conditions which cause excessive daytime sleepiness. In the United States, modafinil is FDA-approved for the treatment of the following in adults:

  • Narcolepsy: First-line treatment; Modafinil is used to treat the daytime fatigue associated with narcolepsy, and it has not been shown to improve symptoms of cataplexy.
  • Sleep Work Shift Disorder: First-line treatment
  • Obstructive sleep apnea: Adjunct to continuous positive airway pressure (CPAP)

Additionally, modafinil has reported efficacy for the following “off-label” indications:

  • Attention-deficit hyperactivity disorder[1][2]: Some evidence of efficacy exists in the pediatric population. A recent study of adult ADHD patients found no benefit of modafinil.[3]
  • Acute unipolar and bipolar depressive episodes[4]
  • Cocaine dependence: Evidence regarding the efficacy of modafinil for this purpose appears mixed[5][6]
  • Cancer-related fatigue: Evidence regarding the efficacy of modafinil for this use appears mixed.[7][8]
  • Multiple sclerosis-related fatigue[9]

The use of modafinil as a “cognitive enhancer” in healthy subjects has been suggested in the literature; however, the precise benefits and risks associated with this use remain uncertain.[10][11]

Mechanism of Action

Modafinil is known to be a weak inhibitor of dopamine reuptake, which may be its primary clinically important property. It has little to no in vivo affinity for the serotonin (5HT) or norepinephrine (NE) transporters, although elevated concentrations of NE and 5HT in the prefrontal cortex and hypothalamus have been observed following modafinil administration, possibly as an indirect effect of increased extracellular dopamine.[12] Additionally, modafinil has been postulated to increase signaling in the hypothalamic orexin and histamine neurotransmitter pathways,[13] and animal studies have also suggested a glutamatergic effect.[14] A potential advantage of modafinil is its very low observed propensity for causing euphoric effects associated with traditional psychostimulants (e.g., cocaine, amphetamine). This has been attributed to differences in its interaction with the dopamine transporter at the molecular level.[15] In several laboratory studies of healthy subjects, modafinil has also been shown to reduce the euphoric effects of cocaine.[16][17]

Modafinil exists as a racemic mixture of S- and R-enantiomers. Of note, the R-enantiomer is thought to be the source of modafinil’s psychotropic properties and is marketed independently as armodafinil.

Administration

Modafinil is available exclusively in the form of oral tablets; the usual dose is 200mg once daily. It is insoluble in aqueous solution and therefore cannot be administered intravenously. The elimination half-life of a single dose in healthy subjects is approximately 15 hours.[18] Maximum plasma concentration is reached 2-4 hours after administration. Modafinil undergoes hepatic metabolism via multiple pathways, including CYP3A4. 80% of the dose is recovered in the urine in the form of metabolites. Severe renal and/or hepatic impairment are known to cause significantly increased steady-state drug concentrations. Dose reduction is recommended in patients with severe hepatic impairment.

Adverse Effects

Modafinil is generally well-tolerated stimulant. The most commonly reported adverse effects of modafinil (less than 10% of users) are a headache, nausea, and decreased appetite. Other commonly reported adverse effects (5% to 10% of users) include anxiety, insomnia, dizziness, diarrhea, and rhinitis.

Regarding serious adverse effects, cases of Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug rash with eosinophilia and systemic symptoms (DRESS) have been reported in postmarketing surveillance. These life-threatening rashes associated with modafinil appear to be extremely rare, although the precise incidence rates are not known. Most of the reported cases have occurred within six weeks of drug initiation. Therefore, any patient who develops a rash during this time frame is advised to notify the prescribing physician immediately.

Contraindications

There are few, if any, absolute contraindications to the use of modafinil. The following is a list of relative contraindications, cautions, and special considerations: 

  • Cardiovascular disease: Modafinil is not recommended in patients with documented left-ventricular hypertrophy or with a history of previous cardiotoxicity related to psychostimulant use. It should be used with caution in patients with uncontrolled hypertension, unstable angina, or recent myocardial infarction.
  • Hepatic impairment: Dose reduction to a maximum of 100mg daily is recommended in patients with severe hepatic impairment.
  • Renal impairment: Modafinil should be used with caution in patients with severe renal impairment. However, no recommendations for renal dosing exist.
  • Psychiatric disorders: Modafinil should be used with caution in patients with a history of psychosis and/or mania. Such patients should be monitored for hallucinations, delusions, mania, aggression, and suicidal ideation upon starting modafinil. Discontinuation is advised if these symptoms develop.
  • Tic disorders: Limited evidence suggests that all CNS stimulants may exacerbate tics in patients with pre-existing tic disorders. A baseline assessment of tics is recommended prior to initiating treatment.
  • Pregnancy: There is no evidence to suggest or exclude harm to the human fetus associated with modafinil. However, an increased risk of abortion and intrauterine growth restriction has been observed in some animal studies. Risks and benefits of therapy during pregnancy should be carefully considered.
  • Lactating women: It is unknown if modafinil is excreted in breast milk. 

Monitoring

There is no requirement for specific monitoring of patients receiving modafinil. However, a variety of drug-drug interactions are possible. Modafinil is a substrate of hepatic CYP3A4, a moderate inducer of CYP3A4, and a weak inhibitor of CYP2C19. 

Modafinil may decrease serum concentrations of other drugs to a clinically significant extent, including the following:

  • Antihepaciviral combination products
  • Antiretroviral combination products
  • Clarithromycin
  • Clozapine
  • Cyclosporine
  • Estrogen derivatives: In patients using combined oral contraceptive pills (OCP), the manufacturer recommends that patients use an alternative method of contraception, instead of or in addition to OCP, during and until 1 month after completing modafinil therapy.
  • Guanfacine
  • Lurasidone
  • Nimodipine
  • Opioid medications (e.g., codeine, fentanyl, hydrocodone)
  • Ranolazine
  • Zolpidem

Serum concentrations of modafinil may be decreased to a clinically significant extent in the presence of drugs that induce CYP3A4. These include rifampin, phenytoin, St. John’s Wort, and efavirenz.

Serum concentrations of modafinil may be increased to a clinically significant extent in the presence of drugs that inhibit CYP3A4. These include ketoconazole, itraconazole, ritonavir, and clarithromycin.

Toxicity

Case reports of modafinil overdose/toxicity are rare. Clinical manifestations of modafinil overdose are relatively mild but may include hypertension, tachycardia, agitation, and/or psychosis. Symptoms typically respond to supportive therapy, although augmentation with benzodiazepines is occasionally required.

Enhancing Healthcare Team Outcomes

Modafinil is a stimulant medication that is generally safe, well-tolerated, and carries very low potential for abuse and dependence. It is used to treat excessive daytime sleepiness associated with narcolepsy, sleep work shift disorder, and obstructive sleep apnea. For these conditions, it is often used in conjunction with other medical and lifestyle treatments. Most patients can safely receive modafinil, although it should be used cautiously in patients with structural cardiac disease, severe hepatic impairment, or a history of psychosis/mania. Although no specific monitoring is recommended for patients on modafinil, nurses, pharmacists and physicians should be aware of the variety of possible drug-drug interactions, notably including oral contraceptive pills.


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Modafinil - Questions

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A 22-year-old male presents with a 3-month history of excessive daytime sleepiness that is relieved by short naps. He is having difficulty maintaining passing grades during his senior year of college. He reports that sometimes he is unable to move for several minutes upon awakening, which frightens him. During the day, he has experienced several episodes of unexplained loss of muscle tone. His vital signs and physical exam are unremarkable. An electrolyte panel, complete blood count, and CT scan of the head are normal. Given the most likely diagnosis, which of the following is indicated as first-line pharmacotherapy?



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In the treatment of narcolepsy, modafinil primarily has which of the following beneficial effects?



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A 28-year-old male comes to his primary care provider due to a 6-week history of extreme fatigue. He explains that he has been falling asleep frequently during meetings at work to the chagrin of his boss. He also experiences extreme fatigue on weekends but feels much better after a 20- to 30-minute nap. He states that his sleep duration is normal, although he occasionally sees "scary ghosts and things that aren't really there" upon awakening in the morning. On a review of systems, he relates that a month ago he suddenly felt "jelly-legged" and fell to the ground while laughing at a friend's joke. He initially attributed this incident to having "a few beers," but a similar event occurred again last weekend when he had not been drinking. He has no significant medical history and takes no prescribed medications. His vital signs are within normal limits. His body mass index is 23 kg/m2. The physical exam is unremarkable, and an electrolyte panel, complete blood count, and CT scan of the head are normal. Given the most likely diagnosis, what is the most appropriate initial pharmacotherapy?



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A 48-year-old male is diagnosed with obstructive sleep apnea (OSA) by polysomnography. He had been experiencing excessive daytime sleepiness for six months. He is started on a weight-reduction program as well as a nocturnal continuous positive airway pressure (CPAP). At his two-month follow-up visit, he reports a 5-pound weight loss, but states, "I can't wear that mask you gave me. It makes me claustrophobic. I can't sleep at night because I feel like I'm going to die." Over the next year, the provider revisits the topic repeatedly, but the patient remains intolerant of CPAP. Ultimately, the patient is started on modafinil, with significant improvement in daytime fatigue. This is most likely due to a medication effect upon which neurotransmitter system?



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A 25-year-old female with a new diagnosis of narcolepsy is started on modafinil at a dose of 200 mg once daily. Which of the following comorbid conditions would necessitate treatment at a lower dose of modafinil?



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A 19-year-old female comes to her primary care provider for a routine wellness check. Since her last visit, she received a new diagnosis of narcolepsy, for which treatment with modafinil and sodium oxybate was initiated. She reports that her symptoms are well-controlled with this treatment regimen. Her other medical problems are stable and include asthma, bipolar II disorder, and impaired glucose tolerance. Other medications are escitalopram, lamotrigine, metformin, a combined oral contraceptive pill, and inhaled albuterol as needed. The provider should be most concerned about a drug-drug interaction between modafinil and which of the following?



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What is the chemical relationship between modafinil and armodafinil?



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Modafinil - References

References

Biederman J,Swanson JM,Wigal SB,Kratochvil CJ,Boellner SW,Earl CQ,Jiang J,Greenhill L, Efficacy and safety of modafinil film-coated tablets in children and adolescents with attention-deficit/hyperactivity disorder: results of a randomized, double-blind, placebo-controlled, flexible-dose study. Pediatrics. 2005 Dec     [PubMed]
Goez HR,Scott O,Nevo N,Bennett-Back O,Zelnik N, Using the test of variables of attention to determine the effectiveness of modafinil in children with attention-deficit hyperactivity disorder (ADHD): a prospective methylphenidate-controlled trial. Journal of child neurology. 2012 Dec     [PubMed]
Arnold VK,Feifel D,Earl CQ,Yang R,Adler LA, A 9-week, randomized, double-blind, placebo-controlled, parallel-group, dose-finding study to evaluate the efficacy and safety of modafinil as treatment for adults with ADHD. Journal of attention disorders. 2014 Feb     [PubMed]
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. The Journal of clinical psychiatry. 2013 Nov     [PubMed]
Kampman KM,Lynch KG,Pettinati HM,Spratt K,Wierzbicki MR,Dackis C,O'Brien CP, A double blind, placebo controlled trial of modafinil for the treatment of cocaine dependence without co-morbid alcohol dependence. Drug and alcohol dependence. 2015 Oct 1     [PubMed]
Dackis CA,Kampman KM,Lynch KG,Plebani JG,Pettinati HM,Sparkman T,O'Brien CP, A double-blind, placebo-controlled trial of modafinil for cocaine dependence. Journal of substance abuse treatment. 2012 Oct     [PubMed]
Brown JN,Howard CA,Kemp DW, Modafinil for the treatment of multiple sclerosis-related fatigue. The Annals of pharmacotherapy. 2010 Jun     [PubMed]
Gilleen J,Michalopoulou PG,Reichenberg A,Drake R,Wykes T,Lewis SW,Kapur S, Modafinil combined with cognitive training is associated with improved learning in healthy volunteers--a randomised controlled trial. European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology. 2014 Apr     [PubMed]
Battleday RM,Brem AK, Modafinil for cognitive neuroenhancement in healthy non-sleep-deprived subjects: A systematic review. European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology. 2016 Feb     [PubMed]
Wisor J, Modafinil as a catecholaminergic agent: empirical evidence and unanswered questions. Frontiers in neurology. 2013 Oct 7     [PubMed]
Spathis A,Fife K,Blackhall F,Dutton S,Bahadori R,Wharton R,O'Brien M,Stone P,Benepal T,Bates N,Wee B, Modafinil for the treatment of fatigue in lung cancer: results of a placebo-controlled, double-blind, randomized trial. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2014 Jun 20     [PubMed]
Hovey E,de Souza P,Marx G,Parente P,Rapke T,Hill A,Bonaventura A,Michele A,Craft P,Abdi E,Lloyd A, Phase III, randomized, double-blind, placebo-controlled study of modafinil for fatigue in patients treated with docetaxel-based chemotherapy. Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer. 2014 May     [PubMed]
Ishizuka T,Murotani T,Yamatodani A, Action of modafinil through histaminergic and orexinergic neurons. Vitamins and hormones. 2012     [PubMed]
Mahler SV,Hensley-Simon M,Tahsili-Fahadan P,LaLumiere RT,Thomas C,Fallon RV,Kalivas PW,Aston-Jones G, Modafinil attenuates reinstatement of cocaine seeking: role for cystine-glutamate exchange and metabotropic glutamate receptors. Addiction biology. 2014 Jan     [PubMed]
Schmitt KC,Reith ME, The atypical stimulant and nootropic modafinil interacts with the dopamine transporter in a different manner than classical cocaine-like inhibitors. PloS one. 2011     [PubMed]
Malcolm R,Swayngim K,Donovan JL,DeVane CL,Elkashef A,Chiang N,Khan R,Mojsiak J,Myrick DL,Hedden S,Cochran K,Woolson RF, Modafinil and cocaine interactions. The American journal of drug and alcohol abuse. 2006     [PubMed]
Hart CL,Haney M,Vosburg SK,Rubin E,Foltin RW, Smoked cocaine self-administration is decreased by modafinil. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 2008 Mar     [PubMed]
Robertson P Jr,Hellriegel ET, Clinical pharmacokinetic profile of modafinil. Clinical pharmacokinetics. 2003     [PubMed]

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