Continuing Education Activity

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, sleep work shift disorder, and obstructive sleep apnea (adjunct to continuous positive airway pressure (CPAP)). It also has several off-label indications. This activity will highlight the mechanism of action, adverse event profile, pharmacology, monitoring, and relevant interactions of modafinil, pertinent for members of the interprofessional team in the treatment of patients with conditions where modafinil has a therapeutic purpose.

Objectives:

• Identify the mechanism of action of modafinil.
• Review the approved and off-label indications for modafinil.
• Summarize the adverse events to modafinil therapy.
• Outline the importance of collaboration and communication among interprofessional team members to improve outcomes and treatment efficacy for patients who might benefit from therapy with modafinil.

Indications

Modafinil is a non-amphetamine central nervous system (CNS) stimulant with wakefulness-promoting properties. It is used in the treatment of conditions that cause excessive daytime sleepiness.

FDA-approved Indications

• 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)

Off-labeled 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 fatigues[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. However, 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. Modafinil exists as a racemic mixture of S- and R-enantiomers. The R-enantiomer is thought to be the source of modafinil’s psychotropic properties and is marketed independently as armodafinil.[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]

Pharmacokinetics

Absorption: Modafinil is readily absorbed after oral administration. It is insoluble in an aqueous solution and therefore cannot be administered intravenously. Maximum plasma concentration is reached 2-4 hours after administration. 

Metabolism: Modafinil undergoes hepatic metabolism via multiple pathways, including CYP3A4. 80% of the dose is recovered in the urine in the form of metabolites.

Elimination: The elimination half-life of a single dose in healthy subjects is approximately 15 hours.[18]  Severe renal and/or hepatic impairment is known to cause significantly increased steady-state drug concentrations. Dose reduction is recommended in patients with severe hepatic impairment.

Administration

Modafinil is available exclusively in the form of 100 mg and 200 mg oral tablets; the usual dose is 200mg once daily. It is classified as a control substance class IV drug. 

Adult Dosing

The recommended dose of modafinil tablets in the treatment of narcolepsy or obstructive sleep apnea is  200 mg orally administered once a day in the morning.

For treatment of shift work disorder, modafinil 200 mg once a day is taken about one hour before the start of the work shift.

Specific Patient Population 

Pediatric Use: Effectiveness and safety in pediatric patients are not established. Modafinil is not FDA-approved for use in the pediatric population for any indication. Serious skin rashes, including Stevens-Johnson syndrome (SJS) and erythema multiforme major (EMM), have been reported with modafinil use in pediatric patients.

Geriatric Use: In elderly patients, modafinil and metabolite elimination might be reduced, so consider using lower doses and closely monitor patients.

Pregnancy: It is classified as pregnancy category C medicine by FDA. 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. The risks and benefits of therapy during pregnancy should be carefully considered.[19]

Lactating Women: It is unknown if modafinil is excreted in breast milk. Use with caution, especially if the newborn infant is exclusively breastfed.[20]

Hepatic Impairment: In patients with severe hepatic impairment, modafinil dose should be reduced by one-half of the usual dosage indicated for the patients. 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.

Adverse Effects

Modafinil is generally a 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.[1]

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 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.[21]

Abuse Potential: In clinical trials, modafinil use produces euphoric and psychoactive effects, altering thinking, mood, feelings, and perception like other CNS stimulants. Assess the risk of potential abuse and use it with caution in patients with a history of drug abuse.

Withdrawal: In one placebo-controlled clinical trial, after nine weeks of modafinil use, the effects of modafinil withdrawal were observed. No withdrawal symptoms were observed in patients with modafinil treatment cessation during 14 days of observation, but in patients with narcolepsy, sleepiness returned.

Contraindications

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

• Dermatological reaction: If serious rash including Stevens-Johnson syndrome develops, discontinue modafinil at the first sign of rash, unless the rash is clearly not drug-related.
• Angioedema and Anaphylaxis Reactions: If suspected, discontinue modafinil.
• Multiorgan Hypersensitivity Reactions: If suspected, discontinue modafinil.
• Persistent Sleepiness: Monitor patients frequently for a degree of sleepiness and, if appropriate, recommend patients to avoid engaging or driving in any other potentially dangerous activity.
• Cardiovascular disease: In patients with preexisting cardiovascular conditions, consider increased monitoring. Modafinil is not recommended in patients with documented left-ventricular hypertrophy or a history of the previous cardiotoxicity related to psychostimulant use. It should be used with caution in patients with uncontrolled hypertension, unstable angina, or recent myocardial infarction.
• 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 before initiating treatment.[22]

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.[18]

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 one 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. Conversely, serum concentrations of modafinil may be increased to a clinically significant extent in the presence of drugs that inhibit CYP3A4. These include azole antifungals (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.[23] The most frequently reported clinical effects were tachycardia, insomnia, agitation, dizziness, and anxiety. About 20 percent of overdose cases require medical treatment. Symptoms typically respond to supportive therapy, although augmentation with benzodiazepines is occasionally required. Other treatments include diphenhydramine, beta-blockers, haloperidol, IV fluid hydration, nitroglycerin, epinephrine, benztropine, and promethazine based on precipitating symptoms.[24]

Enhancing Healthcare Team Outcomes

Modafinil is a stimulant medication that is generally safe, well-tolerated, and carries a 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. It is often used in conjunction with other medical and lifestyle treatments for these conditions. 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 possible drug-drug interactions, including oral contraceptive pills. That is why the prescriber should consult with a pharmacist and conduct a thorough evaluation of all existing medications. Nursing should monitor patient results and also check for signs of adverse reactions at each visit. This interprofessional approach will optimize therapy with modafinil. [Level 5]

Review Questions

• Access free multiple choice questions on this topic.
• Comment on this article.

References

1.

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;116(6):e777-84. [PubMed: 16322134]

2.

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. J Child Neurol. 2012 Dec;27(12):1547-52. [PubMed: 22447850]

3.

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. J Atten Disord. 2014 Feb;18(2):133-44. [PubMed: 22617860]

4.

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 Nov;74(11):1101-7. [PubMed: 24330897]

5.

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 Alcohol Depend. 2015 Oct 01;155:105-10. [PMC free article: PMC4582003] [PubMed: 26320827]

6.

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. J Subst Abuse Treat. 2012 Oct;43(3):303-12. [PMC free article: PMC3378797] [PubMed: 22377391]

7.

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. J Clin Oncol. 2014 Jun 20;32(18):1882-8. [PubMed: 24778393]

8.

Hovey E, de Souza P, Marx G, Parente P, Rapke T, Hill A, Bonaventura A, Michele A, Craft P, Abdi E, Lloyd A., MOTIF investigators. Phase III, randomized, double-blind, placebo-controlled study of modafinil for fatigue in patients treated with docetaxel-based chemotherapy. Support Care Cancer. 2014 May;22(5):1233-42. [PubMed: 24337761]

9.

Brown JN, Howard CA, Kemp DW. Modafinil for the treatment of multiple sclerosis-related fatigue. Ann Pharmacother. 2010 Jun;44(6):1098-103. [PubMed: 20442351]

10.

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. Eur Neuropsychopharmacol. 2014 Apr;24(4):529-39. [PubMed: 24485800]

11.

Battleday RM, Brem AK. Modafinil for cognitive neuroenhancement in healthy non-sleep-deprived subjects: A systematic review. Eur Neuropsychopharmacol. 2016 Feb;26(2):391. [PubMed: 26708317]

12.

Wisor J. Modafinil as a catecholaminergic agent: empirical evidence and unanswered questions. Front Neurol. 2013 Oct 07;4:139. [PMC free article: PMC3791559] [PubMed: 24109471]

13.

Ishizuka T, Murotani T, Yamatodani A. Action of modafinil through histaminergic and orexinergic neurons. Vitam Horm. 2012;89:259-78. [PubMed: 22640618]

14.

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. Addict Biol. 2014 Jan;19(1):49-60. [PMC free article: PMC3535502] [PubMed: 23017017]

15.

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;6(10):e25790. [PMC free article: PMC3197159] [PubMed: 22043293]

16.

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. Am J Drug Alcohol Abuse. 2006;32(4):577-87. [PubMed: 17127546]

17.

Hart CL, Haney M, Vosburg SK, Rubin E, Foltin RW. Smoked cocaine self-administration is decreased by modafinil. Neuropsychopharmacology. 2008 Mar;33(4):761-8. [PubMed: 17568397]

18.

Robertson P, Hellriegel ET. Clinical pharmacokinetic profile of modafinil. Clin Pharmacokinet. 2003;42(2):123-37. [PubMed: 12537513]

19.

Calvo-Ferrandiz E, Peraita-Adrados R. Narcolepsy with cataplexy and pregnancy: a case-control study. J Sleep Res. 2018 Apr;27(2):268-272. [PubMed: 28568319]

20.

Aurora S, Aurora N, Datta P, Rewers-Felkins K, Baker T, Hale TW. Evaluating Transfer of Modafinil Into Human Milk During Lactation: A Case Report. J Clin Sleep Med. 2018 Dec 15;14(12):2087-2089. [PMC free article: PMC6287734] [PubMed: 30518447]

21.

Randomized trial of modafinil as a treatment for the excessive daytime somnolence of narcolepsy: US Modafinil in Narcolepsy Multicenter Study Group. Neurology. 2000 Mar 14;54(5):1166-75. [PubMed: 10720292]

22.

Pliszka S., AACAP Work Group on Quality Issues. Practice parameter for the assessment and treatment of children and adolescents with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 2007 Jul;46(7):894-921. [PubMed: 17581453]

23.

Kandasamy RO, Kaminskaite V, May F. Hyponatraemia and cerebral oedema due to a modafinil overdose. BMJ Case Rep. 2020 Jul 05;13(7) [PMC free article: PMC7337617] [PubMed: 32624486]

24.

Spiller HA, Borys D, Griffith JR, Klein-Schwartz W, Aleguas A, Sollee D, Anderson DA, Sawyer TS. Toxicity from modafinil ingestion. Clin Toxicol (Phila). 2009 Feb;47(2):153-6. [PubMed: 18787992]

Disclosure: Karl Greenblatt declares no relevant financial relationships with ineligible companies.

Disclosure: Ninos Adams declares no relevant financial relationships with ineligible companies.