Background      Modafinil is a non-amphetamine psychostimulant approved for the treatment of excessive daytime somnolence associated with obstructive sleep apnea, narcolepsy, and shift work sleep disorder. This Fast Fact assimilates major findings from the published medical literature on the use of modafinil for symptom management in the seriously ill.  See Fast Facts #173 for additional information on cancer related fatigue (CRF) and Fast Fact #51 for information on psychostimulants in general.

Pharmacology     Although the exact mechanism is unclear, modafinil’s action may involve enhanced catecholaminergic signaling and decreased gamma aminobutryic acid (GABA) release, primarily at the anterior hypothalamus (1,2). Rapidly absorbed after oral ingestion, the drug reaches peak plasma levels in 2-4 hours, with a half-life of 10-13 hours. It is primarily metabolized by the liver, with subsequent renal elimination of inactive metabolites. Compared to other commonly prescribed psychostimulants (e.g. methylphenidate or dextroamphetamine), it has low-abuse potential and less rapid development of tolerance (3). Consequently, modafinil is a scheduled IV controlled substance whereas methylphenidate and many other psychostimulants are controlled II substances.

Research Findings

• In cancer populations: A preliminary placebo-controlled trial resulted in significantly reduced daytime sleepiness in patients with severe CRF treated with daily modafinil (4). In other pilot studies, modafinil was shown to be effective for specific symptoms in a) non-small cell lung cancer (CRF, daytime drowsiness, depression), b) breast cancer (CRF), c) brain cancer (cognitive functioning, mood, and CRF), and d) advanced cancer with Karnofsky performance status of 50-70% (improved attention and psychomotor speed; reduced drowsiness and depression) (2, 5-7). Subsequently, two double-blind, placebo-controlled trials have suggested that modafinil is not associated with any additional benefit over placebo in the management of CRF nor in secondary outcomes such as daytime sleepiness, depression, and quality of life (8,9). Because these studies also associated modafinil with more nausea and vomiting, the National Comprehensive Cancer Network has removed modafinil from its guidelines on CRF management (10).
• In non-cancer conditions: Generally, these smaller controlled trials have generated conflicting results. Compared to placebo, use of modafinil may reduce fatigue in patients with HIV/AIDS and amyotrophic lateral sclerosis (11,12). However, recent studies have not shown significant improvement in fatigue in patients with multiple sclerosis, Parkinson’s disease, and myotonic muscular dystrophy (13-15).
• Comparative data:  There are limited data comparing modafinil and methylphenidate in cancer and non-cancer populations; one open label pilot trial comparing modafinil with methylphenidate in primary brain tumor patients found no significant difference in cognitive improvement between groups (16).

Dosage    Lower doses (50-200 mg, once daily in the morning) are generally prescribed for fatigue and concentration difficulties;higher doses (up to 600 mg/day) are used for excessive sleepiness (17).

Toxicity and Precautions

• More common side effects includes dose related headaches (34%), nausea (11%), nervousness (7%), and diarrhea (6%). Hypertension rarely occurs, but monitoring of blood pressure is recommended (18).
• In patients with severe hepatic impairment, reduce dose by 50%. Safety and efficacy have not been evaluated for patients with renal impairment (19). Use cautiously in patients with bipolar disorder or preexisting psychosis (may stimulate mania/hypomania) and in patients with ischemic or structural heart disease (may precipitate palpitations, tachyarrhythmia, or chest pain) (20).

Cost     Generic modafinil costs approximately $650 for thirty 100 mg tablets compared to about $70 for a comparable month long supply of sixty tablets of 10 mg tablets of generic methylphenidate (20).

Use in Pediatrics    Modafinil’s most established pediatric role is for ADHD management.  However, reports of serious dermatologic adverse effects and psychiatric events led the FDA to limit it as a second or third-line treatment for ADHD.  Therefore, the off-label use of modafinil to treat CRF in children should be strongly cautioned against.

Summary     Palliative care patients are often seriously debilitated by fatigue, excessive daytime somnolence, and depression.  There is conflicting evidence about the usefulness of modafinil in improving CRF. Pending more conclusive randomized controlled trials, its use is likely limited by cost, gastrointestinal side effects, and availability.

References

1. Lin J-S, Hou Y, Jouvet M. Potential brain neural targets for amphetamine-, methylphenidate-, and modafinil-induced wakefulness, evidenced by c-fos immunochemistry in the cat. Proc Natl Acad Sci USA. 1996; 93:14128-14133.
2. Ludorff LE, Jonsson BH, Sjogren P. Modafinil for attentional and psychomotor dysfunction in advanced cancer: a double-blind, randomized, cross-over trial. Palliat Med. 2009; 23(8): 731-738.
3. Webster L, Andrews M, Stoddard G. Modafinil treatment of opioid-induced sedation. Pain Med. 2003; 4:135-140.
4. Jean-Pierre P, Morrow GR, Roscoe JA. A phase 3 randomized, placebo-controlled, double-blind, clinical trial of the effect of modafinil on cancer-related fatigue among 631 patients receiving chemotherapy. Cancer. 2010; 116:3513-3520.
5. Spathis A, Dhillan R, Booden D, et al. Modafinil for the treatment of fatigue in lung cancer: a pilot study. Palliat Med. 2009; 23:325-331.
6. Morrow GR, Gillies LJ, Hickok JT, et al. The positive effect of the psychostimulant modafinil on fatigue from cancer that persists after treatment is completed. J Clin Oncol.  2005; 3(Suppl.):8012.
7. Kaleita TA, Wellisch DK, Graham CA, et al. Pilot study of modafinil for treatment of neurobehavioral dysfunction and fatigue in adult patients with brain tumors. J Clin Oncol. 2006; 24(Suppl.):1503.
8. Spathis A, Fife K, et al.  Modafinil for the treatment for fatigue in lung cancer: results of a placebo controlled, double-blind, randomized trial.  Journal of Clinical Oncology 2014;32:1882-88.
9. Hover E, de Souza P, Marx G, et al.  Phase III, randomized, double-blind, placebo-cotrolled study of modafinil for fatigue in patients treated with docetaxel-based chemotherapy.  Support Care Cancer 2014; 22:1233-1242.
10. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Cancer-Related Fatigue (version 2.0), 2015.
11. Rabkin JG, McElhiney MC, Rabkin R, McGrath P. Modafinil treatment for fatigue in patients with HIV/AIDS: a placebo controlled study. J Clin Psych. 2010; 71(6):707-715.
12. Rabkin JG, Gordon PH, McElhiney M, et al. Modafinil treatment of fagitue in patients with ALS: a placebo-controlled study. Muscle Nerve.  2009; 39:297-303.
13. Moller F, Poettgen J, Broemel F, et al. HAGIL (Hamburg Vigil Study): a randomized placebo-controlled double-blind study with modafinil for treatment of fatigue in patients with multiple sclerosis. Mult Scler.  2011; 17:1002-1009.
14. Seppi K, Weintraub D, Coelho M, et al. The Movement disorder society evidence-based medicine review update: treatments for the non-motor symptoms of Parkinson’s disease. Movement Disorders. 2011; 26(S3):42-80.
15. Orlikowski D, Chevret S, Quera-Salva MA, et al. Modafinil for the treatment of hypersomnia associated with myotonic muscular dystrophy in adults: a multicenter, prospective, randomized, double-blind, placebo-controlled, 4-week trial. Clin Therap. 2009; 31(8):1765-1773.
16. Gehring K, Patwardhan SY, Collins R, et al. A randomized trial on the efficacy of methylphenidate and modafinil for improving cognitive functioning and symptoms in patients with a primary brain tumor. J Neurooncol. 2012; 107(1):165-7.
17. Harris JD. Fatigue in chronically ill patients. Curr Opin Supp Pall Care. 2008; 2:180-186.
18. Modafinil: drug information. In PDR® Electronic Library™ (n.d.). Retrieved on May 10, 2012, from http://www.thomsonhc.com . Greenwood Village, CO : Thomson Reuters (Healthcare) Inc.
19. Wingo AP, Ghaemi SN. Frequency of stimulant treatment and of stimulant-associated mania/hypomania in bipolar disorder patients. Psychopharmacol Bull. 2008; 41(4):37-47.
20. Modafinil: drug information. In: UpToDate, Post TW (Ed), UpToDate, Waltham, MA. (Accessed November 25, 2015).

Authors’ Affiliations: Johns Hopkins University School of Medicine, Baltimore, MD (JC); Medical College of Wisconsin; Clinical Center, National Institutes of Health, Bethesda, MD (HG).

Conflicts of Interest Statement: The authors have disclosed no relevant conflicts of interest.

Version History: First electronically published in August 2012.  Significant revision occurred in November 2015 by Elizabeth L Thiel MD to reflect the evolution in the published literature on modafinil.