# 259 Modafinil

FAST FACTS AND CONCEPTS #259 PDF

Authors: Jennifer Cheng MD and Hunter Groninger MD

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. Expanding research demonstrates potential indications for modafinil in cancer and non-cancer palliative care settings. This Fast Fact reviews use of modafinil for symptom management in the seriously ill.

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 methylphenidate, modafinil has low-abuse potential and less rapid development of tolerance (3).

Research Findings:

  • In cancer populations: One placebo-controlled trial with a 200 mg daily dose of modafinil resulted in significantly reduced excessive daytime sleepiness in patients with severe chemotherapy related fatigue (4). Modafinil has also been shown to be effective for specific symptoms in non-small cell lung cancer (fatigue, daytime drowsiness, depression), in breast cancer (fatigue), and in brain cancer (cognitive functioning, mood, and fatigue, and activity) (5) (6) (7). Finally, in advanced-stage cancer patients with Karnofsky performance status of 50-70%, modafinil 200 mg daily improved attention and psychomotor speed as well as subjective scores of drowsiness and depression (2).
  • 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 (8, 9). However, recent studies have not shown significant improvement in fatigue in patients with multiple sclerosis, Parkinson’s disease, and myotonic muscular dystrophy (10, 11, 12).

There are limited data comparing modafinil and methylphenidate in cancer and non-cancer populations; one open label pilot trial comparing modafinil with methylphenidate immediate release and methylphenidate sustained release in primary brain tumor patients found no significant difference in cognitive improvement between groups (13). Studies (4), (6), (7), (10) were sponsored by modafinil’s manufacturer.

Dosage: Lower doses (50-200 mg, once daily in the morning) are generally prescribed for fatigue and concentration difficulties, and higher doses (up to 600 mg/day) are used for excessive sleepiness (14).

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 (15).
  • In patients with severe hepatic impairment, reduce dose by 50%. Safety and efficacy have not been evaluated for patients with renal impairment (15). Use cautiously in patients with bipolar disorder or preexisting psychosis (may stimulate mania/hypomania) (16) and in patients with ischemic or structural heart disease (may precipitate palpitations, tachyarrhythmia, or chest pain) (15).

Cost: Modafinil costs approximately $608 for thirty 100 mg tablets compared to $33 for thirty tablets of methylphenidate 10 mg (17).

Summary: Palliative care patients are often seriously debilitated by fatigue, excessive daytime somnolence, and depression and modafinil may reduce these symptoms. Pending more conclusive randomized controlled trials, its use is likely limited by cost and availability. Nonetheless, even now modafinil may have a therapeutic niche when methylphenidate use is contraindicated or limited due to side effects.

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. 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.
  9. 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.
  10. 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.
  11. 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.
  12. 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.
  13. 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.
  14. Harris JD. Fatigue in chronically ill patients. Curr Opin Supp Pall Care. 2008; 2:180-186.
  15. 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.
  16. 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.
  17. Drugstore.com Online Pharmacy - Prescription Drugs, Health and Beauty, plus More. Available at: http://drugstore.com.  Accessed: 15 Mar 2012.

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

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

Fast Facts and Concepts are edited by Drew A Rosielle MD, Palliative Care Program, University of Minnesota Medical School and Fairview Health Services, and are published by the End of Life/Palliative Education Resource Center at the Medical College of Wisconsin. For more information write to: drosiel1@fairview.org.  More information, as well as the complete set of Fast Facts, are available at EPERC: http://www.mcw.edu/eperc.  

Copyright/Referencing Information: Users are free to download and distribute Fast Facts for educational purposes only.  Cheng J, Groninger H. Modafinil.  Fast Facts and Concepts. November 2012; 259.  Available at:  http://www.eperc.mcw.edu/EPERC/FastFactsIndex/ff_259.htm.

Disclaimer: Fast Facts and Concepts provide educational information. This information is not medical advice. Health care providers should exercise their own independent clinical judgment. Some Fast Facts cite the use of a product in a dosage, for an indication, or in a manner other than that recommended in the product labeling. Accordingly, the official prescribing information should be consulted before any such product is used.

ACGME Competencies: Patient Care, Medical Knowledge

Keywords: Non Pain Symptoms and Syndromes