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Research Letters |

Trends in On-label and Off-label Modafinil Use in a Nationally Representative Sample FREE

Renée A. Peñaloza, MS; Urmimala Sarkar, MD, MPH; David M. Claman, MD; Theodore A. Omachi, MD, MBA
[+] Author Affiliations

Author Affiliations: Institute for Health Policy Studies (Ms Peñaloza), Divisions of General Internal Medicine (Dr Sarkar) and Pulmonary, Critical Care, and Sleep Medicine (Drs Claman and Omachi), Department of Medicine, and the Cardiovascular Research Institute (Dr Omachi), University of California, San Francisco; and the Center for Vulnerable Populations, San Francisco General Hospital, San Francisco (Dr Sarkar).


JAMA Intern Med. 2013;173(8):704-706. doi:10.1001/jamainternmed.2013.2807.
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Modafinil is a nonamphetamine stimulant approved for narcolepsy, obstructive sleep apnea, and shift-work sleep disorder.1 Off-label use is often recommended, but regulatory agencies have raised concerns about hypersensitivity reactions and neuropsychiatric adverse effects.1,2 It is unclear how often and for which conditions modafinil is being prescribed in clinical practice.

Using the National Ambulatory Medical Care Survey, a nationally representative sample of ambulatory visits, we examined modafinil use from January 1, 2002, through December 31, 2009.3 We categorized patients by whether or not they had an on-label indication for modafinil, defining off-label use as the absence of an on-label diagnosis, and examined the association between modafinil use and specific off-label indications.1 We further examined modafinil use among patients treated by psychiatrists, neurologists, pulmonologists, and otolaryngologists relative to primary care physicians and other specialists. Finally, we examined the association between modafinil use and other centrally acting medications that might interact with modafinil: antidepressants, benzodiazepines, and amphetamines. In multivariate logistic regression, modafinil use was the outcome, and the predictor variables of interest were, in separate models, diagnostic indication, physician specialty, and concurrent medication. Analyses controlled for age, sex, race/ethnicity, payer, geographic region, and survey year. Analyses were survey weighted and performed using statistical software (Stata/IC, version 12; StataCorp). A supplemental description of our methods is available online (eMethods).

The number of patients receiving modafinil increased almost 10-fold during the study period, from 57 768 in 2002 to 555 691 in 2009. On-label use increased by less than 3-fold, whereas off-label use increased more than 15-fold (Figure). Across all years, 89% of patients prescribed modafinil did not have an on-label diagnosis, and patients with depression and multiple sclerosis accounted for 18% and 12%, respectively, of all modafinil prescriptions. Multivariate analyses demonstrated an association between modafinil use and each examined potential off-label indication: multiple sclerosis, (odds ratio [OR], 84.6; 95% CI, 50.0-143.0), Parkinson disease (19.4; 6.7-56.1), chronic fatigue syndrome (23.4; 4.6-118.0), depression (10.8; 6.0-19.5), and attention-deficit/hyperactivity disorder (5.4; 2.3-12.6) relative to the absence of a given diagnosis (eTable 1). Patients treated by psychiatrists (OR, 21.1; 95% CI, 13.2-33.7) and neurologists (19.7; 12.3-31.5) had higher odds of receiving modafinil relative to primary care physicians and other specialists, whereas patients seeing pulmonologists and otolaryngologists were not statistically more likely to be receiving modafinil (eTable 2). Each examined medication class was associated with increased odds of concurrently receiving modafinil: antidepressants (OR, 8.4; 95% CI, 5.4-13.2), benzodiazepines (5.0; 3.5-10.3), and amphetamines (8.7; 4.2-18.6). Altogether, 45% of patients receiving modafinil were also receiving an antidepressant, whereas 15% were receiving a benzodiazepine and 6%, an amphetamine.

Place holder to copy figure label and caption
Graphic Jump Location

Figure. The number of patients receiving modafinil for on-label vs off-label use. Limit lines indicate standard error.

These analyses indicate the rapid recent increase in modafinil use and suggest that most prescriptions are for off-label indications. That modafinil appears strongly associated with depression and multiple sclerosis is especially noteworthy given that the trials on which the US Food and Drug Administration approved modafinil excluded patients with such diseases.47 Similarly, antidepressants and benzodiazepines were excluded from these trials.47

To place temporal trends into context, certain events related to modafinil's marketing and adverse event reporting should be noted. Cephalon, Inc, which markets modafinil, was sued by multiple US states for promoting modafinil for off-label indications and agreed to a multimillion dollar settlement in 2008.8 This may suggest that some degree of off-label marketing was responsible for increases in off-label use. Nonetheless, substantial increases in modafinil use occurred between 2008 and 2009, after this case was settled. Of note, modafinil use declined substantially between 2005 and 2006. This may have been the result of reports released during that time of modafinil-associated hypersensitivity reactions.9 Despite that precipitous 1-year decline, modafinil use soon recovered.

Our study has important limitations. Data about the specific diagnosis for which modafinil was prescribed were not available. In addition, only the top 3 diagnoses per encounter were listed, and we cannot exclude the possibility that an on-label indication may have existed. Nonetheless, the results strongly suggest that off-label indications are responsible for a large share of prescriptions given that patients receiving modafinil without an on-label diagnosis increased by 15-fold while those with an on-label diagnosis increased by only 3-fold. Also, off-label indications for which modafinil has commonly been recommended are strongly associated with its use. Finally, patients are much more likely to be receiving modafinil if they are being seen by a psychiatrist or neurologist—specialists who treat off-label indications, such as depression, multiple sclerosis, and Parkinson disease.

Modafinil use is increasing rapidly, which appears in large part to result from off-label prescribing. Given that modafinil is often being used in patients with comorbid conditions and concurrent medications that do not reflect the populations that formed the basis for regulatory approval, this raises concerns about the potential for adverse events and indicates the need for further study of unapproved indications.

Correspondence: Dr Omachi, Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, University of California, San Francisco, 3333 California St, Ste 270, San Francisco, CA 94118 (omachi@ucsf.edu).

Published Online: March 18, 2013. doi:10.1001/jamainternmed.2013.2807

Author Contributions: Ms Peñaloza and Dr Omachi had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Peñaloza, Sarkar, and Omachi. Acquisition of data: Peñaloza and Omachi. Analysis and interpretation of data: Peñaloza, Claman, and Omachi. Drafting of the Manuscript: Peñaloza and Omachi. Critical revision of the manuscript for important intellectual content: Sarkar, Claman, and Omachi. Statistical analysis: Peñaloza and Omachi. Obtaining funding: Omachi. Study supervision: Claman and Omachi.

Conflict of Interest Disclosure: None reported.

Funding/Support: This research was supported by grant K23 HL102159 from the National Heart, Lung, and Blood Institute, National Institutes of Health.

Ballon JS, Feifel D. A systematic review of modafinil: potential clinical uses and mechanisms of action.  J Clin Psychiatry. 2006;67(4):554-566
PubMed   |  Link to Article
European Medicines Agency.  Assessment report for modafinil containing medicinal products. In: Patient Health Protection. 7th ed. London, England: European Medicines Agency; 2011:17-25
Centers for Disease Control and Prevention.  National Ambulatory Medical Care Survey (NAMCS) Micro-data File Documentation. Hyattsville, MD: National Center for Health Statistics; 2009
US Modafinil in Narcolepsy Multicenter Study Group.  Randomized trial of modafinil for the treatment of pathological somnolence in narcolepsy.  Ann Neurol. 1998;43(1):88-97
PubMed   |  Link to Article
Pack AI, Black JE, Schwartz JR, Matheson JK. Modafinil as adjunct therapy for daytime sleepiness in obstructive sleep apnea.  Am J Respir Crit Care Med. 2001;164(9):1675-1681
PubMed   |  Link to Article
Kingshott RN, Vennelle M, Coleman EL, Engleman HM, Mackay TW, Douglas NJ. Randomized, double-blind, placebo-controlled crossover trial of modafinil in the treatment of residual excessive daytime sleepiness in the sleep apnea/hypopnea syndrome.  Am J Respir Crit Care Med. 2001;163(4):918-923
PubMed   |  Link to Article
Czeisler CA, Walsh JK, Roth T,  et al; US Modafinil in Shift Work Sleep Disorder Study Group.  Modafinil for excessive sleepiness associated with shift-work sleep disorder.  N Engl J Med. 2005;353(5):476-486
PubMed   |  Link to Article
Kesselheim AS, Mello MM, Studdert DM. Strategies and practices in off-label marketing of pharmaceuticals: a retrospective analysis of whistleblower complaints.  PLoS Med. 2011;8(4):e1000431
PubMed  |  Link to Article   |  Link to Article
Food and Drug Administration; Department of Health and Human Services; Center for Drug Evaluation and Research.  Psychopharmacologic drug advisory committee [transcript]. March 23, 2006. http://www.fda.gov/ohrms/dockets/ac/06/transcripts/2006-4212T1-Part1.htm. Accessed May 19, 2012

Figures

Place holder to copy figure label and caption
Graphic Jump Location

Figure. The number of patients receiving modafinil for on-label vs off-label use. Limit lines indicate standard error.

Tables

References

Ballon JS, Feifel D. A systematic review of modafinil: potential clinical uses and mechanisms of action.  J Clin Psychiatry. 2006;67(4):554-566
PubMed   |  Link to Article
European Medicines Agency.  Assessment report for modafinil containing medicinal products. In: Patient Health Protection. 7th ed. London, England: European Medicines Agency; 2011:17-25
Centers for Disease Control and Prevention.  National Ambulatory Medical Care Survey (NAMCS) Micro-data File Documentation. Hyattsville, MD: National Center for Health Statistics; 2009
US Modafinil in Narcolepsy Multicenter Study Group.  Randomized trial of modafinil for the treatment of pathological somnolence in narcolepsy.  Ann Neurol. 1998;43(1):88-97
PubMed   |  Link to Article
Pack AI, Black JE, Schwartz JR, Matheson JK. Modafinil as adjunct therapy for daytime sleepiness in obstructive sleep apnea.  Am J Respir Crit Care Med. 2001;164(9):1675-1681
PubMed   |  Link to Article
Kingshott RN, Vennelle M, Coleman EL, Engleman HM, Mackay TW, Douglas NJ. Randomized, double-blind, placebo-controlled crossover trial of modafinil in the treatment of residual excessive daytime sleepiness in the sleep apnea/hypopnea syndrome.  Am J Respir Crit Care Med. 2001;163(4):918-923
PubMed   |  Link to Article
Czeisler CA, Walsh JK, Roth T,  et al; US Modafinil in Shift Work Sleep Disorder Study Group.  Modafinil for excessive sleepiness associated with shift-work sleep disorder.  N Engl J Med. 2005;353(5):476-486
PubMed   |  Link to Article
Kesselheim AS, Mello MM, Studdert DM. Strategies and practices in off-label marketing of pharmaceuticals: a retrospective analysis of whistleblower complaints.  PLoS Med. 2011;8(4):e1000431
PubMed  |  Link to Article   |  Link to Article
Food and Drug Administration; Department of Health and Human Services; Center for Drug Evaluation and Research.  Psychopharmacologic drug advisory committee [transcript]. March 23, 2006. http://www.fda.gov/ohrms/dockets/ac/06/transcripts/2006-4212T1-Part1.htm. Accessed May 19, 2012

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