Rapid Recent Rise in Modafinil Use

Pauline Anderson

March 22, 2013

Prescriptions for the narcolepsy drug modafinil have rapidly increased in recent years, and most of this increase is due to off-label use, according to a new study.

Because much of this use is among patients with depression and multiple sclerosis (MS) — conditions that were excluded from clinical trials that formed the basis of regulatory approval of this drug — there is a concern about the potential for adverse events, said study author David M. Claman, MD, professor of medicine and director of the University of California at San Francisco Sleep Disorders Center.

Many drugs are used off label, but the expansion of modafinil within a relatively short period of time is "striking," said Dr. Claman.

The study appeared in a Research Letter published online March 18 in JAMA Internal Medicine

15-Fold Increase

Using the National Ambulatory Medical Care Survey, a representative sample of ambulatory visits, researchers examined modafinil use from January 1, 2002, to December 31, 2009.

During that period, the number of patients receiving modafinil increased almost 10-fold, from 57,768 to 555,691. On-label use increased by less than 3-fold, but off-label use (where there was no on-label diagnosis) increased more than 15-fold.

Across all years, 89% of patients prescribed modafinil did not have an on-label diagnosis. Patients with depression accounted for 18% of all modafinil prescriptions, and those with multiple sclerosis, 12%.

The study found an association between modafinil use and several off-label indications, including MS (odds ratio [OR], 84.6, 95% confidence interval [CI], 50.0 - 143.0), Parkinson's disease (OR, 19.4; 95% CI, 6.7 - 56.1), chronic fatigue syndrome (OR, 23.4; 95% CI, 4.6 - 118.0), depression (OR, 10.8; 95% CI, 6.0 – 19.5), and attention deficit/hyperactivity disorder (ADHD) (OR, 5.4; 95% CI, 2.3 - 12.6) relative to the absence of a given diagnosis.

According to the authors, the association between modafinil and depression and MS is especially noteworthy given that the trials on which the US Food and Drug Administration (FDA) approved the drug excluded patients with these diseases.

Patients treated by psychiatrists (OR, 21.1) and neurologists (OR, 19.7) had higher odds of receiving modafinil relative to primary care physicians and other specialists, the study found.

Altogether, 45% of patients receiving modafinil were also receiving an antidepressant, whereas 15% were also receiving a benzodiazepine and 6% an amphetamine. The authors noted that the clinical trials of modafinil excluded antidepressant and benzodiazepine use.

The authors noted that the company that markets modafinil, Cephalon Inc, was sued by several US states for promoting modafinil for off-label indications and agreed to a settlement in 2008. That marketing might explain some of the increase in off-label use, but there was still a substantial increase in use after the case was settled.

Dr. Claman speculated that drug companies are now "better at staying within FDA-approved guidelines" for marketing.

Although the paper raises the concern about the increased off-label use of modafinil, it doesn't determine whether this is a "big concern" because of drug interactions and adverse effects or a "small concern" in that it seems to be well tolerated, said Dr. Claman.

To help address that question, Dr. Claman advocates what he calls a "post drug release registry" of patients taking modafinil for nonapproved indications that could be administered by the FDA, pharmacies, or the drug company itself. Such a registry, he said, would provide better information about adverse-effect risk profiles in the "real world" that were unavailable with the more restricted and limited FDA studies.

Increase Not Surprising

For sleep expert Merrill S. Wise, MD, Methodist Health Care Sleep Disorders Center, Memphis, Tennessee, who is on the board of the American Academy of Sleep Medicine, the rapid increase in prescriptions for modafinil is not surprising.

"While I confine my clinical use of modafinil almost exclusively to FDA 'on-label' indications, I see patients with some regularity who come to me already receiving modafinil or the newer form, armodafinil, for sleepiness in association with depression, multiple sclerosis, chronic fatigue syndrome, and several other conditions."

Clinical trials that include patients with depression and MS taking modafinil or armodafinil for sleepiness would be helpful, said Dr. Wise.

"Patients and healthcare providers would benefit from additional data regarding adverse side effects and reactions to modafinil in these patient groups. In particular, we would benefit from having a clearer understanding of which individuals are at increased risk for allergic/hypersensitivity reactions to modafinil."

Reports indicate that the FDA did not approve modafinil in children partly because of rare reports of a serious skin rash.

Dr. Wise noted that the research letter does not address the presence or extent of "drug diversion" or selling modafinil to nonpatients. "Although this is theoretically a contributor to the increase in off-label use, there isn't much evidence of modafinil being a popular drug of abuse, and laboratory animal studies don't suggest much tendency for addiction."

It could be argued, though, that modafinil is a safer than traditional stimulants and certainly a lot safer than abusing illicit substances such as cocaine, he said.

Another sleep specialist, Marc Raphaelson, MD, medical director, SleepMed, Washington, DC region, is also not surprised at the increasing off-label use of modafinil. Much of this can be attributed, he said, to the fact that there is no approved treatment for the "enormous" number of people with idiopathic sleepiness or hypersomnolence.

"There are a lot of people who are sleepy but don't meet the strict diagnostic criteria for narcolepsy, so anything you treat them with is going to be off-label," said Dr. Raphaelson.

"It's not that doctors are throwing drugs at people who don't need them; it's that we have people with real, severe sleepiness, we can't get an exact diagnosis, there's no on-label therapy, and we're not just going to send them home to have car crashes," he said.

Dr. Raphaelson also noted that some patients develop tolerance to stimulants typically used for ADHD.

The study was supported by a grant from the National Institutes of Health/National Heart, Lung, and Blood Institute. Dr. Claman, Dr. Wise, and Dr. Raphaelson have disclosed no relevant financial relationships.

JAMA Intern Med. Published online March 18, 2013. Abstract

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