Dangers of Modavigil

25 June 2002

Published in The Age

Time may be our most essential commodity: it’s the fruit of worldly success, and the true currency of parental love. Getting more of it is an old dream, and the science of life-extension - of delaying death - is booming accordingly.

But death is not the only time-robber: there’s also sleep. And although it affords us a dream-life, lays down memory, and allows tissue to regenerate, science is now preparing to invade of the realm of sleep as well.

The advance guard is the new drug Modavigil, owned by the US pharmaceutical company Cephalon, which displays an unprecedented ability to “promote wakefulness” without being a stimulant. Modavigil can keep people awake and functioning (for 60 hours in one trial) without the unpleasant side-effects of, say, amphetamines or coffee. It joins one other drug in an entirely new class known as the eugeroics.

People commonly “feel normal” on Modavigil. And unlike amphetamine-users, Modavigil-takers can sleep if they want to. In the US, Modavigil is growing in popularity with healthy people (called “normals” in the trade) who wish to stay awake for social or work reasons.

The drug “works selectively on the sleep/wake centres of the brain believed to regulate normal wakefulness by activation of the cerebral cortex,” says Cephalon spokeswoman Sheryl Williams. Unlike more conventional stimulants, Modavigil “does not interfere with sleep because it does not elevate motor activity, which hypes the person up.”

But Modavigil isn’t without its downside. In one study, the drug induced headache in 23 percent of users, and nervousness in 12 percent. Other “common” side-effects include anxiety, depression, dizziness, infection, loss of muscle strength, lung problems, nausea, runny nose and sore throat. Modavigil also appears to decrease the effectivenes of oral contraceptives.

But, significantly, Modavigil-takers tend not to suffer impaired concentration or micro-sleeps, as do those who stay awake with mainstream stimulants. Two small double-blind trials suggested that amphetamine (one of the old-style stimulants) and Modavigil both kept people awake during the day when required, but that Modavigil alone did not impair nighttime sleep.

Modavigil will be available in Australia later this year. Therapeutic Goods Administration (TGA) spokesman John Noble says the drug is approved for “improving wakefulness in patients with excessive daytime sleepiness associated with narcolepsy”, a condition which causes its sufferers to involuntarily fall asleep at inappropriate times. The drug is approved for narcolepsy in several other countries too.

However Modavigil is also available through a website in the Channel Islands, prescription-free, to anyone willing to pay. (Whether the drug would pass customs in the countries of receipt is a different matter, though trade is obviously sufficient to support this web-based company.) The Age asked Sheryl Williams, spokeswoman for Cephalon in the US, whether the company approved of this practice.

Modavigil, she said, “is a prescription drug and should be obtained as a result of a careful medical evaluation and prescription from a licensed medical doctor.”

So has Cephalon declined to supply the Channel Islands company, where such safeguards clearly aren’t enforced?

“Cephalon sells it products to wholesalers who then sell the product to retailers and mail order and online pharmacies,” she said. “Therefore we are not the direct provider of the product to this site.”

In territories where Cephalon marketed the drug, Modavigil had $US150 million in sales last year. That’s an awful lot of people with narcolepsy, which - according to Associate Professor Trevor Norman from the University of Melbourne’s Department of Psychiatry - “is not a particularly common disorder”.

Since its approval by the US Food and Drug Administration (FDA) in December 1998, Modavigil has had a chequered history. In May 2001 it came through a trial on “excessive daytime sleepiness” (EDS) in Parkinson’s patients with flying colours. It looks promising for EDS from sleep apnea too. But in January this year, Cephalon was handed an official reprimand from the FDA for misleading advertising.

Cephalon’s literature had claimed that Modavigil could treat fatigue, tiredness, decreased activity, lack of energy and sleepiness in otherwise healthy people. But the drug had not been tested for these things, and the FDA found Cephalon’s advertising to be “overwhelmingly misleading”. It ordered it withdrawn.

Nevertheless, these claims go to the nub of the growing debate over Modavigil. If the drug is eventually shown to reduce the sleep requirement of healthy people, its market will expand geometrically. But could this happen now, before the appropriate studies have been done? John Noble from the TGA says:

“The practice of prescribing drugs for unapproved usages is referred to as the ‘off-label’ use of a medicine. The Commonwealth does not regulate the way in which an individual doctor prescribes a medication for an individual patient. This is a clinical judgement made by the practitioner for the individual patient.”

Given there’s no law preventing doctors from prescribing Modavigil “off-label”, what is to stop Modavigil usage spreading to truck drivers, shift-workers and party animals? By allowing such prescribing, are our federal authorities opening the door to abuses of the drug?

“I do not believe that potential abuse by a few should preclude a beneficial drug coming on to the market,” says Melbourne University’s Associate Professor Trevor Norman. “On the other hand intermittent use by people for the purpose of staying awake longer may ultimately be detrimental to normal sleep patterns by disrupting circadian rhythms... Since the drug has some effects on the central nervous system there might be an effect on psychomotor performance.”

Melbourne pharmacist Lesley Braun has several concerns, including Modavigil’s unstudied potential “to interact with other drugs in a powerful way”.

She is also concerned that “adverse effects developing in people as they unknowingly take the ‘wrong’ drug combination is one of the methods being used to detect interactions. Is this ethical with such a powerful drug?”

Then there’s the matter of Modavigil’s abuse potential:

“Have there been any studies to look at its effects on vigilance, and cognitive function, with long-term use in healthy people?” Braun asks.

“The signs of fatigue and sleepiness in a healthy person are important indicators that the body and/or mind require rest and relaxation. If these indicators are abolished, and people become insensitive to their body’s needs, it may well end up that the ongoing strain will lead to detrimental effects on the immune system, endocrine system and other vital processes.

“If a healthy person feels they require a stimulant on an ongoing basis, it is time to seek the help of a health professional who can look at the many aspects involved such as diet, lifestyle, sleep patterns and emotional issues.”

The US military is studying Modavigil as a way to keep soldiers and fighter pilots awake on long missions. According to a company spokesman, Modavigil’s Australian distributor, CSL, will not be marketing the drug to the Australian military.

However Sheryl Williams from Cephalon in the US says: “We plan to submit an a supplemental new drug application to the FDA by the end of 2002. That application will include studies of narcolepsy, sleep apnea and shift work sleep disorder. The intent is to have a broader label for treatment of sleep disorders.”

One way or another, it seems that the Realm of Morpheus is about to come under sustained attack.