What is/are Modafinil?
Modafinil is a wakefulness-promoting drug (eugeroic) that is approved by the United States' Food and Drug Administration (FDA) for the treatment of narcolepsy, shift work sleep disorder and excessive daytime sleepiness associated with obstructive sleep apnea.
In the United States, modafinil is approved by the U.S. Food and Drug Administration only for the treatment of narcolepsy, shift work sleep disorder, and as an adjunct treatment for obstructive sleep apnea/hypopnea. In some countries, it is also approved for other hypersomnias, like idiopathic hypersomnia. The usual prescribed dosage for these disorders is 200 mg once a day (less commonly, 100 to 400 mg/day in one or two doses).
For conditions other than shift work sleep disorder, modafinil is normally taken in one dose in the morning or in two doses in the morning and at midday. It is generally not recommended to take modafinil after noon: modafinil is a relatively long-acting drug with a half-life of 15 hours, and taking it during the later part of the day carries a risk of sleep disturbances.
Because of the risk for development of skin or hypersensitivity reactions and neuropsychiatric disorders, the European Medicines Agency has recommended that new patient prescriptions should only be to treat sleepiness associated with narcolepsy. Because any serious side effects will usually appear within the first twelve weeks, the guidance does not require patients already receiving treatment to stop taking the drug.
Modafinil was shown to be an effective treatment for attention deficit hyperactivity disorder(ADHD); however, in 2006, it was found by the FDA to be unfit for use by children for that purpose. It was rejected primarily due to two cases of serious skin rash, suspected to have been Erythema multiforme or Stevens–Johnson syndrome, among 933 subjects receiving the drug. Cephalon's own label for Provigil now discourages its use by children for any purpose.
Other potentially effective, but unapproved uses include the treatment of depression, bipolar depression, opiate and cocaine dependence, Parkinson's disease, schizophrenia, and disease-related fatigue, as well as fatigue that is the side effect of another medication.
Modafinil may be also an effective and well-tolerated treatment in patients with seasonal affective disorder.
A randomized double-blind study of modafinil showed that normal healthy volunteers between the ages of 30-44 showed general improvement in alertness as well as mood. In the three-day study, counterbalanced, randomized, crossover, inpatient trial of modafinil 400 mg was administered as well as a placebo to the control group. The conclusion demonstrated that modafinil may have general mood-elevating effects in particular for the adjunctive use in treatment-resistant depression.
Modafinil used alone has been reported to be effective in a subgroup of individuals with depersonalization disorder; the subgroup of people with depersonalization disorder most likely to respond are those who have attentional impairments, under-arousal and hypersomnia. However, clinical trials have not been conducted. Dr. Evan Torch calls a combination of an SSRI and Modafinil "the hidden pearl that can really help depersonalization disorder".
There is disagreement to whether the cognitive effects modafinil showed in healthy non-sleep-deprived people are sufficient to consider it to be a cognitive enhancer. The researchers agree that modafinil improves some aspects of working memory, such as digit span, digit manipulation and pattern recognition memory, but the results related to spatial memory, executive function and attention are equivocal. Some of the positive effects of modafinil may be limited to "lower-performing" individuals. One study found that modafinil restored normal levels of learning ability in methamphetamine addicts, but had no effect on non-addicts.
There is evidence of neuroprotective effects in rats.
Modafinil has also found off-label use with the neurological fatigue reported by some with multiple sclerosis. In 2000, Cephalon conducted a study to evaluate modafinil as a potential treatment for MS-related fatigue. A group of 72 people with MS of varying degrees of severity tested two different doses of modafinil and an inactive placebo over nine weeks. Fatigue levels were self-evaluated on standardized scales. Participants taking a lower dose of modafinil reported feeling less fatigued and there was a statistically significant difference in fatigue scores for the lower dose versus the placebo. The higher dose of modafinil was not reported to be significantly more effective.
Modafinil is also used off-label to treat sedation and fatigue in many conditions, including depression, fibromyalgia, chronic fatigue syndrome, myotonic dystrophy, opioid-induced sleepiness, spastic cerebral palsy, and Parkinson's disease. Modafinil has been shown to improve excessive daytime somnolence and fatigue in primary biliary cirrhosis.
It has been reported to reduce jet lag and increase subjective mood and friendliness among shift workers. It is also prescribed by sleep physicians for delayed sleep phase syndrome, which causes excessive daytime somnolence when the natural (delayed) diurnal rhythm is replaced by a socially determined earlier or forward shifted sleep schedule. The resultant wakefulness and neuro-behavioural impairments are comparable to those of travel-associated jet lag and persist as long as the forward shifted sleep schedule is maintained. A similar phenomenon commonly experienced by students and workers with varying sleep schedules during the week is often referred to as "social jet lag" and has been implicated in metabolic disorders and obesity.
Modafinil is under investigation as a possible method to treat cocaine dependence, for several reasons involving biochemical mechanisms of the two drugs, as well as the observation that clinical effects of modafinil are largely opposite to symptoms of cocaine withdrawal.
The pilot 8-week double-blind study of modafinil for cocaine dependence (2004) produced inconclusive results. The number of cocaine-positive urine samples was significantly lower in the modafinil group as compared to the placebo group in the middle of the trial, but by the end of the 8 weeks the difference stopped being significant. Even before the treatment began, the modafinil group had lower cocaine consumption further confounding the results. As compared to placebo, modafinil did not reduce cocaine craving or self-reported cocaine use, and the physicians ratings were only insignificantly better. Dan Umanoff, of the National Association for the Advancement and Advocacy of Addicts, criticized the authors of the study for leaving the negative results out of the discussion part and the abstract of the article.
A later double-blind study of modafinil in people seeking treatment for cocaine dependence found no statistically significant effect on the rate of change in percentage of cocaine non-use days, but noted a significant improvement in some secondary outcomes such as the maximum number of consecutive non-use days for cocaine.
Post-chemotherapy cognitive impairment
Modafinil has been used off-label in trials with people with symptoms of post-chemotherapy cognitive impairment, also known as "chemobrain", but in 2011 it was found to be no better than placebo. As of 2011 there was no evidence to support using it to reduce fatigue in palliative care.
Studies on modafinil (even those on healthy weight individuals) indicate that it has an appetite reducing/weight loss effect. All studies on modafinil in the Medline database that are for one month or longer which report weight changes find that modafinil users experience weight loss compared to placebo. In 2008, one small-scale study on individuals performing simulated shift work quantified the effect as a 18% decrease in total caloric intake on 200 mg/day, and a 38% decrease on 400 mg/day.
However, the prescribing information for Provigil notes that "There were no clinically significant differences in body weight change in patients treated with PROVIGIL compared to placebo-treated patients in the placebo-controlled clinical trials."
In experimental studies, the appetite reducing effect of modafinil appears to be similar to that of amphetamines, but, unlike amphetamines, the dose of modafinil that is effective at decreasing food intake does not significantly increase heart rate. Also, an article published in the Annals of Clinical Psychiatry, presented the case of a 280 pound patient (BMI=35.52) who lost 40 pounds over the course of a year on Modafinil (to 30.44 BMI). After three years, his weight stabilized at a 50 pound weight loss (29.59 BMI). The authors conclude that placebo controlled studies should be conducted on using Modafinil as a weight loss agent. Conversely, a US patent (#6,455,588) on using modafinil as an appetite stimulating agent has been filed by Cephalon in 2000.
Modafinil has received some publicity in the past when several athletes (such as sprinter Kelli White in 2004, cyclist David Clinger and basketball player Diana Taurasi in 2010) were discovered allegedly using it as a performance-enhancing doping agent. (Taurasi and another player, Monique Coker, tested at the same lab, were later cleared.) It is not clear how widespread this practice is. The BALCO scandal brought to light an as-yet unsubstantiated (but widely published) account of Major League Baseball's all-time leading home-run hitter Barry Bonds' supplemental chemical regimen that included Modafinil in addition to anabolic steroids and human growth hormone. Modafinil has been shown to prolong exercise time to exhaustion while performing at 85% of VO2max and also reduces the perception of effort required to maintain this threshold. Modafinil was added to the World Anti-Doping Agency "Prohibited List" in 2004 as a prohibited stimulant (see Modafinil Legal Status).
In the 1980s, modafinil was used by French students. Recently modafinil has become popular in performance-enhancing use by university students and corporate executives in the United Kingdom. Some students obtain the drug through illicit means (diversion of prescribed medication), whilst others obtain it through online pharmacies.
Military and law enforcement
Militaries of several countries are known to have expressed interest in Modafinil as an alternative to amphetamines—the drug traditionally employed in combat situations where troops face sleep deprivation, such as during lengthy missions. The French government indicated that the Foreign Legion used modafinil during certain covert operations. The United Kingdom's Ministry of Defence commissioned research into modafinil from QinetiQ and spent £300,000 on one investigation. In 2011, the Indian Air Force announced that modafinil was included in contingency plans. The Indian Armed Forces Medical Services is researching its use.
In the United States military, Modafinil has been approved for use on certain Air Force missions, and it is being investigated for other uses. One study of helicopter pilots suggested that 600 mg of modafinil given in three doses can be used to keep pilots alert and maintain their accuracy at pre-deprivation levels for 40 hours without sleep. However, significant levels of nausea and vertigo were observed. A second helicopter study found modafinil was comparable to dextroamphetamine and was well-tolerated. Another study of fighter pilots showed that modafinil given in three divided 100 mg doses sustained the flight control accuracy of sleep-deprived F-117 pilots to within about 27 percent of baseline levels for 37 hours, without any considerable side effects. In an 88-hour sleep loss study of simulated military grounds operations, 400 mg/day doses were mildly helpful at maintaining alertness and performance of subjects compared to placebo, but the researchers concluded that this dose was not high enough to compensate for most of the effects of complete sleep loss. In law enforcement, tactical paramedics in Maryland (US) may administer 200 mg of modafinil once daily in order to "enhance alertness / concentration" and "facilitate functioning with limited rest periods."
The Canadian Medical Association Journal also reports that Modafinil is used by astronauts on long-term missions aboard the International Space Station. Modafinil is "available to crew to optimize performance while fatigued" and helps with the disruptions in circadian rhythms and with the reduced quality of sleep astronauts experience.
Modafinil is less likely than its parent drug, adrafinil, to cause side-effects such as stomach pain, skin irritation, anxiety and (with prolonged use) elevated liver enzymes. Common side effects of modafinil include:
Serious side effects include:
- Back pain
- Stuffy nose
- Upset stomach
- Trouble sleeping
- Serious rash
- Serious allergic reaction involving the liver or blood cells
- Mouth sores
- Blistering or peeling skin
- Swelling of the face, eyes, lips, tongue, legs, or throat
- Trouble swallowing or breathing
- Shortness of breath
In 2007, the FDA ordered Cephalon to modify the Provigil leaflet in bold-face print of several serious and potentially fatal conditions attributed to modafinil use, including toxic epidermal necrolysis (TEN), DRESS syndrome, and Stevens-Johnson syndrome (SJS). The long term safety and effectiveness of modafinil have not been determined. Modafinil may have an adverse effect on hormonal contraceptives, lasting for a month after cessation of dosage.
In mice and rats, the median lethal dose (LD50) of modafinil is approximately or slightly greater than 1250 mg/kg. Oral LD50 values reported for rats range from 1000 mg/kg to 3400 mg/kg. Intravenous LD50 for dogs is 300 mg/kg. Clinical trials on humans involving taking up to 1200 mg/day for 7 to 21 days and known incidents of acute one-time overdoses up to 4500 mg did not appear to cause life-threatening effects, although a number of adverse experiences were observed, including excitation or agitation, insomnia, anxiety, irritability, aggressiveness, confusion, nervousness, tremor, palpitations, sleep disturbances, nausea, and diarrhea. As of 2004, FDA is not aware of any fatal overdoses involving modafinil alone (as opposed to multiple drugs, including modafinil). Consequently, oral LD50 of modafinil in humans is not known exactly. However, it appears to be higher than oral LD50 of caffeine. Bastuji and Jouvet describe a suicide attempt using 4500 mg of modafinil; the patient survived with no long-term effects but temporary nervousness, nausea, and insomnia. A similar incident involving a suicide attempt by a 15 year old female using 5000 mg of the drug (102 mg/kg) was observed in 2008 in Israel; the patient experienced severe headache, nausea, abdominal pain, dyskinesia, insomnia, and mild tachycardia, but no cardiovascular distress or abnormalities in liver and kidney function, and recovered in a few days without any apparent long-term effects.
Modafinil may induce severe dermatologic reactions requiring hospitalization. From the date of initial marketing, December 1998, to January 30, 2007, FDA received six cases of severe cutaneous adverse reactions associated with modafinil, including erythema multiforme (EM), SJS, TEN, and DRESS involving adult and pediatric patients. The FDA issued a relevant alert. In the same alert, the FDA also noted that angioedema and multi-organ hypersensitivity reactions have also been reported in postmarketing experience.
This article uses material from the Wikipedia article Modafinil, which is released under the Creative Commons Attribution-Share-Alike License 3.0.