Modafinil and its R-enantiomer armodafinil are central nervous system stimulants used to improve wakefulness in patients with excessive sleepiness. Both modafinil and armodafinil are associated with a low rate of serum aminotransferase elevations during therapy, but they have not been implicated in cases of clinically apparent acute liver injury.
Background
Modafinil (moe daf' i nil) is a non-amphetamine central nervous system (CNS) stimulant whose mechanism of action is not entirely clear. Modafinil is structurally unrelated to the amphetamines, and it does not appear to affect release of CNS norepinephrine or dopamine. Modafinil is a racemic mixture of S and R enantiomers, whereas armodafinil (ar" moe daf' i nil) is the R enantiomer only. Both enantiomers have CNS-activating actions, but they differ in pharmacokinetics and half-life. Modafinil and armodafinil increase wakefulness and both have been shown to be helpful in conditions with excessive sleepiness (narcolepsy, obstructive sleep-apnea and shift-work sleep disorder) and have been studied off-label to treat fatigue associated with chronic illness such as cancer, Parkinson’s disease, HIV/AIDs and multiple sclerosis. Modafinil was approved for use in the United States in 1998 and armodafinil in 2007. Modafinil is available in tablets of 100 and 200 mg in generic forms and under the brand name Provigil; the usual dose in adults being 200 mg once daily in the morning or an hour before a work shift. Armodafinil is available in tablets of 50, 150 and 250 mg under the brand name Nuvigil; the usual dose in adults being 150 to 250 mg once daily. Armodafinil is also approved for treatment of sleepiness due to jet lag, a lower dose of 50 to 150 mg being recommended. The most common side effects of both agents include headache, anxiety nervousness, nausea, decreased appetite, palpitations and disturbed sleep. Modafinil and armodafinil are now classified as category IV controlled substances, indicating that they have a potential for abuse and can lead to physical or psychological dependence.
Hepatotoxicity
In clinical trials, modafinil and armodafinil were associated with a low rate of serum aminotransferase and alkaline phosphatase elevations (<1%). Furthermore, despite wide-scale use, there have not been reports of clinically apparent liver injury due to modafinil or armodafinil. Rare instances of hypersensitivity reactions and even Stevens Johnson syndrome have been reported after modafinil use and these reactions may be accompanied by evidence of hepatic involvement or injury.
Mechanism of Injury
The mechanism by which modafinil and armodafinil might cause liver injury is unknown. Modafinil is extensively metabolized in the liver but has few drug-drug interactions.
Central nervous system stimulants used for attention deficit disorder, narcolepsy or excessive sleepiness include methylphenidate, atomoxetine, modafinil, armodafinil and the amphetamines. Stimulants that are no longer used for medical conditions but that are abused include cocaine and methylenedioxymetamphetamine, which is also known as ecstasy.
