What is the role of modafinil and armodafinil in the treatment of primary hypersomnia?

Updated: Sep 05, 2018
  • Author: Adrian Preda, MD; Chief Editor: Ana Hategan, MD, FRCPC  more...
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Modafinil, a 1:1 racemic mixture of (R)-(-) and (S)-(-) enantiomers, and armodafinil, the isolated (R)-(-) enantiomer, have proved clinically useful in the treatment of narcolepsy and other causes of excessive daytime sleepiness, such as idiopathic hypersomnolence. [29] It is a psychostimulant that enhances wakefulness and vigilance, but its pharmacologic profile is notably different from the amphetamines, methylphenidate, or cocaine. Modafinil is less likely to produce side effects such as jitteriness, anxiety, or excess locomotor activity or to lead to a hypersomnolent rebound effect. Modafinil, with its 1:1 racemic mixture has an estimated elimination half-life of 4 hours for the S-enantiomer and 15 hours for the R-enantiomer, functionally producing an estimated 9–14 hours half-life. Given the enantiomeric differences, armodafinil has a longer elimination half-life of around 10–15 hours. [3, 30, 63]

The mechanism of action of modafinil is not fully understood. Modafinil induces wakefulness in part by its action in the anterior hypothalamus. Its dopamine-releasing action in the nucleus accumbens is weak and dose dependent; the likelihood of a euphoric response, and, therefore, the abuse potential and tolerance, is small.

Modafinil has central alpha 1-adrenergic agonist effects (ie, it directly stimulates the receptors). Modafinil inhibits the reuptake of noradrenaline by the noradrenergic terminals on sleep-promoting neurons of the ventrolateral preoptic nucleus (VLPO). More significant, perhaps, is its ability to increase excitatory glutaminergic transmission and reduce local gamma-aminobutyric acid (GABA)–ergic transmission, thereby diminishing GABA(A) receptor signaling on the mesolimbic dopamine terminals. [30, 31]

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