Modafinil as a Catecholaminergic Agent: Empirical Evidence and Unanswered Questions

Abstract

Modafinil, in its two clinical formulations (Provigil® and Nuvigil®), is a widely prescribed wake-promoting therapeutic agent. It binds competitively to the cell-membrane dopamine (DA) transporter and is dependent on catecholaminergic (dopaminergic and adrenergic) signaling for its wake-promoting effects. The clinical spectrum of effects for modafinil is distinct from the effects seen with other catecholaminergic agents. Relative to other commonly used agents that act through catecholaminergic mechanisms, modafinil has a relatively low abuse potential, produces wakefulness with an attenuated compensatory sleep recovery thereafter, and does not ameliorate cataplexy in narcolepsy. These clinically relevant phenomenological differences between modafinil and agents such as amphetamines and cocaine do not eliminate catecholaminergic effects as a possible mediator of its wake-promoting action; they merely reflect its unique pharmacological profile. Modafinil is an exceptionally weak, but apparently very selective, DA transporter inhibitor. The pharmacodynamic response to modafinil, as measured by DA levels in brain microdialyzate, is protracted relative to other agents that act via catecholaminergic mechanisms. The conformational constraints on the interaction of modafinil with the DA transporter – and probably, as a consequence, its effects on trace amine receptor signaling in the catecholaminergic cell – are unique among catecholaminergic agents. These unique pharmacological properties of modafinil should be considered both in seeking to thoroughly understand its putatively elusive mechanism of action and in the design of novel therapeutic agents.

New developments in the management of narcolepsy

“…Fos immunoreactivity is increased in the tuberomammillary nucleus and in the hypocretin neurons in the perifornical area of the hypothalamus 26. Modafinil binds competitively to dopamine transporter in the cell membrane and is dependent on catecholaminergic (dopamine and adrenergic) signaling for wake promotion 27. Modafinil is a very weak but also very selective dopamine transporter inhibitor 27.…”

Challenges in the development of therapeutics for narcolepsy

“…The mechanism of action of modafinil is still not fully understood but likely involves the dopamine transporter (DAT) to inhibit DA reuptake (Wisor, 2013). Modafinil has been shown to bind the DAT with very low affinity but high selectivity, with no binding at norepinephrine or serotonin transporters (Mignot et al, 1994b).…”

“…Although both enantiomers of amphetamine are equipotent at reducing REM sleep (Nishino and Mignot, 2011), l -amphetamine is more effective than d -amphetamine in decreasing cataplexy (Mignot, 2012). The anticataplectic effects of amphetamine may relate to its action at transporters for norepinephrine and/or serotonin, as selective DAT inhibition fails to reduce cataplexy (Wisor, 2013). Unlike modafinil, amphetamine has several other actions that lead to an unfavorable side effect profile, such as vasoconstriction and cardiac stimulation resulting from increased noradrenaline in the periphery.…”

Adverse Health effects Associated with Shift Work

“…Therapy:Melatonin may increase sleep length during both daytime and night-time sleep in people wo work at night shifts.Zopiclone has also been investigated as a potential treatment, but it is unclear if it is effective in increasing daytime sleep in shift workers. There are no reports of side effects [3].Modafinil and RModanifil are useful to improve alertness and reduce sleepiness in shift workers [3].Modanifil has a low risk of abuse compared to other similar agents [65].In post-marketing surveillance Modanifil was associated with severe Steven Johnson syndrome. The European Medicines Agency withdrew the license for Modanifil for shift workers for the European market because it judged that the benefits did not outweigh the side effects [3]..Using caffeine and naps before night shifts can decrease sleepiness.Caffeine also shown to reduce errors made by shift workers [3].…”