Modafinil

Other Names:

(RS)-2-(diphenylmethylsulfinyl)acetamide, Provigil, Modalert, Modiodal, Alertec, Modavigil, Carim, Modasomil, Resotyl, Stavigile, Vigia, Vigil.

Background:

Modafinil is a, Schedule IV, racemic CNS stimulant with unique properties. Secondary to its indicated uses, modafinil is currently classified as a wakefulness promoting agent. Its pharmacologic profile is most likened to something in between methylphenidate and amphetamine [3]. Modafinil is currently indicated to treat: excessive sleepiness associated with narcolepsy, obstructive sleep apnea/hypopnea syndrome, and shift work sleep disorder.

Active ingredients:

(RS)-2-(diphenylmethylsulfinyl)acetamide (Modafinil).

Inactive ingredients:

lactose, microcrystalline cellulose, pregelatinized starch, croscarmellose sodium, povidone, and magnesium stearate [3].

Mode of action:

The exact mode of action of modafinil remains elusive; as such, studies in rats, have revealed that the mechanism by which modafinil operates is centered around CNS levels of histamine. After dosing modafinil, there was shown to be an increase in both histamine, centered in the anterior hypothalamus, and locomotor activity. Moreover, once effective dosage of each was reached, the increase in locomotor activity resulting from modafinil was seen to be on par with that of methylphenidate. It was also noted that, unlike methylphenidate, when α-fluoromethylhistidine, a potent inhibitor of histidine decarboxylase, was administered and neuronal histamine concentration were depleted, so was modafinil’s effects [7].

In other studies, modafinil was found to piggyback the orexinergic systems, in mice. It was found that, in orexin neuron-ablated mice, modafinil failed to mount an effect, suggesting hypothalamic orexinergic neurons role within modafinil’s histaminergic pathway, primary. Furthermore, it has been postulated that modafinil increases hypothalamic histamine via attenuation of the GABAergic neurons that influence the orexinergic system [6].

Benefits:

The primary benefit for which modafinil is currently prescribed is in wakefulness promoting. In normal conditions, sleep deprivation has been shown to impair hippocampal-dependent memory. Modafinil has been shown to prevent impairment of cognitive function by reducing the number of errors compared to placebo and by upregulating synapsin I expression within the dorsal hippocampus [5]. In a study involving sleep deprived ER physicians, modafinil displayed ability to improve performance on tests of higher cognitive function, compared to the baseline, albeit, failed to show gains in performance, with respect to psychomotor tasks [9]. Similarly, in studies concerning patients dependent on methamphetamine, modafinil showed a direct relationship between cognitive improvement and amount of methamphetamine use [2].

There have been attempts, by the owners of the original patent, to clear modafinil as indicated for conditions of  ADHD/ADD. However, such attempts have proven unwielding; as study after study has proven it ineffective for purposes of attention deficit in adults [1]. In children, however, when compared to methylphenidate, using the Test of Variables of Attention, modafinil proved to be as effective as when considering the improvements seen [4].

Common side effects:

Weight loss, decreased appetite, insomnia, headache, nausea, nervousness, dry mouth, and hypertension.
May have some abuse potential, although none have been reported to date [8].

Other Information:

Both British and American military units are known to use modafinil to improve cognitive functioning in extended low-sleep, high-stress scenarios. Tactical paramedics in Maryland administer modafinil to police and law enforcement when they are dealing with high-risk, large-scale operations in order to increase functioning and alertness. The French Foreign Legion has admitted to giving its soldiers modafinil during covert operations. It is also used by astronauts on board the International Space Station.A study of modafinil’s use in US Helicopter Pilots showed that given modafinil, pilots were able to function at normal levels for up to 40 hours with no sleep.

Sources:

1.    Arnold VK, Feifel D, Earl CQ, Yang R, Adler LA. A 9-Week, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Dose-Finding Study to Evaluate the Efficacy and Safety of Modafinil as Treatment for Adults With ADHD. J Atten Disord. 2012 May 22. [Epub ahead of print] PubMed PMID: 22617860.

2.    Dean AC, Sevak RJ, Monterosso JR, Hellemann G, Sugar CA, London ED. Acute modafinil effects on attention and inhibitory control in methamphetamine-dependent humans. J Stud Alcohol Drugs. 2011 Nov;72(6):943-53. PubMed PMID: 22051208; PubMed Central PMCID: PMC3211965.

3.    FEDERAL DRUG ADMINISTRATION. “PROVIGIL® (modafinil) Tablets [C-IV]” 2004. Federal Drug Administration. Jan 2004. <http://www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4325b_04_08_Modafinil%20Label.pdff>.

4.    Goez HR, Scott O, Nevo N, Bennett-Back O, Zelnik N. Using the Test of Variables of Attention to Determine the Effectiveness of Modafinil in Children With Attention-Deficit Hyperactivity Disorder (ADHD): A Prospective Methylphenidate-Controlled Trial. J Child Neurol. 2012 Mar 23. [Epub ahead of print] PubMed PMID: 22447850.
5.    He B, Peng H, Zhao Y, Zhou H, Zhao Z. Modafinil treatment prevents REM sleep deprivation-induced brain function impairment by increasing MMP-9 expression. Brain Res. 2011 Dec 2;1426:38-42. Epub 2011 Sep 9. PubMed PMID: 22036079.
6.    Ishizuka T, Murotani T, Yamatodani A. Action of modafinil through histaminergic and orexinergic neurons. Vitam Horm. 2012;89:259-78. PubMed PMID: 22640618.

7.    Ishizuka T, Murakami M, Yamatodani A. Involvement of central histaminergic systems in modafinil-induced but not methylphenidate-induced increases in locomotor activity in rats. Eur J Pharmacol. 2008 Jan 14;578(2-3):209-15. Epub 2007 Sep 26. PubMed PMID: 17920581.

8.    Kumar R. Approved and investigational uses of modafinil : an evidence-based review. Drugs. 2008;68(13):1803-39. Review. PubMed PMID: 18729534

9.    Sugden C, Housden CR, Aggarwal R, Sahakian BJ, Darzi A. Effect of pharmacological enhancement on the cognitive and clinical psychomotor performance of sleep-deprived doctors: a randomized controlled trial. Ann Surg. 2012 Feb;255(2):222-7. PubMed PMID: 21997802.