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Modafinil (Provigil, Modalert) - is a wakefulness-promoting agent, used to treat narcolepsy, shift work sleep disorder and excessive daytime sleepiness in obstructive sleep apnea (OSA) sufferers.
Modafinil is a racemic compound.
Modafinil chemical name is 2-[(diphenylmethyl)sulfinyl]acetamide.
Modafinil molecular formula is C15H15NO2S.
Modafinil molecular weight is 273.36.
Modafini is primarily indicated to improve wakefulness in adult patients with excessive sleepiness associated with narcolepsy, obstructive sleep apnea/hypopnea syndrome, and shift work sleep disorder.
Modafinil (Provigil and generics) is available in 100 mg and 200 mg tablets for oral ingestion. Modafinil can also be crushed into a fine powder and insufflated, which produces a much quicker onset. Anecdotal reports indicate that the length of the main experience is not affected.
The main effects of Modafinil are similar to those of more prominent stimulants such as amphetamines, but the effects are generally milder, as Modafinil is not known to have significant dopaminergic activity. produces wakefulness, increased locomotor activity, euphoric effects, alterations in mood, perception, and thinking similar to some stimulants. Side effects can include but are not limited to:
Serious side effects can occur, which are explained in the Dangers of Modafinil section.
Modafinil's mechanism of action has not been fully elucidated. It promotes wakefulness, and has a vaguely similar physiological profile to that of more powerful stimulants such as amphetamines and methylphenidate, but its pharmacological profile is not the same.
Modafinil does not bind to noradrenaline, serotonin, dopamine, GABA, adenosine, histamine-3, melatonin, or benzodiazepine receptors. In addition, it does not inhibit MAO-B or phosphodiesterases II-V.
Modafinil does not agonize dopamine receptors. In vitro, modafinil binds to the DRT and increases extracellular concentrations of dopamine, however it does not modify dopamine release. In addition, modafinil's effects are not attenuated by dopamine antagonists such as haloperidol.
It has been proposed that modafinil acts via modification of the adrenergic system, however it does not appear to be a direct or indirect alpha-1 agonist; interestingly, its effects are attenuated by alpha-1 receptor antagonists such as prazosin.
In the cat, modafinil (at therapeutic doses) increases neuronal activation in much more discrete brain regions than amphetamine or methylphenidate. This finding's relevance to humans is unknown.
Modafinil is reinforcing, and in rats has cocaine-like discriminative stimulus effects. In one study it produced up to a 67% increase in cocaine-lever responding, and produced full substitution in four out of six rats tested.
Modafinil is a racemic compound. Its l-isomer has a half life almost three times that of its d-somer. After steady-state has been achieved (usually 2-4 days of dosing), its trough concentration after once daily dosing consists of 90% l-modafinil and 10% d-modafinil. After multiple doses, effective half-life is 15 hours.
Rapid absorption, with peak plasma concentrations at 2-4 hours. Food does not affect modafinil bioavailability but it may delay absorption. Modafinil is distributed in body tissue with a Vd of 0.9L/kg.
Approximately 90% is eliminated by liver and subsequent renal elimination of metabolites.
Metabolism occurs through hydrolytic deamidation, S-oxidation, aromatic ring hydroxylation, and glucoronide conjugation. Less than 10% is excreted unchanged. In one study the largest presence of the drug in the urine was in the form of modafinil acid (which has been shown to be inactive).
Modafinil may have an inductive effect on its own metabolism at chronic doses of 400mg/day, via induction of CYP3A4. It is also a reversible inhibitor of CYP2C19.
[h4]The Modafinil Experience[h4]
Modafinil usually has a length of about 5-10 hours total. Onset begins 20-60 minutes after ingestion, with a 10-30 minute come up. Onset can be delayed an hour or so if taken with food, but eating will not affect Modafinil's effectiveness once it begins. The effects will plateau for about 3.5-5 hours, and then gradually decrease during the comedown which lasts 1-3 hours. After effects (e.g. continued minor stimulation) may occur for 2-6 hours after the experience is over.
In 2006 study showed that Modafinil had the potential to have efficacy in atypical depression (with features of hypersomnia, hyperphagia, anergia and rejection sensitivity); The results in the open label part of the study suggested that Modafanil was safe and effective for this patient population. (2)
2004 study on effects of modafinil on working memory processes in non sleep deprived humans showed that a single dose (200 mg) of Modafinil resulted in subtle improvements of performance in the difficult conditions of two working memory tasks ... (3)
A helicopter simulator study, investigating the efficacy of Modafinil for sustaining the alertness and performance of aviators, demonstrated that modafinil attenuated a number of performance and mood-based problems associated with sleep loss. (4)
There is also some evidence that Modafinil has neuroprotective effects (5)
In 2004, Guardian investigation has learned that over the previous six years, the Ministry of Defence has bought significant quantities of Provigil. According to figures released by the Defence Medical Supplies Agency, which provides medical items "to sustain UK military capability", the MoD has bought more than 24,000 tablets of Provigil between 1998 - 2004 (10)
In 2007 FDA advised on revised labeling updates safety information to include warnings regarding serious rash, including Stevens-Johnson Syndrome (SJS) and hypersensitivity reactions, and psychiatric symptoms. Rare cases of serious or life-threatening rash, including Toxic Epidermal Necrolysis, and Drug Rash with Eosinophilia and Systemic Symptoms have been reported in adults and children in worldwide postmarketing experience. Angioedema and multi-organ hypersensitivity reactions have also been reported in postmarketing experience.
The use should be immediately discontinued if a rash or other hypersensitivity reaction occurs. In addition, psychiatric adverse experiences (including anxiety, mania, hallucinations, and suicidal ideation) have been reported in patients treated with Modafinil. Caution should be exercised when Modafinil is taken by patients with a history of psychosis, depression, or mania. (6)
There has been concern about the psychosis-inducing property of Modafinil. There are documented reports of 2 cases of irritability and aggression related to modafinil use in bipolar disorder. (11)
Modafinil is a Schedule IV drug in the United States. However, a prodrug, called Adrafinil, is unscheduled and unregulated. The only difference between the two drugs is that Adrafinil has a hydroxyl group in place of one of the hydrogens of the amine. There is a thread about the conversion of Adrafinil to Modafinil here.
Modafinil is a white to off-white, crystalline powder that is practically insoluble in water and cyclohexane. It is sparingly to slightly soluble in methanol and acetone. PROVIGIL (Cephalon, Inc.) tablets contain 100 mg or 200 mg of modafinil and the following inactive ingredients: lactose, microcrystalline cellulose, pregelatinized starch, croscarmellose sodium, povidone, and magnesium stearate.
Alertec is a form of Modafinil available in Canada.
Alertec (Shire Pharmaceuticals) pills contain 100mg of Modafinil. Alertec pills also contain the inactive ingredients lactose, maize starch, magnesium monosilicate, sodium croscarmellose polyvidone, magnesium stearate and talc. (9)
Modalert is available from Sun Pharmaceuticals in India in 200 mg pills.
Modafinil is a non-narcotic Schedule IV drug. This means it is illegal to sell without a DEA license and illegal to buy or possess without a license or prescription.
Modafanil is listed in Part I of Schedule F of Canada's Food and Drug Regulations, requiring a prescription for human use and for veterinary use.
Modafinil is available with a prescription under the name Modavigil.
Modafinil is available with a prescription under the name Provigil.
Modafinil is sold in Mexico as Modiadal and it does not appear to be controlled.
Available by prescription, unscheduled, and cleared for personal import from other countries.
Modafinil and its chemical precursor Adrafinil were developed by Lafon Laboratories, a French company acquired by Cephalon in 2001.
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(2) Sandeep Vaishnavi, MD, PhD, Kishore Gadde, MD, Sayed Alamy, MD, Wei Zhang, MD, PhD, Kathryn Connor, MD and Jonathan R.T. Davidson, MD (2006). Modafinil for Atypical Depression: Effects of Open-label and Double-blind Discontinuation Treatment (Electronic version). Psychopharmacology, 26, 373-378.
(3) Ulrich Müller, Nikolai Steffenhagen, Ralf Regenthal, Peter Bublak (2004). Effects of modafinil on working memory processes in humans (Electronic version). Psychopharmacology, 177, 161-169.
(4) John A. Caldwell Jr, J. Lynn Caldwell, Nicholas K. Smythe III, Kecia K. Hall (2000). A double-blind, placebo-controlled investigation of the efficacy of modafinil for sustaining the alertness and performance of aviators: a helicopter simulator study (Electronic version). Psychopharmacology, 150, 272-282.
(5) Jenner, P; Zeng, B.-Y.; Smith, L.A.; Pearce, R.K.B.; Tel, B.; Chancharme, L.; Moachon, G. (July 2000). Antiparkinsonian and neuroprotective effects of modafinil in the mptp-treated common marmoset (Electronic version). Experimental Brain Research 133 (2): 178188.
(11) Sanjeev Ranjan, Prabha S. Chandra. Modafinil-induced irritability and Aggression? A report of 2 bipolar patients (Electronic version).
Journal of Clinical Psychopharmacology, Volume 25, Number 6, December 2005
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