The drug was primarily developed in France by the emeritus experimental medicine professor and neurophysiologist Michel Jouvet at Lafon Laboratories. The drug was first developed in the late 1970s during the invention of a series of benzhydryl sulfinyl compounds. This includes adrafinil and was offered as an experimental treatment option for narcolepsy back in 1986. Modafinil came into being since it was the primary metabolite of the drug mentioned above. It lacked the -OH group on the last amide which gives it a similar effect to the parent drug but has greater use. It has been used in France since 1994 under the brand name Modiodal.
Contrary to popular belief Michel Jouvet did not discover adrafinil, but since he was a very prominent sleep researcher he popularised the drug using his unique position to communicate his research which was build upon the research of others.
Scientists quickly isolated the key metabolites of adrafinil (especially R-modafinil) leading to other versions of the drug: modafinil and adrafinil
Initial Discovery of Adrafinil
Adrafinil (a modafinil precursor) began in 1974-France at the pharmaceutical company Lafon Laboratories. Two scientists called Gombert and Assous were examining drugs in the category of central nervous system agents, in particular analgesics (pain killers). They discovered a new molecule called adrafinil, chemical name: 2-(Benzhydrylsulfinyl)acetohydroxamic acid.
Testing of Adrafinil
Lafon Labratories having just discovered a novel molecule delegated kinetic testing of the drug to two groups of employees: (Rombert & Duteil) and (Milhaud & Klein). The testing of adrafinil was first performed by the pharmacologists Rombert and Duteil who discovered that mice given adrafinil exhibited a great increase in physical activity. Further pharmacological testing on monkeys by Milhaud and Klein revealed that adrafinil increased nocturnal activity of monkeys fourfold, the activity level becoming identical to day-time activity. The stimulating effect of doses of 90 and 120 mg (per kilogram of weight) persisted approximately 36 hours after administration.
Michel Jouvet, an experimental researcher associated with Group Lafon got wind of the vigilance-promoting properties of adrafinil and decided to do some experimentation of his own. Michel Jouvet is greatly known for his sleep-related research in cats and co-discovery of REM sleep via EGG studies. He coined the term “paradoxical sleep”. During 1979-1977 Jouvet tested adrafinil on cats. His work is unpublished however Billiard in “Narcolepsy and Hypersomnia” (2001) explains that Jouvet’s administration of adrafinil resulted in increased EEG wakefulness in cats.
Jouvet, having seen adrafinils efficacy in increasingly complex mammals (mice, cats, monkeys), decided the next step was to treat humans. During 1977-1978 he prescribed adrafinil to narcoleptic patients with mixed results.
Discovery of Modafinil
At this point in time adrafinil had already snowballed in the French drug research community. Although it had no practical application yet in humans researchers would see it’s potential. As a sulfinyl based stimulant it had all of the good effects of traditional stimulants but none of the major drawbacks such as psychosis, personality change or addictive potential.
This interest led to a deeper study into the drug, in particular kinetic studies – which examine how a molecule reacts and what it may be made up of. In 1976 the kinetic study of adrafinil led to the discovery of an active metabolite, referred to as modafinil. This new molecule appeared more effective than adrafinil. Modafinil lacks adrafinil’s terminal amide hydroxyl group and is thus better tolerated with fewer side-effects.
Testing of Modafinil
The newly discovered modafinil (an adrafinil derived molecule) went through the same stages of development and pharmacological testing as adrafinil leading to the similar demonstrations of:
- modafinil implicated in increase of locomotor activity in the mouse
- modafinil leading to an increase of EEG wakefulness in the cat
- modafinil causing an increase in nocturnal activity in the rhesus monkey
In early 1983 Jouvet and colleagues in Lyon administered modafinil to narcoleptic and idiopathic hypersomnia patients with unexpectedly great results, demonstrating the first successful treatment of idiopathic hypersomnia and narcolepsy with modafinil. This is the first study and first clinical publication involving this drug.
In 1984 Lafon decided to start clinical trials in both healthy people and narcoleptics. The first studies of modafinil on night sleep and daytime sleepiness in healthy volunteers were conducted by goldenberg and Saletu – goldenberg and colleagues found decreased total sleep time, decreased NREM stages and no modification of REM sleep. Saletu and colleagues compared the effect of modafinil on nocturnal sleep compared with amphetamines, the drop in sleep efficiency was smaller with modafinil.
Registration and Approval of Modafinil
The first study and clinical publication on modafinil came from Jouvet’s center in Lyon these studies and the first randomized placebo-controlled study led to theofficial registration of modafinil in France in June 1992 followed by it’s commercial availability there from September 1994. Thus Modafinil was approved for sale in France by 1994, followed by other European countries during late-1990’s. It was also approved in the US in 1998.
Further research including clinical trials and placebo-controlled randomized studies were conducted by Cephalon in 1993 who originally leased the rights from Lafon, but eventually purchased the company in 2001. In the United States modafinil received orphan drug status in 1993 and became commercially available.
The first doping incident involving modafinil was reported in 2003 at the Track and Field World Championships. Subsequently, it was prohibited in sports together with adrafinil. Modafinil was also mentioned as a drug used by the athletes in the BALCO case (known for the introduction of the designer steroid gestrinome).
In 2007-USA as a result of FDA approval Cephalon began to market the r-enantiomer of modafinil called armodafinil (brand name Nuvigil). In 2011 Teva brought Cephalon along with all intellectual property including modafinil and armodafinil. After protracted patent litigations, anti-trust accusations and negotiations – modafinil first became available in the USA in 2012.
In 2011 French FDA withdrew marketing for adrafinil citing that the risks of taking the drug do not outweigh the benefits. Subsequently Cephalon stopped manufacturing it’s brand adrafinil Olmifon
Modafinil – Patents and Legal Battles
On December 24, 2002, Generic drug manufacturers Mylan; Teva; Barr; and Ranbaxy detecting the expiration of modafinil’s patent granting Cephalon exclusive marketing rights – asked the FDA for approval to manufacture an market their generic versions of modafinil.
The FDA in January 2010 denied a request by Cephalon to market Nuvigil (armodafinil) as the first medical treatment for jet lag. As of October 31, 2011, USA. Patent No. RE 37,516 (a reissue of the original patent) has been declared invalid (unenforceable). It claimed compositions of modafinil, using it to treat neurological conditions and some excipients.
Cephalon made an agreement with major generics manufacturers Barr Pharmaceuticals, Teva, Ranbaxy Laboratories, and Watson Pharmaceuticals between 2005 and 2006 to delay sales of generic modafinil in the US until April 2012. Litigation arising from these agreements is still pending including an FTC suit filed in April 2008.
In the United Kingdom, Mylan LDT. received marketing approval to sell generic modafinil produced by Orchid in January 2010; Cephalon sued to prevent sale, and lost the patent trial in November.
The FTC in 2011 approved the Cephalon-Teva merge under specific conditions: granting generic rights to US manufacturers.
Since the clutches of legal litigation have lessened in 2012 modafinil has since become more widespread in America, Canada and Europe. As a result great number of generic brands have emerged in South America and in particular Asia.
India (the biggest exporter of generic pharmaceuticals) now produces the bulk of generic modafinil in the form of brands like Modalert (Modafinil by SUN Pharma), Modvigil (modafinil by HAB Pharma), Waklert (armodafinil by SUN Pharma), Artvigil (armodafinil by SUN Pharma).
The use of adrafinil has subsided since the 2011 French discontinuation however there is a large body of people buying it online because in Canada, America, UK, and Europe it is not a prescription drug or otherwise regulated unlike modafinil / armodafinil thus it is legal to import.