Modafinil: Preclinical, Clinical, and Post-Marketing Surveillance—A Review of Abuse Liability Issues

Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
Annals of Clinical Psychiatry (Impact Factor: 2.36). 04/2004; 16(2):101-9. DOI: 10.1080/10401230490453743
Source: PubMed


Modafinil is an agent that is frequently used in the treatment of narcolepsy. More recently it has been used in the treatment of a variety of psychiatric, neurological, and medical illnesses. Due to its ability to improve wakefulness, modafinil has been viewed as a stimulant. Based on the potential for modafinil to become widely used in a variety of syndromes and settings, evidence from preclinical in vitro and in vivo studies, human laboratory studies, and post-marketing experiences examining the potential abuse liability of modafinil were reviewed. Initial evidence suggests that modafinil has limited potential for large-scale abuse.

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    • "Thus, the c-Fos seen in the striatum after modafinil may actually be in the neurons that are selectively not related to its wake-promoting effect. Given the current view of the role of striatal dopaminergic transmission in addictive behaviors,23 these findings raise the interesting question of why (ar)modafinil’s abuse potential and addictive properties are so much lower than that of methamphetamine,24,25 which is an important area of future research. "
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    ABSTRACT: Armodafinil is the pharmacologically active R-enantiomer of modafinil, a widely prescribed wake-promoting agent used to treat several sleep-related disorders including excessive daytime sleepiness associated with narcolepsy, shift work sleep disorder, and obstructive sleep apnea/hypopnea syndrome. Remarkably, however, the neuronal circuitry through which modafinil exerts its wake-promoting effects remains unresolved. In the present study, we sought to determine if the wake-promoting effects of armodafinil are mediated, at least in part, by inhibiting the sleep-promoting neurons of the ventrolateral preoptic (VLPO) nucleus. To do so, we measured changes in waking following intraperitoneal administration of armodafinil (200 mg/kg) or the psychostimulant methamphetamine (1 mg/kg) in rats with cell-body specific lesion of the VLPO. Rats with histologically confirmed lesions of the VLPO demonstrated a sustained increase in wakefulness at baseline, but the increase in wakefulness following administration of both armodafinil and methamphetamine was similar to that of intact animals. These data suggest that armodafinil increases wakefulness by mechanisms that extend beyond inhibition of VLPO neurons.
    Nature and Science of Sleep 05/2014; 6:57-63. DOI:10.2147/NSS.S53132
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    • "Because it was rapidly shown that modafinil is pharmacologically distinct from amphetamine (but less so from methylphenidate) in some animal tests, and that abuse potential for the compound was low, the mode of action of modafinil was touted as totally different from other stimulants, and did not involve dopamine [27, 28]. Indeed, after more than 20 years of experience with the compound, abuse with dependence remains rare, although there is no doubt that the compound is misused to increase performance rather than to treat disease in some cases [28]. In the late 1980s, studies at Stanford showed that the compound had very similar properties to very selective DAT reuptake inhibitors in a canine model of narcolepsy [29]. "
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    ABSTRACT: Narcolepsy and other syndromes associated with excessive daytime sleepiness can be challenging to treat. New classifications now distinguish narcolepsy/hypocretin deficiency (also called type 1 narcolepsy), a lifelong disorder with well-established diagnostic procedures and etiology, from other syndromes with hypersomnolence of unknown causes. Klein-Levin Syndrome, a periodic hypersomnia associated with cognitive and behavioral abnormalities, is also considered a separate entity with separate therapeutic protocols. Non hypocretin-related hypersomnia syndromes are diagnoses of exclusion. These diagnoses are only made after eliminating sleep deprivation, sleep apnea, disturbed nocturnal sleep, and psychiatric comorbidities as the primary cause of daytime sleepiness. The treatment of narcolepsy/hypocretin deficiency is well-codified, and involves pharmacotherapies using sodium oxybate, stimulants, and/or antidepressants, plus behavioral modifications. These therapies are almost always needed, and the risk-to-benefit ratio is clear, notably in children. Detailed knowledge of the pharmacological profile of each compound is needed to optimize use. Treatment for other syndromes with hypersomnolence is more challenging and less codified. Preferably, therapy should be conservative (such as modafinil, atomoxetine, behavioral modifications), but it may have to be more aggressive (high-dose stimulants, sodium oxybate, etc.) on a case-by-case, empirical trial basis. As cause and evolution are unknown in these conditions, it is important to challenge diagnosis and therapy over time, keeping in mind the possibility of tolerance and the development of stimulant addiction. Kleine-Levin Syndrome is usually best left untreated, although lithium can be considered in severe cases with frequent episodes. Guidelines are provided based on the literature and personal experience of the author.
    Journal of the American Society for Experimental NeuroTherapeutics 10/2012; 9(4):739-52. DOI:10.1007/s13311-012-0150-9 · 5.05 Impact Factor
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    • "Together, these recent findings indicate that modafinil, even when taken alone, may have addictive potential. Despite its profile as a modest reinforcer there are no published case reports of addiction to modafinil, and several studies have reported that modafinil lacks a drug-induced " high " [25] [26] [27] [28]; for review see [28]. This may be because modafinil is used orally, and has a relatively slow peak time (2–4 h) and long half-life (10–12 h), compared to the stimulants of abuse (i.e., smoked or snorted cocaine and methamphetamine). "
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    ABSTRACT: Modafinil is a wake-promoting drug effective at enhancing alertness and attention with a variety of approved and off-label applications. The mechanism of modafinil is not well understood but initial studies indicated a limited abuse potential. A number of recent publications, however, have shown that modafinil can be rewarding under certain conditions. The present study assessed the reinforcing properties of modafinil using conditioned place preference and locomotor sensitization in mice. Experiment 1 examined a high dose of modafinil (75mg/kg) as well as its interactions with cocaine (15mg/kg). Cocaine alone and modafinil co-administered with cocaine induced sensitization of locomotor activity; modafinil alone showed little or no locomotor sensitization. Animals given modafinil alone, cocaine alone, and modafinil plus cocaine exhibited a strong and roughly equivalent place preference. When tested for sensitization using a low challenge dose of modafinil, cross-sensitization was observed in all cocaine-pretreated mice. Experiment 2 examined a low dose of modafinil that is similar to the dose administered to humans and has been shown to produce cognitive enhancements in mice. Low dose modafinil (0.75mg/kg) did not produce conditioned place preference or locomotor sensitization. Together, these results suggest that modafinil has the potential to produce reward, particularly in cocaine addicts, and should be used with caution. However, the typical low dose administered likely moderates these effects and may account for lack of addiction seen in humans.
    Behavioural brain research 08/2012; 235(2):105-12. DOI:10.1016/j.bbr.2012.07.039 · 3.03 Impact Factor
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