Modafinil for the treatment of cocaine dependence

“N IH -PA Author M anuscript N IH -PA Author M anuscript N IH -PA Author M anuscript administration in rats (Boutrel et al., 2005).”

“Via its actions on the hypocretin/orexin system (Scammell et al., 2000) and the glutamate/GABA (gammaAminobutyric Acid) systems (Ferraro et al., 1997) modafinil could help restore the homeostasis disturbed by chronic cocaine use.”

“Finally, modafinil was safe and well tolerated in Phase I interaction studies with cocaine (Donovan et al., 2005; Dackis et al., 2003), and in a pilot study on cocaine dependence treatment (n = 62) it was superior to placebo at promoting cocaine abstinence (Dackis et al., 2005).”

“Our results are in line with those from other recent clinical trials for treatment of stimulant dependence (Kampman et al., 2004; Elkashef et al., 2008), where no single medication has been shown to help most patients, but rather, some subgroups seem to respond to a specific medication.”

“Modafinil improves cognition and mood (Turner et al., 2004; Taneja et al., 2007), and has shown efficacy in the treatment of child and adult attention deficit hyperactivity disorder (Lindsay et al., 2006).”

“Our results are in line with those from other recent clinical trials for treatment of stimulant dependence (Kampman et al., 2004; Elkashef et al., 2008), where no single medication has been shown to help most patients, but rather, some subgroups seem to respond to a specific medication.”

“Briefly, modafinil has stimulant properties, which could be therapeutic for alleviating some stimulant withdrawal symptoms (Malcolm et al., 2002; Jasinski, 2000), and in human laboratory test paradigms it has been found to attenuate subjective responses to cocaine (Dackis et al., 2003) and the…”

“A third trial (Anderson et al., 2009) demonstrated no overall efficacy in the primary outcome measure (total percentage of nonuse days) but post hoc analyses revealed an increased number of consecutive nonuse days, reduced craving, and an increased percentage of nonuse days among patients without a history of alcohol…”

“, [12, 63, 64, 176]), its effects on sleep and its pro-cognitive effects position it as the best candidate at present for a viable pharmacotherapy for cocaine use disorders.”

“for the treatment of cocaine dependence [178] and possibly methamphetamine dependence [179].”

“For example, Modafinil, a catecholaminergic agonist, increases extracellular dopamine in the prefrontal cortex, and has been investigated for its applicability in treating cocaine dependence (Anderson et al., 2009; Dackis et al., 2004).”

“, 2005), a multi-site clinical trial was negative (Anderson et al., 2009).”

“A recent multicenter clinical trial found that modafinil decreased cocaine use and craving in cocainedependent subjects without co-morbid alcohol dependence (Anderson et al., 2009).”

“Accordingly, we failed to confirm earlier encouraging reports that modafinil promotes abstinence in cocaine dependence (Anderson et al., 2009; Dackis et al., 2005).”

“Compared to non-dependent controls and CUD alone, CUD + AUD individuals displayed greater gliosis in the white matter of the frontal lobe that persisted through at least 4-months of abstinence.”

“However, despite initial promise for modafinil, it appears that comorbid alcohol use as well as gender and concomitant behavioral therapy may be important qualifiers for effectiveness in relapse prevention (Anderson et al., 2009; Dackis et al., 2012).”

“Hence, understanding neural correlates to these deficits and implementing cognitive enhancement through therapeutic intervention may, therefore, be beneficial in the treatment strategy for at least some individuals (Anderson et al. 2009; Brady et al. 2011; Heinzerling et al. 2010).”

“However, CU with other substances is associated with greater severity of use and likelihood of overdose, more treatment admissions, and worse treatment outcomes compared to the use of cocaine alone (Anderson et al., 2009; Kampman et al., 2015; McCall Jones et al., 2017).”

“A 12-week multisite trial then compared placebo (n = 72) and modafinil [200 (n = 69) and 400 mg (n = 68); Anderson et al., 2009].”

“Modafinil has been used in several trials of treatment for cocaine dependence, with mixed results (Dackis et al., 2005; Anderson et al., 2009).”

“With regard to its effect upon cocaine use, modafinil was examined in a randomized, double-blind, placebo-controlled study (N = 210) at two doses (200 mg and 400 mg); however, no significant differences were observed between the modafinil and placebo groups in their change in the average weekly percentage of cocaine n…”

“Modafinil, an alpha-adrenergic/glutamate agonist, is another promising treatment for cocaine dependence, which is based on glutamate modulation; it has shown some success in clinical trials.(92,93) Nevertheless, its subjacent mechanism does not totally rely on glutamate and, rather, can be explained by the synergism o…”

“Several randomized clinical trials have also found some support for modafinil’s efficacy in reducing cocaine use in various groups (Anderson et al., 2009; Dackis, Kampman, Lynch, Pettinati, & O’Brien, 2005; Dackis et al., 2012).”

“There are no approved medications to treat cocaine addiction and multiple therapeutic approaches have failed in double-blind, placebo-controlled trials (Anderson et al. 2009; Elkashef et al. 2006; Kahn et al. 2009; Montoya & Vocci, 2009).”

“However, at the end of that 12-week trial there was no evidence of a decrease in total days of abstinence (76).”

“However, post-hoc analyses from one study revealed that while modafinil maintenance had no effect on cocaine abstinence, those without a history of alcohol use disorder (AUD) exhibited increased percentage of days abstinent by week [27].”

“…trial of 210 treatment-seeking cocainedependent patients randomized to placebo or one of two doses (200 or 400 mg/day)ofmodafinil foundnosignificant effect ofmodafinil on study retention, counseling attendance, or cocaine use in the full sample over the 12-week study period (Anderson et al., 2009).”

“However, the follow-up multi-site trial of 210 participants randomized to placebo, modafinil 200 mg/daily, or modafinil 400 mg daily, showed no advantage of modafinil on the primary outcome measure.[36] Secondary outcomes, including reduction of craving and the maximum number of consecutive non-use days for cocaine, f…”

“Results from these trials have sometimes shown a positive effect of modafi nil on stimulant abstinence, but the results have been variable (see Anderson et al., 2009; Heinzerling et al., 2010; McGaugh et al., 2009; Shearer et al., 2009).”

“, psychostimulants including modafinil and methylphenidate) for stimulant addictions (Anderson et al., 2009; Castells et al., 2010; Dackis et al., 2005, 2012; Longo et al., 2010).”

“In a separate study, modafinil treatment was associated with more days of abstinence from cocaine, when combined with weekly one-hour psychotherapy sessions.(115) In another study, modafinil increased the likelihood of negative urine samples and chances of achieving cocaine abstinence for more than 3 weeks after treat…”

“An example of the challenge posed by poly-drug addiction is the impact of alcohol dependence on the efficacy of modafinil in treating cocaine dependence (Anderson et al., 2009; Vocci and Elkashef, 2005).”

“, 2005, 2003) was dimmed by subsequent negative clinical trials (Anderson et al., 2009; Dackis et al., 2012).”

“More recently, Anderson et al. (2009) found a significant effect of modafinil that increased weekly percentage of cocaine non-use days in the subgroup of cocaine dependent patients without comorbid alcohol dependence, but not in the total sample. d-Amphetamine enhances dopaminergic functioning via…”

“Other than this collection of SR-AMP findings, the only other instance of concordance between human laboratory and clinical trial efficacy findings for an anti-cocaine medication has occurred with modafinil (Dackis et al , 2005; Hart et al , 2008; Anderson et al , 2009).”

“The second double-blind placebo‐controlled trial with modafinil in 210 cocaine dependent patients showed that modafinil reduced craving and reduced the number of days that cocaine was used in cocaine dependent patients, but only in those without a history of alcohol dependence (Anderson et al., 2009).”

“Further, results from a recent clinical trial indicate that MOD treatment was correlated with increased periods of abstinence in cocaine addicts with comorbid alcohol dependence (Anderson et al., 2009).”

“regard to average weekly percentage of cocaine nonuse days [121].”

“A number of clinical studies suggest that the wake-promoting drug modafinil may improve the clinical outcomes for treatment of cocaine dependence (Anderson et al., 2009; Dackis, Kampman, Lynch, Pettinati, & O’Brien, 2005; Dackis et al., 2003; Hart, Haney, Vosburg, Rubin, & Foltin, 2008), although a…”

“Modafinil does not appear to decrease cocaine use in cocaine-dependent individuals who are also heavy alcohol users — the reasons for this are unclear (Anderson et al., 2009).”

“2008), increased the maximum number of non-use days, and reduced craving in cocaine addicts (Anderson et al. 2009).”

“A 12-week multi-site trial compared placebo (n = 72) and modafinil (200 [n = 69] and 400 mg [n = 68]) [137].”

“, 2010) and its lack of clinical efficacy in the treatment of cocaine dependence, showing that it has low reinforcing effects of its own (Anderson et al., 2009).”

“Modafinil in combination with individual behavioral therapy was effective in increasing cocaine non-use days in participants without comorbid alcohol dependence and in reducing cocaine cravings [55].”

“A heavy drinking day was defined by 5 or more standard drinks for men, and 4 or more for women (Anton et al., 2006).”

“In 2 placebo-controlled RCTs in cocaine-dependent patients, modafinil (200 mg – 400 mg/day) was shown to reduce craving and increase cocaine abstinence compared to placebo (total N=272) (Anderson et al., 2009; Dackis et al., 2005).”

“Such information is particularly relevant to the interpretation of a possible sleep-directed pharmacologic treatment for cocaine, as these variables may contribute substantially to variation in treatment response (e.g. co-morbid alcohol dependence; Anderson et al., 2009).”

“Therefore, we examined the role of nucleus accumbens extracellular glutamate and the group II metabotropic glutamate receptor (mGluR2/3) in modafinil effects.”

“Although it has been shown that modafinil reduces craving for cocaine (Hart et al , 2008), a recent preclinical study reported that modafinil (128 mg/kg) alone can reinstate an extinguished CPP for cocaine (Bernardi et al , 2009); note, though, that the effects of modafinil pretreatment on…”

“In large, multi-site clinical trial (Anderson et al., 2009), in which bout 40% of participants also met criteria for alcohol dependence, hese results were not replicated.”

“…targeting additional mechanisms, for example inhibition of dopamine reuptake or metabolism (e.g., bupropion, disfulfiram, methyphenidate, modafinil, Anderson et al., 2009; Poling et al., 2006; Schottenfeld et al., 2014; Winhusen et al., 2006) and replenishment of dopamine stores (e.g., levodopa,…”

“Collective evidence to date suggests that as monotherapies neither modafinil (Dackis et al., 2012; Anderson et al., 2009) nor SSRIs (Pani et al.”

“Modafinil is a nonamphetamine psychostimulant that was initially approved for the treatment of narcolepsy but was subsequently shown to have success in clinical trials treating cocaine dependence (Anderson et al., 2009; Dackis, Kampman, Lynch, Pettinati, & O’Brien, 2005; Dackis et al., 2003).”

“However, after results from two negative modafinil studies were reported early in the recruitment period (Anderson et al., 2009; Dackis et al., 2012), we discontinued this medication.”

“Further, promising anti-cocaine medications, notably modafinil, are often less effective in patients who simultaneously abuse cocaine and ethanol (Anderson et al., 2009).”

“…modafinil achieved abstinence for longer periods and provided significantly fewer positive urine samples (Dackis et al., 2005); however, the efficacy of modafinil as a therapeutic may be limited to populations that are not dually dependent on cocaine and alcohol (A. L. Anderson et al., 2009).”

“Recent clinical trials have shown promising results for modafinil as a treatment for stimulant use disorders (Dackis et al., 2005; Hart et al., 2008; Anderson et al., 2009; Heinzerling et al., 2010; Kampman et al., 2015).”

“Drug and Alcohol Dependence, 104(1-2), 133–139.”

“In fact, even when Anderson and colleagues re-analyzed their data using the primary outcome as Dackis and colleagues [73] (missing urine samples coded cocaine positive) they still found no significant effect [77].”

“…as treatments for stimulant dependence specifically because of their role as cognitive enhancers as this effect may facilitate and improve the efficacy of behavioral interventions (Anderson et al., 2009; Bisaga et al., 2010; Carroll et al., 1998; Malcolm et al., 2005; Schmitz et al., 2010).”

“Larger multicenter clinical trials of modafinil have found modestly positive outcomes in psychostimulant abusers (Anderson et al., 2009).”

“Among studies administering modafinil, two [38,51] out of seven studies [38,42–44,46,51,52] found significant improvements in cocaine craving; as did another three studies administering amphetamine [48], lisdexamphetamine [55] and methamphetamine [54].”

“…modafinil may improve the clinical outcomes for treatment of cocaine dependence by reducing self-reports of craving and cocaine-induced euphoria (Anderson et al. 2009; Dackis et al. 2005; Dackis et al. 2003; Hart et al. 2008) through a possible DAT-mediated mechanism (Volkow et al. 2009;…”

“Of these agents, the psychostimulant modafinil has shown promising effects, in terms of increased and protracted cocaine abstinence, in several studies (Anderson et al., 2009; Dackis et al., 2005; Kampman et al., 2015); however, in a recent randomised controlled study in crackcocaine dependent patients, we found that…”

“Although a measure of cocaine use, such as self-reported cocaine use confirmed by urine BE, is typically chosen as the primary outcome measure in treatment studies of cocaine dependence (Anderson et al., 2009), the CCQ-Brief was selected as the primary endpoint as the proposed mechanism of action of the metyrapone/oxa…”

“[50] tested the efficacy of modafinil on 210 cocaine treatment seekers, in a double blind, placebo controlled study with 12 weeks of treatment and a 4-week follow-up.”

“Potential participants were excluded if they reported lifetime dependence on substances other than cocaine and nicotine, or current alcohol use in excess of 350 grams (25 standard drinks) perweek for the pastmonth (to approximate the population that appears to respond best tomodafinil; Anderson et al., 2009); if they…”

“Interestingly, in another study carried out on 125 cocainedependent subjects, the major finding was that modafinil decreased craving and cocaine use, but only in subjects without co-morbid alcohol dependence (Anderson et al., 2009).”