Modafinil for the treatment of methamphetamine dependence

https://doi.org/10.1016/j.drugalcdep.2011.07.007Get rights and content

Abstract

Aim

Modafinil was tested for efficacy in decreasing use in methamphetamine-dependent participants, compared to placebo.

Methods

This was a randomized, double-blind, placebo-controlled study, with 12 weeks of treatment and a 4-week follow-up. Eight outpatient substance abuse treatment clinics participated in the study. There were 210 treatment-seekers randomized, who all had a DSM-IV diagnosis of methamphetamine dependence; 68 participants to placebo, 72 to modafinil 200 mg, and 70 to modafinil 400 mg, taken once daily on awakening. Participants came to the clinic three times per week for assessments, urine drug screens, and group psychotherapy. The primary outcome measure was a methamphetamine non-use week, which required all the week's qualitative urine drug screens to be negative for methamphetamine.

Results

Regression analysis showed no significant difference between either modafinil group (200 or 400 mg) or placebo in change in weekly percentage having a methamphetamine non-use week over the 12-week treatment period (p = 0.53). Similarly, a number of secondary outcomes did not show significant effects of modafinil. However, an ad-hoc analysis of medication compliance, by urinalysis for modafinil and its metabolite, did find a significant difference in maximum duration of abstinence (23 days vs. 10 days, p = 0.003), between those having the top quartile of compliance (>85% of urines were positive for modafinil, N = 36), and the lower three quartiles of modafinil 200 and 400 mg groups (N = 106).

Conclusions

Although these data suggest that modafinil, plus group behavioral therapy, was not effective for decreasing methamphetamine use, the study is probably inconclusive because of inadequate compliance with taking medication.

Introduction

Methamphetamine (meth) is a synthetic stimulant which, along with other amphetamines, was widely prescribed in the US in the 1950s and 1960s for obesity and ‘depression’ (Grinspoon and Hedblom, 1975). The drug's label was revised by the Food and Drug Administration (FDA) in 1975 to that of a Class II controlled substance. Although still approved for Attention Deficit Hyperactivity Disorder (ADHD) in children older than six, and as a short-term adjunct for obesity, the drug is often manufactured illegally in small ‘home’ or large ‘super’ labs, using ephedrine, pseudoephedrine, or P-2-P (phenyl-2-propanone) as a precursor (Drug Enforcement Administration, 2005). In 2009, about 1.2 million Americans age 12 and older had used methamphetamine illicitly at least once in the year prior to being surveyed (Substance Abuse and Mental Health Services Administration, 2010). The United Nations estimated that there were about 14–53 million annual users globally, among persons aged 15–64 years (UNODC, 2010).

Dependence on methamphetamine can be a devastating illness, with ill effects and associations across the lifespan, at home and in the community. Neonates who were prenatally exposed to meth had a higher incidence of being small for gestational age, after adjusting for alcohol and tobacco exposure and other covariates (Nguyen et al., 2010). A sample of 526 meth dependent adults, who took part in the Methamphetamine Treatment Project of SAMHSA's Center for Substance Abuse Treatment, were reassessed three years later. Almost half of them (48%) met DSM-IV criteria for a current or past psychiatric disorder other than substance use, and 29% had antisocial personality disorder (Glasner-Edwards et al., 2010). Three of the major illicit drugs associated with criminality were assessed over a 10 year follow-up. The courses of almost 1800 heroin, cocaine, and methamphetamine users showed that meth users had earlier initiation of drug use than cocaine users (age 19.6 vs. 23.0 yrs), and spent more months incarcerated than cocaine users (10.5 vs. 6.3), though less than heroin users (34.7). Meth users were also more likely to be women than were heroin or cocaine users (46% vs. 11% or 29%), and had a relatively high percentage of drug injection (44% vs. 90% or 27%; Hser et al., 2008).

In contrast to methamphetamine, modafinil is a novel, non-amphetamine psychostimulant, first approved by the US Food and Drug Administration (FDA) in 1998 for the treatment of narcolepsy, and later for shift work sleep disorder, and as an adjunct for obstructive sleep apnea (Cephalon Inc., 2007). It is an effective wake-promoting agent, but its mechanism of action differs in some ways from that of the amphetamines, cocaine, or methylphenidate (Ballon and Feifel, 2006). Modafinil has distinctive actions on the hypocretin/orexin system (Scammell et al., 2000) and the glutamate/GABA (gamma-Aminobutyric Acid) systems (Ferraro et al., 1999), as well as some dopamine-mediated (Wisor et al., 2001) and alpha-adrenergic effects (Stone et al., 2002) that resemble those of more traditional stimulants.

There are several rationales for using modafinil to treat methamphetamine dependence. For example, modafinil has stimulant properties, which could be therapeutic for alleviating some stimulant withdrawal symptoms (McGregor et al., 2008). In animal testing it has been found to attenuate reinstatement of meth self-administration (Reichel and See, 2010). Also, modafinil appears to have lower abuse potential than methylphenidate or amphetamine (Jasinski, 2000, Myrick et al., 2004). Modafinil improves cognition and mood (Turner et al., 2004, Taneja et al., 2007), and has shown efficacy in the treatment of child and adult ADHD (Lindsay et al., 2006). Modafinil has been used in several trials of treatment for cocaine dependence, with mixed results (Dackis et al., 2005, Anderson et al., 2009). Finally, modafinil was safe and well tolerated in a Phase I interaction study with intravenous methamphetamine (unpublished data, Jones, 2007).

Section snippets

Methods

The objectives of this study were to evaluate the efficacy and safety of modafinil relative to placebo, for reducing methamphetamine use in meth-dependent outpatients, as assessed by qualitative or quantitative urine drug screens. The study had a double-blind, placebo-controlled, parallel-group design in which, after a 3-week screening/baseline period, participants were randomly assigned with equal probability to one of three treatment groups to receive 400 mg modafinil, 200 mg modafinil, or

Baseline demographics

Fig. 1 shows flow diagram of the numbers of study participants, from consent through randomization and on to completion of the study. The screen failure rate was 51% (226/440). The most common reasons for failure in screening were: (1) not willing and able to comply with study procedures, including ‘did not return to clinic’ (54%); (2) did not provide a methamphetamine-positive urine during the 3-week screening period (19%); (3) had current dependence on a psychoactive substance other than

Discussion

In this study, the effect of modafinil on the planned primary outcome (methamphetamine non-use weeks) was not significant. Also, the ‘terminal abstinence’ outcome, which is recently preferred by the FDA and Cochrane reviews, did not show a medication effect. In addition, other secondary outcome measures did not show significant effects of modafinil to decrease the amount of meth used or increase the length of abstinence (prevent relapse). However, the measurement of study drug in the urine,

Role of funding source

Funding for this study was provided by NIDA Contract # Y1-DA-4006-01. The National Institute on Drug Abuse-NIH had a major role in study design, in the analysis and interpretation of data, and in the writing and submission of this manuscript for publication.

Contributors

Authors Ann Anderson and Ahmed Elkashef wrote the first draft of the manuscript, and Ann Anderson edited the final draft. Shou-Hua Li, Kousick Biswas, Frances McSherry and Tyson Holmes did the statistical design, analyses, reports and editing. Erin Iturriaga contributed literature searches and descriptions of the study population and treatments. Roberta Kahn summarized the adverse events data. Nora Chiang provided chemical assay materials. Elmer Yu and Ahmed Elkashef contributed summaries of

Conflict of interest

All authors declare that they have no conflicts of interest, i.e., no actual or potential conflict of interest including any financial, personal or other relationships with people or organizations within three years of beginning the work submitted that could inappropriately influence, or be perceived to influence, this work.

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