Modafinil and cocaine: a double-blind, placebo-controlled drug interaction study

https://doi.org/10.1016/S0376-8716(02)00335-6Get rights and content

Abstract

Modafinil is a novel compound that is approved for the treatment of narcolepsy. It is now being studied as a potential treatment for cocaine dependence. Cocaine withdrawal symptoms are associated with poor clinical outcome and are likely to be reversed by modafinil. In addition, the neurotransmitter actions of modafinil are opposite to cocaine-induced neuroadaptations affecting dopamine and glutamate reward circuits. Since cocaine-dependent subjects might use cocaine during a clinical trial with modafinil, this study tested the safety of intravenous cocaine (30 mg) in combination with modafinil. Each of seven subjects received a baseline (open-label) cocaine infusion. Three subsequent cocaine infusions were administered after subjects received 4 days of low dose modafinil (200 mg/day), high dose modafinil (400 mg/day), or placebo in randomized double-blind sequences. One subject received placebo prior to all infusions. Our results indicate that co-administering modafinil and a single dose of intravenous cocaine is not associated with medical risk in terms of blood pressure, pulse, temperature, or electrocardiogram measures. Furthermore, pretreatment with modafinil did not intensify cocaine euphoria or cocaine-induced craving. In fact, cocaine euphoria was significantly blunted (P=0.02) in one of our subjective measures.

Introduction

Cocaine dependence remains a disorder for which no pharmacological treatment exists, although considerable advances in the neurobiology of this addiction should guide future medication development. Numerous lines of evidence conclude that cocaine euphoria involves the activation of brain reward circuits that are subsequently dysregulated after repeated cocaine administration (Koob et al., 1998, Dackis and O'Brien, 2002a, Dackis and O'Brien, 2002b). Pharmacological agents capable of reversing cocaine-induced neuroadaptations are logical choices to ameliorate clinical features of this illness, including withdrawal, craving, and hedonic dysregulation (Dackis and O'Brien, 2002a). Modafinil, a wakefulness-promoting drug approved for narcolepsy, has neurotransmitter actions that are opposite to cocaine-induced neuroadaptations affecting dopamine (DA) and glutamate reward circuits. Repeated cocaine administration depletes glutamate (Keys et al., 1998) while modafinil increases brain glutamate (Perez de la Mora et al., 1999, Pierard et al., 1995, Ferraro et al., 1998). DA depletion by cocaine (Dackis and Gold, 1985, Wu et al., 1997, Volkow et al., 1997) might also be reversed as a result of modafinil's inhibition of GABA release (Perez de la Mora et al., 1999) because reward-related midbrain DA neurons are under tonic inhibitory regulation by GABA projections (Dackis and O'Brien, 2002a).

Modafinil's stimulant-like action should also reduce cocaine withdrawal symptoms, including hypersomnia, anergia, depressed mood, hyperphagia, psychomotor retardation, and poor concentration (Satel et al., 1991, Weddington et al., 1990, Gawin and Kleber, 1986, Cottler et al., 1993, Coffey et al., 2000). Since severe cocaine withdrawal has been linked to poor clinical outcome (Kampman et al., 2001, Mulvaney et al., 1999), its reversal might be clinically advantageous. In addition, since modafinil has some cocaine-like discriminative stimulus effects in animals (Gold and Balster, 1996) and some stimulant-like subjective effects in humans (Jasinski, 2000), it might perform a substitution therapy function in cocaine-dependent patients. Furthermore, modafinil has low abuse potential (Jasinski, 2000, Jasinski and Kovacevic-Ristanovic, 2000), good tolerability (Menza et al., 2000, Lyons and French, 1991), and a neurochemical profile that differs markedly from that of cocaine and amphetamine (Ferraro et al., 1997, Mignot et al., 1994, Akaoka et al., 1991, Lyons and French, 1991, Lin et al., 1996, Simon et al., 1995). These attributes identify modafinil as a potentially efficacious compound for the treatment of cocaine dependence.

Given the high recidivism rates associated with cocaine dependence (Alterman et al., 1994, Alterman et al., 1996b, Alterman et al., 1996a, Carroll et al., 1991, Carroll et al., 1994, Kang et al., 1991, Higgins et al., 1993), there is significant risk that cocaine will be used by subjects enrolled in clinical trials. Therefore, a drug interaction study with modafinil and cocaine is warranted to maximize subject protection. Although no such study has yet been reported, modafinil has been co-administered with dextroamphetamine (Wong et al., 1998b) and methylphenidate (Wong et al., 1998a), and neither of these studies reported untoward medical complications or pharmacokinetic interactions. Intravenous cocaine infusions in the laboratory have not been found to produce subsequent deleterious changes in cocaine use patterns (Kaufman et al., 2000). The current safety study was conducted to evaluate the effect of modafinil pretreatment on physiological and subjective responses to intravenous cocaine administration.

Cocaine has well-documented effects on blood pressure, pulse, temperature, and cardiac function. Its sympathomimetic action produces tachycardia and hypertension (Cascella et al., 1989) that can be sufficiently severe to cause brain hemorrhage (Jacobs et al., 1989, Nolte et al., 1996) and cerebral infarction (Kokkinos and Levine, 1993, Daras et al., 1991). Cocaine is also thermogenic and has been reported to cause fatal hyperthermia (Loghmanee and Tobak, 1986, Wetli and Fishbain, 1985). Deleterious effects on cardiac function are substantiated by numerous case reports of arrhythmias, myocardial infarction and sudden death (Lange and Hillis, 2001, Combs and Acosta, 1990, Chakko and Myerburg, 1995). Cocaine specifically increases the QTc interval (QT interval corrected for heart rate), which may lead to ventricular tachycardia, ventricular fibrillation, and asystole (Gamouras et al., 2000, Kerns et al., 1997). In recommended doses (200–400 mg/day), modafinil produces a 2% incidence of hypertension, although excessive doses (800 mg/day) can lead to significant hypertension and tachycardia (Wong et al., 1999). In addition, chest pain, palpitations, dyspnea and transient ischemic T-wave changes on electrocardiogram (ECG) have been reported in three patients with pre-existing mitral valve prolapse or left ventricular hypertrophy. Modafinil is thermogenic in animal studies (Lin et al., 1992) but human reports are conflicting (Pigeau et al., 1995, Brun et al., 1998, Bourdon et al., 1994). Given these reports, and the possibility that modafinil might exacerbate the medical risk of cocaine administration, we assessed blood pressure, pulse, temperature, and ECG function in this drug interaction study.

As a secondary objective, we also evaluated the impact of modafinil pretreatment on the subjective responses to cocaine. Aside from producing intense euphoria, cocaine has the ability to stimulate its own craving shortly after administration (Jaffe et al., 1989, O'Brien et al., 1992). Since any amplification of cocaine-induced euphoria or craving by modafinil could be clinically deleterious, these subjective states were specifically evaluated. Side effects and adverse events were also carefully measured to further assess potential interactions and tolerability. The results of our double blind, placebo-controlled, drug interaction study are presented below.

Section snippets

Subjects

Subjects were recruited from cocaine-dependent individuals (between the ages of 18 and 50) presenting for treatment to the Department of Veterans Affairs Medical Center (DVAMC) in Philadelphia. All participants had full access to treatment and received aftercare referrals at the conclusion of the study. Individuals were excluded if they had a current diagnosis of substance dependence (except cocaine or nicotine), significant medical disease (especially hypertension, seizures, arrhythmia

Results

The set of physiology measures is comprised of four vital sign responses (diastolic blood pressure, systolic blood pressure, pulse, and temperature), ECG monitoring, cocaine levels, and prolactin levels. The set of subjective measures is comprised of the ARCI, the Subjective Symptom Checklist, and the VAS. Tests of carryover, period, and period by treatment effects are necessary pre-requisites for the analysis of any crossover design, as the presence of such effects can suggest the need to

Discussion

The primary goal of this safety study was to determine whether medically significant complications would result from the co-administration of modafinil and cocaine. We found no evidence of modafinil exacerbating cocaine-induced increases in blood pressure, pulse, or temperature, or that adverse ECG effects resulted from this combination. Analysis of cocaine levels confirmed that our results were not confounded by significant differences in levels across periods. The results are limited by the

Acknowledgements

Supported by Interagency Agreements (Y01-DA30012-02) between NIDA and the Philadelphia VA Medical Center and NIDA Grants DA P60-05186 and DA P50-12756. Modafinil and matched placebo tablets were provided as a grant by Cephalon, Inc.

References (81)

  • L. Ferraro et al.

    The effects of modafinil on striatal, pallidal and nigral GABA and glutamate release in the conscious rat: evidence for a preferential inhibition of striato-pallidal GABA transmission

    Neurosci. Lett.

    (1998)
  • L. Ferraro et al.

    The vigilance promoting drug modafinil decreases GABA release in the medial preoptic area and in the posterior hypothalamus of the awake rat: possible involvement of the serotonergic 5-HT3 receptor

    Neurosci. Lett.

    (1996)
  • G.A. Gamouras et al.

    Cocaine abuse: repolarization abnormalities and ventricular arrhythmias

    Am. J. Med. Sci.

    (2000)
  • A. Imperato et al.

    Chronic cocaine alters limbic extracellular dopamine. Neurochemical basis for addiction

    Eur. J. Pharmacol.

    (1992)
  • K.M. Kampman et al.

    Reliability and validity of the cocaine selective severity assessment

    Addict. Behav.

    (1998)
  • M.J. Kaufman et al.

    Illicit cocaine use patterns in intravenous-naı̈ve cocaine users following investigational intravenous cocaine administration

    Drug Alcohol Depend.

    (2000)
  • W. Kerns et al.

    Cocaine-induced wide complex dysrhythmia

    J. Emerg. Med.

    (1997)
  • J. Kokkinos et al.

    Stroke

    Neurol. Clin.

    (1993)
  • G.F. Koob et al.

    Neuroscience of addiction

    Neuron

    (1998)
  • J.S. Lin et al.

    Role of catecholamines in the modafinil and amphetamine induced wakefulness, a comparative pharmacological study in the cat

    Brain Res.

    (1992)
  • F.D. Mulvaney et al.

    Cocaine abstinence symptomatology and treatment attrition

    J. Subst. Abuse Treat.

    (1999)
  • S. Nicolaidis et al.

    Nonamphetamine awakening agent modafinil induces feeding changes in the rat

    Brain Res. Bull.

    (1993)
  • C. Pierard et al.

    Effects of a vigilance-enhancing drug, modafinil, on rat brain metabolism: a 2D COSY 1H-NMR study

    Brain Res.

    (1995)
  • M.W. Robertson et al.

    Apparent synaptic dopamine deficiency induced by withdrawal from chronic cocaine treatment

    Brain Res.

    (1991)
  • T.A. Rugino et al.

    Effects of modafinil in children with attention-deficit/hyperactivity disorder: an open-label study

    J. Am. Acad. Child Adolescence Psychiatry

    (2001)
  • P. Simon et al.

    Non-amphetaminic mechanism of stimulant locomotor effect of modafinil in mice

    Eur. Neuropsychopharmacol.

    (1995)
  • S. Tanganelli et al.

    Modafinil and cortical gamma-aminobutyric acid outflow. Modulation by 5-hydroxytryptamine neurotoxins

    Eur. J. Pharmacol.

    (1995)
  • R.A. Wise

    Neurobiology of addiction

    Curr. Opin. Neurobiol.

    (1996)
  • J.C. Wu et al.

    Decreasing striatal 6-FDOPA uptake with increasing duration of cocaine withdrawal

    Neuropsychopharmacology

    (1997)
  • A.I. Alterman et al.

    Effectiveness and costs of inpatient versus day hospital cocaine rehabilitation

    J. Nerv. Ment. Dis.

    (1994)
  • A.I. Alterman et al.

    A quasi-experimental comparison of the effectiveness of 6-versus 12-hour per week outpatient treatments for cocaine dependence

    J. Nerv. Ment. Dis.

    (1996)
  • K.M. Beusterien et al.

    Health-related quality of life effects of modafinil for treatment of narcolepsy

    Sleep

    (1999)
  • L. Bourdon et al.

    Effect of modafinil on heat production and regulation of body temperatures in cold-exposed humans

    Aviat. Space Environ. Med.

    (1994)
  • J. Brun et al.

    Effect of modafinil on plasma melatonin, cortisol and growth hormone rhythms, rectal temperature and performance in healthy subjects during a 36 h sleep deprivation

    J. Sleep Res.

    (1998)
  • K.M. Carroll et al.

    A comparative trial of psychotherapies for ambulatory cocaine abusers: relapse prevention and interpersonal psychotherapy

    Am. J. Drug Alcohol Abuse

    (1991)
  • K.M. Carroll et al.

    Psychotherapy and pharmacotherapy for ambulatory cocaine abusers

    Arch. Gen. Psychiatry

    (1994)
  • S. Chakko et al.

    Cardiac complications of cocaine abuse

    Clin. Cardiol.

    (1995)
  • A.B. Combs et al.

    Toxic mechanisms of the heart: a review

    Toxicol. Pathol.

    (1990)
  • C.A. Dackis et al.

    Cocaine dependence: the challenge for pharmacotherapy

    Curr. Opin. Psychiatry

    (2002)
  • C.A. Dackis et al.

    The neurobiology of addiction

  • Cited by (0)

    View full text