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