A double blind, placebo-controlled trial that combines disulfiram and naltrexone for treating co-occurring cocaine and alcohol dependence☆
Introduction
Patients who have co-occurring cocaine and alcohol dependence comprise a large proportion of the cocaine-addicted population (Gossop, Manning, & Ridge, 2006b), and suffer more adverse addiction-related consequences, have greater psychosocial problems, are inherently inconsistent at showing up for treatment visits, and have higher rates of recidivism than patients dependent only on cocaine or on alcohol (Brady et al., 1995, Carroll et al., 1993, Flannery et al., 2004, Heil et al., 2001, Mengis et al., 2002). Also, concurrent use of cocaine and alcohol produces cocaethylene (Gossop et al., 2006a, Harris et al., 2003), an active transesterified metabolite associated with more lethality than cocaine alone (Pennings, Leccese, & Wolff, 2002) and toxicity (Harris et al., 2003, Hearn et al., 1991, Pennings et al., 2002).
Thus, this treatment-refractory population may require a pharmacological approach, added to traditional counseling, which effectively targets the potentially different neurobiology of the combination of cocaine and alcohol dependencies. Historically, there have been many attempts to test medications for the treatment of either cocaine or alcohol dependence alone. Presently, the Food and Drug Administration (FDA) has approved medications for treating alcohol dependence, but none have been approved for treating cocaine dependence (Vocci, Acri, & Elkashef, 2005). Notably, there have been few attempts to evaluate medications in clinical trials for treating the co-occurrence of cocaine and alcohol dependence.
One reasonable treatment approach of co-occurring cocaine and alcohol dependence, which has been tried but has thus far failed, is giving an FDA-approved alcohol-reducing medication (added to counseling) that will decrease alcohol drinking, and, in turn, indirectly promote cocaine abstinence. It is well known that the use of one addictive substance often leads to the use of another addictive one. However, two double blind, placebo-controlled studies of 50 mg/day of naltrexone, an FDA-approved medication for treating alcohol dependence, did not reduce alcohol or cocaine use in cocaine-alcohol dependent outpatients, compared to placebo treatment (Hersh et al., 1998, Schmitz et al., 2004). Nonetheless, some preliminary data have suggested that a higher dose of naltrexone (150 mg/day) may be useful in reducing cocaine and alcohol use in cocaine-alcohol dependent patients (Oslin, Pettinati, Volpicelli, Wolf, & O′Brien, 1999), but more so in men than in women (Pettinati et al., in press).
Another rationale, and a novel approach, to treating the co-occurrence of cocaine and alcohol dependence is to combine two medications, one of which will decrease cocaine use and the other of which will decrease alcohol use. In recent years, there have been a series of double blind, placebo-controlled clinical trials of combination medications for treating primarily alcohol or drug dependence in patients without concomitant psychiatric disorders (see, e.g., Ait-Daoud et al., 2001, Anton et al., 2006, Kampman et al., 2006, Kiefer and Wiedemann, 2004), including adding disulfiram to naltrexone (Petrakis et al., 2005), or to acamprosate — another FDA-approved medication for treating alcohol dependence (Besson, Aeby, Kasas, Lehert, & Potgieter, 1998). The treatment strategy tested in the present study was combining two medications (added to twice weekly sessions of cognitive behavioral therapy) to treat patients presenting with dual cocaine and alcohol dependence. One medication was selected to reduce cocaine use (disulfiram — see below the rationale for doing so), and the second medication was selected to reduce alcohol use — plus its FDA approval in 1994 for treating alcohol dependence (naltrexone).
Selecting a medication to reduce cocaine use was a more difficult task than choosing one to reduce alcohol use because there are no FDA-approved medications for treating cocaine dependence. However, recent controlled trials of several medications, namely, disulfiram, topiramate, modafinil, and others, suggested that some medications added to counseling may provide an advantage over placebo treatment for cocaine dependence (see respectively: Carroll et al., 2004, Dackis et al., 2005, Kampman et al., 2004). To date, however, disulfiram has had more published articles than any other medication in support for its use in the treatment of cocaine dependence (see Carroll et al., 2004, Carroll et al., 2000, Carroll et al., 1998, Gossop and Carroll, 2006, Grassi et al., 2007), particularly in men (Nich et al., 2004, Petrakis et al., 2000).
Disulfiram originally was approved in 1951 for promoting abstinence from alcohol, but it has been used only modestly since its approval to treat alcohol dependence (Suh, Pettinati, Kampman, & O′Brien, 2006). While disulfiram has an appeal in the context of the present study because of its known action in deterring alcohol use, it was selected for the present study primarily as a treatment for reducing cocaine use. Disulfiram′s mechanism of action for reducing cocaine use is believed to be different from its mechanism for promoting abstinence from alcohol. Essentially, disulfiram′s effect on decreasing alcohol use is that it inhibits the enzyme, aldehyde dehydrogenase, which is necessary for fully metabolizing alcohol, leaving an increased concentration of acetaldehyde, which causes unpleasant sensations (Suh et al., 2006). Potentially, disulfiram′s mechanism of action for reducing cocaine use is that it inhibits dopamine beta-hydroxylase, an enzyme that normally converts dopamine to noradrenaline (Kosten et al., 2002, McCance-Katz et al., 1998a), and hence, increases the concentration of dopamine more than what is observed when cocaine is taken alone. Furthermore, disulfiram, when coupled with cocaine use, impedes cocaine metabolism by inhibiting plasma and microsomal carboxylesterases and plasma cholinesterase (McCance-Katz, Kosten, & Jatlow, 1998b). In some studies, the combination of disulfiram and cocaine has resulted in a higher than expected plasma-cocaine concentration, and a longer than expected cocaine-elimination half-life (Hameedi et al., 1995, McCance-Katz et al., 1998a). These effects of the disulfiram–cocaine interaction might result in an exacerbation of negative effects of cocaine, such as anxiety, paranoia, and cardiovascular response (McCance-Katz et al., 1998a, McCance-Katz et al., 1998b).
In a controlled clinical trial for treating cocaine dependence with disulfiram, Carroll et al. (2004) found that disulfiram significantly reduced cocaine use in patients with cocaine dependence. Of interest, however, disulfiram did not seem to provide the same advantage over placebo in reducing cocaine use in cocaine-dependent patients who regularly drank a substantial amount of alcohol. The results of this Carroll study, while encouraging for treating cocaine dependence, did not address how to treat the highly prevalent cocaine-dependent group with alcohol dependence.
With respect to the treatment in the present study for the patient′s alcohol dependence, the daily, oral version of naltrexone was selected to be given in combination with disulfiram. Naltrexone is an opioid receptor antagonist that has been found in a number of trials to reduce heavy drinking in alcoholics (see review by Pettinati et al., 2006). A preponderance of evidence from pre-clinical and clinical studies suggests that the therapeutic effect of naltrexone in alcoholism stems from its ability to attenuate alcohol-induced euphoria (O´Malley et al., 1992, Volpicelli et al., 1990) by inhibiting the release of beta-endorphin (Volpicelli, Watson, King, Sherman, & O′Brien, 1995). Notably, naltrexone may also have direct therapeutic effects on cocaine use, independent of its effects on alcohol consumption, although to date, clinical trials have not proven its effectiveness in reducing cocaine use at the 50 mg/day dose (Hersh et al., 1998, Schmitz et al., 2004). Furthermore, studies have failed to demonstrate that naltrexone has an effect on cocaine euphoria in humans (Sofuoglu et al., 2003, Walsh et al., 1996). Nonetheless, pre-clinical studies have demonstrated that cocaine releases beta-endorphin (Beakeland, Lundwall, Kissin, & Shanahan, 1971), and that naltrexone and other opioid antagonists reduce rates of cocaine self-administration in animals (Paille et al., 1995, Pelc et al., 1997, Sass et al., 1996). Chronic exposure to both alcohol and cocaine result in dynorphin upregulation (Dackis & O′Brien, 2003), which may contribute to dopamine hypoactivity in both conditions (De Witte et al., 2005, Fuller and Gordis, 2004, Suh et al., 2006). This neuroadaptation may be reversed by naltrexone′s antagonism of kappa-opioid receptors, by which dynorphin inhibits dopamine activity. In summary, the present study evaluated in a controlled clinical trial the effect of treating cocaine-alcohol dependence with the combination of disulfiram and naltrexone added to twice weekly sessions of cognitive behavioral therapy.
Section snippets
Patients
The patients were 208 men and women between the ages of 18 and 65 who had a DSM-IV diagnosis of both cocaine and alcohol dependence. Patients with dependence on substances other than cocaine and alcohol, except nicotine addiction, were excluded. Patients needed to have used a minimum of $100 worth of cocaine and drank an average of 12 standard alcoholic drinks a week during the month before treatment. Psychiatric exclusion criteria included active psychosis, mania, dementia, or the need for
Demographic and pre-treatment alcohol and cocaine use
The average age of the patients for the N = 208 sample was approximately 41 years old. Most were African American men (88.9%) and most smoked crack cocaine (78.9%). The mean number of years of education completed for the sample was 12.3 years. On average, patients had said they had in the month prior to treatment used cocaine 45.8% of the days, and drank alcohol on 56% of the days, with 48.8% heavy drinking days in the same pre-treatment month.
Overall, the four study groups, DISULF, NTX, DISULF +
Discussion
Co-occurring cocaine and alcohol dependence is highly prevalent in the United States and is also very difficult to treat successfully. Adding pharmacotherapies that target one or both of these dependencies to an accepted counseling/psychosocial treatment for cocaine and alcohol dependence, i.e., CBT, was evaluated in this double blind, placebo-controlled study combining disulfiram and naltrexone as a treatment regimen for attaining abstinence in cocaine and/or alcohol use. Disulfiram and
Acknowledgments
The work was supported by grants from the National Institute on Drug Abuse (P60 DA05186 to Dr. O′Brien; P50 DA12756 to Dr. Pettinati). Dupont Pharmaceuticals generously donated naltrexone and matching placebo.
We thank Thea Gallis, Thomas Whittingham, William Dundon, and Donna Giles for their technical assistance.
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A portion of this paper was presented in a symposium conducted at the annual meeting of the College on Problems of Drug Dependence, Orlando, Florida.