The American Journal on Addictions, 23: 591–597, 2014 Copyright © American Academy of Addiction Psychiatry ISSN: 1055-0496 print / 1521-0391 online DOI: 10.1111/j.1521-0391.2014.12146.x
A Pilot Trial of Injectable, Extended‐Release Naltrexone for the Treatment of Co‐Occurring Cocaine and Alcohol Dependence Helen M. Pettinati, PhD,1 Kyle M. Kampman, MD,1 Kevin G. Lynch, PhD,1 William D. Dundon, PhD,1 Elizabeth M. Mahoney, MS,1 Michael R. Wierzbicki, PhD,2 Charles P. O’Brien, MD, PhD1 1
Department of Psychiatry, Center for the Studies of Addiction, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania 2 Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania
Background: There is a high co‐occurrence of cocaine and alcohol use disorders, and patients with both of these problems are difficult to treat. There is a reasonable rationale and some empirical data to justify a pilot trial of an injectable, extended‐release formulation of naltrexone for treating co‐occurring cocaine and alcohol addiction. Methods: Eighty cocaine (n ¼ 80) and alcohol dependent, treatment‐ seeking subjects were randomly assigned to receive either two monthly extended‐release injections of naltrexone or two matching placebo injections in an 8‐week clinical trial, with weekly medical management plus cognitive behavioral therapy visits. Results: No differences in reduction in cocaine or alcohol use were observed between the injectable naltrexone and placebo groups during the 8‐week trial. Conclusions: Injectable extended‐release naltrexone, while an ideal method for ensuring medication adherence in these traditionally hard‐ to‐treat patients, did not result in any measurable reduction in cocaine or alcohol use over the course of 8 weeks of treatment. (Am J Addict 2014;23:591–597)
INTRODUCTION Patients with comorbid cocaine and alcohol dependence provide a unique challenge for addiction treatment providers. Epidemiological studies report a high co‐occurrence of cocaine and alcohol dependence.1,2 That is, among those with a cocaine use disorder, 79.4% also have an alcohol use disorder.2 These individuals are also difficult to treat. They tend to have more Received December 13, 2013; revised April 21, 2014; accepted May 1, 2014. Address correspondence to Dr. Kampman, Department of Psychiatry, University of Pennsylvania, Perelman School of Medicine, 3900 Chestnut Street, Philadelphia, PA 19104‐6178. E‐mail: [email protected]
psychosocial problems, are more likely to be non‐adherent with treatment regimens, and, in general, have worse treatment outcomes compared to patients addicted to either cocaine or alcohol alone.3–7 Difficulties in treating these patients may be a result of having two addictions, or, potentially, of “co‐using” cocaine with alcohol, which produces a metabolite (cocaethylene). Cocaethylene is purported to have higher addiction potential than either cocaine or alcohol alone.8,9 As there are no medications approved by the Food and Drug Administration (FDA) for treating a cocaine use disorder, it is reasonable to investigate whether medications that are FDA‐ approved for treating alcohol use disorders might impact cocaine use in patients with comorbid alcohol and cocaine dependence. This approach is substantiated by observations that alcohol drinking or cocaine use may act as “conditioned cues” for each other. Thus, a medication that might reduce excessive drinking may also, in turn, reduce cocaine use, and, thus, interfere in the “conditioned” sequencing of the two substances that typically leads to continued use of both substances.3,10–13 Furthermore, there has been some empirical support for a higher dose (150 mg/day) of naltrexone, a medication that is FDA‐ approved for alcohol dependence, to reduce cocaine and alcohol use in cocaine and alcohol‐dependent male patients.14 However, lower doses of naltrexone have not been shown to affect treatment response,15–17 although poor response rates may have been due to non‐adherence to the typical required daily pill taking with oral naltrexone. Naltrexone is an effective and well‐tolerated pharmacotherapy for reducing heavy drinking.18,19 However, adherence to a regimen of daily oral naltrexone has been problematic. In fact, we have observed a substantive impact of medication non‐adherence on drinking outcomes in a number of alcohol treatment studies. For example, we reported a large naltrexone (vs. placebo) effect 591
size for relapse in patients who consistently took their medication and attended research visits (.74), and a small or negative effect size in non‐adherent patients (.27).20 In 2006, the FDA approved an extended‐release naltrexone injection (VIVITROL1) for treating alcohol dependence that provides effective drug plasma levels for 30–40 days. FDA approval was based on a treatment course of 6 month injections21). Each injection ensured 100% adherence to naltrexone treatment for approximately 1 month. Thus, if there is a chance that these dually addicted patients will reduce their cocaine and/or alcohol use, it would be important to evaluate the extended‐release formulation of naltrexone because it would allow us to accurately evaluate naltrexone’s effects in medication‐adherent patients. Therefore, we conducted a double blind, placebo‐controlled clinical exploratory trial to evaluate the use of extended‐release naltrexone over a course of 8 weeks for treating individuals with co‐occurring cocaine and alcohol dependence. Eight weeks has been found in previous trials to be a trial duration that enables sufficient retention of cocaine‐addicted patients to discern a medication versus placebo difference.22
METHODS Participants There were 80 men and women between the ages of 18 and 65 years who were recruited from the greater Philadelphia area and attended visits at the University of Pennsylvania’s Addiction Treatment Research Center. They were recruited through community advertisements aimed at treatment‐ seeking individuals with both DSM‐IV cocaine and alcohol dependence. Subjects enrolled in the study were not involved in other types of addiction treatment, but self‐help, support groups were encouraged. Subjects were eligible if they: (a) met DSM‐IV criteria for both cocaine and alcohol dependence; (b) reported at least $200 worth of cocaine use in the month prior to study enrollment; (c) drank a minimum of 12 standard drinks of alcohol on average per week during the month prior to coming in to the center; and (d) were able to achieve 3 consecutive days of abstinence from alcohol just prior to randomization. Subjects dependent on any drugs other than cocaine, alcohol, or nicotine were excluded from the trial. If clinically indicated, subjects completed outpatient detoxification. Subjects with a history of current severe psychiatric symptoms, use of any investigational medication taken within the last 30 days, AIDS or other serious illness which may have required hospitalization during the study, or impaired renal function or known liver disease, were excluded from the study. Pregnant women or women who refused to use acceptable forms of birth control were excluded from the study. Potential subjects were also screened for illnesses that would preclude the use of naltrexone and for a Body Mass Index that would put them at a greater risk for an injection site reaction. Design and Procedures All subjects signed informed consent prior to conducting treatment procedures that were administered by a nurse 592
practitioner. Eligible subjects agreed to a 10‐week study that included a 1‐week screening/baseline collection; an 8‐week double blind, placebo‐controlled trial with three weekly visits; and a 1‐week follow‐up, final study visit. Eligible subjects were randomized to receive either injectable, extended‐release naltrexone (380 mg) or a matching placebo injection using an urn randomization method for assigning treatment.23 Urn randomization included three variables: (a) gender; (b) low versus high frequency of alcohol use (less than or equal to 68% days drinking vs. more than 68% days drinking in 30 days prior to the study, as determined by the Timeline Followback method (TLFB)); and (c) positive or negative urine drug screen (UDS) for the benzoylecgonine metabolite, or cocaine use, at the initial visit. Each subject received two injections of 380 mg extended‐ release naltrexone or a matching placebo injection, one at randomization and the second at 4 weeks later. Subjects were required to attend three visits per week during the 8‐week trial at which time urine samples and research assessments were collected. On a once‐a‐week basis, subjects met with a nurse trained in Medical Management24 and also with a Master’s level therapist for Cognitive Behavior Therapy (CBT). The CBT manual was adapted from the National Institute on Alcohol Abuse and Alcoholism Project MATCH manual25 for the treatment of both alcohol and cocaine dependence. Subjects were reimbursed $5 and were given two transit tokens at each visit. At the final study visit, they received an additional $20 to reimburse them for completing all research procedures. There were 191 cocaine‐ and alcohol‐dependent subjects who signed consent and began screening. Forty‐two subjects (22%) failed to show for visits to complete the screening assessments, 33 (17%) met exclusion criteria, 19 (10%) failed to meet inclusion criteria, and 17 (9%) withdrew consent. Study recruitment ended when our goal of 80 randomized subjects was achieved. This study was reviewed and approved by the University of Pennsylvania Institutional Review Board (clinicaltrials.gov identifier: NCT00777062). Assessments In order to evaluate the eligibility criteria, subjects completed screening assessments conducted in the week prior to the 8‐week medication trial. Medical screening included a complete medical history and physical examination performed by a nurse practitioner. Baseline laboratory testing included a chemistry screen, complete blood count, urinalysis, UDS, and a 12‐lead EKG. Women received urine pregnancy testing prior to starting medications and at monthly intervals during the clinical trial. Demographic measures were obtained from the Addiction Severity Index.26 Psychiatric diagnoses were obtained from master’s level clinicians using the Mini‐International Neuropsychiatric Interview (MINI).27 Vital signs and adverse events (AEs) were measured weekly. AEs were measured using a modified version of the Systematic Assessment of Treatment Emergent Effects (SAFTEE).28 The primary exploratory outcome measures were cocaine use derived from qualitative UDS collected three times per week, and drinking measures derived from the TLFB.29 For the
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UDS, the urine sample temperature was taken at the time of collection. Samples less than 90° or greater than 100° F were not accepted. The urine was then tested at the Philadelphia Veterans Administration lab, with results reported as positive or negative for benzolecgonine, the cocaine metabolite. If the metabolite levels were above 300 ng/ml, the sample was recorded as positive for cocaine. The TLFB method is a 15– 30 minute, semi‐structured interview administered by experienced research technicians, that uses the recall of critical life events and a personalized calendar to prompt recall of alcohol drinking frequency (days) and quantity (number of standard drinks per day) during the inquiry period (up to 90 days). The TLFB method has been adapted to also collect information from the subject about daily drug use of cocaine or other drugs of abuse.30,31 In addition to cocaine use, the subject was also asked about the daily amount of money spent on cocaine. The TLFB was given in screening to record alcohol and cocaine use in the three months prior to study entry. It was also utilized weekly during the treatment period to provide a continuous daily record of self‐reported alcohol and cocaine use during the 8‐week treatment. Statistical Methods Baseline measures between the active medication and placebo groups were compared using t‐tests for continuous variables and chi‐square tests for dichotomous variables. Cocaine use was measured by UDSs, combined with self‐ report. Our primary cocaine use outcome was defined as follows: a week was regarded as a USE week if any of the three urine tests collected in a week were positive for cocaine use (regardless of how many were provided), or if the participant reported cocaine use for any day in the week; a week was regarded as a NON‐USE week if the participant provided at least two UDS negative for cocaine use and no UDS positive for use, and reported no use. Otherwise, a week was regarded as a missing week. We also examined this cocaine use outcome where missing weeks were regarded as USE weeks. That is, analyses were conducted with missing ignored and with missing counted as positive for cocaine use. Initial analyses collapsed the results over the 8‐week treatment period. We compared groups using chi‐square analyses on the percentage of subjects without cocaine use for at least 3 weeks during the trial, percentage of subjects without cocaine use for at least 3 consecutive weeks during the trial, and percentage of subjects without cocaine use in the last 3 weeks of treatment. Generalized estimating equations (GEEs) models were also used to estimate the effects of medication group and time on the log‐ odds of use across the treatment period. The explanatory variables in these models were a binary factor for medication, terms for time effects, and group by time interactions, with a working correlation of compound symmetry, and with empirical standard errors used for inference. In these models, we were interested in weekly rates of use, so time was coded in weekly units. Alcohol use was measured using the TLFB method from which the number of days of abstinence from drinking and no heavy drinking days were determined. A heavy drinking day Pettinati et al.
was defined for males as drinking five or more drinks in 1 day, and for females as drinking four or more drinks in 1 day. Alcohol drinking analyses also were conducted with missing days ignored and with missing days counted as a drinking or a heavy drinking day. Initial analyses collapsed the results over the 8‐week treatment period. We compared groups using chi‐ square or t‐tests on mean percent days of drinking, mean percent days of heavy drinking, mean drinks per drinking day, percentage of subjects abstinent from alcohol or percentage of subjects with no heavy drinking. GEE models were also used to estimate the effects of medication group and time on the mean responses across the treatment period. Finally, we compared groups on their combined weekly use of both cocaine and alcohol, in a manner similar to those described above.
RESULTS Baseline Demographics and Substance Use Table 1 presents the demographic and pre‐treatment clinical data for the total sample, and for the active medication and placebo groups. Overall, 81.3% were males and the mean age was 47.9 (SD ¼ 6.6) years. Most were African‐American (87.5%) with a mean of 12.8 (SD ¼ 1.8) years of education. The majority smoked crack cocaine (80%) and the mean years of cocaine use were 16.6 (SD ¼ 8.6) years. On average, subjects had used alcohol for 21.6 (SD ¼ 21.6) years. In the 30 days prior to enrolling in the study, subjects used cocaine about 15 days, spending on average $829.30 (SD ¼ $708.20). Over the same time period, heavy drinking occurred on average 16 of 30 days, with a mean of 13.3 (SD ¼ 9.3) drinks per drinking day. This sample had on average 2.9 (SD ¼ 3.3) prior drug treatments and 2.6 (SD ¼ 3.0) prior alcohol treatments. The groups did not differ significantly on any of these variables (all p > .05). Our clinic is located in West Philadelphia and this sample is representative of the treatment‐seeking cocaine and alcohol‐dependent individuals in our geographic area. Treatment Retention and Medication Adherence Few subjects were lost to follow‐up. Seventy‐five of the 80 subjects completed the final visit, 36/39 (92.3%) in the active medication group and 39/41 (95.1%) in the placebo group (chi‐ square ¼ .27, df ¼ 1, p ¼ .60). The mean number of subject visits attended by the active medication and placebo groups were 20.5 (SD ¼ 7.2) and 21.4 (SD ¼ 6.5), respectively, and did not differ significantly (t ¼ .62, df ¼ 78, p ¼ .54). In the active medication group, 28/39 (71.8%) received both injections and in the placebo group, 34/41 (82.9%) received both injections. This difference was not statistically significant (chi‐square ¼ 1.42, df ¼ 1, p ¼ .23). UDS Results Exploratory treatment outcome measures for cocaine and alcohol use during the trial expressed as group percentages or means are provided in Table 2.
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TABLE 1. Subject characteristics and pre‐treatment measures of cocaine and alcohol use expressed as group percentages or means (with standard deviations)
Variable
Total
Ext–rls Ntx
Placebo
Mean age % male % African‐American Mean years of education Mean proportion of days employed in past 30 % smoked route of cocaine use Mean years cocaine use Mean years alcohol use to intoxication % days cocaine use in past 30 $ spent for cocaine in past 30 % days alcohol use in past 30 % days heavy alcohol use in past 30 Mean drinks per drinking day in past 30 Number of prior drug treatments Number of prior alcohol treatments
N ¼ 80 47.9 (6.6) 81.3% 87.5% 12.8 (1.8) .30 (.3) 80.0% 16.6 (8.6) 21.6 (10.6) 49.7% (.27) 829.3 (708.2) 62.4% (0.27) 54.1% (0.29) 13.3 (9.3) 2.9 (3.3) 2.6 (3.0)
N ¼ 39 47.5 (7.0) 76.9% 84.6% 12.6 (1.6) .24 (.3) 76.9% 15.2 (8.3) 19.3 (10.2) 46.5% (.25) 752.9 (603.3) 58.8% (.26) 49.0% (.28) 14.0 (11.1) 2.8 (3.1) 2.3 (2.5)
N ¼ 41 48.4 (6.3) 85.4% 90.2% 12.9 (2.0) .35 (.3) 82.9% 18.0 (8.8) 23.8 (10.7) 52.8% (.28) 901.8 (796.1) 65.9% (0.29) 59.1% (.30) 12.7 (7.4) 3.0 (3.5) 2.8 (3.5)
Significance p .541 .338 .525 .458 .138 .502 .149 .063 .297 .351 .249 .125 .611 .468 .784
Ext‐rls Ntx ¼ extended‐release naltrexone. TABLE 2. Outcome measures of cocaine and alcohol use expressed as group percentages or means (with standard deviations)
Variable
Total
Ext‐rls Ntx
Placebo
Significance
N ¼ 80
N ¼ 39
N ¼ 41
p
Cocaine outcomes % Subjects w/no cocaine use for at least 3 weeks Missing ¼ Ignored 32.5% Missing ¼ USE 21.3% % Subjects w/no cocaine use for at least 3 consecutive weeks Missing ¼ Ignored 23.8% Missing ¼ USE 17.5%
33.3% 23.1%
31.7% 19.5%
.877 .697
23.1% 17.9%
22.0% 17.1%
.904 .918
% Subjects w/no cocaine use in the last 3 wks Missing ¼ Ignored Missing ¼ USE
11.3% 5.0%
5.1% .0%
17.1% 9.8%
.091 .045
28.7% (27.9) 17.9% (22.5) 7.1 (4.9)
29.8% (27.6) 18.1% (22.6) 7.0 (4.3)
27.6% (28.5) 17.8% (22.6) 7.3 (5.4)
.723 .954 .843
13.8% 11.3%
10.3% 7.7%
17.1% 14.6%
.376 .326
23.8% 18.8%
20.5% 15.4%
26.8% 22.0%
.507 .452
Combined cocaine and alcohol outcomes % Subjects without cocaine use for 3 weeks and no heavy drinking Missing ¼ Ignored 13.8% 12.8% Missing ¼ USE and/or heavy drinking 7.5% 5.1%
14.6% 9.8%
.814 .432
Alcohol outcomes Mean % days any drinking Mean % days heavy drinking Mean drinks per drinking day % Subjects abstinent Missing ¼ Ignored Missing ¼ Drinking % Subjects with no heavy drinking Missing ¼ Ignored Missing ¼ Heavy drinking
Ext‐rls Ntx ¼ extended‐release naltrexone.
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There were no significant differences between medication and placebo groups on percent subjects without cocaine use for at least 3 weeks, at least 3 consecutive weeks, or for the 3 weeks at the end of treatment. The results were similar whether missing weeks were ignored or considered as USE weeks. For the outcome with missing weeks ignored, a main effects GEE model showed no significant difference in the rates of use between the two groups (x2(1) ¼ .26, p ¼ .61) with the odds of use in extended‐release naltrexone being 1.26 times the odds of use in placebo. There was a significant group by time interaction, in which the effect of extended‐release naltrexone relative to placebo in the period prior to the second injection differed from the corresponding effect in the period after the second injection (x2(1) ¼ 5.01, p ¼ .02). In the early period, the odds of use for placebo was 1.09 times the odds of use for extended‐release naltrexone (p ¼ .85), while in the later period the odds of use for extended‐release naltrexone was 1.77 times the odds of use for placebo (p ¼ .24). When missing weeks were imputed as USE weeks, the interaction was not significant (x2(1) ¼ 2.05, p ¼ .15), and there was no overall effect of treatment (x2(1) ¼ .09, p ¼ .76) and the odds of use for extended‐release naltrexone was 1.24 times the odds for placebo. Self‐reports of Alcohol Consumption Compared to baseline drinking, there was a drop in the percent days of drinking (from 62.4% to 28.7%) and percent days of heavy drinking (from 54.1% to 17.9%). However, there were no significant differences between groups on mean percent days of drinking, mean percent days of heavy drinking, mean drinks per drinking day, percentage of subjects abstinent, or percentage of subjects with no heavy drinking. The results were similar whether missing drinking variables were ignored or considered as drinking or as heavy drinking. Combined Cocaine and Alcohol Outcomes We considered the percentage of subjects without cocaine use for at least 3 weeks during the trial along with no heavy drinking on those weeks. There were no significant differences between groups (12.8% for Extended‐release naltrexone and 14.6% for placebo; p ¼ .81). Other combinations of cocaine and alcohol outcomes yielded similar results. Adverse Events AEs were assessed at each visit. AEs were mainly mild and generally evenly distributed between the extended‐ release naltrexone and placebo groups. Extended‐release naltrexone per se was generally well tolerated, with the only AE noted to occur more frequently among extended‐release naltrexone‐treated subjects than placebo‐treated subjects was swelling at the injection site (56% vs. 32% c2 ¼ 5.01, p ¼ .03). The following AEs occurred in greater than 10% of the subjects and there were no statistical differences between groups. The AE is listed first with the percentage of subjects for extended‐release naltrexone and placebo, respectively, listed in parentheses: aches and pains (33%, 50%); nausea Pettinati et al.
(49%, 24%); headache (28%, 22%); backache (13%, 12%); fatigue (13%, 10%); and weight loss (10%, 10%). There were nine Serious Adverse Events (SAEs), five in the extended‐release naltrexone group, and four in the placebo group (see Table 3).
DISCUSSION This was a pilot double blind, placebo‐controlled trial that investigated whether a 30‐day, 380 mg injection extended‐ release formulation of naltrexone (VIVITROL1), given twice over the course of 8 weeks, would be helpful in treating patients with co‐occurring cocaine and alcohol dependence. There are both theoretical and empirical justifications for pursuing a study of this medication in this type of patient population. The 30‐day injection also allowed for a more accurate evaluation of naltrexone’s efficacy because each injection ensures 100% medication adherence for 30 days in traditionally non‐adherent patients. Outcome evaluations revealed no significant differences between medication and placebo groups with respect to the proportion of subjects without cocaine use for at least 3 trial weeks, at least 3 consecutive trial weeks, or for the 3 weeks at the end of the treatment trial. Also, there were no significant differences between groups in the trial on mean percent days of drinking, mean percent days of heavy drinking, mean drinks per drinking day, percentage of subjects abstinent, or percentage of subjects with no heavy drinking. There were several limitations in this pilot study. Treatment‐seeking individuals who agree to participate in clinical research trials may not generalize to those seeking treatment in non‐research treatment programs. In addition, treatment was limited to 8 weeks and two injections. The length of the trial was somewhat arbitrary and briefer than most established addiction treatment clinical programs because we only wanted to determine if there was a signal
TABLE 3. Adverse events reported by at least 10% of subjects in a 2‐month extended‐release naltrexone trial.
Variable
Ext‐rls Ntx
Placebo
Swelling at injection site Aches and pains Nausea Headache Upper respiratory tract infection Backache Fatigue Weight loss
N ¼ 39 56% 33% 49% 28% 23% 13% 13% 10%
N ¼ 41 32% 50% 25% 32% 22% 12% 10% 10%
Ext‐rls Ntx ¼ extended‐release naltrexone. Reported by significantly more subjects in the Vivitrol group compared to the placebo group chi‐square 5.01 p ¼ .03.
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that would encourage a longer, more expensive course of treatment. However, this trial may have been too brief to provide an adequate amount of treatment for this difficult‐to‐ treat population. Finally, the majority of subjects in this sample were African‐Americans. Oslin and colleagues32 have shown that patients who have a specific functional polymorphism of the u‐opioid receptor gene (OPRM1) respond better to naltrexone than those without it. Our negative results might be due to the fact that fewer than 5% of African‐Americans have this polymorphism. Nonetheless, the research on this polymorphism is in its infancy and more studies are needed before drawing conclusions based on genetics. Thus, in this study the injectable, extended‐release naltrexone, while an ideal method for ensuring medication adherence in traditionally hard‐to‐treat patients, resulted in no measurable reduction in cocaine or alcohol use over the course of 8 weeks of treatment, compared to a placebo injection, in patients with comorbid cocaine and alcohol dependence. These patients continue to provide a unique challenge for addiction treatment providers. The study was funded by a Center grant P50 DA 12756 (H.M. Pettinati, Center Director) from the National Institute of Health/National Institute on Drug Abuse, Rockville, MD. Study medication and matching‐placebo injections were provided by Alkermes. Statistical assistance for one of the authors (MRW) was supported by a National Institute of Health training grant – T32 MH065218. We thank our Studies of Addiction Treatment Research Center team for conducting this trial. In particular, we want to thank Marcia Commins, Amy Henninger, Tamara Roth, and Thera Wolven for technical assistance. Declaration of Interest The authors alone are responsible for the content and writing of this paper. Alkermes provided Dr. Pettinati with the medication and matching placebo for this study. Dr. Pettinati, Dr. Kampman, and Dr. O’Brien have occasionally received consultation fees from Alkermes, but none in the past 3 years. None of the authors hold any patents nor stock in any relevant company. REFERENCES 1. Midanik LT, Tam TW, Weisner C. Concurrent and simultaneous drug and alcohol use: Results of the 2000 national alcohol survey. Drug Alcohol Depend. 2007;90:72–80. 2. Stinson FS, Grant BF, Dawson DA, et al. Comorbidity between DSM‐IV alcohol and specific drug use disorders in the United States: Results from the National Epidemiologic Survey on Alcohol and Related Conditions. Drug Alcohol Depend. 2005;80:105–116. 3. Brady K, Sonne S, Randall C, et al. Features of cocaine dependence with concurrent alcohol abuse. Drug Alcohol Depend. 1995;39:69–71. 4. Brower KJ, Blow FC, Hill EM, et al. Treatment outcome of alcoholics with and without cocaine disorders. Alcohol Clin Exp Res. 1994;18: 734–739.
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A Pilot Trial of Injectable, Extended‐Release Naltrexone for the Treatment of Co‐Occurring Cocaine and Alcohol Dependence Helen M. Pettinati, PhD,1 Kyle M. Kampman, MD,1 Kevin G. Lynch, PhD,1 William D. Dundon, PhD,1 Elizabeth M. Mahoney, MS,1 Michael R. Wierzbicki, PhD,2 Charles P. O’Brien, MD, PhD1 1
Department of Psychiatry, Center for the Studies of Addiction, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania 2 Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania
Background: There is a high co‐occurrence of cocaine and alcohol use disorders, and patients with both of these problems are difficult to treat. There is a reasonable rationale and some empirical data to justify a pilot trial of an injectable, extended‐release formulation of naltrexone for treating co‐occurring cocaine and alcohol addiction. Methods: Eighty cocaine (n ¼ 80) and alcohol dependent, treatment‐ seeking subjects were randomly assigned to receive either two monthly extended‐release injections of naltrexone or two matching placebo injections in an 8‐week clinical trial, with weekly medical management plus cognitive behavioral therapy visits. Results: No differences in reduction in cocaine or alcohol use were observed between the injectable naltrexone and placebo groups during the 8‐week trial. Conclusions: Injectable extended‐release naltrexone, while an ideal method for ensuring medication adherence in these traditionally hard‐ to‐treat patients, did not result in any measurable reduction in cocaine or alcohol use over the course of 8 weeks of treatment. (Am J Addict 2014;23:591–597)
INTRODUCTION Patients with comorbid cocaine and alcohol dependence provide a unique challenge for addiction treatment providers. Epidemiological studies report a high co‐occurrence of cocaine and alcohol dependence.1,2 That is, among those with a cocaine use disorder, 79.4% also have an alcohol use disorder.2 These individuals are also difficult to treat. They tend to have more Received December 13, 2013; revised April 21, 2014; accepted May 1, 2014. Address correspondence to Dr. Kampman, Department of Psychiatry, University of Pennsylvania, Perelman School of Medicine, 3900 Chestnut Street, Philadelphia, PA 19104‐6178. E‐mail: [email protected]
psychosocial problems, are more likely to be non‐adherent with treatment regimens, and, in general, have worse treatment outcomes compared to patients addicted to either cocaine or alcohol alone.3–7 Difficulties in treating these patients may be a result of having two addictions, or, potentially, of “co‐using” cocaine with alcohol, which produces a metabolite (cocaethylene). Cocaethylene is purported to have higher addiction potential than either cocaine or alcohol alone.8,9 As there are no medications approved by the Food and Drug Administration (FDA) for treating a cocaine use disorder, it is reasonable to investigate whether medications that are FDA‐ approved for treating alcohol use disorders might impact cocaine use in patients with comorbid alcohol and cocaine dependence. This approach is substantiated by observations that alcohol drinking or cocaine use may act as “conditioned cues” for each other. Thus, a medication that might reduce excessive drinking may also, in turn, reduce cocaine use, and, thus, interfere in the “conditioned” sequencing of the two substances that typically leads to continued use of both substances.3,10–13 Furthermore, there has been some empirical support for a higher dose (150 mg/day) of naltrexone, a medication that is FDA‐ approved for alcohol dependence, to reduce cocaine and alcohol use in cocaine and alcohol‐dependent male patients.14 However, lower doses of naltrexone have not been shown to affect treatment response,15–17 although poor response rates may have been due to non‐adherence to the typical required daily pill taking with oral naltrexone. Naltrexone is an effective and well‐tolerated pharmacotherapy for reducing heavy drinking.18,19 However, adherence to a regimen of daily oral naltrexone has been problematic. In fact, we have observed a substantive impact of medication non‐adherence on drinking outcomes in a number of alcohol treatment studies. For example, we reported a large naltrexone (vs. placebo) effect 591
size for relapse in patients who consistently took their medication and attended research visits (.74), and a small or negative effect size in non‐adherent patients (.27).20 In 2006, the FDA approved an extended‐release naltrexone injection (VIVITROL1) for treating alcohol dependence that provides effective drug plasma levels for 30–40 days. FDA approval was based on a treatment course of 6 month injections21). Each injection ensured 100% adherence to naltrexone treatment for approximately 1 month. Thus, if there is a chance that these dually addicted patients will reduce their cocaine and/or alcohol use, it would be important to evaluate the extended‐release formulation of naltrexone because it would allow us to accurately evaluate naltrexone’s effects in medication‐adherent patients. Therefore, we conducted a double blind, placebo‐controlled clinical exploratory trial to evaluate the use of extended‐release naltrexone over a course of 8 weeks for treating individuals with co‐occurring cocaine and alcohol dependence. Eight weeks has been found in previous trials to be a trial duration that enables sufficient retention of cocaine‐addicted patients to discern a medication versus placebo difference.22
METHODS Participants There were 80 men and women between the ages of 18 and 65 years who were recruited from the greater Philadelphia area and attended visits at the University of Pennsylvania’s Addiction Treatment Research Center. They were recruited through community advertisements aimed at treatment‐ seeking individuals with both DSM‐IV cocaine and alcohol dependence. Subjects enrolled in the study were not involved in other types of addiction treatment, but self‐help, support groups were encouraged. Subjects were eligible if they: (a) met DSM‐IV criteria for both cocaine and alcohol dependence; (b) reported at least $200 worth of cocaine use in the month prior to study enrollment; (c) drank a minimum of 12 standard drinks of alcohol on average per week during the month prior to coming in to the center; and (d) were able to achieve 3 consecutive days of abstinence from alcohol just prior to randomization. Subjects dependent on any drugs other than cocaine, alcohol, or nicotine were excluded from the trial. If clinically indicated, subjects completed outpatient detoxification. Subjects with a history of current severe psychiatric symptoms, use of any investigational medication taken within the last 30 days, AIDS or other serious illness which may have required hospitalization during the study, or impaired renal function or known liver disease, were excluded from the study. Pregnant women or women who refused to use acceptable forms of birth control were excluded from the study. Potential subjects were also screened for illnesses that would preclude the use of naltrexone and for a Body Mass Index that would put them at a greater risk for an injection site reaction. Design and Procedures All subjects signed informed consent prior to conducting treatment procedures that were administered by a nurse 592
practitioner. Eligible subjects agreed to a 10‐week study that included a 1‐week screening/baseline collection; an 8‐week double blind, placebo‐controlled trial with three weekly visits; and a 1‐week follow‐up, final study visit. Eligible subjects were randomized to receive either injectable, extended‐release naltrexone (380 mg) or a matching placebo injection using an urn randomization method for assigning treatment.23 Urn randomization included three variables: (a) gender; (b) low versus high frequency of alcohol use (less than or equal to 68% days drinking vs. more than 68% days drinking in 30 days prior to the study, as determined by the Timeline Followback method (TLFB)); and (c) positive or negative urine drug screen (UDS) for the benzoylecgonine metabolite, or cocaine use, at the initial visit. Each subject received two injections of 380 mg extended‐ release naltrexone or a matching placebo injection, one at randomization and the second at 4 weeks later. Subjects were required to attend three visits per week during the 8‐week trial at which time urine samples and research assessments were collected. On a once‐a‐week basis, subjects met with a nurse trained in Medical Management24 and also with a Master’s level therapist for Cognitive Behavior Therapy (CBT). The CBT manual was adapted from the National Institute on Alcohol Abuse and Alcoholism Project MATCH manual25 for the treatment of both alcohol and cocaine dependence. Subjects were reimbursed $5 and were given two transit tokens at each visit. At the final study visit, they received an additional $20 to reimburse them for completing all research procedures. There were 191 cocaine‐ and alcohol‐dependent subjects who signed consent and began screening. Forty‐two subjects (22%) failed to show for visits to complete the screening assessments, 33 (17%) met exclusion criteria, 19 (10%) failed to meet inclusion criteria, and 17 (9%) withdrew consent. Study recruitment ended when our goal of 80 randomized subjects was achieved. This study was reviewed and approved by the University of Pennsylvania Institutional Review Board (clinicaltrials.gov identifier: NCT00777062). Assessments In order to evaluate the eligibility criteria, subjects completed screening assessments conducted in the week prior to the 8‐week medication trial. Medical screening included a complete medical history and physical examination performed by a nurse practitioner. Baseline laboratory testing included a chemistry screen, complete blood count, urinalysis, UDS, and a 12‐lead EKG. Women received urine pregnancy testing prior to starting medications and at monthly intervals during the clinical trial. Demographic measures were obtained from the Addiction Severity Index.26 Psychiatric diagnoses were obtained from master’s level clinicians using the Mini‐International Neuropsychiatric Interview (MINI).27 Vital signs and adverse events (AEs) were measured weekly. AEs were measured using a modified version of the Systematic Assessment of Treatment Emergent Effects (SAFTEE).28 The primary exploratory outcome measures were cocaine use derived from qualitative UDS collected three times per week, and drinking measures derived from the TLFB.29 For the
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UDS, the urine sample temperature was taken at the time of collection. Samples less than 90° or greater than 100° F were not accepted. The urine was then tested at the Philadelphia Veterans Administration lab, with results reported as positive or negative for benzolecgonine, the cocaine metabolite. If the metabolite levels were above 300 ng/ml, the sample was recorded as positive for cocaine. The TLFB method is a 15– 30 minute, semi‐structured interview administered by experienced research technicians, that uses the recall of critical life events and a personalized calendar to prompt recall of alcohol drinking frequency (days) and quantity (number of standard drinks per day) during the inquiry period (up to 90 days). The TLFB method has been adapted to also collect information from the subject about daily drug use of cocaine or other drugs of abuse.30,31 In addition to cocaine use, the subject was also asked about the daily amount of money spent on cocaine. The TLFB was given in screening to record alcohol and cocaine use in the three months prior to study entry. It was also utilized weekly during the treatment period to provide a continuous daily record of self‐reported alcohol and cocaine use during the 8‐week treatment. Statistical Methods Baseline measures between the active medication and placebo groups were compared using t‐tests for continuous variables and chi‐square tests for dichotomous variables. Cocaine use was measured by UDSs, combined with self‐ report. Our primary cocaine use outcome was defined as follows: a week was regarded as a USE week if any of the three urine tests collected in a week were positive for cocaine use (regardless of how many were provided), or if the participant reported cocaine use for any day in the week; a week was regarded as a NON‐USE week if the participant provided at least two UDS negative for cocaine use and no UDS positive for use, and reported no use. Otherwise, a week was regarded as a missing week. We also examined this cocaine use outcome where missing weeks were regarded as USE weeks. That is, analyses were conducted with missing ignored and with missing counted as positive for cocaine use. Initial analyses collapsed the results over the 8‐week treatment period. We compared groups using chi‐square analyses on the percentage of subjects without cocaine use for at least 3 weeks during the trial, percentage of subjects without cocaine use for at least 3 consecutive weeks during the trial, and percentage of subjects without cocaine use in the last 3 weeks of treatment. Generalized estimating equations (GEEs) models were also used to estimate the effects of medication group and time on the log‐ odds of use across the treatment period. The explanatory variables in these models were a binary factor for medication, terms for time effects, and group by time interactions, with a working correlation of compound symmetry, and with empirical standard errors used for inference. In these models, we were interested in weekly rates of use, so time was coded in weekly units. Alcohol use was measured using the TLFB method from which the number of days of abstinence from drinking and no heavy drinking days were determined. A heavy drinking day Pettinati et al.
was defined for males as drinking five or more drinks in 1 day, and for females as drinking four or more drinks in 1 day. Alcohol drinking analyses also were conducted with missing days ignored and with missing days counted as a drinking or a heavy drinking day. Initial analyses collapsed the results over the 8‐week treatment period. We compared groups using chi‐ square or t‐tests on mean percent days of drinking, mean percent days of heavy drinking, mean drinks per drinking day, percentage of subjects abstinent from alcohol or percentage of subjects with no heavy drinking. GEE models were also used to estimate the effects of medication group and time on the mean responses across the treatment period. Finally, we compared groups on their combined weekly use of both cocaine and alcohol, in a manner similar to those described above.
RESULTS Baseline Demographics and Substance Use Table 1 presents the demographic and pre‐treatment clinical data for the total sample, and for the active medication and placebo groups. Overall, 81.3% were males and the mean age was 47.9 (SD ¼ 6.6) years. Most were African‐American (87.5%) with a mean of 12.8 (SD ¼ 1.8) years of education. The majority smoked crack cocaine (80%) and the mean years of cocaine use were 16.6 (SD ¼ 8.6) years. On average, subjects had used alcohol for 21.6 (SD ¼ 21.6) years. In the 30 days prior to enrolling in the study, subjects used cocaine about 15 days, spending on average $829.30 (SD ¼ $708.20). Over the same time period, heavy drinking occurred on average 16 of 30 days, with a mean of 13.3 (SD ¼ 9.3) drinks per drinking day. This sample had on average 2.9 (SD ¼ 3.3) prior drug treatments and 2.6 (SD ¼ 3.0) prior alcohol treatments. The groups did not differ significantly on any of these variables (all p > .05). Our clinic is located in West Philadelphia and this sample is representative of the treatment‐seeking cocaine and alcohol‐dependent individuals in our geographic area. Treatment Retention and Medication Adherence Few subjects were lost to follow‐up. Seventy‐five of the 80 subjects completed the final visit, 36/39 (92.3%) in the active medication group and 39/41 (95.1%) in the placebo group (chi‐ square ¼ .27, df ¼ 1, p ¼ .60). The mean number of subject visits attended by the active medication and placebo groups were 20.5 (SD ¼ 7.2) and 21.4 (SD ¼ 6.5), respectively, and did not differ significantly (t ¼ .62, df ¼ 78, p ¼ .54). In the active medication group, 28/39 (71.8%) received both injections and in the placebo group, 34/41 (82.9%) received both injections. This difference was not statistically significant (chi‐square ¼ 1.42, df ¼ 1, p ¼ .23). UDS Results Exploratory treatment outcome measures for cocaine and alcohol use during the trial expressed as group percentages or means are provided in Table 2.
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TABLE 1. Subject characteristics and pre‐treatment measures of cocaine and alcohol use expressed as group percentages or means (with standard deviations)
Variable
Total
Ext–rls Ntx
Placebo
Mean age % male % African‐American Mean years of education Mean proportion of days employed in past 30 % smoked route of cocaine use Mean years cocaine use Mean years alcohol use to intoxication % days cocaine use in past 30 $ spent for cocaine in past 30 % days alcohol use in past 30 % days heavy alcohol use in past 30 Mean drinks per drinking day in past 30 Number of prior drug treatments Number of prior alcohol treatments
N ¼ 80 47.9 (6.6) 81.3% 87.5% 12.8 (1.8) .30 (.3) 80.0% 16.6 (8.6) 21.6 (10.6) 49.7% (.27) 829.3 (708.2) 62.4% (0.27) 54.1% (0.29) 13.3 (9.3) 2.9 (3.3) 2.6 (3.0)
N ¼ 39 47.5 (7.0) 76.9% 84.6% 12.6 (1.6) .24 (.3) 76.9% 15.2 (8.3) 19.3 (10.2) 46.5% (.25) 752.9 (603.3) 58.8% (.26) 49.0% (.28) 14.0 (11.1) 2.8 (3.1) 2.3 (2.5)
N ¼ 41 48.4 (6.3) 85.4% 90.2% 12.9 (2.0) .35 (.3) 82.9% 18.0 (8.8) 23.8 (10.7) 52.8% (.28) 901.8 (796.1) 65.9% (0.29) 59.1% (.30) 12.7 (7.4) 3.0 (3.5) 2.8 (3.5)
Significance p .541 .338 .525 .458 .138 .502 .149 .063 .297 .351 .249 .125 .611 .468 .784
Ext‐rls Ntx ¼ extended‐release naltrexone. TABLE 2. Outcome measures of cocaine and alcohol use expressed as group percentages or means (with standard deviations)
Variable
Total
Ext‐rls Ntx
Placebo
Significance
N ¼ 80
N ¼ 39
N ¼ 41
p
Cocaine outcomes % Subjects w/no cocaine use for at least 3 weeks Missing ¼ Ignored 32.5% Missing ¼ USE 21.3% % Subjects w/no cocaine use for at least 3 consecutive weeks Missing ¼ Ignored 23.8% Missing ¼ USE 17.5%
33.3% 23.1%
31.7% 19.5%
.877 .697
23.1% 17.9%
22.0% 17.1%
.904 .918
% Subjects w/no cocaine use in the last 3 wks Missing ¼ Ignored Missing ¼ USE
11.3% 5.0%
5.1% .0%
17.1% 9.8%
.091 .045
28.7% (27.9) 17.9% (22.5) 7.1 (4.9)
29.8% (27.6) 18.1% (22.6) 7.0 (4.3)
27.6% (28.5) 17.8% (22.6) 7.3 (5.4)
.723 .954 .843
13.8% 11.3%
10.3% 7.7%
17.1% 14.6%
.376 .326
23.8% 18.8%
20.5% 15.4%
26.8% 22.0%
.507 .452
Combined cocaine and alcohol outcomes % Subjects without cocaine use for 3 weeks and no heavy drinking Missing ¼ Ignored 13.8% 12.8% Missing ¼ USE and/or heavy drinking 7.5% 5.1%
14.6% 9.8%
.814 .432
Alcohol outcomes Mean % days any drinking Mean % days heavy drinking Mean drinks per drinking day % Subjects abstinent Missing ¼ Ignored Missing ¼ Drinking % Subjects with no heavy drinking Missing ¼ Ignored Missing ¼ Heavy drinking
Ext‐rls Ntx ¼ extended‐release naltrexone.
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There were no significant differences between medication and placebo groups on percent subjects without cocaine use for at least 3 weeks, at least 3 consecutive weeks, or for the 3 weeks at the end of treatment. The results were similar whether missing weeks were ignored or considered as USE weeks. For the outcome with missing weeks ignored, a main effects GEE model showed no significant difference in the rates of use between the two groups (x2(1) ¼ .26, p ¼ .61) with the odds of use in extended‐release naltrexone being 1.26 times the odds of use in placebo. There was a significant group by time interaction, in which the effect of extended‐release naltrexone relative to placebo in the period prior to the second injection differed from the corresponding effect in the period after the second injection (x2(1) ¼ 5.01, p ¼ .02). In the early period, the odds of use for placebo was 1.09 times the odds of use for extended‐release naltrexone (p ¼ .85), while in the later period the odds of use for extended‐release naltrexone was 1.77 times the odds of use for placebo (p ¼ .24). When missing weeks were imputed as USE weeks, the interaction was not significant (x2(1) ¼ 2.05, p ¼ .15), and there was no overall effect of treatment (x2(1) ¼ .09, p ¼ .76) and the odds of use for extended‐release naltrexone was 1.24 times the odds for placebo. Self‐reports of Alcohol Consumption Compared to baseline drinking, there was a drop in the percent days of drinking (from 62.4% to 28.7%) and percent days of heavy drinking (from 54.1% to 17.9%). However, there were no significant differences between groups on mean percent days of drinking, mean percent days of heavy drinking, mean drinks per drinking day, percentage of subjects abstinent, or percentage of subjects with no heavy drinking. The results were similar whether missing drinking variables were ignored or considered as drinking or as heavy drinking. Combined Cocaine and Alcohol Outcomes We considered the percentage of subjects without cocaine use for at least 3 weeks during the trial along with no heavy drinking on those weeks. There were no significant differences between groups (12.8% for Extended‐release naltrexone and 14.6% for placebo; p ¼ .81). Other combinations of cocaine and alcohol outcomes yielded similar results. Adverse Events AEs were assessed at each visit. AEs were mainly mild and generally evenly distributed between the extended‐ release naltrexone and placebo groups. Extended‐release naltrexone per se was generally well tolerated, with the only AE noted to occur more frequently among extended‐release naltrexone‐treated subjects than placebo‐treated subjects was swelling at the injection site (56% vs. 32% c2 ¼ 5.01, p ¼ .03). The following AEs occurred in greater than 10% of the subjects and there were no statistical differences between groups. The AE is listed first with the percentage of subjects for extended‐release naltrexone and placebo, respectively, listed in parentheses: aches and pains (33%, 50%); nausea Pettinati et al.
(49%, 24%); headache (28%, 22%); backache (13%, 12%); fatigue (13%, 10%); and weight loss (10%, 10%). There were nine Serious Adverse Events (SAEs), five in the extended‐release naltrexone group, and four in the placebo group (see Table 3).
DISCUSSION This was a pilot double blind, placebo‐controlled trial that investigated whether a 30‐day, 380 mg injection extended‐ release formulation of naltrexone (VIVITROL1), given twice over the course of 8 weeks, would be helpful in treating patients with co‐occurring cocaine and alcohol dependence. There are both theoretical and empirical justifications for pursuing a study of this medication in this type of patient population. The 30‐day injection also allowed for a more accurate evaluation of naltrexone’s efficacy because each injection ensures 100% medication adherence for 30 days in traditionally non‐adherent patients. Outcome evaluations revealed no significant differences between medication and placebo groups with respect to the proportion of subjects without cocaine use for at least 3 trial weeks, at least 3 consecutive trial weeks, or for the 3 weeks at the end of the treatment trial. Also, there were no significant differences between groups in the trial on mean percent days of drinking, mean percent days of heavy drinking, mean drinks per drinking day, percentage of subjects abstinent, or percentage of subjects with no heavy drinking. There were several limitations in this pilot study. Treatment‐seeking individuals who agree to participate in clinical research trials may not generalize to those seeking treatment in non‐research treatment programs. In addition, treatment was limited to 8 weeks and two injections. The length of the trial was somewhat arbitrary and briefer than most established addiction treatment clinical programs because we only wanted to determine if there was a signal
TABLE 3. Adverse events reported by at least 10% of subjects in a 2‐month extended‐release naltrexone trial.
Variable
Ext‐rls Ntx
Placebo
Swelling at injection site Aches and pains Nausea Headache Upper respiratory tract infection Backache Fatigue Weight loss
N ¼ 39 56% 33% 49% 28% 23% 13% 13% 10%
N ¼ 41 32% 50% 25% 32% 22% 12% 10% 10%
Ext‐rls Ntx ¼ extended‐release naltrexone. Reported by significantly more subjects in the Vivitrol group compared to the placebo group chi‐square 5.01 p ¼ .03.
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that would encourage a longer, more expensive course of treatment. However, this trial may have been too brief to provide an adequate amount of treatment for this difficult‐to‐ treat population. Finally, the majority of subjects in this sample were African‐Americans. Oslin and colleagues32 have shown that patients who have a specific functional polymorphism of the u‐opioid receptor gene (OPRM1) respond better to naltrexone than those without it. Our negative results might be due to the fact that fewer than 5% of African‐Americans have this polymorphism. Nonetheless, the research on this polymorphism is in its infancy and more studies are needed before drawing conclusions based on genetics. Thus, in this study the injectable, extended‐release naltrexone, while an ideal method for ensuring medication adherence in traditionally hard‐to‐treat patients, resulted in no measurable reduction in cocaine or alcohol use over the course of 8 weeks of treatment, compared to a placebo injection, in patients with comorbid cocaine and alcohol dependence. These patients continue to provide a unique challenge for addiction treatment providers. The study was funded by a Center grant P50 DA 12756 (H.M. Pettinati, Center Director) from the National Institute of Health/National Institute on Drug Abuse, Rockville, MD. Study medication and matching‐placebo injections were provided by Alkermes. Statistical assistance for one of the authors (MRW) was supported by a National Institute of Health training grant – T32 MH065218. We thank our Studies of Addiction Treatment Research Center team for conducting this trial. In particular, we want to thank Marcia Commins, Amy Henninger, Tamara Roth, and Thera Wolven for technical assistance. Declaration of Interest The authors alone are responsible for the content and writing of this paper. Alkermes provided Dr. Pettinati with the medication and matching placebo for this study. Dr. Pettinati, Dr. Kampman, and Dr. O’Brien have occasionally received consultation fees from Alkermes, but none in the past 3 years. None of the authors hold any patents nor stock in any relevant company. REFERENCES 1. Midanik LT, Tam TW, Weisner C. Concurrent and simultaneous drug and alcohol use: Results of the 2000 national alcohol survey. Drug Alcohol Depend. 2007;90:72–80. 2. Stinson FS, Grant BF, Dawson DA, et al. Comorbidity between DSM‐IV alcohol and specific drug use disorders in the United States: Results from the National Epidemiologic Survey on Alcohol and Related Conditions. Drug Alcohol Depend. 2005;80:105–116. 3. Brady K, Sonne S, Randall C, et al. Features of cocaine dependence with concurrent alcohol abuse. Drug Alcohol Depend. 1995;39:69–71. 4. Brower KJ, Blow FC, Hill EM, et al. Treatment outcome of alcoholics with and without cocaine disorders. Alcohol Clin Exp Res. 1994;18: 734–739.
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