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Addictive Behaviors 33 (2008) 651 – 667
A double blind, placebo-controlled trial that combines disulfiram and naltrexone for treating co-occurring cocaine and alcohol dependence ☆
Helen M. Pettinati a,⁎, Kyle M. Kampman a , Kevin G. Lynch a , Hu Xie a , Charles Dackis a , Amanda R. Rabinowitz a , Charles P. O′Brien a,b
Center for the Study of Addictions, Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, United States b Philadelphia Veterans Affairs Medical Center, Philadelphia, PA 19104, United States
Abstract Background: This is a double blind, placebo-controlled trial that evaluated the efficacy of disulfiram, naltrexone and their combination in patients with co-occurring cocaine and alcohol dependence. Methods: 208 patients were randomized to disulfiram (250 mg/day), naltrexone (100 mg/day), the combination, or placebo for 11 weeks. Outcomes were in-trial abstinence from cocaine and/or alcohol. Results: Few safety concerns were reported, although medication adherence was low in a number of patients for both medications, alone or in combination. In the primary analyses (GEE modeling), abstinence from cocaine as measured by cocaine-negative urines and days of self-reported abstinence from cocaine or alcohol did not differ between placebo and any of the medication groups. However, patients taking disulfiram (alone or in combination) were most likely to achieve combined abstinence from cocaine and alcohol. Secondary analyses revealed that patients taking the disulfiram–naltrexone combination were most likely to achieve 3 consecutive weeks of abstinence from cocaine and alcohol.
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. ⁎ Corresponding author. University of Pennsylvania Treatment Research Center, 3900 Chestnut Street, Philadelphia, PA 19104, United States. Tel.: +1 215 222 3200x139; fax: +1 215 386 5106. E-mail address: email@example.com (H.M. Pettinati). 0306-4603/$ - see front matter © 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.addbeh.2007.11.011
1995. and have higher rates of recidivism than patients dependent only on cocaine or on alcohol (Brady. but none have been approved for treating cocaine dependence (Vocci. Carroll. Cocaine. Pettinati et al. DeLaune. However. 2006b). 2002) and toxicity (Harris et al. 2002). Badger. Presently. More patients taking the disulfiram–naltrexone combination achieved 3 consecutive weeks of abstinence in treatment than placebo-treated patients. compared to placebo treatment (Hersh. Wolf. 2001. & Bryant. Heil. Prihoda. Volpicelli. 2004). In recent years. there have been a series of double blind. 2005). Alcohol. Hearn. & Ridge. & Wolff. 1998. and. & Kranzler. 2001. & Higgins. did not reduce alcohol or cocaine use in cocaine-alcohol dependent outpatients. Adinoff & Malcolm. 2003). Pennings. Morgenstern. & O′Brien. Keywords: Combining medications. Manning. Ait-Daoud. 2006a. One reasonable treatment approach of co-occurring cocaine and alcohol dependence. Wechsberg & Litten. in press). 2004. © 2007 Elsevier Ltd.652 H. 1999). Mengis. & Hargita. an active transesterified metabolite associated with more lethality than cocaine alone (Pennings. but more so in men than in women (Pettinati et al. 2002). & Wolff. there have been few attempts to evaluate medications in clinical trials for treating the co-occurrence of cocaine and alcohol dependence.. Another rationale. are inherently inconsistent at showing up for treatment visits. Introduction Patients who have co-occurring cocaine and alcohol dependence comprise a large proportion of the cocaine-addicted population (Gossop. & Ridge. indirectly promote cocaine abstinence. & Jones. added to traditional counseling. Sonne. in turn. Schmitz. Rose. Van Kirk. Leccese. an FDA-approved medication for treating alcohol dependence. Harris. . Leccese. & Elkashef. & Grabowski. Johnson. It is well known that the use of one addictive substance often leads to the use of another addictive one.. McKay. Thus. and a novel approach. placebo-controlled clinical trials of combination medications for treating primarily alcohol or drug dependence in patients without concomitant psychiatric disorders (see. Sayre. Flannery. All rights reserved. 2003. Also. Nonetheless. placebo-controlled studies of 50 mg/day of naltrexone. Manning. & Hall. which has been tried but has thus far failed. the Food and Drug Administration (FDA) has approved medications for treating alcohol dependence. have greater psychosocial problems. 1991. Clinical trial. to treating the co-occurrence of cocaine and alcohol dependence is to combine two medications. Notably. Historically. Wagner. Stotts. two double blind. and suffer more adverse addictionrelated consequences. Acri. some preliminary data have suggested that a higher dose of naltrexone (150 mg/day) may be useful in reducing cocaine and alcohol use in cocainealcohol dependent patients (Oslin.M. concurrent use of cocaine and alcohol produces cocaethylene (Gossop. Rounsaville. Ciarleglio & Mash. there have been many attempts to test medications for the treatment of either cocaine or alcohol dependence alone. Mendelson. e. / Addictive Behaviors 33 (2008) 651–667 Conclusion: There was an association between disulfiram treatment and abstinence from cocaine and alcohol. is giving an FDA-approved alcohol-reducing medication (added to counseling) that will decrease alcohol drinking. Pettinati. Maude-Griffin. Everhart. Naltrexone. Disulfiram. one of which will decrease cocaine use and the other of which will decrease alcohol use.g. Randall. 1993.. which effectively targets the potentially different neurobiology of the combination of cocaine and alcohol dependencies. this treatment-refractory population may require a pharmacological approach. Medication non-adherence 1. Delucchi.
1995. increases the concentration of dopamine more than what is observed when cocaine is taken alone. / Addictive Behaviors 33 (2008) 651–667 653 Anton et al. Ball. topiramate. . such as anxiety. disulfiram′s mechanism of action for reducing cocaine use is that it inhibits dopamine beta-hydroxylase. Dackis. & O′Brien.. Kosten. McCance-Katz. 2006). & Nencinia. disulfiram... & Potgieter. In some studies. when coupled with cocaine use. Pettinati. Pettinati. Pettinati et al. suggested that some medications added to counseling may provide an advantage over placebo treatment for cocaine dependence (see respectively: Carroll et al. 2006. While disulfiram has an appeal in the context of the present study because of its known action in deterring alcohol use.. 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. & Jatlow. 1998a). Kasas. Kampman et al. One medication was selected to reduce cocaine use (disulfiram — see below the rationale for doing so). 1998). & O′Brien. Petrakis et al. Of interest. Cioceb. Ball. impedes cocaine metabolism by inhibiting plasma and microsomal carboxylesterases and plasma cholinesterase (McCance-Katz. George. did not address how to treat the highly prevalent cocaine-dependent group with alcohol dependence. and others. modafinil. Carroll. In a controlled clinical trial for treating cocaine dependence with disulfiram. which causes unpleasant sensations (Suh et al. it was selected for the present study primarily as a treatment for reducing cocaine use. Antonillia. Cubellsa. 2007). 2004. namely. which is necessary for fully metabolizing alcohol. 1998a). 2000). Furthermore. particularly in men (Nich. and a longer than expected cocaine-elimination half-life (Hameedi et al. Kampman... Kiefer & Wiedemann. including adding disulfiram to naltrexone (Petrakis et al. 1998a. Disulfiram originally was approved in 1951 for promoting abstinence from alcohol. 2004. however. Essentially. 2004). however. However. 2002. and cardiovascular response (McCance-Katz et al. & Jatlow. Lynch. Disulfiram′s mechanism of action for reducing cocaine use is believed to be different from its mechanism for promoting abstinence from alcohol. Kampman. leaving an increased concentration of acetaldehyde. disulfiram. Lehert. Grassi. These effects of the disulfiram–cocaine interaction might result in an exacerbation of negative effects of cocaine. recent controlled trials of several medications. Carroll. 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. Nich. 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. McCance. & Rounsaville. McCance-Katz. & Jatlow. 2006. Nich.. while encouraging for treating cocaine dependence. & Carroll. 1998... 2000. McCance-Katz. Aeby. paranoia. Rounsaville. 1998b). & Rounsaville. 2004. and hence. 2005). Gossop & Carroll. aldehyde dehydrogenase. Kosten. (2004) found that disulfiram significantly reduced cocaine use in patients with cocaine dependence.H. Potentially. disulfiram′s effect on decreasing alcohol use is that it inhibits the enzyme.. 2006. Mccance. Petrakis. and the second medication was selected to reduce alcohol use — plus its FDA approval in 1994 for treating alcohol dependence (naltrexone).M. Carroll et al.b). The results of this Carroll study. To date. an enzyme that normally converts dopamine to noradrenaline (Kosten. 2006). or to acamprosate — another FDA-approved medication for treating alcohol dependence (Besson. but it has been used only modestly since its approval to treat alcohol dependence (Suh. Kampman et al. & Kosten. Frankforter. 2005. 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. Dei Giudicib. Kosten. 2004). the combination of disulfiram and cocaine has resulted in a higher than expected plasmacocaine concentration.
Psychiatric exclusion criteria included active psychosis. & Koob. Kissin. Meyer. Methods 2. Sass. Parot. i. Nonetheless. & Kranzler. Fuller & Gordis. Schottenfeld. by which dynorphin inhibits dopamine activity. King. Volpicelli. Those patients who appeared to meet criteria in a telephone interview were invited to the Treatment Research Center (TRC) for a screening evaluation. independent of its effects on alcohol consumption. breastfeeding. & Bigelow. 1995). Kosten. dementia. Sherman. 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. Eligible patients entered .. Schmitz et al. pre-clinical studies have demonstrated that cocaine releases beta-endorphin (Beakeland. Medical exclusion criteria included pregnancy. Furthermore. Notably. were excluded. 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. Perkins.. Alterman. and significant hepatocellular injury. Lundwall. Walsh. Sullivan. except nicotine addiction.e. & Zieglgansberger. Van Kirk.1. Procedures Patients were treatment-seeking cocaine users recruited through community advertisements and professional referrals. 2. before starting study medication. 1998. Watson. 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. Chronic exposure to both alcohol and cocaine result in dynorphin upregulation (Dackis & O′Brien. 1995. & Rounsaville. 1997. 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. Gavrilovic. If clinically indicated. Lion. achieve 3 days of abstinence from alcohol. the daily. Littleton. clinical trials have not proven its effectiveness in reducing cocaine use at the 50 mg/day dose (Hersh. & Shanahan. which may contribute to dopamine hypoactivity in both conditions (De Witte. 1996). 2. oral version of naltrexone was selected to be given in combination with disulfiram. Patients with dependence on substances other than cocaine and alcohol. 1990) by inhibiting the release of beta-endorphin (Volpicelli. Royer. Verbanck. Jaffe. 2003). 2004). Preston. 2006). mania.654 H. active hepatitis. Singha. / Addictive Behaviors 33 (2008) 651–667 With respect to the treatment in the present study for the patient′s alcohol dependence. and all patients who were included in the study had signed informed consents prior to screening. 2006). Soyka. 1971). 1992. & Oliveto. Guelfi. although to date. In summary. Chang.2. 2005. Pelc. 1996). Mann. Garner. and that naltrexone and other opioid antagonists reduce rates of cocaine self-administration in animals (Paille. Pettinati et al. 2003. The study was approved by the University of Pennsylvania′s Institutional Review Board. Suh et al. Petrakis. O′ Brien. 2004. Steru. or the need for treatment with psychiatric medications. 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 alcoholinduced euphoria (O′Malley. & Lehert. studies have failed to demonstrate that naltrexone has an effect on cocaine euphoria in humans (Sofuoglu. Le Bon.. McCance-Katz. & Hayashida. This neuroadaptation may be reversed by naltrexone′s antagonism of kappa-opioid receptors. & O′Brien. & Parot.M. patients had to successfully complete outpatient alcohol detoxification.. naltrexone may also have direct therapeutic effects on cocaine use.
434 cocaine-alcohol dependent patients were invited to screen for this study. Therapists received weekly supervision by a doctoral-level therapist with over 15 years experience in treating cocaine dependence. individual therapy sessions were audiotaped and a random sample of tapes from each therapist was listened to by the therapists′ supervisor to address any CBT drift. and. Design Randomized patients were assigned to 250 mg/day of disulfiram (DISULF. in press). Patients were also assigned to receive 250 mg of disulfiram. 1999. Litt. 1992). or to double placebo (PLAC. 342 (79%) signed consent and agreed to begin screening. patients received twice weekly individual cognitive behavioral therapy (CBT) utilizing the CBT therapy manual and supporting materials that were developed for the National Institute on Alcohol Abuse and Alcoholism Project MATCH (Kadden. patients who tolerated the medications would be prescribed the maximum doses of 250 mg/day of disulfiram (or matching placebo) and 100 mg/day of naltrexone (or matching placebo). significantly elevated blood pressure or higher than 3. our prior studies suggested that doses higher than 50 mg/day may result in better outcomes in patients with the combination of cocaine and alcohol dependence (Oslin et al.H. n = 52). 2. 37 (15%) were excluded during the screening period based on the specific eligibility criteria: 10 were excluded for medical reasons (e. Of those remaining (245 consented patients). n = 49). both medications were tapered. In the last 2 weeks of the trial. following 2 weeks of screening.. In the 4th week of treatment. / Addictive Behaviors 33 (2008) 651–667 655 a 13-week trial that included a 2-week pre-treatment/screening phase and an 11-week randomized medication phase. There were 97 consented patients (28%) who never returned after signing consent for the first screening session. 100 mg/day of naltrexone (NTX.M. Of these. starting in the first treatment week on the 5th day.g. In addition to medication or placebo pills. or Week 13 since signing consent. Naltrexone′ s recommended daily dose is 50 mg/day. The remaining 208 patients entered the randomized medication phase of the trial. taking disallowed medications. Patients were continued at these daily dosages of each medication or placebo through to end of 11 treatment weeks. n = 54). and pharmacotherapy was completed by the end of Week 11 (Week 13 since signing consent). .1. The basic format was accepted. and 9 were excluded for disallowed psychiatric diagnoses (e.2. 100 mg/day of naltrexone or placebo in the morning. & Busher. CBT was provided by Master′s level therapists with training in delivering CBT. All patients received the same number of pills (active medication and/or placebo pills). bipolar disorder or psychosis). Cooney. 18 were excluded for not meeting cocaine and/or alcohol dependence diagnostic criteria. In addition. or for concomitant opiate abuse or dependence. regardless of group or week of treatment. n = 53). Pettinati et al.g. also. although specific procedures were adapted by our group for treatment of both cocaine and alcohol dependence.. Patients received their first dose of randomized medications in the 3rd week of the study. Pettinati et al. Patients were assigned for the first 2 days of the 11week treatment phase to receive either 50 mg/day of naltrexone or placebo in the morning. the combination of disulfiram and naltrexone (DISULF+NTX. During the 4 years of recruitment for this trial. then on the 3rd day of the treatment week.5 times normal liver function tests). but for this study we chose a target dose of 100 mg/day because this higher daily dose will last longer in patients — better ensuring the medication′s action in patients if they tend to be medication non-adherent. The disulfiram target dose of 250 mg/day is the one that is recommended in its label. Study medication was dispensed in clearly labeled blister cards at a once-a-week medical evaluation visit.
Specimens were analyzed for benzoylecgonine (BE) by fluorescent polarization assay. Spitzer. Cocaine abstinence was determined for each week by 3 weekly cocaine-negative urine samples. complete blood count. If any samples during a given study week were positive for BE or missing. Pettinati et al. semistructured interview that uses the recall of critical life events and a personalized calendar to prompt recall of alcohol drinking frequency (days) and quantity (number of drinks per day) during the inquiry period (up to 90 days).2. bilirubin. 1995).M. Fahrenheit were not accepted (Fewer than 1% urine specimens were outside this range). A secondary analysis with this combined abstinence index compared the number of patients who were able to achieve 3 consecutive weeks of continuous abstinence from both alcohol and cocaine while in treatment.2. Urine drug screen (UDS) tests were obtained 3 times weekly during the 2 screening weeks and the 11 weeks while in treatment. 1992). Urine collection was not observed but urine specimen temperature was monitored. urine pregnancy testing and a 12 lead EKG. Urine specimens temperatures lower than 90°. abstinence from alcohol for a given study week was determined by self-report derived from the TLFB method. urinalysis. The TLFB method has been adapted by our laboratory. The primary in-trial outcome measure of daily alcohol use was the patient′s self-report collected via the Timeline Followback method (TLFB) (Sobell & Sobell. we also chose to evaluate outcomes that reflected the combination of both alcohol and cocaine use. The recalled information on alcohol use is recorded for each day on the personalized calendar. Use information was also collected for each day in treatment. / Addictive Behaviors 33 (2008) 651–667 2. the week was coded as non-abstinent. Any alcohol use during a given study week resulted in that week being coded as a nonabstinent week. which is to get patients to achieve a stable period of continuous abstinence. to also collect information from the patient about daily use of cocaine or other abused drugs. Measures Psychiatric diagnoses were obtained by master′s level clinicians using the Structured Clinical Interview for DSM-IV (SCID) (First. Gibbon. Breathalyzer readings were collected at each visit throughout the study to ensure that research data were not collected from patients with a positive breathalyzer. In addition to examining cocaine and alcohol outcomes separately. and then repeating outcome analyses with this index as the primary outcome measure. Pretreatment laboratory testing included a chemistry screen. plus dollars worth of cocaine used per day. One of these outcomes involved creating an abstinence index that combined the separately constructed cocaine and alcohol use/non-use. A urine specimen was also collected at a single follow-up visit that was scheduled for 6 months after the end of the trial to assess the patient′s status following treatment. including the personalized calendar. Abstinence from cocaine for approximately 3–4 consecutive weeks has been shown to be predictive of long-term cocaine abstinence . The latter measure has been used in a number of studies because it is thought to represent a primary goal of short-term treatment. a similar procedure was used in this study to recall daily use of cocaine. updated at each research visit to create a continuous daily record of cocaine and alcohol use or abstinence in the 3 months prior to treatment and all during the treatment period. A 30-day alcohol and drug use selfreport was also collected at a single follow-up visit that was scheduled for 6 months after the end of the trial to assess the patient′s status following treatment. & Williams. Specimens were analyzed qualitatively N /=300 ng/ml of BE was considered drugpositive. The TLFB was administered by a research technician. The TLFB was given in screening to record use of alcohol and cocaine in the 3 months immediately preceding treatment entry.656 H. indicating recent cocaine use. The TLFB is a 15–30 minute. For alcohol. who had received training in administering the TLFB. Thus. Medical screening included a complete medical history and physical examination conducted by a certified nurse practitioner. or greater than 100°.
NTX. missing weeks were imputed as positive/use. Kintaudi. and both. & Ling. In addition. Park & Lee. so we chose to reduce the number of time points per patient by coding each of the 11 weeks as a use or non-use week. Falcione. Kosten. / Addictive Behaviors 33 (2008) 651–667 657 (Carroll et al. 1992). The patients were initially compared on a variety of demographic and pre-treatment characteristics. 6 during the 2week pre-randomization phase. In fitting these models to the data. 1959). Other measures included the Hamilton Rating Scales of Depression (Hamilton. and also performed pattern-mixture analyses.3. and 2) abstinence from alcohol. Primary and secondary outcomes were analyzed using generalized estimating equations (GEE) models. but characteristics that showed significant imbalance across the groups were considered for inclusion as covariates in supplementary analyses. using logistic regression for categorical characteristics. rather than including each urine per week in the model. 1992). and linear regression (ANOVA) for continuous characteristics. This allows us to . Our pattern-mixture analyses compared subjects that provided complete data versus data from those that prematurely left the study or provided only partial data (Hedeker & Gibbons. We. The two primary outcome measures were: 1) abstinence from cocaine. To assess the sensitivity of the results to the imputation of missing urines/weeks as positive/use.. Pattern-mixture models augment the GEE models described above by including a variable describing the pattern of missing data in the study as a main effect and as an interaction effect with the group and time variables. 1999). we re-ran the analyses with missing observations ignored. They were administered at pre-treatment and at the end of treatment to measure the number of mood and anxiety symptoms. Statistical analysis The main analyses in this paper were by intention-to-treat. The protocol called for three urines to be collected per patient each week. Pettinati et al. 2. and some group by time interactions. DISULF + NTX. & Schottenfeld. & Wager. to assess how well the randomization had balanced patient characteristics across the four treatment groups. and lower order effects contained in a significant interaction effect were also included. Thus. also reduces the risk of overestimating drug use due to BE carryover. GEE approaches work best when the data are in the form of a smaller number of repeated measurements for each of many patients (Sharples & Breslow. rather than visits. yielding a possible 39 urines per patient. therefore. Charuvastra. Ocepek-Welikson.M. a combination measure of abstinence from both cocaine use (based on UDS) and alcohol use (based on TLFB) was also created for both primary and secondary analyses. Markowitz. 1992). Adverse events were measured at each medical evaluation visit using the Systematic Assessment for Treatment Emergent Effects (Rabkin. The models included terms for use status during the pre-randomization phase. which is a standard practice in clinical trials for which cocaine abstinence is a primary outcome (Shoptaw. naltrexone present/absent). alcohol. and 33 during the 11-week treatment phase. 1997.H. together with linear and quadratic time effects. the primary outcome analyses did not include additional covariates. With respect to the repeated binary outcomes of abstinence from cocaine. and this status was included as a covariate in the GEE model. Empirical (sandwich) standard errors were used to assess significance. Using weeks as the time units of analysis. medication group (disulfiram present/absent. Morgan. 1994. 1960) and of Anxiety (Hamilton. Secondary outcomes included abstinence from heavy drinking (defined as drinking 5 or more standard drinks in one day for men and 4 or more for women). 2002). evaluated the proportion of patients in each of the four treatment groups (DISULF. PLAC) that were able to attain 3 consecutive weeks of abstinence from both cocaine and alcohol while in treatment. terms were included if they were significant at the 5% level. The urines submitted during the pre-randomization phase were used to determine use/non-use status prior to randomization.
/ Addictive Behaviors 33 (2008) 651–667 model differences in longitudinal behavior across missing data patterns. The patients on average attended 9.2 or 56% of 11 weeks. 3.3. We also assessed the effects of medication adherence and medication exposure on the comparisons of medication groups.7% NTX. As the results of the “missing = use” and “missing = ignored” analyses were virtually identical. and attended at least one CBT session a week for a mean number of 6. As each of these groups included at least two time points. 32.2. with 48. 3.16). patients had said they had in the month prior to treatment used cocaine 45. 40. Pettinati et al. Medication adherence while in treatment and medication exposure to full 11-week trial dosage Medication adherence and exposure measures were based on pill counts. Chi square tests showed no significant difference in discontinuation rates across the four groups (Pearson chi square = 5.8% DISULF + NTX. While these analyses are not bias-protected by the initial randomization.1% of the sample. and the number of pills taken over the maximum number of pills available to any given patient who completed the full 11 weeks of treatment (medication exposure). and PLAC were very similar in demographics and pre-treatment alcohol and cocaine use characteristics (see Table 1). and to assess whether there are group by missing-pattern interaction effects. and drank alcohol on 56% of the days.2. as well as for those “exposed” to 80% of medication taken by completers. Results 3.8% heavy drinking days in the same pre-treatment month. this study repeated the same sets of analyses for the subset of patients who took at least 80% of the medication while in treatment. distinguishing between subjects who provided complete data and those who missed at least one visit. p = 0.6% DISULF. There were no significant differences in either the mean number of CBT sessions or mean number of weeks where a CBT session was attended across the four groups. Beyond the intent-to-treat analysis. We used the number of pills taken over number of pills prescribed for an individual patient while in treatment (measure of medication adherence). DISULF + NTX. DISULF. we report on the “missing = use” and pattern-mixture analyses only. The mean number of years of education completed for the sample was 12. we used a binary variable as an indicator of missing pattern. Treatment attendance Records of patient self-reported cocaine and alcohol use via the TLFB were complete for 85.658 H.M.9%) and most smoked crack cocaine (78. df = 3.7% PLAC.3 years. Demographic and pre-treatment alcohol and cocaine use The average age of the patients for the N = 208 sample was approximately 41 years old.9%).8% of the days.7 or 44% of a possible 22 CBT sessions. The percent of patients per treatment group who discontinued treatment before the end of the trial were: 22. NTX. Overall. 3. they provide a useful measure of whether overall medication effects are affected by non-adherence while in treatment. and 40. Medication exposure is .1. Most were African American men (88. the four study groups. Medication adherence was defined as the percentage of pills ingested based on the number prescribed while the patient was in the trial. In our models. On average. as well as by poor exposure to a full course of pharmacotherapy. using returned blister cards and discussion with the patient at weekly intervals. this allowed us to examine the influence of missing pattern on rate of change over time.
7) 9.9% (.0 (7.6 (6.6% 12. preventing us from conducting a meaningful post-hoc exploratory analyses of outcome results with only those patients who had either taken 80% of the medications while in the trial or had been exposed to at least 80% of the medications overall.1 (7.32 (0.24) 12. 3.3% 87.8% 11.3) 81.6% 13.2) 48.4% (. df = 3..7) DISULF+NTX 49 40.3) 78.19).6) 11.7 (6.6 (1401.28) 1081.9) 20. and heavy drinking.28) 49.4) 8.8% 12.25) 47.4 (7.8) 20.3) 22.2) 43.7% of naltrexone. the amount of pill taking expected in patients who completed 11 weeks of treatment and were 100% adherent over the 11-week trial. As Table 2 shows.8% of patients who took 80% of their pills while in treatment.6) 7.5) 70.7 (1.9) 57. and these analyses are described below. rates of self-reported abstinence for cocaine.0% 86. and this rate was comparable for all four treatment groups (chi square = 4. and anxiety.8) 54.7 (6.3) 7. mood.2) 67.25) 13.6) 12.8 (7. mood.27 (0.6 (8.36).5 (1680.8) 75.4% 14.3 (10.4.8 (6.3% (.3 (1114.H.25) 14.7) 45.4 (19. compared to 58.7% (.2 (2. NTX = naltrexone.9 (7.4 (6.0% (.6) 6.9 (2. and there were also no differences in naltrexone versus disulfiram adherence rates in patients while in treatment.7) 0. D&A = Drug and Alcohol.5% (.3 (6.7% 12.3) 81. p = 0.25) 1153.3 (8.6) 0.29) 17. Pettinati et al.6) 0. and anxiety are listed for informational purposes for all four groups in Table 2. df = 3.8) 56.1% (. i.7 (7.1 (1173.9) 0.8% (.6) 67. PLAC = placebo.0) 2. any drinking.9) 45.34 (0. Primary and secondary outcome analyses Some key in-trial and end-of-trial variables representing cocaine use.2 (10. more than half of the placebo group reported no heavy drinking across the entire .25) 1149.8 (6.8) NTX 52 41. although the difference in medication exposure rates between the two medications was not significant (chi square = 3. were high.9) 4.M.33 (0. Outcome analyses focused primarily on the urine drug screen results and self-reported cocaine and alcohol use. For example. / Addictive Behaviors 33 (2008) 651–667 659 Table 1 Patient characteristics and pre-treatment measures of drug use.9) PLAC 54 41.1% of the patients received 80% or more of the maximum possible number of disulfiram pills.5% 12.e.0) 3. Nonetheless. There were 45.8 (7.6 (8.8) 9.4% 92.9 (8.79.0% (. the medication adherence and exposure rates indicated only a modest exposure to these medications in this trial.0) DISULF = disulfiram.9% 88.4 (8.2 (7.28) 49.25) 49. p = 0.5% 12.8% (.7 (9.2. defined as the percentage of pills ingested based on the number of pills that comprised the “planned maximum dose”.1 (1.2) 22.1% (. expressed as percents or means (with standard deviations) Variable N 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 problem use % 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/drinking day in past 30 Number of prior D&A treatments Hamilton Anxiety Rating Scale Hamilton Depression Rating Scale DISULF 53 42.3) 73. alcohol use. Only 35.4 (7.24) 1048.2 (3.2 (1. suggesting that patients received more exposure to naltrexone than disulfiram.3 (5.6) 55.0% (.5) 3.
0. 314 (65. 7.6% [0. 1807 (78. This indicated that in this sample. / Addictive Behaviors 33 (2008) 651–667 Table 2 In-trial continuous outcomes for cocaine and alcohol use. 4. Mulgrew. Patients who had provided BE-positive urines in the screening period had higher rates of missing and/or BE-positive urines during the treatment phase: OR = 5.5 [2.0] 5.0. & Randall.06.6% [1. 54.4. 1. Of the total collected urines. PLAC = placebo. 170] 2. 18.88)].3] 2.0.8% [2. Of those collected.0] DISULF = disulfiram.6] 18.660 H. Cocaine abstinence (TLFB self-report) Of the 2288 urine specimens expected to be collected during the treatment period. 300] 2. despite admission of cocaine use. 63. 9. 7.1% [0. 6.7] 4.9] PLAC 54 5. Hersh. 11.3. Zanis. but there were no significant time or medication effects.2%) were self-reported by patients as positive for cocaine. 3. McLellan.25 per week [p = 0. All groups showed an increase in the odds of a missing and/or BE-positive urine across time. NTX = naltrexone.4] $47. Patients who self-reported cocaine use in the screening period were significantly more likely to self-report cocaine use in the treatment phase (p b 0. with missing weeks regarded as use.001. 2.1] 45. 95% CI = (0.0 [1.2. 11.0. 66. 7.5% [27. .09.5] 0% [0.5 [50.5 [20. self-reported cocaine use is relatively reliable. 3. 2004. A similar GEE model for self-reported cocaine use.001). 18.5%) urine specimens were found negative for cocaine. the pattern of use across the four groups was about the same as in the UDS analyses.5% [40. 95% CI = (1.6.6] NTX 52 7. 11.4% [1.1.6% [0. 3.2] $107.3. log transformations failed to adequately reduce skewness. 95% CI = (3. showed a trend towards fewer patients using cocaine in the disulfiram groups [OR for use = 1. 6.06. 8. there were 358 (19.6% [0.0 [1.6.0 [0. 2.0. rather than days of use.6% [1.7%) were consistent with self-report.0] 3.1% [0.3. As a result.3] $195 [50.2] $88. 1368 (75. However.0. These figures are comparable to previous studies using self-report data in cocaine-dependent samples (Carroll et al.0 [3.4.M.7] 28. 5.3. 3. 27.6% [0.5 [45. treatment period. 200] 2.0 [2.0.8] 9.1.2% [9.5 [2.9.16)]. 1999. we focused on monthly abstinence as our primary measure..1] 1.0] 3.001.7] 23. BE = benzoylecgonine.0 [2. 10. 6. 8. 7.9] DISULF + NTX 49 4.2% [2. & Kranzler.6% [0.0] 5.0] 5. with the odds ratio increasing by a factor of 1. 81. p = 0.40)].5] 54.2% [2.3.8%) urines that were positive for cocaine but patients denied cocaine use.98.3% [0. Pettinati et al.0.5] 9. Van Kirk.0] 3.21 [p b 0. 36. Cocaine abstinence (urine drug screens — UDS) A full GEE model of the log-odds of missing and/or BE-positive urines showed no medication effects significant at the 5% level.1] 0. Since the % days responses contained many zeroes.9%) were actually collected. and 81 (4.0] 3.45. 260] 3. Of the 481 missing urine specimens.6% [9. 1994). 7. 1.3% [1.8] 0.1. expressed as median percentages or medians (w/95% confidence intervals) N DISULF 53 In-trial outcomes % days cocaine use % BE-negative urines (missing ignored) % BE-negative urines (missing BE-positive) $ spent for cocaine % days alcohol use % days heavy alcohol use End-of-Tx scale scores Hamilton Anxiety Rating Scale Hamilton Depression Rating Scale 5.
For example. self-reported cocaine use. p b 0. Periods of abstinence A non-parametric approach to evaluating combined abstinence from both cocaine and alcohol during the trial compared the four treatment groups on the number of patients who achieved 3 consecutive weeks of continuous abstinence from both cocaine and alcohol while in treatment. submitted significantly more BE-negative urine specimens during the trial (24/33 or 73% vs 9/33 or 27% BE-negative specimens.3).04).3.13.65)].5. reported a significantly lower percentage of drinking days during the trial (3. p = 0. and the pattern variable retained as a main effect only. There were no significant time or naltrexone effects with the combined index of abstinence. / Addictive Behaviors 33 (2008) 651–667 661 3. respectively. This measure has been shown to be predictive of long-term cocaine abstinence in previous trials.M.6. and included it as a main effect and interaction effect in the GEE models for the cocaine UDS. self-reported alcohol use.H.0% vs 10. 3. we observed that disulfiram was associated with significantly lower rates of use as indexed by the cocaine UDS (p = 0. followed by a leveling off later in the treatment phase. patients with 3 consecutive weeks of abstinence. 3. and combined alcohol-cocaine use outcome variable (p = 0.02. Evaluation of combined abstinence from both cocaine and alcohol A similar GEE model to what has just been described for evaluating separately cocaine and alcohol use during the trial was also performed for combined abstinence using a combination of UDS cocaine results and self-reported alcohol use. While interpretation of these results is complicated by the fact that we are considering a post-randomization variable. 3. None of the interactions between the treatment factors and the pattern variable was significant (all p-values N 0. df = 206.02). and at the 6-month follow-up visit.4. t = −12. This analysis showed significantly more abstinence in patients taking disulfiram. A similar GEE model for the presence of heavy drinking showed an overall increase in rates of alcohol use over time [OR = 1. These interactions were due to the disulfiram only and naltrexone only groups showing faster initial rates of increase in drinking than the other two groups. Alcohol abstinence (TLFB self-report) A similar GEE model for the presence of any drinking showed linear and quadratic time trend interactions with the medication groups (p = 0. t = 4. were more likely to submit a BE-negative urine specimen (60% vs 30%.4. compared to patients without 3 consecutive weeks of abstinence.02.02. In this trial. the ability to achieve 3 consecutive weeks of abstinence while in treatment was found to be a significant predictor of higher rates of abstinence from alcohol and cocaine during the trial and at the 6-month follow-up visit (64% of patients attended the 6month follow-up visit). 95% CI = (1. p b 0.04 for the linear effect). Pattern mixture models We used a binary indicator of treatment completion as our pattern variable for these analyses. 95% CI = (1. and p = 0. 2.02). df = 1. When the interaction terms were removed. respectively. df = 126. Pettinati et al. and combined cocaine/alcohol use analyses. OR = 1. there were no significant medication group differences at any time point.4.3% days drinking.0.64 [p = 0. 1.02 for the quadratic effect.7. However. they provide support for the disulfiram effect observed in the “missing = use” urine analyses reported above. respectively. chi square = 13. although abstinent days were not significantly different from the placebo group per se via post-hoc analyses.04.001).4. cocaine self-report (p = 0.4. .001).26)]. suggesting that the effects of the medications did not differ across completers and non-completers. but there were no significant effects for medication group.4.
Based on findings from previous trials. PLAC = 15. drowsiness (39. Adverse events (AEs) ranged from mild to severe.6%). The percent of cocaine-alcohol dependent patients (via DSM-IV criteria) that achieved at least 3 consecutive weeks of abstinence from both cocaine and alcohol in an 11-week controlled clinical trial of four randomized groups.8. p = 0.0%. df = 1. the ability to achieve 3 weeks of continuous abstinence is a strong predictor of treatment response and long-term abstinence from both cocaine and alcohol.7%.5%) vs 39/165 (23.04). Table 3 provides the prevalence of the most Fig. respectively.0%. NTX = 17. Pettinati et al. or 250 mg/day of disulfiram. df = 3. chi square = 4.3%. or the combination of these two medications at the dosages specified.4%).4.4%).4%) and nausea (40. and self-report being abstinent from alcohol in the 30 days prior to their follow-up visit (17/43 (39. as well as data from this trial. . 3. The most frequently reported AEs were headache (64. / Addictive Behaviors 33 (2008) 651–667 p = b 0. anxiety/irritability (53.001). 1 shows the proportion of patients in each of the four treatment groups who achieved 3 consecutive weeks of abstinence from both cocaine and alcohol during the trial.05).662 H. assigned to placebo.5. 1. Significantly more patients treated with the combination of disulfiram and naltrexone achieved 3 consecutive weeks of abstinence from both cocaine and alcohol compared to the other 3 medication groups (DISULF + NTX = 34. DISULF = 17. Adverse events (AEs) There were no patient deaths or serious medical conditions during the clinical trial.4%). p = . Fig. chi square = 7. or 100 mg/day of naltrexone.M.
Differential reporting on these two events is predictable. NTX (%) N = 52 63 40 46 38 38 29 19 23 8 13 21 8 DISULF + NTX (%) N = 49 73 49 61 57 43 33 33 29 10 14 10 8 PLAC (%) N = 54 54 28 52 26 50 28 28 19 9 9 11 12 68 42 55 42 45 32 11 17 15 17 15 13 DISULF = disulfiram. placebo-controlled study combining disulfiram and naltrexone as a treatment regimen for attaining abstinence in cocaine and/or alcohol use. or placebo.01. with twice weekly CBT for 11 weeks in patients with co-occurring cocaine and alcohol dependence. / Addictive Behaviors 33 (2008) 651–667 663 Table 3 Patient percentages reporting frequent adverse events during treatment (frequent adverse events are those reported in 10% or more of patients) Adverse event DISULF (%) N = 53 Headache Drowsiness Anxiety/irritability Nausea⁎⁎ Upper respiratory tract infection Decreased sexual desire Increased sexual desire⁎ Vomiting Skin rash Difficulty achieving orgasm Toothache Diarrhea ⁎p = 0. the event is usually most salient in patients who become abstinent during treatment. Disulfiram and naltrexone have both been approved by the FDA for alcohol dependence. the placebo group reported a lower frequency of nausea compared to the other three medication groups. With respect to increased sexual desire. With respect to nausea..H. Thus. reported by 10% or more patients).e. This also was the group who were most likely to achieve 3 consecutive weeks of combined abstinence from both cocaine and alcohol while in treatment. the patient group with the highest frequency of reports of increased sexual desire was the group who were taking the combination of disulfiram and naltrexone.e.M. independently.05. i. Of note. In addition. in-trial reductions in cocaine and. patients who reported higher rates of heavy drinking in the pre-treatment period had higher rates . ⁎⁎p = 0. or their combination. Discussion Co-occurring cocaine and alcohol dependence is highly prevalent in the United States and is also very difficult to treat successfully. frequent AEs reported in this study (i. NTX = naltrexone. or 250 mg/day disulfiram. this trial evaluated the use of 100 mg/day naltrexone.. Patients who had provided BE-positive urines in the screening period had higher rates of missing and/or BE-positive urines during treatment. alcohol use occurred but were not significantly different on continuous outcome measures across the four study groups treated with either naltrexone or disulfiram or both or neither (placebo). Adding pharmacotherapies that target one or both of these dependencies to an accepted counseling/psychosocial treatment for cocaine and alcohol dependence. PLAC = placebo. Nausea and increased sexual desire were the only two events that differed across the groups. 2004). Using GEE analyses. CBT. with disulfiram also being shown to reduce cocaine use in cocaine-dependent patients (Carroll et al.. Pettinati et al. 4. was evaluated in this double blind.
Rhines. 2006). non-parametric analyses that were used in this trial suggested that some of the patients in this trial benefited from the combination of 250 mg/day of disulfiram plus 100 mg/day of naltrexone for 11 weeks in that increases in combined abstinence from cocaine and alcohol could be observed in over 30% of the patients who received both active medications. Suh et al. Volpicelli. Essentially. Smith.664 H. may be different from clinical patients who are not asked to meet research eligibility criteria. Fuller & Gordis. Still. & Levine. McCarty.. and also the majority of patients went to fewer than 50% of their CBT sessions. 2005) and naltrexone (Pettinati et al.. the medication adherence rates for patients taking 80% of their medications while in treatment were found to be similar for the two medications. it is possible that the high nonadherence and poor medication exposure rates were attributable to the patient population and not the medications selected. the lack of a consistent effect in the GEE outcome analyses using continuous outcome measures suggested that these treatments alone or in combination are unlikely to be robust enough to generalize an advantage to most patients who enter treatment with both cocaine and alcohol dependence. Treatment non-adherence was comparable across the four study groups. Because patients with both cocaine and alcohol dependence tend to have high treatment non-adherence rates. The achievement of 3 consecutive weeks of abstinence from both cocaine and alcohol was also shown in this study to be a significant predictor of more abstinence during the trial and at a 6-month follow-up visit. Taking fewer pills than prescribed for the full treatment period has also been consistently reported in alcohol dependent populations for both disulfiram (Fuller. There was a finding that the patients from the two disulfiram groups tended to have greater combined abstinence from cocaine and alcohol during treatment. Pettinati et al. therefore. compared to the other 3 treatment groups. 2006. Clinically. Also. which has been associated with clinical significance. In summary. there were no serious adverse effects. The apparent discrepancy in results between the GEE analyses and a non-parametric approach that targets 3 consecutive weeks of abstinence may indicate a difficulty in the sensitivity of traditional outcome measures to target levels of treatment response in the patient groups who traditionally include many patients who are treatment non-adherent. in this study. Patient adherence to medication regimens were generally poor. medication exposure to either medication was modest at best.M. and non-adherence likely contributed to the inconsistency in results. On the other hand. & O′Brien. Using a non-parametric approach. While typically disulfiram has had much higher non-adherence problems than naltrexone (De Witte et al. 2004. General adverse effects were in the mild to moderate range and typical for these medications. Rhines. / Addictive Behaviors 33 (2008) 651–667 of alcohol drinking during treatment. suggesting that the majority of the patients took less than 80% of the targeted 11-week course of the expected medication regimen. 1997). the high levels of patient non-adherence to treatment regimens may have weakened the analysis to provide statistically confident results. In addition. although there was a non-significant difference that indicated patients overall ingested more naltrexone than disulfiram (medication exposure rates). Volpicelli.. No patient was discontinued or said they would discontinue treatment because of a physical complaint that was reported as an adverse event. the patients in this study demonstrated less than optimal medication adherence while in treatment (b 50% took 80% of their medications). we would need to identify the patients whom we think will adhere to taking medications before initiating either or . Rieckmann. Limitations to this study are that patients in this study agreed to participate in a research clinical trial and. we found that significantly more patients treated with the combination of disulfiram and naltrexone achieved 3 consecutive weeks of continuous abstinence from both cocaine and alcohol while in treatment. Alterman. 2005.
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