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Drug and Alcohol Dependence 81 (2006) 137148

Treatment of methadone-maintained patients with adult ADHD: Double-blind comparison of methylphenidate, bupropion and placebo
Frances R. Levin , Suzette M. Evans, Daniel J. Brooks, Aparna S. Kalbag, Fatima Garawi, Edward V. Nunes
New York State Psychiatric Institute, Department of Psychiatry, College of Physicians and Surgeons of Columbia University, 1051 Riverside Drive, Unit 66, New York, NY 10032, USA Received 15 October 2004; received in revised form 18 May 2005; accepted 15 June 2005

Abstract The purpose of this double-blind, three-arm, 12-week trial was to compare the efcacy of sustained-release methylphenidate or sustainedrelease bupropion to placebo in treating adult attention decit hyperactivity disorder (ADHD) symptoms. The randomized sample consisted of 98 methadone-maintained patients who were predominately male (57%) and 40% Caucasian, 40% Hispanic and 20% African American. All participants met DSM-IV criteria for adult ADHD, with 53% meeting DSM-IV criteria for cocaine dependence/abuse. In addition to medication and treatment as usual at a methadone program, individuals received weekly individual cognitive behavioral treatment. Other than current employment status, there were no signicant demographic differences across the three treatment groups. Seventy percent completed the 12-week trial. There were no differences in retention rate based on treatment group. A reduction in ADHD symptoms using the adult ADHD rating scale was observed in all three groups, but there were no signicant differences in outcome between treatments. The placebo response rate was high, with 46% of the placebo group self-reporting substantial improvement in their ADHD symptoms (>30% reduction in adult ADHD rating scale). Using other ADHD outcome measures, the placebo response and medication response rates were substantially lower. There was no evidence of misuse of medication or worsening of cocaine use among those randomized to methylphenidate. Taken together, sustained-release methylphenidate or sustained-release bupropion did not provide a clear advantage over placebo in reducing ADHD symptoms or additional cocaine use in methadone-maintained patients. 2005 Elsevier Ireland Ltd. All rights reserved.
Keywords: Methadone; ADHD; Methylphenidate; Bupropion

1. Introduction Attention decit hyperactivity disorder (ADHD) is a disorder characterized by inattention, hyperactivity and impulsivity (APA, 1994). Although it is commonly recognized to be a childhood disorder, a substantial number of individuals have persistence of symptoms into adulthood (Gittleman et al., 1985; Weiss and Hechtman, 1986; Wender, 1995; Mannuzza and Klein, 2000). Whereas it is estimated that 15% of adults have ADHD (Wilens et al., 1995; Levin and

Corresponding author. Tel.: +1 212 543 5896; fax: +1 212 543 6018. E-mail address: frl2@columbia.edu (F.R. Levin).

Kleber, 1995), recent prevalence studies in various substance abuse samples have obtained rates ranging from 15 to 24% (Levin et al., 1998a; King et al., 1999; Clure et al., 1999; Schubiner et al., 2000), suggesting that this disorder merits clinical attention in substance abuse treatment settings. Compared to adults without psychiatric disorders, those with ADHD complete less schooling, hold lower-ranking occupations, suffer from poor self-esteem, exhibit social skills decits, and report greater psychological distress (Mannuzza and Klein, 2000; Murphy et al., 2002). Clearly, these ADHD-associated decits may exacerbate impairments observed among substance abusers and may impede the effectiveness of substance abuse treatment (Wise et al., 2001;

0376-8716/$ see front matter 2005 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.drugalcdep.2005.06.012

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F.R. Levin et al. / Drug and Alcohol Dependence 81 (2006) 137148

Levin et al., 2004). One substance-dependent group that may particularly benet from treatment for ADHD is methadonemaintained patients. Heroin use, as compared with cocaine or alcohol use, is associated with longer treatment careers, less-stable employment histories, a greater number of arrests, and a greater number of illegal activities among treatment enrolled drug-dependent patients (Anglin et al., 1997). Furthermore, social and job-seeking skill decits are well documented among methadone-maintained patients (Childress et al., 1991; Stanton et al., 1982). Concomitantly, these decits are associated with poor-treatment outcomes, inuence the chronicity of treatment utilization, and predict drug-treatment outcome during any single treatment episode (Anglin and Hser, 1990; Mason et al., 1998; Hubbard et al., 1989; McLellan et al., 1982, 1986). Similar to other substance-abusing populations, methadone-maintained patients appear to have an over representation of adult ADHD (King et al., 1999). It is reasonable to posit that opiatedependent individuals with adult ADHD may be subjected to a double jeopardy effect and benet from treatment that targets their ADHD symptoms. Most of the treatment studies for adult ADHD have focused on non-substance-abusing populations. Although some small controlled trials have investigated the utility of cognitive-remediation approaches (Stevenson, 1996; Stevenson et al., 2002) and some clinical descriptions of psychotherapeutic approaches for treating ADHD adults (Aviram et al., 2001; Weinstein, 1994) exist, most of the empirical literature has focused on pharmacologic approaches. Based on a recent review, there is empirical evidence supporting the efcacy of both stimulant and non-stimulant medications for the treatment of adult ADHD (Wilens, 2003), although longer term studies supporting the efcacy and tolerability have only been conducted with stimulants. Stimulants are commonly used for ADHD. Evidence to date suggests that administration of oral methylphenidate to cocaine-dependent individuals with or without ADHD does not appear to lead to abuse of the medication or to increase cocaine craving or use (Levin et al., 1998b; Schubiner et al., 2002; Roache et al., 2000; Grabowski et al., 1997). However, since stimulants raise concerns of abuse potential, sustainedrelease preparations or non-stimulant medications effective for ADHD are often rst-line treatments with substancedependent patients. A number of studies in both children and adults suggest that bupropion is effective in treating ADHD (Casat et al., 1987; Barrickman et al., 1995; Conners et al., 1996; Wender and Reimherr, 1990; Wilens et al., 2001) and given its low abuse potential, it may be a viable alternative to stimulant medication for substance-abusing individuals with ADHD (Levin et al., 2002). There are less data regarding what treatments are effective for substance-abusing adults with ADHD. A few open trials suggest that methylphenidate or bupropion may reduce both ADHD symptoms and alcohol/cocaine use (Levin et al., 1998b, 2002; Somoza et al., 2004). It may be that stimulant medications improve cocaine use in adult cocaine abusers

with ADHD through an indirect effect (i.e., improvement in ADHD symptoms leads to less impulsive cocaine use or selfmedication with cocaine) or a direct agonist effect. However, there are little controlled data to support either hypothesis. To date, there has been only one published double-blind placebo controlled, trial in cocaine-dependent individuals with ADHD (Schubiner et al., 2002). This study found that clinicians were more likely to observe notable improvements in ADHD symptoms among those receiving methylphenidate compared to those receiving placebo. However, self-reported ratings of ADHD were not signicantly different between the two groups, and there were no differences in the reduction of cocaine use for the two treatment arms. Thus, the reduction in ADHD symptoms did not alter cocaine use. At present, there are limited controlled data supporting the use of medication for substance abusers with ADHD. Thus, the purpose of this study was to compare the efcacy of sustained-release methylphenidate (MPH), sustainedrelease bupropion (BPR), and placebo in methadonemaintained patients with adult ADHD. Given that early preliminary case reports and open studies suggested that cocaine-dependent individuals with ADHD had reductions in their cocaine use when they were treated with MPH or BPR for their ADHD (Levin et al., 1998b, 2002), the second aim was to determine if active medication treatment reduced cocaine use among those methadone maintenance patients with both adult ADHD and cocaine dependence/abuse.

2. Methods 2.1. Participants Participants were recruited at ve local methadone treatment programs by research staff, using yers posted in the programs and by local advertising. All new and established patients at the methadone clinics were asked to complete two self-report instruments (described below) that were used to identify potential ADHD symptoms in childhood and adulthood. Based on this initial screen, likely candidates were asked to attend a screening visit. All screening participants underwent a detailed medical and psychiatric assessment. The medical screening included a complete history and physical exam, an electrocardiogram and laboratory tests (including hematology, blood chemistry [including liver function tests], thyroid stimulating hormone, and blood pregnancy test for females). The psychiatric evaluation included the structured clinical interview for DSMIV(SCID) Axis I disorders (First et al., 1995) and the antisocial personality module of the structured clinical interview for DSM-IVAxis II disorders (First et al., 1994). Study inclusion required participants to meet DSM-IV (American Psychiatric Association, 1994) criteria for opiate dependence and adult ADHD, to be between the age of 18 and 60, and on the same dose of methadone for at least 3 weeks.

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Participants were excluded if they (1) met DSM-IV criteria for current psychiatric disorders (other than ADHD or substance abuse) which required psychiatric intervention or had a history of an eating disorder; (2) were physiologically dependent on either sedatives or alcohol, such that medical attention was required during periods of abstinence or signicant reduction in amount of use; (3) exhibited suicidal or homicidal behavior within the past 2 years; (4) were taking any prescription psychotropic medications other than methadone; (5) had an unstable medical condition that would make participation hazardous (i.e., uncontrolled diabetes); (6) had a known sensitivity to MPH or BPR; (7) were nursing and/or pregnant; and (8) could not read or understand the self-report assessment forms unaided and/or were so severely impaired they could not comply with the requirements of the study, and were therefore unable to give full and informed consent. All participants gave written informed consent before both the screening and the study procedures. The study was approved by the Institutional Review Boards of the New York State Psychiatric Institute, Columbia University, Long Island Jewish Medical Center, and the Addiction Research and Treatment Corporation. 2.2. Settings Most participants for this project were recruited at several community-based methadone programs in the New York City area. Some individuals were recruited through advertisement and treated at the New York State Psychiatric Institute. Combined, the methadone programs had over 1900 methadone maintenance patients enrolled, 62% were male, 35% were non-Hispanic Caucasian, 25% were Hispanic and 40% were African American, and they also evaluated approximately 70 new patients each month for participation in their programs. 2.3. Study procedures This study was a double-blind, placebo-controlled, randomized, three-arm trial comparing sustained-release MPH, sustained-release BPR and placebo. The trial length was 12 weeks and included a 2-week placebo lead-in phase, a 2-week dose titration period followed by 8 weeks at a stable dose. Because BPR is a large tablet, which cannot t into commercially available capsules, and should not be cut due to its instability (GlaxoSmithKline, personal communication), a double-dummy design was employed. All patients received two capsules and two tablets twice per day, even when maintained on placebo. Following 2 weeks of placebo lead-in, participants were randomized into one of the three arms. Randomization was stratied by site, and by the amount of recent cocaine use (no use, low use as dened as <10 days/month and $200/month spent, and high use as dened as 10 days/month and $200/month spent). Within each site, patients were stratied by gender and ethnicity. Gradual increases in medication doses occurred during a

2-week titration period that was followed by an 8-week maintenance phase when MPH and BPR dosages were held constant. During the titration phase, the standard formulation of MPH was administered twice a day, starting at 10 mg/day. This dose was increased by 10 mg/day, up to 40 mg/day. At this time, the sustained-release formulation replaced the standard formulation and was administered as two 20 mg doses (one in the morning, and one in the afternoon). The dose was then increased to the maximal dose of 80 mg/day, depending on patient tolerance of MPH. Patients who could not tolerate a dose of at least 40 mg/day of MPH were discontinued. BPR (sustained-release formulation) was started at 100 mg/day and increased by 100 mg by the end of the rst week of the titration phase. If tolerated, by the end of the second week, patients received 200 mg in the morning and 200 mg in the afternoon, for the maximum dose of 400 mg/day. Patients who could not tolerate a dose of at least 200 mg/day of BPR were discontinued. BPR was obtained directly from GlaxoSmithKline. Medication dose adjustments were determined by a physician. Folic acid in the form of a 1 mg tablet was added to all placebo capsules in an attempt to improve the blind. Also, after 49 randomized patients, riboavin (approximately 100 mg/day) was added to all capsules in an effort to track compliance. The urine samples obtained three-times a week were examined under an ultraviolet (UV) lamp in order to observe uorescence signifying the consumption of the study capsules. At each of the three weekly visits, participants were asked to provide a urine specimen, complete forms, have their vital signs and side effects assessed, and received medication until their next visit and were compensated $3.00 in cash for transportation costs. All clinical assessments of drug use and ADHD symptoms were conducted on a weekly basis. Monthly blood pregnancy tests for women were collected. All participants attended weekly individual cognitive behavioral therapy. To ensure that all patients receive the same dose of cognitive behavioral therapy, a structured relapse prevention manual designed by Carroll et al. (1994) was used. This manual was modied for use with individuals with ADHD. For example, although completing out-of-session homework assignments are a necessary task in most cognitive-behavioral approaches, it was often times necessary to provide in-session time to complete homework assignments. Also, when a new paradigm for understanding or reducing drug use behavior was presented (e.g., functional analysis, refusal skills) it was necessary to often check in with participants and ensure that they had in fact grasped the new information and were able to use the newly introduced skills. Since most participants had difculties in continuously attending to verbal information, visual diagrams, such as those used in node-link mapping (Dansereau et al., 1995) were often used to ensure adequate training in cognitive-behavioral therapy skills. Sessions were audio-taped to be reviewed during supervision with a seniorlicensed clinical psychologist.

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2.4. Assessments 2.4.1. Screening Participants were asked to ll out two self-report instruments: (1) the Wender Utah rating scale (Ward et al., 1993), and (2) the adult ADHD rating scale (AARS; Murphy and Barkley, 1996). The Wender Utah rating scale is a retrospective self-rating scale developed for adults consisting of 25 questions regarding childhood behaviors. Each item is rated 0 (not at all) to 4 (very much). A total score of 36 was used to indicate the possible presence of childhood ADHD. The AARS is an 18-item self-report questionnaire that represents the most common problems experienced by patients with adult ADHD derived from DSM-IV criteria. Each item is rated on a scale of 0 (not at all) to 3 (severe). The AARS can be scored in several ways, but for this study, we primarily used the total cutoff of 23 to be indicative of possible adult ADHD-like symptoms. If candidates had an elevated score on either the Wender Utah rating scale or the AARS, they were asked to participate in a 34 h clinical interview that primarily involved the administration of the SCID I. To establish a current ADHD diagnosis, the KIDSCID (KSCID), an SCID-like module designed for use in childhood ADHD was modied for use in adult ADHD (Hien et al., 1994). In order to meet criteria for adult ADHD, participants had to meet DSM-IV criteria for childhood ADHD and have persistent ADHD symptoms that occurred from childhood into the present. In addition to the KSCID, the Utah Criteria for ADHD in adults, a semi-structured interview developed by Wender et al. (1985) was also used to identify childhood and adult ADHD. Diagnoses were determined by clinicians who had either a Ph.D., Psy.D. or M.A. degree in Clinical Psychology. The training of the interviewers was extensive and is well described in a previous paper (Levin et al., 1998a). All of the clinicians who carried out the diagnostic assessment for ADHD were part of the research team trained by Dr. Levin who has extensive experience in diagnosing and treating individuals with ADHD. Each clinician was observed while conducting several interviews using the SCID and KSCID module for ADHD. Further, each of the interviewers completed written narratives that were used in supervision with a senior licensed clinical psychologist and were reviewed by the principal psychiatrist (FRL). If there were any questions regarding a diagnostic assessment, these were resolved at the meeting and Dr. Levin would independently evaluate the patient. For the majority of patients enrolled in the study, Dr. Levin obtained the treatment consent and this procedure further ensured that reliable diagnoses were made. A recent drug-use questionnaire was administered at screening to assess patterns of lifetime drug use and recent use during the 30 days prior to evaluation. The addiction severity index was used at baseline to provide composite scores for seven areas of functioning (medical, employment, drug use, alcohol use, illegal activity, family and social relations, and psychiatric status).

2.4.2. Treatment phase Weekly assessments of ADHD symptoms were carried out using the WenderReimherr adult attention decit disorder scale (WRAADDS; Wender et al., 1985), the clinical global improvement scale (CGI; Guy, 1976) for ADHD symptoms, and the AARS. The WRAADDS is a semi-structured interview that consists of the seven target symptoms that are the dening attributes of the Utah Criteria: attention, hyperactivity, temper, mood instability, over-reactivity, disorganization and impulsivity. Anchor points range from 0 (none) to 4 (very much). On a weekly basis, the research psychiatrist rated the severity of the ADHD symptoms on the CGI, as well as any improvement in ADHD symptoms relative to baseline. Severity scores ranged from 1 (no pathology) to 7 (extreme pathology). Improvement scores ranged from 1 (very much improved) to 7 (very much worse). Drug use assessments included a self-report and urine toxicology completed at every visit. Urine samples were tested for cocaine metabolites, opiates, methadone, benzodiazepine, amphetamine and marijuana, and scored as positive or negative based on standard NIDA guidelines for cut-off points (e.g. 300 ng/ml for cocaine). New cocaine use was determined using a method developed by Preston et al. (1998). Using pharmacokinetic criteria applied to quantitative benzoylecgonine concentration data, new use can be distinguished from no new use among cocaine positive urine samples. 2.5. Outcomes Weekly AARS scores were used as the primary ADHD outcome measure. Two outcome measures based on AARS were compared: (1) the proportion of participants in each treatment arm reporting a 30% reduction or more in the AARS from baseline, and (2) the proportion of participants in each treatment group reporting a 30% reduction or more in the AARS and a CGI ADHD rating of less than 3 at the end of study. Two additional instruments were examined to assess ADHD symptoms: (1) total WRAADDS score each week, and (2) CGI ADHD improvement scores that were dichotomized (those achieving an improvement score of 1 or 2 were considered to show clinically signicant improvement). To assess drug use over the course of the 10-week treatment phase following randomization, the proportion of positive weeks using any drugs (opiates, cocaine, marijuana, amphetamine and benzodiazepine) was examined. A week was considered positive for drug use if the self-report indicated any drug use in that week, and/or (1) no urine samples were collected, (2) only one (out of a possible three) urine sample was collected (regardless of toxicology result), or (3) any urine sample out of two or three samples collected tested positive for any drug. The analysis for the proportion of cocaine positive weeks was compared in the same way for the cocaine dependent/abusing subgroup. A urine specimen was determined positive for cocaine, following the method described by Preston et al. (1998). A categori-

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cal response measure (2 or more abstinent weeks) was also compared. 2.6. Data analysis All analyses were carried out on the intent-to-treat population and all tests were two-tailed with the alpha signicance level set at 0.05. Baseline demographic variables and screening measure variables were compared across groups using chi-square for categorical variables and one-factor (treatment) ANOVA for continuous variables. Retention rates across the groups were compared using KaplanMeier survival curves and the log-rank test. Categorical outcome measures were compared between treatment groups using the chi-square statistic and logistic regression. A 30% reduction in AARS was chosen as the primary ADHD outcome measure because it is a clinically meaningful level of improvement and is a standard outcome used in numerous pharmacologic treatment studies that have focused on adults with ADHD (Wilens et al., 1999, 2001; Spencer et al., 1995, 2005). However, a combined outcome measure in which a treatment response is dened as greater than 30% improvement in AARS and a CGI ADHD rating of less than 3 was also used, since it incorporates both self-reported and clinician-rated improvement and has been used in community-based pharmacologic trials with non-substance abusing adults with ADHD (Spencer et al., 1995, 2005; Kooij et al., 2004). Weekly AARS and WRAADDS scores, as well as the drug-use outcomes (any drugs, cocaine), were further analyzed using general estimating equations (GEE, as implemented by SASs PROC GENMOD), with the outcome modeled as a function of time, treatment assignment, time by treatment interaction, and a baseline covariate of the outcome variable. Given baseline differences in employment, we also entered employment status (employed/not employed) as a factor in the model to examine the effect of employment status on the outcome and possible interactions with treatment condition.

issue (knee surgery) and two were dropped because of side effects (see Section 3.8). The other ve individuals dropped because they were either non-compliant, no longer interested or leaving treatment at their methadone clinic. In the MPH group, four patients were no longer interested in participating, one was dropped because of side effects (see Section 3.8), two left their methadone clinics to enroll in drug detoxication programs, three were incarcerated, and one was removed from the protocol because he had under-reported his benzodiazepine use at baseline. In the BPR group, three patients were no longer interested in participating, three were dropped because they were non-compliant, three were removed because of psychiatric problems (depression, mood instability and one decided to be treated for ADHD elsewhere), and one left to attend a drug detoxication program. No differential attrition was observed. 3.2. Baseline demographic, clinical characteristics and treatment retention Table 1 summarizes the results of baseline comparisons among the three treatment arms for the 98 participants randomized. Other than current employment status, no signicant group differences were detected in terms of demographics, baseline ADHD symptoms, substance abuse or psychiatric characteristics. With respect to current employment status, more patients were employed in the BPR group compared to the MPH and placebo groups (placebo = 43%, MPH = 58%, BPR = 89%; 2 = 13.56, p = 0.001, df = 2). Although a minority of patients had been enrolled in the methadone maintenance programs for less than 12 weeks (34%), the majority had been enrolled for more than 6 months (58%), with the mean time on methadone maintenance in their current program being 24 months (29 months). Sixty-nine participants completed the 12-week trial (71%) and time-to-event analysis revealed no group differences with respect to retention (Log-Rank 061, p = 0.74, df = 2); 76% (25 out of 33) of the placebo group, 66% (21 out of 32) of the MPH group, and 70% (23 out of 33) of the BPR group, completed the study. Baseline demographic characteristics for the cocaine-using subgroup did not differ across groups except for current employment status (placebo = 32% (6/19), MPH = 62% (8/13), BPR = 100% (15/15); 2 = 16.61, p < 0.001, df = 2). Pattern of cocaine use at baseline among the cocaine using subgroups did not differ across groups (see Table 1). 3.3. Compliance Compliance was good as measured by self-reported medication compliance and by three-times per week riboavin uorescence testing. The mean proportion of self-reported missed doses did not differ between the three groups, with each group missing about 5% of their doses (F(2,95) = 0.003, p = 0.997). For the patients for whom riboavin data were available (n = 49), the proportion of positive uo-

3. Results 3.1. Participant ow A total of 2715 methadone patients were screened with the AARS and WURS, and of those, 526 individuals reported ADHD-like symptoms and agreed to a screening interview. Fig. 1 outlines the patient ow during the screening process and throughout the randomized trial. One-hundred and fteen individuals met inclusion/ exclusion criteria and entered the study. Ninety-eight participants completed the placebo lead-in and were randomized to one of three treatment arms. Following randomization, in the placebo group, one individual was removed from the protocol because of a pre-existing unrelated medical

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Fig. 1. Participants progress through the screening, entry, randomization and medication phases of the treatment trial.

rescence results indicated that compliance did not differ across groups (placebo = 0.83, MPH = 0.77, BPR = 0.91; F(2,46) = 0.94, p = 0.40). Throughout the 5-year period in which this study was conducted, there were no reports from the counsellors, other clinical staff, or patients that study medication was being diverted. Importantly, none of the patients reported that the medication made them feel high or euphoric. 3.4. ADHD symptoms outcome As can be seen in Table 2, a substantial proportion of patients met the standard response criterion of at least a 30% reduction in the AARS (placebo 46%, MPH 34%, BPR 49%; 2 = 1.46, p = 0.48, df = 2), or the alternate criterion of a CGI ADHD improvement score of 1 or 2 (placebo 39%, MPH 19%, BPR 30%; 2 = 3.34, p = 0.19, df = 2). Using the combined outcome measure of at least a 30% reduction in AARS and a CGI ADHD rating of less than 3 at end of study,

the placebo response rate was substantially lower than the AARS measure alone (21% versus 46%) but there remained no signicant group differences (placebo 21%, MPH 9%, BPR 15%; 2 = 1.76, p = 0.42, df = 2). Odds ratios and 95% condence intervals were obtained from tting a logistic regression with the dichotomous outcome based on a 30% reduction in the AARS as the dependent measure and treatment assignment as the predictor. The odds of achieving a 30% reduction in AARS were greater in the BPR group than in the placebo group but not signicantly (odds ratio = 1.28, 95% CI = 0.48 to 3.37), while the odds were lower for the MPH group compared to placebo group, again, not signicantly (odds ratio = 0.53, 95% CI = 0.191.50). Using the combined AARS and CGI outcome measure, the odds of treatment response were lower in both active arms than in the placebo arm, but not signicantly (odds ratio BPR versus placebo = 0.66, 95% CI = 0.192.35; odds ratio MPH versus placebo = 0.38, 95% CI = 0.091.64).

F.R. Levin et al. / Drug and Alcohol Dependence 81 (2006) 137148 Table 1 Baseline demographic and clinical characteristics of randomized methadone maintenance patients with ADHDa Placebo (n = 33) Demographics Age (years) Male Race Black Hispanic White Education (years) Currently married Currently employedb Average income Meth. dose (mg) ADHD WURS AARS ADHD CGI severity WRAADS Current substance use disordersc Alcohol Marijuana Cocaine Opiate Psychiatric disorders Current Affective Anxiety Lifetime Affective Anxiety Pattern of drug use of cocaine users (n) Agerst use Ageregular use Use (in days)last 30 days Total amount spentlast 30 days Route Inhale IV Smoke
a

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MPH (n = 32) 40 (6) 19 (59%) 7 (22%) 13 (41%) 12 (37%) 12 (3) 7 (21%) 18 (58%) $19157 ($13972) 83 (23) 58.60 (18.74) 33.00 (11.40) 5.2 (0.82) 19.22 (3.55) 7 (22%) 5 (16%) 13 (41%) 15 (47%)

BPR (n = 33) 38 (8) 19 (66%) 6 (18%) 13 (39%) 14 (42%) 12 (2) 8 (24%) 25 (89%) $21866 ($13927) 87 (37) 60.40 (19.10) 33.24 (11.10) 5.0 (0.92) 19.76 (4.20) 5 (15%) 8 (24%) 18 (54%) 17 (51%)

2 or F, p 0.52, 0.59 0.16, 0.92 0.23, 0.99

d.f. 2, 95 2 4

39 (8) 18 (55%) 7 (21%) 13 (39%) 13 (39%) 12 (3) 3 (9%) 13 (43%) $20700 ($15675) 81 (37) 61.21 (21.90) 34.61 (11.70) 5.3 (0.70) 20.18 (3.84) 5 (15%) 5 (15%) 21 (64%) 20 (61%)

0.37, 0.69 2.92, 0.23 13.60, 0.001 0.15, 0.86 0.27, 0.76 0.14, 0.86 0.20, 0.82 1.66, 0.19 0.50, 0.61 0.68, 0.71 1.15, 0.56 3.50, 0.17 1.28, 0.53

2, 95 2 2 2, 46 2, 92 2, 95 2, 95 2, 95 2, 95 2 2 2 2

6 (18%) 7 (21%) 11 (33%) 1 (3%) 21 21 (7) 26 (7) 12 (11) $505 ($568) 8 (38%) 4 (19%) 9 (43%)

5 (16%) 4 (12%) 11 (34%) 4 (12%) 13 19 (5) 26 (5) 14 (10) $537 ($762) 3 (23%) 6 (46%) 4 (31%)

6 (18%) 6 (18%) 9 (27%) 1 (3%) 18 20 (5) 24 (8) 14 (11) $575 ($573) 5 (28%) 2 (11%) 11 (61%)

0.098, 0.95 0.884, 0.64 0.44, 0.8 0.28, 98c 0.35, 0.70 0.34, 0.72 0.35, 0.71 0.05, 0.95 0.21, 52d

2 2 2

2, 49 2, 48 2, 49 2, 43

Data obtained during screening for trial prior to initiation of any study procedures. Values in the table are N (%) for categorical variables, or mean (S.D.) for continuous variables. b Dened as fulltime or part-time employment, student or in military service. c Subjects either abuse or are dependent. d Fisher exact test showing p-value, n.

Table 2 ADHD treatment response in randomized methadone maintenance patients with ADHDa Placebo (n = 33) AARSb CGIc AARS + CGId
a b c d

MPH (n = 32) 34% (11) 19% (6) 9% (3)

BPR (n = 33) 49% (16) 30% (10) 15% (5)

2 , p 1.46, 0.48 3.34, 0.19 1.76, 0.42

d.f. 2 2 2

46% (15) 39% (13) 21% (7)

Values in the table are percent (N). Responders are those participants that report >30% drop in AARS scores at end of study compared to baseline. Responders are those participants that achieve a CGI ADHD improvement rating <3 at end of study. Responders are those participants that report >30% drop in AARS scores and a CGI ADHD rating <3 at end of study.

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Fig. 2. Mean AARS scores over 10-week treatment phase.

Time-course analysis of AARS using GEE yielded signicant effects of time (improvement in scores over time, Z = 3.80, p = 0.0001) and baseline score (baseline values highly correlated with values of outcome, Z = 5.21, p < 0.0001), but no effect of treatment and no interaction of treatment by time. Employment status was marginally signicant (Z = 1.89, p = 0.06), with subjects who were unemployed observing a greater decrease in AARS severity than those employed. Fig. 2 plots the predicted mean response over time for the three treatment arms. On average, AARS severity reduced by 21% for the placebo group, compared to 24% of the BPR group and 12% for the MPH group, with no statistically signicant differences among the groups. These ndings were paralleled in the analysis of the WRAADDS total scores, which also showed signicant time and baseline covariate effects but no treatment effects. Secondary analyses were conducted to explore whether baseline level of ADHD severity inuenced response rates. When the participants were analyzed based on ADHD severity at baseline (using a median split with a cutoff of 32 on the AARS), no signicant differences were observed across the groups for those with low baseline ADHD severity and those with high baseline severity, conrming no baseline by treatment interaction. 3.5. Substance use outcome The proportion of weeks positive for any drug was high during the treatment phase of the trial (above 0.90, Table 3)

across all three treatment groups with no signicant differences among the groups (F(2,92) = 0.79, p = 0.46). Ten patients achieved two consecutive weeks of abstinence during the treatment phase of the trial (ve patients in the placebo group, three in the MPH group, and two in the BPR group). Logistic regression of the any drug use outcome (1 if week is positive, 0 otherwise) using GEE did not reveal signicant differences across the groups in the likelihood of observing a drug positive week, although during the rst three weeks, all three treatment groups increased use of drugs. The proportion of weeks positive for opiates was 0.41 for the placebo group compared to 0.34 for the MPH group and 0.38 for the BPR group (F(2,92) = 0.37, p = 0.72). Subgroup analysis of current cocaine abusing/dependent patients (n = 52) similarly revealed large proportions of cocaine positive weeks (above 0.85) with no signicant differences among treatment arms (F(2,47) = 0.17, p = 0.84). For current cocaine abusing/dependent individuals, only seven patients achieved 2 weeks of cocaine abstinence at any point during the trial (placebo 3, MPH 2, BPR 2). GEE analysis of the cocaine use outcome (week positive/negative for cocaine) using logistic regression did not identify signicant differences in the likelihood of observing a cocaine positive week over the course of the treatment. 3.6. Analysis of other outcome measures Other outcome measures were assessed for the three treatment arms. These included: adherence to methadone maintenance and severity of various problem areas (e.g., social, legal, family) as assessed by the Addiction Severity Index. None of the three treatment arms were shown to be superior based on these outcome measures (data not presented). All three groups self-reported being adherent to their methadone maintenance over 96% of the days while in the trial. This was conrmed with over 98% of their urine samples testing positive for methadone. 3.7. Analysis of moderators To explore whether treatment effects might reside within clinically relevant subgroups of patients, we examined the

Table 3 Drug use outcome in randomized methadone maintenance patients with ADHD during 10-week treatment phasea Placebo (n = 33) Any drug use Proportion of positive weeks for any drugb Percent with 2 or more abstinent weeks 0.91 (0.09) 15% (5) Placebo (n = 21) Cocaine use Proportion of positive weeks for Cocaineb Percent with 2 or more abstinent weeks
a b

MPH (n = 32) 0.94 (0.08) 9% (3) MPH (n = 13) 0.86 (0.25) 15% (2)

BPR (n = 33) 93 (0.08) 6% (2) BPR (n = 18) 0.91 (0.23) 11% (2)

F or 2 , p 0.79, 0.46 1.48, 0.48 F or 2 , p 0.17, 0.84 0.11, 0.95

d.f. 2, 92 2 d.f. 2, 47 2

0.86 (0.28) 14% (3)

Values are mean (S.D.) or percent (N). No data was available during the treatment phase for four subjects (out of 98) for the any drug use measure, and data on two subjects (out of 52) was missing for the cocaine using subgroup.

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following variables as moderators of treatment effects: presence/absence of employment, presence/absence of comorbid affective or anxiety disorder; presence/absence of antisocial personality disorder; presence/absence of cocaine use at baseline; severity of ADHD (baseline AARS score); and days per week using any drug at baseline. The effect of each moderator was explored using categorical response (>30% reduction in AARS) as the outcome of a logistic regression with treatment and moderator as categorical predictors. No signicant differences in treatment response were detected when groups were compared based on employment status (treatment by employment interaction, 2 = 0.04, p = 0.98, df = 2), although participants not currently employed had higher treatment response in all three arms. Thirty-two percent of those currently employed attained a 30% improvement in AARS, with no signicant differences between the three treatment arms (31% placebo, 17% methylphenidate, 44% bupropion; 2 = 3.6, p = 0.17, df = 2). For those participants not currently employed, 49% attained an improvement (53% placebo, 38% methylphenidate, 67% bupropion; 2 = 1.05, p = 0.59, df = 2). Logistic regression examining the effect of affective and/or anxiety disorder on treatment revealed no signicant treatment by comorbidity interaction effect (2 = 3.63, p = 0.16, df = 2). Within the subgroup with affective/anxiety disorder, greater response rates were observed for methylphenidate (33%) and bupropion (45%) than placebo (17%) (2 = 2.24, p = 0.33, df = 2). For the subgroup without affective/anxiety disorder, methylphenidate had lower response (26%) than either bupropion (50%) or placebo (57%) (2 = 4.79, p = 0.09, df = 2). None of these differences were signicant (including presence/absence of antisocial personality disorder; cocaine use at baseline; severity of ADHD (based on baseline AARS score); and days per week using any drug at baseline). 3.8. Safety Side effects were rated on a scale of 03 (0 = none, 1 = mild, 2 = moderate, 3 = severe). Only side effects rated moderate or severe were included in the analysis. A variety of side effects were reported across all three groups but there were no signicant group differences. The most frequently reported side effects were fatigue (placebo group, 9%) and increased sweating (MPH group, 6% and BPR group, 9%). A total of three patients were removed from the trial because of reported side effects. One individual was removed from the placebo group because of nosebleeds in the absence of hypertension. Another individual in the placebo group reported fatigue. Her dose was lowered but she subsequently was dropped because the side effect persisted. A patient in the MPH group complained of psychomotor agitation. His dose was lowered, but because he was unable to tolerate at least 40 mg/day, he was removed from the trial. Four other individuals had their doses lowered (three in the MPH group, one in the BPR group). All four were able to continue in the trial. No group differences were observed with respect to side effects.

4. Discussion The results of this study do not support an advantage of sustained-release MPH or sustained-release BPR over placebo for the treatment of adult ADHD in methadonemaintained patients. Further, for those methadonemaintained patients who concurrently abused cocaine and received active medication, there was no differential improvement in drug use. Although, one small study (n = 48) found that MPH was superior to placebo for cocaine-dependent individuals with ADHD using physician-rated indices (Schubiner et al., 2002), similar to this current trial, those patients receiving MPH did not demonstrate a greater reduction in self-reported ADHD symptoms, cocaine use or positive urinalysis results. Thus, the hypothesis that MPH might exert a direct agonist effect resulting in a reduction of cocaine use was not supported. This is consistent with prior ndings with MPH in cocaine-dependent patients without ADHD (Grabowski et al., 1997), but contrasts recent studies that have found that high doses of dextroamphetamine might reduce cocaine use in cocaine-dependent individuals without ADHD (Grabowski et al., 2001, 2004; Shearer et al., 2003). This current trial is the rst double-blind, placebocontrolled trial evaluating pharmacologic agents for methadone-maintained patients with ADHD. However, consistent with other trials in which stimulants have been given to cocaine-dependent individuals (Grabowski et al., 1997, 2001, 2004; Schubiner et al., 2002; Shearer et al., 2003), there was no evidence of abuse. The medications were well tolerated without untoward side effects. There are several possible explanations for why the results from this trial were negative. First, the placebo response rate using the AARS outcome measure was high. Forty-six percent of the placebo group had a 30% improvement in symptoms on the AARS which is substantially higher than placebo response rates in pharmacologic trials conducted in non-substance abusing populations (Wilens et al., 1996, Wilens et al., 1999, 2001), and would make the detection of a medication effect less likely. One factor that might have led to an abnormally high placebo response rate was that the placebo group had a higher unemployment rate than those randomized to the MPH and BPR groups. One might expect that individuals who are not working might have fewer opportunities to experience the consequences of ADHD-related problems, such as not paying attention to details or completing work. This in turn might lead to the placebo groups overestimation of their improvement in their ADHD symptoms. However, the majority of individuals in each treatment arm met criteria for adult ADHD, combined type. Therefore, there were numerous symptoms that led to dysfunction outside of the work setting, particularly for methadone-maintained patients who have to arrive on time for appointments, sit still during therapy sessions, or wait patiently. Improvement of these types of symptoms might be accurately assessed outside of work situations.

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Unlike numerous studies conducted in non-substance abusing adult ADHD populations, all three treatment arms in this study had similar response rates (with the MPH response lower than both placebo and BPR, although not signicantly). It may be that chronic drug use caused symptoms mimicking ADHD, and therefore, improvement in ADHD symptoms might have been a function of time and possibly reduced drug use rather than improvement of underlying ADHD symptoms in response to specic medication treatment. Mitigating this possibility is the fact that the diagnosis of ADHD is not made based on current symptomatology alone, and requires the persistence of childhood symptoms into adulthood, and has been made reliably and in other samples of substance abusers (Schubiner et al., 2000, 2002; Clure et al., 1999). Another possible explanation for a similar improvement in ADHD symptoms in all three treatment arms is that patients treated within methadone programs might be more likely to want to please staff, even research staff, and therefore, might have over-endorsed the improvement in their ADHD symptoms. Whereas the AARS outcome measure led to a high placebo response rate, using the combined AARS and CGI ADHD outcome measure led to a placebo response rate comparable to the rate found in a recently conducted pharmacologic study with non-substance-abusing adults with ADHD (21% versus 19%; Spencer et al., 2005). Still, this lower placebo response rate did not lead to detection of medication effects. Furthermore, for both outcome measures, the 95% condence intervals of the odds ratios were wide, implying that the odds ratio estimates are not precise and that inadequate sample size and low statistical power might be factors contributing to the negative ndings. Substance abusers may be less responsive to standard medication treatments for ADHD, possibly because of past or current prolonged exposure to multiple drugs, and this may have contributed to the lack of a medication effect. In this patient population, the vast majority continued to abuse substances. It may be that substance abusers with ADHD required higher doses of stimulants (or non-stimulants) to obtain a therapeutic benet than those used in this trial. Further, the older, sustained-release formulation of MPH has been found to be less effective in treating ADHD than newer, long-acting formulations (Markowitz et al., 2003; Swanson et al., 2003) and this may have contributed to the blunted treatment response. Medication noncompliance may have also contributed to the lack of therapeutic benet from either MPH or BPR. However, patients were fairly compliant, as measured by riboavin uorescence testing and by self-reported medication compliance, as well as good treatmentretention rates. Further, few patients requested a reduction or discontinuation of medication because of intolerable side effects. Although we cannot be sure that all of the medication was taken as prescribed and that some diversion of medication did not occur, the investigators had a longstanding presence at the clinics

and would have been likely to hear about diversion and abuse through counsellors or other patients. Another reason to explain the poor medication response rates might be the additional psychiatric comorbidities. Similar to the Schubiner et al. (2002) trial with cocainedependent adults with ADHD, concomitant anxiety disorders and substance-induced mood symptoms were common. In this study, there is some suggestion that among individuals with comorbid anxiety and/or depression, the individuals receiving active medication, and particularly BPR, had greater improvement in their ADHD symptoms than those receiving placebo although the effect did not reach statistical signicance. A power analysis found that a total sample of 146 might detect signicant differences in the proportions for the three groups, given the observed response rates and estimates of variability. Why there was a lower placebo response rate among those with additional Axis I comorbidities compared to those with no additional Axis I disorders remains unclear. There are mixed data regarding whether childhood ADHD and comorbid psychiatric disorders are less responsive to stimulants (Pliska, 1992; Wozniak and Biederman, 1996; Jensen et al., 2001), but to our knowledge there are no studies demonstrating that children or adults with ADHD and additional Axis I comorbidities do better on stimulants or other ADHD treatment medications than those with no additional psychiatric disorders. One explanation why adult substance abusers with comorbid psychiatric disorders may have had a lower placebo response rate is that they experienced greater distress and were less likely to overestimate their clinical improvement in ADHD symptoms, unless there was a true medication effect. Alternatively, there may be another underlying variable that produced a lower placebo response rate in this subgroup of patients. The current study does not provide clear support for the use of BPR or MPH for methadone-maintained patients. Using the AARS measure alone, there was a higher placebo response rate and lower medications response rates than other controlled studies conducted with ADHD adults (Wilens et al., 1999, 2001; Spencer et al., 1995, 2005). Alternatively, using the combined AARS and ADHD CGI outcome measure, the placebo rate was comparable to a recently published large study with non-substance abusing adults (Spencer et al., 2005) but the MPH medication group response rates was substantially lower (Spencer et al., 2005). Even though there were no improvements in cocaine use based on treatment arm, there was no evidence of medication misuse or untoward side effects. Future trials might consider using higher doses of medication, particularly newer, possibly more effective, long-acting stimulant formulations. Also, outcome measures that use more objective behavioral targets (e.g., work performance) or other targets that do not depend on employment (e.g., timely attendance at groups, feedback from counselling staff). Despite the fact that substance abusers with ADHD are a particularly impulsive group, and can be difcult to recruit for treatment of their ADHD (King et al., 1999), the retention rates in this study were good and

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comparable to rates obtained in other pharmacologic treatment trials with methadone-maintained patients (Nunes et al., 1998; Petrakis et al., 1998; Kosten et al., 1992). Because of the small sample size and the focus on methadone-maintained patients, the generalizability to other substance-abusing populations needs to be approached cautiously.

Acknowledgements This research was supported by NIDA grants R01 DA00144 and KO2 00465 and K02 DA00288. We want to thank the staff of Bridge Plaza Methadone Clinic, the Addiction Research and Treatment Corporation program, and the Long Island Jewish Medical Center methadone program, specically, Drs. Brady, Primm, Brown, Seltzer, Ms. Edwards and Ms. Chu for their support in facilitating the work for this project. We also wish to thank Ramon Barrameda, Pamela Donaldson, Maria Grotz, Carol Klimpchek and Carol Russo for nursing support and Ron Aviram and Amy Mahony for their clinical support. Dr. Levin is a consultant for Eli Lily and Company, Shire Pharmaceuticals Group, and Ortho-McNeil Pharmaceutical Inc. Also she has investigator-initiated grants with Eli Lily and Company and UCB Pharma Inc.

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