Randomized Controlled Pilot Trial of Cabergoline, Hydergine and Levodopa/Carbidopa: Los Angeles Cocaine Rapid Efficacy Screening

100•••• Original Article Cabergoline, hydergine, levodopa/carbidopa Steven Shoptaw et al. RESEARCH REPORT

Randomized controlled pilot trial of cabergoline, hydergine and levodopa/carbidopa: Los Angeles Cocaine Rapid Efﬁcacy Screening Trial (CREST)

Steven Shoptaw1, Donnie W. Watson2, Chris Reiber1, Richard A. Rawson1, Margaret A. Montgomery3, Maria D. Majewska3 & Walter Ling1 UCLA Integrated Substance Abuse Programs, Los Angeles, CA1 , Friends Research Institute, Inc., Los Angeles, CA2 and National Institute on Drug Abuse, Division of Treatment Research and Development, Bethesda, MD, USA3

Correspondence to: ABSTRACT Steven Shoptaw PhD UCLA/Integrated Substance Abuse Programs Aim This study tested three dopaminergic medications against a common 11075 Santa Monica Blvd unmatched placebo condition: hydergine 1 mg three times daily (n = 15); Suite 200 levodopa/carbidopa 25/100 mg three times daily (n = 15); cabergoline 0.5 mg Los Angeles per week (n = 15); and placebo three times daily (n = 15) as potential pharma- CA 90025 USA cotherapies for cocaine dependence. E-mail: [email protected] Design The four-parallel group, Cocaine Rapid Efficacy Screening Trial (CREST) design featured a 2-week baseline period followed by randomization to an 8-week medication condition that included 1 hour per week of cognitive RESEARCH REPORT behavioral drug counseling. A safety evaluation was conducted 4 weeks after termination. Measures Outcomes included cocaine metabolites measured in urine, retention and self-reports for drug use, cocaine craving, clinical improvement, mood and HIV risk behaviors. Results Participants assigned to receive cabergoline provided more urine samples negative for cocaine metabolites (42.4%) than those assigned to receive placebo (25.0%), a statistically significant difference after controlling for baseline differences in self-reported cocaine use (F = 2.95, df = 3; P = 0.05). Cabergoline- treated participants demonstrated a significant improvement over placebo from baseline to week 8 when measured using the Addiction Severity Index (ASI) employment subscale (overall change = - 0.09, SD = 0.10, t = 2.36, P < 0.05). Safety and adverse event measures showed similar rates and types of complaints by treatment condition. Conclusions These results, combined with the apparent safety of cabergoline when used with this population, provide empirical support for conducting a larger study of the medication.

KEYWORDS Cabergoline, cocaine, hydergine, levodopa/ carbidopa, out-patient.

INTRODUCTION the nucleus accumbens are part of a cascade that com- prises the brain’s reward circuitry (see Self & Nestler Cocaine produces multiple effects on the brain and the 1995). Substances including opiates, ethanol, nicotine relationship of these to the development of cocaine depen- (Calabresi et al. 1989; Nisell et al. 1994; Pontieri et al. dence is not entirely understood. It is known that dopam- 1996) and cannabinoids (Chen et al. 1990) also indirectly ine neurons in the ventral tegmental area that project into cause release of dopamine from the ventral tegmental area

Cabergoline, hydergine, levodopa/carbidopa 79

(Imperato & DiChiara 1986; Leone et al. 1991; Johnson & itary adenomas (Colao et al. 2000), and in the control of North 1992). Cocaine acts to inhibit the uptake of dopam- clinical and hormonal features of dopamine-sensitive ine after its release into the synapse, thereby increasing acromegalic patients (Muratori et al. 1997). Among synaptic dopamine at the nucleus accumbens. humans, cabergoline improves motor functions damaged Medications that modify dopamine neurotransmitter by Parkinson’s disease when used alone or in combination levels should alter cocaine use in humans (see Jentsch with L-dopa in a dose-related fashion (Inzelberg et al. & Taylor 1999). Laboratory rats self-administer both 1995; Ahlskog et al. 1996; Hutton et al. 1996; Steiger et al. amphetamine (Hoebel et al. 1983) and dopamine (Dwor- 1996) and relieved Parkinsonian symptoms in mon- kin et al. 1986) directly into the nucleus accumbens. keys with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine- Bilateral injections of dopamine receptor antagonists into induced nigrostriatal depletion (Calon et al. 2000). These the nucleus accumbens or lesions of the ventral tegmen- reports indicate that cabergoline is efficient in ameliorating tal area neurons that project to the nucleus accumbens disorders associated with dopamine deficiency and hence attenuate the reinforcing effects of cocaine (Dworkin et al. is an appropriate candidate for this screening trial. 1988); yet these same dopaminergic medications, when evaluated in treatment-seeking, cocaine-dependent Levodopa/carbidopa humans, show no effects in altering cocaine use. As yet there is no consistent evidence that dopaminergic medi- Levodopa/carbidopa (Sinemet®) is an approved medica- cations reduce cocaine use when evaluated in placebo- tion for the treatment of symptoms of Parkinson’s disease. controlled, randomized trials (Ling & Shoptaw 1997, de Levodopa is a precursor of dopamine and increases the Lima et al. 2002). store of available central dopamine in dopamine-deficient The slate of approved medications with dopaminergic individuals (Cotzias et al. 1969). Carbidopa is a decarbox- activity has yet to be completely studied. Hence, to study ylase inhibitor that acts peripherally to prevent degrada- dopaminergic medications previously untested for tion of levodopa, thereby increasing efficiency of central cocaine dependence, the Los Angeles site for the Clinical dopamine availability. In theory, the dopamine precursor Rapid Efficacy Screening Trial (CREST) program funded action of levodopa/carbidopa may allow for a more rapid by the National Institute on Drug Abuse evaluated three return to natural dopamine levels following cocaine dis- agents compared to a common placebo condition for continuation. An early placebo-controlled, randomized their ability to reduce cocaine use: cabergoline 0.5 mg study of 30 cocaine-dependent participants appearing at once weekly (Dostinex®, a long-acting dopamine receptor an emergency room within 24 hours of their last use of agonist that acts postsynaptically), levodopa/carbidopa cocaine reported no statistically significant differences in 25 mg/100 mg three times daily (Sinemet®, a dopamine ratings of ‘crash’, ‘depression’, ‘anergia’ or ‘craving’ precursor that increases dopamine concentrations pre- when treated using 400 mg levodopa and 100 mg carbi- synaptically) and hydergine 1 mg three times daily (a dopa or placebo (Wolfsohn et al. 1993). Although there mixed dopamine agonist and antagonist). are no published reports of outcomes using levodopa/carbidopa with cocaine-dependent individuals, its ability to alter dopamine availability make this medication another Evidence supporting these medications appropriate candidate for the screening trial.

Cabergoline Hydergine Cabergoline (Dostinex®), a medication with a half-life of 63–69 hours, is approved for treating Parkinson’s disease Hydergine enhances cognition and improves memory and hyperprolactinemia. Cabergoline binds to D2 dopam- in patients with dementia (Thienhaus et al. 1987; ine receptors in the pituitary, which in turn may account Schneider & Olin 1994). In addition, hydergine is thought for its inhibition of prolactin secretion and its use as a to increase cerebral glucose metabolism in the cortex prolactin-lowering agent (Webster et al. 1994). Although (Nagasawa et al. 1990), to improve cognitive deficits and there are no published reports on the use of cabergoline as mood symptoms in elderly patients (Rouy et al. 1989), to a cocaine pharmacotherapy, bromocriptine, another D2 improve sleep and depression in ethanol-related enceph- dopamine receptor agonist, reduced ratings of cocaine alopathy (Datta et al. 1987) and to maintain physical and craving among cocaine-dependent individuals in a double- mental health among healthy individuals (Huber et al. blind, placebo-controlled study (Dackis et al. 1987). 1986). Hydergine enhances cerebral blood flow by caus- Cabergoline is superior to bromocriptine in efficacy and ing vasodilation and its properties as a mixed agonist/ tolerability, and may be regarded as the treatment of choice antagonist at postsynaptic D1 receptors and pre- and for hyperprolactinemic disorders, either idiopathic postsynaptic D2 receptors may account for its ability to (Webster et al. 1993, 1994; Webster 1999) or due to pitu- correct monoamine disturbances in the central nervous

80 Steven Shoptaw et al. system (Goldstein 1985; Markstein 1985). There are no ications for cocaine dependence. Interested individuals published reports of prior use of hydergine with human telephoned a toll-free number and scheduled an intake cocaine-dependent individuals. The activity of hydergine appointment to meet with a counselor to discuss the at selective dopamine receptor sites also makes this treatment research and meet with a study physician to medication appropriate for screening. conduct the consent process. The design for the CREST paradigm features multiple active medication conditions and a common placebo to Clinical trial phase support efficient safety and efficacy evaluations. The CREST objective was to determine whether any of the The study employed a flexible 2-week, non-medication screened medications demonstrated sufficient safety and screening period followed by an 8-week medication efficacy compared to placebo to invest resources for con- phase. After providing informed consent, participants ducting larger, adequately powered trials. We predicted were scheduled to return to clinic on each Monday, that participants in the experimental conditions would Wednesday and Friday. For up to 4 weeks during the demonstrate superior reductions in their cocaine use screening period, participants attended clinic to complete when compared to those assigned to receive placebo. safety visits, complete questionnaires and provide urine samples. The screening period was flexible, to allow participants up to 4 weeks to gather two urine samples pos- METHODS itive for cocaine metabolite and 2 reported days of cocaine use within a single 2-week period. Once cleared to receive Participants medication by the study physician, randomization occurred. At the randomization visit, participants Participants were 60 out-patients seeking enrollment in a ingested the first dose of study medication under direct study of experimental medications for cocaine depen- observation of the research pharmacist. Afterwards, par- dence. All participants met these inclusion criteria: (1) ticipants attended individual counseling sessions (30 current cocaine dependence verified by the Structured minutes each) on two of the 3-weekly study visits. During Clinical Inventory for the Diagnostic and Statistical Manual the medication phase, participants returned to clinic version IV (DSM-IV) (SCID); (2) two substantiated epi- thrice weekly to monitor their physical safety, to provide sodes of cocaine use in a 2-week baseline period; (3) seek- urine samples, to receive counseling, to conduct a pill ing treatment for cocaine dependence; (4) if female and of count and to complete questionnaires. Participants con- childbearing potential, used reliable birth control meth- tinued in the study for 8 weeks following randomization ods; and (5) access to sufficient resources to attend clinic (n = 31). Participants were discontinued early if they reliably (e.g. bus/car, working telephone number). Partic- missed four consecutive clinic visits (n = 29). At the end of ipants met none of the exclusion criteria: (1) concurrent the eighth week (or in the case of early termination), par- dependence upon substances other than cocaine, nico- ticipants completed a physical examination, with safety tine or caffeine as verified by the SCID; (2) participation in laboratory values and electrocardiograms (ECGs), to pro- a clinical trial in the past 30 days; (3) medical conditions vide additional safety information. A follow-up visit was that would preclude safe study participation or that conducted 30 days after the last clinic visit to verify the would alter metabolism or excretion of study medica- general medical status of participants. tions; (4) psychiatric conditions that required medical or behavioral intervention; (5) recent therapy (past 60 days) with any opiate substitution; (6) suicide risk; (7) Psychosocial counseling known sensitivity to hydergine, levodopa/carbidopa or The manual-driven psychosocial protocol provided a cabergoline; and (8) history of asthma or seizures. behavioral counseling platform upon which to conduct the medication evaluations. The cognitive behavioral Procedures program used (Brief et al. 1998) teaches individuals to identify and eliminate triggers associated with drug All procedures conducted during this study were relapse, to cope with cravings, to increase and maintain reviewed and approved by the Long Beach Research motivation and commitment to stop, to refine problem Foundation Human Subjects Protection Committee. solving, to emphasize drug refusal skills and to adopt a general coping plan. Prior to the start of the study, the therapist for the study (master’s level) received 2 days of Recruitment training by the intervention developers in the model. To Potential participants were recruited using newspaper maintain adherence to the intervention model, all ses- and radio advertisements of a study of experimental med- sions were videotaped and reviewed during a weekly

Cabergoline, hydergine, levodopa/carbidopa 81 supervision session with a master’s level supervisor. On Urine drug screens. Urine samples were collected on average, participants attended 7.5 counseling sessions each Monday, Wednesday and Friday during the study. (SD = 4.2) over the 8 weeks, with no statistically signifi- All samples were monitored using temperature strips cant differences between conditions. with samples required to register 92∞ to 96∞ F upon delivery to the research assistant to be considered valid. Samples were analyzed for the presence of benzoylec- Medication procedures gonine (BE; the metabolite of cocaine) using immu- All three of the active study medications were delivered in noassay techniques by North-west Toxicology with their commercially available form. Doses delivered and quantitative levels calculated using standard dilution to the number of participants in each medication conditions an upper limit of 150 000 ng/ml BE. Once weekly, a were: (1) hydergine 1 mg three times daily (n = 15); urine sample was analyzed for metabolites of marijuana, levodopa/carbidopa 25/100 mg three times daily opiates, benzodiazepines and amphetamines, also using (n = 15); cabergoline 0.5 mg per week (n = 15); and pla- immunoassay. cebo three times daily (n = 15). The placebo tablets were different in appearance from any of the three active study Retention. Retention in the trial was measured as the medications. Participants were asked during the consent number of clinic visits attended following randomization. process to refrain from identifying their medications using reference texts or other methods. In order to max- Self-report of substance use. Self-report of substance use imize protection of the modified blind in the clinic, per- and associated life-style behaviors were measured using sonnel charged with administering and counting the Addiction Severity Index (ASI; McLellan et al. 1992) medications were kept isolated from the clinical and conducted at screening, at 4 weeks following randomiza- research team during clinic hours. Even including the tion and at treatment termination. The ASI was admin- cabergoline condition, all participants were prescribed istered by trained research assistants and has excellent take-home medications with identical, thrice daily dosing inter-rater and test–retest reliability. Information used instructions as another method for protecting the modi- from the ASI included number of days of substance used fied blind. Participants assigned to all conditions took one in the previous 30 days and the ASI composite scales: dose weekly directly from the research pharmacist, who medical, employment, alcohol, drug, legal, family/social placed the medication directly onto the tongue of the par- and psychiatric. ticipant and provided a sufficient number of tablets for take-home dosing. Participants brought their study medication bottles to each clinic visit to facilitate a pill count. Cocaine craving ratings. Ratings of cocaine craving were After the count, one dose of study medication was con- collected at screening, weekly during the medication ducted in clinic under direct observation, followed by phase and at treatment termination using the Brief Sub- return of the bottle to take home. stance Craving Scale (BSCS). BSCS scores range from 0 to 12. It is a self-administered assessment that participants use to rate cravings for cocaine and is a modification of Assessments the State of Feelings and Cravings questionnaire (Mezin- During the screening phase, participants completed a skis et al. 1998). battery of measures that included safety and efficacy assessments, which were repeated during the medication Global impression ratings. Clinical Global Impression period. Participants received $5 in grocery vouchers each scores as reported by the self (CGI-self) and an observer for six screening and 23 medication-phase research visits (CGI-obs) were collected at screening, weekly during the and an additional $20 in grocery vouchers for complet- medication phase, and at treatment termination. Global ing the termination visit for a maximum value of $165 in ‘severity’ and ‘improvement’ scores were obtained. The vouchers. Vouchers were provided only for completion of CGI features a seven-point Likert scale that assays self and research visits. observer ratings of the ‘severity’ and ‘improvement’ of the cocaine dependence problem [‘At this time overall, how Safety. Safety assessments included a history and physi- do you rate (the participant’s/your) cocaine use and cal examination, a 12-lead ECG and clinical laboratory cocaine related problems?’]. ‘Severity’ was recorded as an studies conducted during screening and at termination. ordered categorical variable with a range from 1 (‘no Vital signs were obtained at each research visit for the symptoms’) to 7 (‘most extreme symptoms’). ‘Improve- first 2 weeks and weekly thereafter to treatment termina- ment’ is also an ordered categorical variable with a range tion. Adverse event reports and concomitant medication from 1 (‘very much improved’) to 7 (‘very much worse’); use were collected weekly. a value of 4 indicates ‘no change’.

82 Steven Shoptaw et al.

Mood indices. Mood measures included the Hamilton iors. The CREST data analysis strategy compared partic- anxiety (Bruss et al. 1994) and depression scales (Hamil- ipants assigned to each experimental condition only to ton 1967; HAM-A/D) at screening and at treatment ter- those assigned to the common placebo. There was no mination and were administered by a trained clinician comparison of outcomes for the experimental conditions via interview format. to each other. The primary marker of treatment response was quantitative urinary BE. Urinary BE results were compiled Psychiatric diagnostic measures using two strategies common to substance abuse trials: Psychiatric diagnostic information was collected during the Treatment Effectiveness Score (TES; Ling et al. 1997), screening using the SCID (Spitzer et al. 1995). SCID infor- which counts the number of urine samples containing no mation verified inclusion/exclusion criteria and esti- drug metabolites; and percentage negative, i.e. the num- mated the extent and nature of comorbidity of psychiatric ber of samples containing no drug metabolites divided by diagnoses. SCID interviewers were trained clinicians with the number of urine samples provided. Both TES and per- masters’ level (or higher) degrees. The senior author centage negative were calculated to measure cocaine use reviewed all SCID interviews. only (TES range = 0–24) and for all drugs tested (i.e. cocaine, amphetamines, benzodiazepines, marijuana and opiates; TES range = 0–8). To address the issue of HIV risk behaviors cocaine metabolites residual in consecutive samples due HIV transmission behaviors were assessed using the risk to the thrice-weekly schedule of collection, ‘new use’ cri- assessment battery (RAB; Navaline et al. 1994), with the teria (Preston et al. 1997) were applied to urine drug recall period shortened to 30 days. screen results using the TES and percentage of negative aggregates. A ‘new use’ required: (1) a sample with urinary BE measured at or above 300 ng/ml; and (2) if the Data analysis immediately prior sample was positive for BE metabolite, All analyses used an ‘intent-to-treat’ approach. Two- failure to observe a reduction of 50% or more of urinary group comparisons of interval level variables were con- BE from the prior sample. ducted using student t-tests. Two-group comparisons of Longitudinal models for estimating condition effects categorical data or interval data that violated assump- on urinary BE included a marginal model using a gen- tions of normality were conducted using appropriate eralized estimating equation (GEE) (Diggle et al. 1994). non-parametric procedures (e.g. c2 tests, Mann–Whitney This procedure models the individual natural log (LN) U-tests). Analyses of variables at the end of screening that of urinary BE values (using a value of 1, for BE = 0) by were associated significantly with assignment to condi- the number of days before or after randomization. tion were included as covariates for outcome analyses. All Spline regression estimates a continuous function to the tests of statistical significance were conducted as two- data by piecing together functions fitted to different por- tailed, with an alpha level of 0.05. Power for the CREST tions of the data. These local functions are joined at a design was low, allowing detection of large effect sizes common ‘knot’ point. In CREST, the urine sample taken only at statistically significant levels. To address the risk of on the day of randomization was the last screening failing to recognize potential medication effects, given the sample and is considered the baseline value or knot low number of participants assigned to each condition, point. For the purpose of these analyses the day of this we chose to accept the risk of spurious findings and did urine sample was considered to be day 0. All other not adopt a family-wise alpha correction for the multiple urine samples were labeled with the number of days comparisons reported. from this day 0. This modeling approach forces a GEE The primary method for determining the safety of the fitted to the screening data as well as the treatment medications involved conducting separate univariate phase with both functions passing through the same comparisons between each medication condition and the urinary BE value at day 0. The model-based estimate at common placebo condition regarding the number of day 0 is the intercept of the GEE fit. reported adverse drug events and the number of abnor- Univariate procedures used case-wise deletion meth- mal lab values. The cardinal method for determining ods for managing missing data. The GEE model used all medication superiority over placebo required reductions available data and was therefore less sensitive to biases in cocaine use as measured by urine samples. Additional from missing data. The combined use of the different analyses determined whether medications demonstrated methods when analyzing the same data provided a sensi- significant effects on other outcomes including retention, tivity analysis strategy that involved both less stringent self-report of substance use, craving ratings, clinical univariate methods and a more conservative modeling impression ratings, mood function and HIV risk behav- approach.

RESULTS cabergoline produced more urine samples that were BE- free than placebo-treated participants, with or without A total of 185 individuals provided written informed con- applying new use criteria, the differences were not statis- sent, of which 60 were randomized. Those who failed to tically significant. Participants assigned to receive complete the screening process did so for the following hydergine produced somewhat higher percentages of reasons. Seven refused to participate, 85 failed screening samples negative for urinary BE than placebo-treated for missing baseline visits, 26 were excluded for medical/ participants, but this difference was neither statistically psychiatric reasons [Purified Protein Derivative + (four)], significant nor were there meaningful differences mea- ECG (four), diabetes (three), HIV + (two), high glucose, sured using the TES. In contrast, univariate analysis of high Liver Function Tests, depression, pregnant, asthma, urine BE results by condition for the fourth, eighth and Graves’ disease, hears voices, high blood pressure (BP), last weeks of the study participants showed cabergoline- hepatitis C, chest pain, multiple medications, heart prob- treated participants to use significantly less cocaine than lems and bipolar disorder), and seven were excluded for those assigned to receive placebo. This effect trended other reasons (comorbid addiction, screening urines all toward significance for participants assigned to caber- negative, left town). African American participants goline compared to placebo during their last week of (72%) screened failed more than all other ethnic groups study participation. No effects in these same time period 2 (28%; c (6) = 15.64; P < 0.05). The groups were similar were observed by condition (Table 3). along all other variables tested. Generalized estimation equations model for urine results

Demographics, substance use, psychiatric and Table 4 shows model-based estimated average BE levels at psychological characteristics the start of the screening period, day 0 (the first day of Characteristics of participants who completed screening study medication) and at week 8 (day 56). From the start by assignment to treatment condition are depicted in of the screening period to day 0, participants generally Table 1. The random assignment resulted in equivalence decreased their cocaine use as indicated by averaged uri- across conditions for most variables. Participants nary BE values, with the exception of hydergine, which assigned to receive cabergoline reported using cocaine for increased (+22%). Model-based estimates of BE values significantly fewer days in the 30 days prior to screening from day 0 to the end of week 8, however, showed sub- than those assigned to receive placebo. ASI composites stantial reductions for the cabergoline condition (-61%) also reflected this difference, with participants in the cab- and the hydergine condition (-79%), with increases ergoline condition scoring significantly lower on the drug observed for the levodopa/carbidopa condition (+56%) use subscale than the placebo condition at screening. and no change for the placebo condition (+5%). This Cabergoline-treated participants also showed signifi- spline GEE solution indicates that the rates of cocaine use cantly lower medical subscales than participants assigned showed substantial and relevant decline both for the cab- to placebo, indicating better general medical health. Due ergoline and hydergine conditions when compared to the to the significant difference in self-report of cocaine use at placebo condition, although neither comparison reached baseline for cabergoline-treated participants, this variable statistical significance. was included as a covariate in all between-group tests between cabergoline and placebo conditions. Retention Figure 1 depicts the proportion of participants retained Urine drug screen analyses over the 8 weeks for the experimental and placebo conditions. Although more participants in the hydergine con- Composites of urine drug screen results dition completed the 8 weeks of the medication study, similar proportions of participants assigned to receive Participants assigned to receive cabergoline provided cabergoline, levodopa/carbidopa and placebo completed 17% more urine samples negative for BE than those the 8 weeks. There were no statistically significant differ- assigned to receive placebo (see Table 2), a statistically ences in retention rates between the experimental and significant difference after controlling for baseline differ- placebo conditions. ences (F = 2.95, df = 3; P = 0.05). After applying new use criteria to the urine drug screen results, the cabergoline- Self-report of drug use, psychological status and HIV treated condition also produced significantly higher transmission behaviors amounts of urine negative (55.8%) for cocaine metabolites than placebo (38.6%; F = 4.02 df = 3; P = 0.02). Analyses of self-report measures revealed few statistically Although the TES indicated that participants assigned to significant differences between the active medication con-

Table 1 Baseline demographic, cocaine-related and psychiatric variables by assignment to condition.

Condition

Cabergoline (n = 15) Levodopa/ carbidopa1 Hydergine (n = 15) Placebo (n = 15) Mean (SD) or % (n = 15) Mean (SD) or % Mean (SD) or % Mean (SD) or %

Demographic variables Age in years 38.5 (SD = 7.9) 39.7 (SD = 6.7) 34.8 (SD = 6.8) 39.5 (SD = 5.8) % Male 73.3% 73.3% 66.7% 66.7% Ethnicity African American 73.3% 53.3% 40.0% 71.4% Caucasian 13.3% 20.0% 13.3% 14.3% Hispanic 6.7% 20.0% 33.3% 7.1% Other 6.7% 6.7% 13.3% 7.1% Marital status Never married 40.0% 23.1% 46.7% 30.8% Married 33.3% 30.8% 26.7% 30.8% Separated/divorced 26.7% 46.1% 26.7% 38.5% Employment Employed 44.4% 33.3% 90.0% 33.3% Unemployed 55.6% 66.7% 10.0% 66.7% Some college 28.6% 30.0% 15.4% 38.5% Substance use variables Days used cocaine in last 302 10.7 (SD = 6.8) 14.7 (SD = 9.8) 13.4 (SD = 9.1) 17.6 (SD = 10.7) Years of cocaine use (life-time) 7.6 (SD = 5.4) 8.9 (SD = 7.6) 8.2 (SD = 7.7) 11.6 (SD = 7.3) Route of administration Oral 0.0% 9.1% 0.0% 0.0% Nasal 11.1% 27.3% 28.6% 23.1% Smoking 88.9% 63.6% 71.4% 76.9% Injection 0.0% 0.0% 0.0% 0.0% Cocaine craving (BSCS) 5.9 (SD = 3.3) 5.3 (SD = 4.3) 6.8 (SD = 3.5) 6.5 (SD = 2.5) Other drug craving (BSCS) 2.9 (SD = 3.9) 3.1 (SD = 4.0) 2.8 (SD = 3.5) 1.8 (SD = 2.6) Addiction Severity Index Medical3 0.00 (SD = 0.00) 0.09 (SD = 0.17) 0.11 (SD = 0.27) 0.15 (SD = 0.23) Employment 0.49 (SD = 0.27) 0.51 (SD = 0.38) 0.29 (SD = 0.28) 0.30 (SD = 0.31) Alcohol 0.18 (SD = 0.18) 0.20 (SD = 0.22) 0.15 (SD = 0.16) 0.11 (SD = 0.09) Drug4 0.19 (SD = 0.08) 0.26 (SD = 0.10) 0.24 (SD = 0.07) 0.27 (SD = 0.07) Legal 0.10 (SD = 0.18) 0.12 (SD = 0.20) 0.02 (SD = 0.08) 0.03 (SD = 0.11) Family/social 0.21 (SD = 0.10) 0.27 (SD = 0.16) 0.22 (SD = 0.16) 0.29 (SD = 0.09) Psychiatric5 0.09 (SD = 0.15) 0.25 (SD = 0.25) 0.28 (SD = 0.20) 0.09 (SD = 0.17) Psychiatric variables % Participants with a non-substance related Axis I Diagnosis Current 6.7% 14.3% 0% 6.7% Life-time 13.3% 21.4% 6.7% 26.7% % Participants with a substance-related Axis I Diagnosis, excluding substance abuse or dependence Current 13.3% 21.4% 26.7% 26.7% Life-time 20.0% 35.7% 33.3% 33.3% % Participants with substance abuse or dependence diagnosis additional to cocaine abuse or dependence Current 26.7% 35.7% 26.7% 40.0% Life-time6 46.7% 71.4% 60.0% 93.3% Percent of participants with alcohol dependence diagnosis Current 20.0% 7.1% 20.0% 0% Life-time 26.7% 21.4% 33.3% 26.7% % Participants with alcohol abuse diagnosis Current 6.7% 14.3% 6.7% 13.3% Life-time 20.0% 28.6% 20.0% 40.0% Psychological variables Hamilton depression 5.2 (SD = 6.3) 10.5 (SD = 9.7) 13.8 (SD = 10.9) 7.3 (SD = 8.0) Hamilton anxiety 4.1 (SD = 3.9) 7.8 (SD = 7.6) 8.9 (SD = 8.5) 4.6 (SD = 4.7) Clinical Global Severity 4.3 (SD = 1.9) 4.5 (SD = 1.5) 5.0 (SD = 0.7) 4.6 (SD = 1.1) HIV risk behavior (RAB) 0.5 (SD = 0.9)7 1.2 (SD = 1.5) 1.1 (SD = 1.1) 1.4 (SD = 1.1)

1One participant in this condition had an invalid SCID and was not included in the analyses of psychiatric variables. 2Cabergoline versus placebo: two- tailed t(27) = - 2.09, P = 0.046. 3Cabergoline versus placebo: two-tailed t(13) = - 2.37, P = 0.03. 4Cabergoline versus placebo: two-tailed t(27) = - 3.36, P = 0.002. 5Levodopa/carbidopa versus placebo: two-tailed t(27) = - 2.11, P = 0.04. 6c2 (3) = 8.1, P = 0.045.

ditions and the common placebo for those who completed

7.4) 35.4) 32.1) 2.9) 32.3) treatment (Table 5). Change from screening to treatment = = = = = completion along the ASI composite scales showed no sta-

6) tistically signiﬁcant changes when analyzed between the = n

Complete ( active medication and placebo conditions, with one exception. Cabergoline-treated participants did better

than those in the placebo condition as measured by the

6.4) 32.4) 30.9) 9.7 (SD 48.6 (SD 2.5) 58.5 (SD 29.6) 3.7 (SD 44.6 (SD ASI employment subscale. No statistically signiﬁcant dif- = = = = = ferences were identiﬁed between the treatment conditions 15) = and the common placebo over the treatment period for n All ( the Hamilton depression, Hamilton anxiety or drug craving scores. Participants reported few HIV risk behaviors as indicated by no injection behaviors and low levels of 6.0) 34.9) 22.9) 4.2 (SD 25.0 (SD 1.9) 38.6 (SD 28.0) 1.5 (SD 20.1 (SD

= = = = = sexual risks. Although participants assigned to the cabergoline condition had lower baseline RAB drug sub- 10)

n scores than the placebo condition, no comparisons were Complete ( signiﬁcantly different between active medication and placebo groups over time. 5.1) 34.9) 24.4) 5.3 (SD 30.7 (SD 1.7) 51.3 (SD 31.7) 1.7 (SD 23.8 (SD = = = = = Observer ratings 15)

= n

All ( Comparison of observer ratings for ‘severity’ and ‘improvement’ between screening and last observer rating collected showed an overall lessening in severity of

8.1) 34.3) 25.6) 4.3 (SD 36.0 (SD 2.7) 54.7 (SD 33.9) 1.7 (SD 31.3 (SD cocaine dependence from baseline to treatment termin- = = = = = ation that occurred at relatively equivalent rates across 6) = all of the treatment conditions. Similarly, observers noted n Complete ( that all conditions improved, but no experimental conditions demonstrated statistically signiﬁcant improvement 0.05. <

over placebo. P 5.7) 36.7) 33.9) 5.8 (SD 28.9 (SD 1.9) 46.9 (SD 32.3) 2.0 (SD 26.2 (SD = = = = =

15) Laboratory values and adverse experiences = n All ( Evaluation of reported of adverse events indicated that there were no statistically or clinically signiﬁcant associations between the type, severity or number of adverse 8.7) 36.4) 24.0) 4.9 (SD 39.0 (SD 3.2) 54.2 (SD 36.9) 1.7 (SD 33.0 (SD = = = = = events and treatment condition. In total, 692 unique

6) adverse events were reported during the trial, none of = n

Complete ( which were serious. No reliable associations existed between reported adverse events and relationship to the study drug. Values that exceeded normal limits for vital

8.0) 35.6)* 27.1)* 13.7 (SD 63.8 (SD 2.9) 74.3 (SD 41.7) 5.0 (SD 61.9 (SD signs, electrocardiogram, complete blood chemistry and = = = = = hematology for all participants at termination showed

15) that 10 participants had a systolic blood pressure greater = eatment condition n Tr M (SD)Cabergoline M (SD) Levodopa/carbidopa M (SD) Hydergine Placebo M (SD) All ( than 140 mmHg (mean = 158.4; SD = 14.7), eight had a diastolic blood pressure greater than 90 mmHg (mean = 101.1; SD = 9.8), four had sodium levels that exceeded 145 mEe/l (mean = 146.8; SD = 1.0), one had a chloride level that exceeded 112 mEq/l (113), eight had triglyceride values that exceeded 240 mg/dl (mean = 449.8; SD = 238.7) and four had GGT values Aggregate measures ofAggregate urine drug treatment condition. screen results by that exceeded 90 U/l (mean = 156.0; SD = 53.6). No apparent association existed between out-of-range values ble 2 Composite TES cocaine cocaine% Negative, cocaine new use, % Negative, all drugsTES, 55.8 (SD all drugs% Negative, 42.4 (SD 6.8 (SD 42.5 (SD 2.5 (SD Ta of after controlling for baseline differences signiﬁcant in self-reported days *Statistically cocaine use, and assignment to condition. A detailed report of the

Table 3 Urine benoylecognine (BE) levels and self-report of days of cocaine use by condition during the fourth and eighth weeks and week of last visit.

Placebo Cabergoline Sinemet Hydergine P-value

Urine BE (–) Week 4 3/10 (30%) 2/11 (18%) 3/13 (23%) 3/13 (23%) 0.965* Week 8 1/6 (17%) 5/7 (71%) 0/6 (0%) 2/10 (20%) 0.028* Week of last visit 1/15 (7%) 7/15(47%) 3/15 (20%) 5/15 (33%) 0.076* Self-report Week 4 3/11 (27%) 8/12 (67%) 3/13 (23%) 4/13 (31%) 0.121* Week 8 4/6 (67%) 6/9 (67%) 4/8 (50%) 5/12 (42%) 0.679* Week of last visit 4/14 (29%) 8/15 (53%) 7/15 (47%) 4/14 (29%) 0.443*

*Applying Fisher’s exact test.

Table 4 Model-based generalized estimation equation estimates of urinary benzoylecgonine (BE) by experimental condition.

Condition

Levodopa/ Cabergoline carbidopa Hydergine Placebo Model-based urinary BE estimates (n = 15) (n = 15) (n = 15) (n = 15)

At baseline 4598 ng/ml 13 568 ng/ml 3207 ng/ml 12 805 ng/ml At day 0 1685 ng/ml 1312 ng/ml 3925 ng/ml 4052 ng/ml At day 56 (end of treatment) 660 ng/ml 2046 ng/ml 842 ng/ml 4236 ng/ml

Figure 1 Proportion of participants retained at each of the study visits over the 8-week treatment period by assignment to condition frequency and severity of reported adverse events and of in-clinic dosing procedures. By contrast, participants the vital signs, electrocardiogram, complete blood chem- in the cabergoline condition took 60.8% of their take- istry and hematology by condition is available by request home medications. This compared with 67.1% of pre- from the lead author. scribed medications taken by participants in the levodopa/carbidopa condition, 55.4% for participants in the hydergine condition and 58.8% for those in Treatment compliance the placebo condition. There were no statistically Compliance with cabergoline administration was signiﬁcant differences measured for medication 100% when participants attended clinic due to the compliance.

Table 5 Change scores from baseline to week 8 in self-reported drug use and psychological variables by assignment to treatment condition.

Levodopa/ Cabergoline Carbidopa Hydergine Placebo Mean (SD) Mean (SD) Mean (SD) Mean (SD)

Drug use variables Addiction Severity Index Medical -0.05 (SD = 0.15) -0.03 (SD = 0.23) 0.03 (SD = 0.13) 0.12 (SD = 0.42) Employment 0.09*(SD = 0.10) 0.02 (SD = 0.20) -0.01 (SD = 0.17) -0.07 (SD = 0.15) Alcohol 0.04 (SD = 0.12) 0.13 (SD = 0.17) -0.06 (SD = 0.08) -0.02 (SD = 0.16) Drugs 0.10 (SD = 0.11) 0.09 (SD = 0.13) 0.08 (SD = 0.10) 0.08 (SD = 0.07) Legal 0.08 (SD = 0.11) 0.02 (SD = 0.27) -0.01 (SD = 0.17) 0.00 (SD = 0) Family/social 0.07 (SD = 0.16) 0.05 (SD = 0.17) 0.04 (SD = 0.06) -0.01 (SD = 0.23) Psychiatric 0.08 (SD = 0.12) 0.09 (SD = 0.26) 0.06 (SD = 0.19) 0.01 (SD = 0.16) Cocaine craving (BSCS) 4.2 (SD = 2.6) 0.2 (SD = 3.7) 3.7 (SD = 3.4) 3.2 (SD = 2.7) Psychological variables Hamilton depression 0.8 (SD = 10.8) -1.1 (SD = 6.9) 6.9 (SD = 10.6) -1.2 (SD = 6.9) Hamilton anxiety 0.2 (SD = 4.6) 0.3 (SD = 4.4) 5.4 (SD = 11.0) -1.0 (SD = 2.6) Clinical Global Severity -1.2 (SD = 1.5) -1.1 (SD = 2.2) -1.2 (SD = 1.5) -1.3 (SD = 0.8) Clinical Global Improvement -2.0 (SD = 1.1) -1.4 (SD = 1.5) -1.4 (SD = 1.1) -1.4 (SD = 1.1)

*t = 2.36, P < 0.05.

DISCUSSION compared to placebo along aggregate measures of urine drug screen results or other outcome measures. This initial Los Angeles-based, CREST evaluated caber- While it is encouraging that there is a consistency of goline, levodopa/carbidopa and hydergine to determine superior findings across multiple measures of outcome, there were sufficient effects in reducing cocaine use for including urine drug screen results (both aggregate mea- any of these medications when compared to placebo to sures and GEE model) for the cabergoline condition over warrant devoting resources for a full-scale study. Univari- placebo, this effect may also be due to a significant finding ate findings indicated statistically significant differences simply by chance, especially given the pilot screening for the cabergoline condition compared to placebo in the design. On the other hand, compliance issues are mini- percentage of urine samples negative for cocaine metab- mized when using cabergoline from using the once- olites when using standard and new use criteria for weekly dosing regimen. The resulting consistent medica- aggregating urine drug screen results. In addition, caber- tion levels may have been partially responsible for goline-treated participants demonstrated relevant reduc- observed cabergoline effects. Nevertheless, performance tions in absolute values of urinary cocaine metabolites of these participants assigned to cabergoline demon- measured during the study as indicated by a spline GEE strates room for improvement. Although the medication regression equation. From baseline assessments, caber- has a long half-life, most of the medication had probably goline-treated participants also reported significant been metabolized by the end of the study week, especially reductions in employment problems as measured by the considering the relatively low dose used in this study ASI when compared to placebo-treated participants. (0.5 mg per week). Options for boosting cabergoline lev- Findings from this screening trial showed there els, including mid-week dosing or higher dosages (e.g. 1 were no statistically significant differences between or 2 mg) each week may be appropriate for enhancing the hydergine and placebo conditions in terms of urine potential cabergoline effects in reducing cocaine use. results analyzed using aggregate measures. However, the The chronic, chaotic effects on behavior caused by GEE model indicated reductions in urinary cocaine cocaine dependence, even for cocaine-dependent individ- metabolite (BE) for the hydergine-treated participants uals participating in an out-patient treatment episode, compared to placebo that were similar in proportion to may have a profound influence on the eventual form of reductions observed for the cabergoline condition. The medication used to treat this disorder. Potential pharma- reduction in cocaine use indicated by the spline GEE cotherapies will probably require long half-lives (as in the regression probably indicated a mild effect (if any) for the case of cabergoline) or involve methods of administration medication, as there were no clinically significant or rel- that provide steady-state delivery over long periods (e.g. evant differences observed for the hydergine condition depot formulations). Similar to many medication studies

© 2005 Society for the Study of Addiction Addiction, 100 (Suppl. 1), 78–90 88 Steven Shoptaw et al. of cocaine pharmacotherapies, this study indicated that a placebo condition and for helping to minimize missing hydergine might reduce cocaine use in humans, data visits. The blinding procedure for the CREST para- although it is highly possible that problems with medica- digm, which involved use of an unmatched placebo, may tion compliance (i.e. missed doses) may have disrupted have contributed to participants decoding their assign- ability for participants to achieve steady-state. Given the ment by comparing study medications to reference texts. relatively few number of participants in this pilot study Such knowledge might influence participants’ expectan- and that that no measures were taken to measure cies for treatment outcome if they are sure they are hydergine levels, no definitive conclusions can be drawn receiving a specific medication. Findings indicate, how- about hydergine efficacy. Medication effects can be mea- ever, that this did not operate to any significant extent. sured only when pills are ingested. Finally, the finding of improvement on the ASI employ- As important as initial efficacy findings, the dose of ment scale should be understood as preliminary and in cabergoline used in this study appeared safe as indicated need of replication. by no reports of serious adverse events for those assigned Despite the limitations, this screening trial used an to receive the medication. Reported adverse events and efficient design for identifying cocaine medications with abnormal laboratory values for cabergoline-treated par- potential, for providing initial indications of safety and ticipants were observed at rates similar to participants efficacy and for documenting procedures that were assigned to receive placebo. Participants in this study implemented carefully. Given the structure of the CREST experienced 8 weeks of exposure to cabergoline, which design and the careful application of the procedure, these provided for extended opportunities for observing the findings indicate that there is sufficient evidence to pro- interaction of this medication with cocaine during peri- ceed with a larger-sized out-patient trial of cabergoline for ods of relapse. Although we observed no interaction cocaine dependence. effects for cocaine and cabergoline when participants relapsed during treatment, it is unknown whether higher Acknowledgements (e.g. 1.0 or 2.0 mg) or more frequent (e.g. twice-weekly) dosages of cabergoline can be used safely with this popu- This study was funded by the National Institute on Drug lation. Individuals with Parkinson’s disease receive dos- Abuse, (NIDA) through Interagency Agreement 1 Y01 ages of cabergoline substantially higher than that DA 50038 (Medications Development Research Unit; evaluated in this protocol. However, it is probably neces- Ling-PI). We wish to thank David Parent and Dan Bloch sary to conduct an interaction study of cabergoline at for statistical support and Angela Namkoong and Tiffanie higher dosages with cocaine prior to implementing an Sim for their support in the preparation of this manu- out-patient study at those dosages. script. We also wish to thank the MDRU Publications There are limitations to these CREST findings. The Committee for their editorial guidance and scientific number of participants randomized to each of the medi- review. cation conditions was low and the number of participants excluded was relatively high. Hence, findings regarding these medications are intended as preliminary and References require replication to confirm effects observed. It is also Ahlskog, J. E., Wright, K. F., Muenter, M. D. & Adler, C. H. possible that a medication tested might be effective for (1996) Adjunctive cabergoline therapy of Parkinson’s disease: reducing cocaine use (e.g. hydergine), but due to compli- comparison with placebo and assessment of dose–responses ance problems might not reach steady state, limiting the and duration of effect. Clinical Neuropharmacology, 19, 202– 212. evaluation of potential medication effects. Complicating Brief, D., Bollinger, A., Horton, G. & LoCastro, J. S. (1998) analyses, missing urine drug samples can interfere when Relapse Prevention Treatment for Cocaine Addiction: the RPT-C testing for medication effects. It remains that approxi- Manual. Bethesda, MD: Medication Development Division, mately one-half of the urine samples were missing across National Institute on Drug Abuse. all conditions. Application of advanced analytical meth- Bruss, G. S., Gruenberg, A. M., Goldsteinm, R. D. & Barber, J. P. 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