Volume 70, Issue 3, 5 June 2003, Pages 315325

Desipramine and contingencymanagement for cocaine and opiate dependence in buprenorphine maintained patients
Thomas Kosten, Alison Oliveto, Alan Feingold, James Poling, Kevin Sevarino, Elinore McCance-Katz, Susan Stine, Gerardo Gonzalez, Kishor Gonsai

Abstract Co-dependence on opiates and cocaine occurs in about 60% of patients entering methadone treatment and has a poor prognosis. However, we recently found that desipramine (DMI) could be combined with buprenorphine to significantly reduce combined opiate and cocaine use among these dually dependent patients. Furthermore, contingencymanagement (CM) has been quite potent in reducing cocaine abuse during methadone maintenance. To test the efficacy of combining CM with these medications we designed a 12-week, randomized, double blind, four cell trial evaluating DMI (150 mg/day) or placebo plus CM or a non-contingent voucher control in 160 cocaine abusers maintained on buprenorphine (median 16 mg daily). Cocaine-free and combined opiate and cocaine-free urines increased more rapidly over time in those treated with either DMI or CM, and those receiving both interventions had more drug-free urines (50%) than the other three treatment groups (2529%). Self reported opiate and cocaine use and depressive and opioid withdrawal symptoms showed no differences among the groups and symptom levels did not correlate with urine toxicology results. Lower DMI plasma levels (average 125 ng/ml) were associated with greater cocaine-free urines. DMI and CM had independent and additive effects in facilitating cocaine-free urines in buprenorphine maintained patients. The antidepressant appeared to enhance responsiveness to CM reinforcement.

1. Introduction Opiate and cocaine dependence are major health problems in the United States and associated with medical complications such as human immunodeficiency virus (HIV) infection, hepatitis infection and endocarditis, and social issues such as unemployment and illegal activity. Methadone or buprenorphine maintenance can improve opiate problems, but neither medication targets cocaine abuse and, indeed, cocaine use may increase in some methadone-maintained patients ( [Kosten et al., 1987], [Zweben and Payte, 1990], [Sorensen and Copeland, 2000] and [Ball and Ross, 1991]). Combined opiate and cocaine dependence is common with rates of 58% among those entering methadone treatment and has a poor prognosis ( [Ball et al., 1988] and [Ball et al., 1989]). For example, in a recent study those opiate dependent patients who presented with both opiate and cocaine positive urines were three times more likely than those with opiates alone to drop out of methadone maintenance (30 vs. 10%) and have substantially fewer opiate and cocaine free urines (3

vs. 43%) in the first month (DeMaria et al., 2000). Thus, more effective maintenance strategies need to be developed for combined opiate and cocaine dependence such as the addition of other medications and/or behavioral therapies to opiate maintenance. In studies examining pharmacotherapies for dual dependence on cocaine and opiates, we have found that desipramine (DMI) may be more effective when combined with buprenorphine than methadone. Previous studies had found that in methadone maintained patients DMI was not effective in reducing cocaine abuse ( [Arndt et al., 1992] and [Kosten et al., 1992a]), and that buprenorphine alone, which had shown some initial promise for cocaine abuse, was not more effective than methadone alone in reducing cocaine abuse among these dually dependent patients ( [Kosten et al., 1989], [Kosten et al., 1992b], [Kosten et al., 1993], [Schottenfeld et al., 1993] and [Schottenfeld et al., 1997]). However, we recently found that DMI could be combined with buprenorphine to significantly reduce combined opiate and cocaine use among these dually dependent patients (Oliveto et al., 1999). Combining DMI with buprenorphine was more effective than placebo DMI, or DMI combined with methadone (Oliveto et al., 1999). We did not find that improvement in depressive symptoms was associated with reductions in opiate and cocaine use, although recent work has suggested that an additive effect of the antidepressant-fluoxetine and contingencymanagement (CM) might be due to its antidepressant effect (Schmitz et al., 1998). Thus, combining buprenorphine and DMI appeared promising for combined cocaine and opiate use. Nevertheless, DMI did not eliminate illicit drug use and to improve its efficacy, we chose a potent behavioral treatmentCM, that might enhance the attainment of initial abstinence, as well as improve both short and long term outcomes of maintenance opiate treatment ( [Carroll, 1997], [Woody et al., 1983], [Woody et al., 1995], [McLellan et al., 1993], [Carroll et al., 1995], [Bigelow et al., 1984], [Stitzer et al., 1979], [Stitzer et al., 1982], [Stitzer et al., 1992], [Stitzer and Bigelow, 1978], [Iguchi et al., 1988], [Magura et al., 1988], [Milby et al., 1978] and [McCaul et al., 1984]). Several notable studies have indicated that CM can be quite potent in an opiate maintenance setting such as methadone, although review of all the CM studies done in methadone treatment settings has indicated that CM would benefit from added interventions such as the DMI we used in the current study ( [Chutuape et al., 1999], [Griffith et al., 2000], [Jones et al., 2001], [Silverman et al., 1996], [Silverman et al., 1998], [Silverman et al., 1999] and [Silverman et al., 2001]). In order to test these issues we designed a study using DMI and CM alone and in combination among buprenorphine maintained patients who had dual dependence on opiates and cocaine. We had three hypotheses. First, both the DMI and CM groups would show a greater reduction in cocaine and opiate use than the groups not getting these treatments. Furthermore, the combined medication and CM group would have an additive effect and a greater reduction in cocaine and opiate use than either CM or DMI alone. Second, like in our previous study, those getting DMI would show no greater reduction in depressive or withdrawal symptoms than those getting placebo (Oliveto et al., 1999). Third, since we had previously found that higher DMI levels were associated with greater opiate free urines, we hypothesized that higher DMI levels would be associated with more opiate and cocaine-free urines (Oliveto et al., 1999). 2. Methods 2.1. Subjects

One hundred and five male and 55 female cocaine-abusing opiate addicts (aged 2165, including 58 African-Americans, 11 Hispanics, and two Native Americans) seeking opiate maintenance treatment were recruited from the general Greater New Haven area after giving written informed consent to participate in a randomized clinical trial approved by the Yale Human Investigations Committee and the VA Connecticut Human Studies Committee. All participants fulfilled the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria for opiate and cocaine dependence, as determined from the Structured Clinical Interview for DSM-IV (SCID), and had positive urine toxicology screens for both drugs. Exclusions included medical reasons for not taking DMI or buprenorphine (i.e. pregnancy, cardiac conduction problems, acute hepatitis), current suicidality or psychosis, inability to read or understand the symptom check lists, current alcohol or sedative dependence, use of non-diuretic antihypertensives or other medications that interact with the study medications. Women of childbearing age were included provided they: (1) had a negative urine pregnancy test; (2) agreed to use adequate contraception to prevent pregnancy during the study; (3) understood the risks of fetal toxicity due to medications while in the study; (4) had monthly pregnancy tests. 2.2. Research design and procedures This 12-week randomized, double-blind, outpatient clinical trial stabilized 160 patients on a median dose of 16 mg buprenorphine after simple randomization to one of four treatment conditions: DMI (150 mg) plus contingencies, DMI without contingencies, placebo plus contingencies, placebo without contingencies (n=40 per cell). Treatment occurred in an outpatient methadone maintenance facility, where sublingual buprenorphine was started at 4 mg daily and shifted to 8 then 12 mg during week 1 and to 16 mg at week 2. Buprenorphine doses were stabilized during the first month, with most subjects on 16 mg and an average dose of 15.8 mg (S.D. 4). The four treatment groups showed no significant difference in dose with the lowest average dose of 15.1 mg for the CM plus DMI group and the highest average dose of 16.6 mg for the CM plus placebo group (F=1.0; P<0.4). DMI was started in week 2 at 50 mg daily and increased by 50 mg every 2 days up to 150 mg total dosage. DMI dosages were held constant during the remaining 10-week trial, and its blood levels were obtained at week 6, 24 h from last 150 mg dose, and evaluated by a non-blind psychiatrist for potentially toxic levels (above 600 ng/ml) and dosage reduction. Patients could request referral to one of the community methadone programs at any time during the study and would be given a 4week taper off buprenorphine before starting in a community methadone program. Urines were collected under observation on Monday, Wednesday and Friday each week before being medicated in order to implement the CM, which began during week 1 along with once weekly supervised, manual guided cognitive behavioral therapy (Carroll, 1997). For the contingency group, urines free from both cocaine and opiates submitted during weeks 112 resulted in a voucher worth a certain monetary value. The first urine was worth $3, which increased by $1 with every consecutive opiate and cocaine-free urine and reset back to the original $3 if heroin or cocaine were detected or a urine sample was missed. Subjects in the CM group who remained abstinent for the full 12 weeks were able to earn goods and services worth a maximum of $738. Vouchers could be exchanged for mutually agreed upon goods and services at any time during the study. Very few times did subjects exchange their vouchers for goods on the day they obtained a voucher; instead they accumulated vouchers for larger goods than a day or week's earnings would allow. These

larger reinforcers were obtained by the next day in most cases, but some requests required up to 5 days for purchase. Thus, immediate reinforcement was uncommon in this study. Subjects not assigned to the CM procedure received monetary vouchers (also exchangeable for mutually agreed upon goods and services) according to a schedule that was not contingent upon illicit opiate and cocaine abstinence. Their vouchers were worth the average value of the contingency subjects for the previous week with a minimum of $3 per week for providing at least one urine sample for the week, regardless of their opiate and cocaine use. All subjects had urines collected thrice weekly, were informed of the results and, if appropriate, received a voucher. Subjects in this quasi-yoked-control group also received feedback concerning their urine results in order to keep the amount of contact with staff consistent. During the trial the rates of missed urines were not different between the CM and non-CM groups. Primary assessments of treatment outcome included treatment retention, illicit opiate and cocaine use (as measured by urine toxicologies), and self-reports. During the study, subjects also participated in weekly group coping skills/relapse prevention therapy and weekly individual therapy sessions. 2.3. Laboratory tests Urine samples were analyzed for the presence of opiates and cocaine metabolites upon submission of urine sample on a thrice-weekly basis. This frequency of urine monitoring allowed us to detect most opiate and cocaine use, including any regular cocaine use. Breath analysis for alcohol was performed bi-weekly on a random basis, although current alcohol dependence was an exclusion. In addition, once weekly urine toxicologies for benzodiazepines and barbiturates were checked. A urine sample was rated positive if the quantity of drug or metabolite was 300 ng/ml for benzoylecognine or benzodiazepine metabolites and greater than 200 ng/ml for opiates. Urine toxicology results were available the next day using an on-site semi-quantitative radioimmunoassay based on the Abbott TDX system. Blood chemistries (SMA 20, CBC) and electrocardiogram (EKG) as well as a general physical examination were performed at intake. Blood levels of DMI were assessed using high-pressure liquid chromatography. A variable wavelength detector set at 210 nm was used for detection with a sensitivity of 5 ng/ml and a CV of 5% at 50 ng/ml. DMI blood levels were assessed at week 6. Due to sample loss, blood levels of DMI were not available on 30 of 160 subjects and 20 other subjects had dropped out before the week 6 bloods were drawn. 2.4. Psychosocial assessments Self reported cocaine and opiate use, as well as opiate withdrawal symptoms were assessed at baseline and weekly using instruments that we have developed in previous studies (Oliveto et al., 1999). Since the time of day for being medicated was between 07:00 and 10:00 h each day, the time of day for these ratings was also relatively standardized. Ratings were done before buprenorphine dosing. At intake, the SCID interview was completed for DSM IV psychiatric diagnoses, including depression and substance use disorders (First et al., 1995). Substance abuse related problems and

psychosocial functioning were assessed at intake using the Addiction Severity Index (ASI), a 140item structured clinical interview using both subjective and objective information to make severity ratings on ten-point scales in seven areas: alcohol and drug use, medical status, legal status, psychiatric symptoms, occupational functioning, and family/social functioning (McLellan et al., 1992). Depressive symptoms were measured at baseline and monthly using the Center for Epidemiologic Studies Depression Inventory (CES-D), and the Hamilton depression scale was used at baseline only. The Hamilton observer rated scale covers 21 symptoms with a total score of 062 and a cutoff for moderate depression of 15 or above (Hamilton, 1960). The CES-D Depression Inventory is a 20 item self-report. Item scores range from 0 to 3 and total scores from 0 to 60 with means for the general population ranging from 8 to 9 and for psychiatric patients 24 (Radloff, 1977). 2.5. Training of raters The raters had previous experience in clinical rating and interviewing and had Bachelors or Masters level education. Under supervision, the rater received 1 month of training on the ASI, SCID and DSM IV. Training included observation of interviews and ratings, co-rating, and interviewing with the supervisor present. In order to conduct interviews for this study, it was required that the rater complete three consecutive conjoint interviews in which DSM-IV diagnoses were in complete agreement with those of more experienced raters. After training, reliability was periodically spotchecked. 2.6. Data analyses Using the intent to treat sample of 160 subjects the four treatment groups were compared for baseline differences using 2 for categorical characteristics and analysis of variance (ANOVA) for continuous variables such as age, CES-D score and withdrawal symptoms. Treatment retention was then compared using survival curves with Cox proportional hazards model and chi squared analyses to compare the number of completers to 12 weeks. The amount of voucher reinforcement across groups was compared using ANOVA. Urine toxicologies were the primary outcome and also used an intent to treat sample. We compared the mean proportion of the three urine samples that were opiate and cocaine-free each week ranging between 0 and 1, as described previously (Oliveto et al., 1999). In order to make urinalyses amenable to ordinal analysis, urinalysis data were first calculated as weekly mean proportion of urines negative for the target drug. Then proportions of greater than 0.5 were recoded as 1, proportions of 0.330.5 were recoded as 2, and proportions of less than 0.33 were recoded as 3. These analyses yielded z tests that assessed the magnitude of the linear increase or decrease in data values over the course of the study as a function of DMI condition and CM group. Cocaine and opiate abstinence were analyzed separately as well as abstinence from both drugs together. We conducted 2 (DMI)2 (contingencies-CM)12 (time) hierarchical linear modeling (HLM) analyses for these comparisons and present the odds ratio (OR) of drug-free urines to total urines as a measure of difference at week 12 ( [Bryk and Raudenbush, 1987] and [Gibbons et al., 1993]). We used the mixor program of Hedeker (University of Chicago) for HLM analyses and spss for other statistics. In reporting significance levels, the HLM models included all interaction terms as well as

the main factors. When the interaction between CM and DMI was significant, we also conducted statistical contrasts between each of the four groups and the other three groups. These contrasts were designed to ascertain whether the combined DMI+CM had an additive effect on cocaine and opiate-free urines. Finally, we compared the rates of opiate and cocaine-free urines in the four treatment groups using an efficacy subsample of 139 subjects, who remained until week 3 when DMI was at a full dose of 150 mg. For comparing the DMI+CM group to the other three treatment groups we used ANOVA and the least squares difference test. Weekly self-reported opiate and cocaine use and withdrawal ratings were analyzed using HLM similarly to the urine toxicology results. Changes in depressive symptoms also were analyzed using an endpoint analysis taking the difference between baseline CES-D score and the CES-D score when leaving treatment, and comparing the four groups. Plasma DMI levels were entered as an HLM covariate in comparing urine toxicologies between the contingent and non-contingent groups. 3. Results 3.1. Baseline characteristics, treatment retention and reinforcement values The 160 subjects who were initially randomized and started on buprenorphine are compared in Table 1 on the baseline and demographic comparisons among the four treatment conditions. These subjects showed no significant differences across groups on demographics, drug and alcohol use or depressive symptoms. Heroin use was daily for almost all subjects and cocaine use was about every other day. Alcohol use was about 3 days/month and sedative use was less than 1 day/month, reflecting our exclusion criterion that urine toxicologies could not contain sedatives at admission. The Hamilton depression score indicated mild depressive symptoms with a mean score of 8 (S.D. 7), and the CES-D was 21 (S.D. 13). The 139 subjects considered in the sub-analyses for week 312 did not differ from the 160 in the complete sample on any demographic or baseline characteristics. Table 1. Means (S.D.) on baseline measures for the four treatment groups Treatment groupsa Measure

DMI+CM DMI+NCM PLA+CM PLA+NCM N Age (years) Sex (# male/female) Race (# W/AA/O)b Education (nhs/hs)c Net income ($/month)d 40 40 40 40

37.1 (8.1) 38.3 (8.0) 35.8 (6.5) 36.5 (9.0) 24/16 20/13/7 12/28 27/13 19/17/4 14/26 26/14 27/12/1 12/28 28/12 23/16/1 13/27

483 (855) 486 (766) 522 (878) 991 (1733)

Treatment groupsa Measure

DMI+CM DMI+NCM PLA+CM PLA+NCM Heroin use (# days/month)e 28.8 (4.1) 27.2 (7.2) 29.1 (2.5) 27.0 (7.6) Cocaine use (# days/month)e 13.8 (10.2) 13.4 (10.2) 16.5 (11.2) 14.0 (9.5) Sedative use (# days/month)e 0.5 (2.9) Alcohol use (# days/month)e 2.4 (3.8) Hamilton depression CES-D-depression Depressive disorder (%) Current major (%) Dysthymia (%) a Treatment groups: DMI+CM-desipramine plus contingency; Pla+CM-placebo plus contingency; DMI+NCM-desipramine plus non contingency; Pla+NCM-placebo plus non contingency. b Race: C, caucasian; AA, African-American; O, hispanic and native American (see text for details). c Education: nhs, non-high school graduate; hs, high school graduate. d Net income ($/month), dollars earned in the month prior to study entry. e #days/month, number of days used substance in the month prior to study entry. Full-size table The average retention was 9.2 weeks (S.D. 3.8) with 78 completing the trial (49%), which did not differ among the four treatment groups, as shown in Fig. 1 (Wilcoxon 0.4; df=3; NS). Primary reasons for premature termination from the study included leaving at the patient's request (n=57), 20 3 35 8 15 8 20 5 9.1 (7.2) 20 (15) 0.8 (2.8) 3.5 (7.1) 8.3 (7.9) 21 (13) 0.05 (0.2) 0.5 (2.4) 4.6 (8.6) 6.6 (6.3) 16 (13) 2.9 (4.2) 8.2 (7.3) 21 (15)

non-compliance with the study protocol (n=18) and missed medications on 3 successive days (n=10). Only eight patients were discharged because they missed more than three consecutive therapy sessions, and only seven patients left due to medical issues, which were all unrelated to the medications. The mean proportion of counseling sessions attended was 63% for weekly groups and 78% for weekly individual sessions, with no difference across the four treatment groups.

Fig. 1. Retention graph for the four treatment groups: desipramine hydrochloride (DMI) (150 mg/day) plus contingencymanagement (DMI+CM) (filled circles) or a non-contingent voucher control (DMI+NCM) (filled squares), placebo plus contingencymanagement (Pla+CM) (open circles) or a non-contingent voucher control (Pla+NCM) (open squares), in 160 opioid dependent cocaine abusers maintained on buprenorphine 16 mg daily (median dose). View thumbnail images While the two CM conditions earned equivalent weekly voucher amounts ($9.90 vs. 9.50; t=0.4; NS), as expected from the study design, the Pla+CM group ($5 [S.D. $12]) earned less than the DMI+CM ($13 [S.D. $17]) or the two non-CM groups $10 (S.D. $6) (F=3.0; df=3159; P<0.03). 3.2. Illicit cocaine and opiate abstinence during the trial As illustrated in Fig. 2 by the bi-weekly rates of opiate and cocaine-free urines, the DMI+CM group attained substantially more opiate and cocaine free urines over time than the other three groups. The HLM results showed a significant increase in both opiate and cocaine-free urines during the trial (Z=3.3; P<0.01), and significant treatment effects for both CM (CM, Z=5.6; P<0.01; timeCM interaction, Z=3.6; P<0.01) and DMI (DMI, Z=5.1; P<0.01; timeDMI interaction, Z=4.8; P<0.01). Using the HLM coefficients, the odds for opiate and cocaine-free urines to total urines at the end of the trial were largest in the DMI+CM group (1.8), smallest for the placebo (Pla) plus non CM group (1.1) and in between for the other two groups (1.5). The two treatments appeared to have an additive effect with a significant DMI by CM interaction (Z=7.8; P<0.01). In the contrast between the DMI+CM group and the other three groups, the time by treatment interaction also was

significant (Z=5.7; P<0.01), but none of the other three contrasts between an individual group and the other three groups were significant. Excluding the first 2 weeks (weeks 312), which were before DMI was at full dosing, confirmed the DMI by CM interaction (Z=5.5; P<0.01). Table 2 presents the rates of cocaine and opiate-free urines for each of the four groups at baseline and during weeks 312 of the trial. As shown using ANOVA in Table 2, the group getting DMI+CM had the largest opiate plus cocaine-free rate (50%) of the four treatments (F=3.2; df=3.138; P<0.05). As also shown in Table 2, the DMI+CM group had the most consecutive weeks of cocaine and opiate abstinence (3.0 vs. 1.3 weeks), and the largest proportion of patients having at least a month of drug abstinence (43%) compared with 19% for the other three groups.

Fig. 2. Bi-weekly percentage of opiate and cocaine-free urines for the four treatment groups: desipramine hydrochloride (DMI) (150 mg/day) plus contingencymanagement (DMI+CM) (filled circles) or a non-contingent voucher control (DMI+NCM) (filled squares), placebo plus contingencymanagement (Pla+CM) (open circles) or a non-contingent voucher control (Pla+NCM) (open squares), in 160 opioid dependent cocaine abusers maintained on buprenorphine 16 mg daily (median dose). View thumbnail images Table 2. Rates of opiate and cocaine-free urines by treatment groups and the statistical interaction between the two treatmentsDMI and CM Time perioda Treatment groupsb Significance comparing DMI+CM to Gps 24c

Drug

DMI+CM DMI+NCM Pla+CM Pla+NCM 1 2 3 4

Drug

Time perioda

Treatment groupsb

Significance comparing DMI+CM to Gps 24c

DMI+CM DMI+NCM Pla+CM Pla+NCM Cocaine Base (%) 40 30 36 32 37 1.8 (2.9) 40 49 NS 2.7/0.05

Week 312 60 (%) Weeks abstaind Opiate+cocaine Base (%) 14

3.7 (4.4) 1.9 (3.6)

2.4 (3.4) 3.4/0.05

8 29

7 25 1.2 (2.6)

14 29

NS 3.2/0.05

Week 312 50 (%) Weeks abstaind Opiate Base (%) 22

3.0 (3.9) 1.6 (3.3)

1.2 (2.5) 4.2/0.02

20 54

13 49

20 43

NS 2.1/0.1

Week 312 65 (%) a

Time period: (a) base-first week in study; (b) week 312: mean for weeks 312 of study, excluding first 2 weeks, which are before DMI started. b Treatment groups: DMI+CM-desipramine plus contingency; Pla+CM-placebo plus contingency; DMI+NCM-desipramine plus non contingency; Pla+NCM, placebo plus non contingency. c Significance: significant difference of DMI by contingency group compared with the other three treatment groups using least squares difference test and one-way ANOVA across the four treatment groups. NS, not significant; F/P, F value from ANOVA/P values for significance.

d Weeks abstain, average number of weeks of continuous abstinence. Full-size table As illustrated in Fig. 3 by the bi-weekly rates of cocaine-free urines, the DMI+CM group attained substantially more cocaine free urines than the other three groups. Cocaine free urines also showed a significant time effect (Z=3.1; P<0.01), DMI effect (DMI, Z=7.2; P<0.01) and CM effect (CM, Z=4.6; P<0.01), although only the CM by time interaction was significant (Z=2.3; P<0.05). Using the HLM coefficients, the OR for cocaine-free urines to total urines at the end of the trial was largest for the DMI+CM group (1.9), smallest for the DMI+nonCM group (1.1) and in between for the Pla+nonCM (1.65) and Pla+CM groups (1.5). The two treatments had an additive effect with a significant DMI by CM interaction (Z=8.6; P<0.01). In the contrast between the DMI+CM group and the other three groups, the time by treatment interaction also was significant (Z=2.4; P<0.02), but none of the other three contrasts between an individual group and the other three groups was significant. Considering only weeks 312 when DMI was at full dosing confirmed the DMI by CM interaction (Z=2.8; P<0.005) and showed interactions between DMI and time (Z=1.9; P<0.05) and between CM and time (Z=1.9; P<0.05) for weeks 312. As shown in Table 2 using ANOVA for weeks 312, the group getting DMI+CM had the largest cocaine-free rate (60%) of the four treatments (F=2.7; df=3.138; P<0.05). As also shown in Table 2, the DMI+CM group had the most consecutive weeks of cocaine abstinence (3.7 vs. 2.0 weeks), and the largest proportion of patients having at least a month of drug abstinence (40%) compared with 22% for the other three groups. Thus, we showed that these two treatments had a significant additive effect on cocaine use after the DMI was started in week 3.

Fig. 3. Bi-weekly percentage of cocaine-free urines for the four treatment groups: desipramine hydrochloride (DMI) (150 mg/day) plus contingencymanagement (DMI+CM) (filled circles) or a non-contingent voucher control (DMI+NCM) (filled squares), placebo plus contingencymanagement (Pla+CM) (open circles) or a non-contingent voucher control (Pla+NCM) (open squares), in 160 opioid dependent cocaine abusers maintained on buprenorphine 16 mg daily (median dose). View thumbnail images Opiate-free urines showed a significant time effect (Z=6.4; P<0.01), but no significant effects for DMI (Z=1.0) or CM (Z=1.3) using HLM. Considering only weeks 312 when DMI was at full dosing, also showed no significant DMI by CM effects or treatment by time interactions. While the group getting DMI+CM had the largest opiate-free rate (65%) of the four treatments, as shown in Table 2, this group was not significantly different from the other three (F=2.1; df=3.138; P<0.1).

Similarly, the weeks of continuous abstinence showed no significant difference among treatments. Thus, these two treatments did not have additive effects on opiate use. Self-reported opiate and cocaine use showed no significant interaction with either DMI or contingency conditions, although self-reported use decreased over time for all four treatment groups. 3.3. Depression and withdrawal symptoms Depressive symptoms on the CES-D showed a substantial time effect with HLM (Z=12.2; P<0.01), but no differences over time between DMI and placebo or between contingent and non-contingent groups. The CES-D scores for the four groups declined from baseline until the last assessment before leaving the study (endpoint) as follows: DMI+CM 12; DMI+nonCM 14; Pla+CM 8; Pla+nonCM 15. At baseline, the withdrawal symptoms were equivalent across the four treatments: DMI+CM 18; DMI+nonCM 13; Pla+CM 14; Pla+nonCM 16 (F=0.5; df=3.145; P<0.6). These withdrawal symptoms significantly declined for all four groups during the study (Z=18.6; P<0.01), but showed no significant differences between the treatments. The reduction in withdrawal symptoms during the first month (using the last weekly assessment before leaving the study, if the patient left before week 5) also was not different among the four groups: DMI+CM 12; DMI+nonCM 6; Pla+CM 6; Pla+nonCM 8 (F=0.9; df=3.145; P<0.5). After the first month, withdrawal symptoms were minimal in all four groups. 3.4. Desipramine plasma levels and side effects DMI plasma levels (125 ng/ml S.D. 135) were not significantly different between the contingency and non-contingency groups, but the increases in cocaine free urines were negatively associated with DMI plasma levels (Z=3.7; P<0.001). This negative association indicated that lower DMI levels were associated with more cocaine-free urines. Opiate free urines were not associated with the DMI plasma levels. Plasma levels did not significantly correlate with retention or with depression or withdrawal symptoms at baseline or the change in these assessments during treatment. No patients discontinued the DMI due to side effects, and as in previous studies, no serious adverse events occurred at the modest dosage of 150 mg daily ( [Oliveto et al., 1999], [Arndt et al., 1992], [Gawin et al., 1989], [Kosten et al., 1992a] and [Weddington et al., 1991]). 4. Discussion Consistent with our first hypothesis, cocaine and combined cocaine and opiate use were reduced by both CM and DMI, and the combination treatment had almost two-fold more efficacy improving cocaine free or opiate and cocaine-free urines than receiving neither CM nor DMI. In comparing the two extreme groups the calculated ORs for cocaine free urines were 1.9 for combined treatment and 1.1 for neither treatment, and during the period on DMI the cocaine-free urine rates were 60% for combined treatment and 40% for the other three treatments together. Combined cocaine and opiate urines also showed this superiority of obtaining both DMI and CM together, but opiates alone did not show superiority of the combined treatment, thereby supporting the relative specificity of this treatment combination for cocaine rather than opiates. The reduction in cocaine use by DMI with

buprenorphine, shown in our previous study, was substantially enhanced by contingencies in the present study (Oliveto et al., 1999). Our second hypothesis was also supported; like the previous study we showed no association of increased abstinence with a reduction in depressive symptoms. We did not support our third hypothesis that DMI plasma levels would be associated with opiatefree urines; instead, lower DMI levels were associated with more cocaine-free urines. In most studies CM has reduced cocaine use less in patients with combined opiate and cocaine dependence than in those patients with primary cocaine dependence. Three studies of cocaineabusing methadone-maintained patients by [Silverman et al., 1996], [Silverman et al., 1998] and [Silverman et al., 1999] are exceptions in attaining rates of abstinence that were equivalent to those reported in primary cocaine dependence ( [Higgins et al., 1991], [Higgins et al., 1993], [Higgins et al., 1994], [Jones et al., 2001], [Chutuape et al., 1999], [Silverman et al., 1996], [Silverman et al., 1998], [Silverman et al., 1999] and [Silverman et al., 2001]). Important differences from ours and others studies were that all the Silverman studies only targeted cocaine with the CM and that voucher values in one study were substantially higher than in other studies including the present study. The typical methadone treated population may be less responsive to CM than the Silverman studies suggest; Griffith's review (Griffith et al., 2000) and recent work by Preston et al. (2000) both found an effect size of 0.25 in methadone maintenance. In the HLM analyses our OR for opiate and cocaine free urines were 27% greater in the patients who got CM (OR 1.65) than in those who did not get CM (OR 1.3). Thus, CM was better than non-CM in our study and the lower rates of opiate and cocaine abstinence in our study appear more typical of the literature than are the greater rates of the Silverman studies. Finally, two studies examining CM with buprenorphine have had contrasting results. A study from Vermont using CM in patients with opiate but no concurrent cocaine dependence found excellent treatment retention and three-fold greater percentage of patients achieving 8 and 12 weeks of continuous opiate abstinence (Bickel et al., 1997). However, CM targeting combined opiate and cocaine dependence in buprenorphine maintained patients found that the CM was not effective, and the investigators suggested that targeting both heroin and cocaine may be less effective than each drug separately (Downey et al., 2000). We targeted both abused drugs in the current study, and found that the antidepressant improved the efficacy of CM for combined use and cocaine use, but not for opiate use. Future studies should examine whether CM may have greater success by targeting only cocaine, not two abused drugs, and by having higher voucher values. Our subjects also accumulated vouchers over several weeks to obtain larger reinforcements such as power tools or television sets rather than getting cash or smaller more immediate gifts. We considered such delayed reinforcement a sign of successful counseling in the use of these vouchers, although using cash directly or smaller more immediate reinforcements might improve the efficacy of CM. A previous trial also found that the antidepressant fluoxetine improved the efficacy of CM (Schmitz et al., 1998). They found that when take-home methadone doses were contingent on drug free urines, this contingency was more effective with fluoxetine at 40 mg than placebo. They suggest that the antidepressant effects of the medication may be important to reverse dysphoric symptoms and increase motivation for change, but did not specifically examine whether reductions in depressive symptoms were associated with a better outcome. In the present study we did not find that reduction in depressive symptoms was greater in the group that had the greatest increase in opiate and cocaine-free urines (DMI+CM). Thus, we found that the antidepressant added more

efficacy to the CM than Schmitz et al. found, but changes in the mild to moderate depressive symptoms in our sample did not appear to be a critical variable distinguishing the treatment groups. This study has several limitations. First, our retention rate of 49% was modest, but close to those seen in several earlier studies of buprenorphine where contingencies were not used. The high retention in the Bickel study using contingencies with buprenorphine probably was due to sample selection of primary opiate dependence without concurrent cocaine dependence (Bickel et al., 1997). In studies of buprenorphine at 8 mg daily, Johnson retained 42% of patients at week 17 and both Ling and our group retained about 50% at week 12 ( [Kosten et al., 1993], [Johnson et al., 1992] and [Ling et al., 1996]). Most recently we retained 66% of patients for 13 weeks on 12 mg buprenorphine (Oliveto et al., 1999). Thus, our retention is comparable to several other buprenorphine studies that have also included cocaine abusers. The CM did not enhance our retention probably due to a relatively low level of reinforcement attained by the CM groups (e.g. only 31% attained a month of abstinence) as well as the undemanding conditions for the non-CM patients to remain in treatment and get vouchers. The non-CM patients could miss treatment once or twice in a week and still get voucher reinforcements, while the CM group could not miss any of the daily sessions to qualify for the escalating vouchers (see Section 2). Thus, the effort required of the non-CM group to complete treatment and continue to get vouchers was less than that required of the CM group. Second, neither improvement in depressive symptoms nor the putative antidepressant mechanism for DMI efficacy through post synaptic catecholamine receptor down-regulation seem likely causes for its enhancement of the CM. Depressive symptoms were relatively low in this sample and the dose and blood levels of DMI were relatively low. If we had found that low blood levels were associated with less cocaine free urines, this might simply have reflected poor medication compliance associated with poor treatment outcome. However, the neurobiological actions of DMI at higher compared with lower blood levels may be important. Higher blood levels of DMI, such as the therapeutic range of 125300 ng/ml for depression, lead to post-synaptic down-regulation of catecholamine receptors, while lower doses only produce reuptake inhibition (Charney et al., 1981). Since our average blood level was low at 125 ng/ml, the association of less cocaine use with lower DMI levels suggests that reuptake inhibition, which is shared with cocaine, may be important for DMI efficacy in cocaine abuse. Natural reinforcement by the vouchers may have been enhanced by DMI's modest reduction in reuptake of dopamine. At high DMI doses down-regulation of postsynaptic receptors would blunt this enhanced reinforcement. In support of this hypothesis, other studies (Grabowski et al., 2001) have suggested that the reuptake inhibition and catecholamine release by modest doses of methamphetamine have had a positive therapeutic effect on cocaine dependence. Third, our opiate and cocaine-free urine rates were modest overall at 50% even in the most effective treatment group. This low rate may reflect the modest contingency amounts earned with an average of $156 for the most successful DMI+CM group and less than half that for the Pla+nonCM group. Others have used much higher voucher values and have reported higher rates of success with CM, but higher amounts may not be realistic for community programs (Petry et al., 2000). In summary, we found a significant and relatively specific reduction in cocaine use by combining DMI with CM for treating buprenorphine maintained cocaine and opiate dependent patients. This

finding was stronger than our previous study showing good efficacy of buprenorphine with DMI for cocaine abuse in this population, and no doubt reflects the added efficacy of CM (Oliveto et al., 1999). Future studies should examine other antidepressants in combination with CM for cocaine use in opiate maintenance treatment and consider other approaches to CM in the community setting (Petry et al., 2000).
Department of Psychiatry, Yale University School of Medicine, VA New England MIRECC, VA Caonnecticut Healthcare System, 950 Campbell Avenue, Bldg. 35, West Haven, CT 06516, USA

Department of Psychiatry, University of Connecticut Health Center, Farmington, CT 06030-2103, USA Department of Psychiatry, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA 23298,

USA
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Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, MI

48207, USA. Received 26 September 2002. Revised 10 January 2003. Accepted 14 January 2003. Available online 11 March 2003