Desipramine and contingency management for cocaine and opiatedependence in buprenorphine maintained patients

Thomas Kosten a,*, Alison Oliveto a, Alan Feingold a, James Poling a, Kevin Sevarino b,Elinore McCance-Katz c, Susan Stine d, Gerardo Gonzalez a, Kishor Gonsai a

a 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, USAb Department of Psychiatry, University of Connecticut Health Center, Farmington, CT 06030-2103, USA

c Department of Psychiatry, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA 23298, USAd Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, MI 48207, USA

Received 26 September 2002; received in revised form 10 January 2003; accepted 14 January 2003

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, contingency management (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 (25�/29%). 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.

# 2003 Elsevier Science Ireland Ltd. All rights reserved.

Keywords: Contingency management; Desipramine; Buprenorphine; Clinical trial; Cocaine dependence; Opiate dependence

1. Introduction

Opiate and cocaine dependence are major health

problems in the United States and associated with

medical complications such as human immunodefi-

ciency virus (HIV) infection, hepatitis infection and

endocarditis, and social issues such as unemployment

and illegal activity. Methadone or buprenorphine main-

tenance can improve opiate problems, but neither

medication targets cocaine abuse and, indeed, cocaine

use may increase in some methadone-maintained pa-

tients (Kosten et al., 1987; Zweben and Payte, 1990;

Sorensen and Copeland, 2000; 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,

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 com-

bined opiate and cocaine dependence such as the

addition of other medications and/or behavioral thera-

pies to opiate maintenance.

* Corresponding author. Tel.: �/1-203-932-5711x7438; fax: �/1-203-

937-4915.

E-mail address: thomas.kosten@yale.edu (T. Kosten).

Drug and Alcohol Dependence 70 (2003) 315�/325

www.elsevier.com/locate/drugalcdep

03765-8716/03/$ - see front matter # 2003 Elsevier Science Ireland Ltd. All rights reserved.

doi:10.1016/S0376-8716(03)00032-2

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. Pre-vious studies had found that in methadone maintained

patients DMI was not effective in reducing cocaine

abuse (Arndt et al., 1992; 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, 1992b,

1993; Schottenfeld et al., 1993, 1997). However, werecently 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 buprenor-

phine 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 contingency

management (CM) might be due to its antidepressant

effect (Schmitz et al., 1998). Thus, combining bupre-

norphine 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 behavioraltreatment*/CM, 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, 1995; McLellan et

al., 1993; Carroll et al., 1995; Bigelow et al., 1984; Stitzer

et al., 1979, 1982, 1992; Stitzer and Bigelow, 1978;

Iguchi et al., 1988; Magura et al., 1988; Milby et al.,

1978; McCaul et al., 1984). Several notable studies haveindicated that CM can be quite potent in an opiate

maintenance setting such as methadone, although re-

view 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, 1998,

1999, 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 de-

pendence on opiates and cocaine. We had three hypoth-

eses. 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 anadditive 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 asso-ciated 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 21�/65, 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 fulfilledthe Diagnostic and Statistical Manual of Mental Dis-

orders (DSM-IV) criteria for opiate and cocaine depen-

dence, 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 toread 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 contra-

ception to prevent pregnancy during the study; (3)

understood the risks of fetal toxicity due to medicationswhile 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) pluscontingencies, DMI without contingencies, placebo

plus contingencies, placebo without contingencies (n�/

40 per cell). Treatment occurred in an outpatient

methadone maintenance facility, where sublingual bu-

prenorphine 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 averagedose 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

T. Kosten et al. / Drug and Alcohol Dependence 70 (2003) 315�/325316

and the highest average dose of 16.6 mg for the CM plus

placebo group (F�/1.0; P B/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 4-week taper off buprenor-

phine before starting in a community methadone

program.

Urines were collected under observation on Monday,

Wednesday and Friday each week before being medi-

cated 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 1�/12

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. Dur-

ing 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 urinetoxicologies 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 electrocardio-

gram (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 notavailable 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 inprevious 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 bu-

prenorphine dosing.

At intake, the SCID interview was completed for

DSM IV psychiatric diagnoses, including depression

and substance use disorders (First et al., 1995). Sub-stance abuse related problems and psychosocial func-

tioning were assessed at intake using the Addiction

Severity Index (ASI), a 140-item structured clinical

interview using both subjective and objective informa-

tion 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

T. Kosten et al. / Drug and Alcohol Dependence 70 (2003) 315�/325 317

depression scale was used at baseline only. The Hamil-

ton observer rated scale covers 21 symptoms with a total

score of 0�/62 and a cutoff for moderate depression of 15

or above (Hamilton, 1960). The CES-D DepressionInventory 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 leveleducation. 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 experiencedraters. After training, reliability was periodically spot-

checked.

2.6. Data analyses

Using the intent to treat sample of 160 subjects the

four treatment groups were compared for baseline

differences using x2 for categorical characteristics andanalysis 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 alsoused 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 of0.33�/0.5 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) hierarchicallinear 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; 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 includedall 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 com-

bined 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 treatmentgroups 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 depressivesymptoms also were analyzed using an endpoint analysis

taking the difference between baseline CES-D score and

the CES-D score when leaving treatment, and compar-

ing 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 nosignificant 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 symptomswith 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 3�/12 did not differ from the 160 in

the complete sample on any demographic or baseline

characteristics.

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 pre-

mature termination from the study included leaving at

the patient’s request (n�/57), non-compliance with the

T. Kosten et al. / Drug and Alcohol Dependence 70 (2003) 315�/325318

study protocol (n�/18) and missed medications on 3

successive days (n�/10). Only eight patients were

discharged because they missed more than three con-

secutive therapy sessions, and only seven patients left

due to medical issues, which were all unrelated to the

medications. The mean proportion of counseling ses-

sions attended was 63% for weekly groups and 78% for

weekly individual sessions, with no difference across the

four treatment groups.

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 B/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 B/0.01),

and significant treatment effects for both CM (CM, Z�/

5.6; P B/0.01; time�/CM interaction, Z�/3.6; P B/0.01)and DMI (DMI, Z�/5.1; P B/0.01; time�/DMI inter-

action, Z�/4.8; P B/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 B/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 B/0.01), but

Table 1

Means (S.D.) on baseline measures for the four treatment groups

Measure Treatment groupsa

DMI�/CM DMI�/NCM PLA�/CM PLA�/NCM

N 40 40 40 40

Age (years) 37.1 (8.1) 38.3 (8.0) 35.8 (6.5) 36.5 (9.0)

Sex (# male/female) 24/16 27/13 26/14 28/12

Race (# W/AA/O)b 20/13/7 19/17/4 27/12/1 23/16/1

Education (nhs/hs)c 12/28 14/26 12/28 13/27

Net income ($/month)d 483 (855) 486 (766) 522 (878) 991 (1733)

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) 0.8 (2.8) 0.05 (0.2) 0.5 (2.4)

Alcohol use (# days/month)e 2.4 (3.8) 3.5 (7.1) 4.6 (8.6) 2.9 (4.2)

Hamilton depression 9.1 (7.2) 8.3 (7.9) 6.6 (6.3) 8.2 (7.3)

CES-D-depression 20 (15) 21 (13) 16 (13) 21 (15)

Depressive disorder (%)

Current major (%) 20 35 15 20

Dysthymia (%) 3 8 8 5

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.

Fig. 1. Retention graph for the four treatment groups: desipramine

hydrochloride (DMI) (150 mg/day) plus contingency management

(DMI�/CM) (filled circles) or a non-contingent voucher control

(DMI�/NCM) (filled squares), placebo plus contingency management

(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).

T. Kosten et al. / Drug and Alcohol Dependence 70 (2003) 315�/325 319

none of the other three contrasts between an individual

group and the other three groups were significant.

Excluding the first 2 weeks (weeks 3�/12), which were

before DMI was at full dosing, confirmed the DMI by

CM interaction (Z�/5.5; P B/0.01). Table 2 presents the

rates of cocaine and opiate-free urines for each of the

four groups at baseline and during weeks 3�/12 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 B/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.

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 B/0.01), DMI effect

(DMI, Z�/7.2; P B/0.01) and CM effect (CM, Z�/4.6;

P B/0.01), although only the CM by time interaction

was significant (Z�/2.3; P B/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 interac-

tion (Z�/8.6; P B/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 B/0.02), but none of the other three contrasts between

an individual group and the other three groups was

significant. Considering only weeks 3�/12 when DMI

was at full dosing confirmed the DMI by CM interac-

tion (Z�/2.8; P B/0.005) and showed interactions be-

Fig. 2. Bi-weekly percentage of opiate and cocaine-free urines for the

four treatment groups: desipramine hydrochloride (DMI) (150 mg/

day) plus contingency management (DMI�/CM) (filled circles) or a

non-contingent voucher control (DMI�/NCM) (filled squares), place-

bo plus contingency management (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).

Table 2

Rates of opiate and cocaine-free urines by treatment groups and the statistical interaction between the two treatments*/DMI and CM

Drug Time perioda Treatment groupsb Significance comparing DMI�/CM to Gps 2�/4c

DMI�/CM DMI�/NCM Pla�/CM Pla�/NCM

1 2 3 4

Cocaine

Base (%) 40 30 32 40 NS

Week 3�/12 (%) 60 36 37 49 2.7/0.05

Weeks abstaind 3.7 (4.4) 1.9 (3.6) 1.8 (2.9) 2.4 (3.4) 3.4/0.05

Opiate�/cocaine

Base (%) 14 8 7 14 NS

Week 3�/12 (%) 50 29 25 29 3.2/0.05

Weeks abstaind 3.0 (3.9) 1.6 (3.3) 1.2 (2.6) 1.2 (2.5) 4.2/0.02

Opiate

Base (%) 22 20 13 20 NS

Week 3�/12 (%) 65 54 49 43 2.1/0.1

a Time period: (a) base-first week in study; (b) week 3�/12: mean for weeks 3�/12 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.

T. Kosten et al. / Drug and Alcohol Dependence 70 (2003) 315�/325320

tween DMI and time (Z�/1.9; P B/0.05) and between

CM and time (Z�/1.9; P B/0.05) for weeks 3�/12. As

shown in Table 2 using ANOVA for weeks 3�/12, the

group getting DMI�/CM had the largest cocaine-free

rate (60%) of the four treatments (F�/2.7; df�/3.138;

P B/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.

Opiate-free urines showed a significant time effect

(Z�/6.4; P B/0.01), but no significant effects for DMI

(Z�/�/1.0) or CM (Z�/�/1.3) using HLM. Considering

only weeks 3�/12 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 B/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 sub-

stantial time effect with HLM (Z�/12.2; P B/0.01), butno 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 (end-

point) as follows: DMI�/CM 12; DMI�/nonCM 14;

Pla�/CM 8; Pla�/nonCM 15.

At baseline, the withdrawal symptoms were equiva-

lent across the four treatments: DMI�/CM 18; DMI�/

nonCM 13; Pla�/CM 14; Pla�/nonCM 16 (F�/0.5;

df�/3.145; P B/0.6). These withdrawal symptoms sig-

nificantly declined for all four groups during the study

(Z�/18.6; P B/0.01), but showed no significant differ-

ences between the treatments. The reduction in with-

drawal 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 amongthe four groups: DMI�/CM 12; DMI�/nonCM 6; Pla�/

CM 6; Pla�/nonCM 8 (F�/0.9; df�/3.145; P B/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 B/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 reten-

tion or with depression or withdrawal symptoms atbaseline 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; 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 receivingneither 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 treat-

Fig. 3. Bi-weekly percentage of cocaine-free urines for the four

treatment groups: desipramine hydrochloride (DMI) (150 mg/day)

plus contingency management (DMI�/CM) (filled circles) or a non-

contingent voucher control (DMI�/NCM) (filled squares), placebo

plus contingency management (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).

T. Kosten et al. / Drug and Alcohol Dependence 70 (2003) 315�/325 321

ment, 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 superiorityof 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 hypoth-esis 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 opiate-free urines; instead,

lower DMI levels were associated with more cocaine-

free urines.

In most studies CM has reduced cocaine use less inpatients with combined opiate and cocaine dependence

than in those patients with primary cocaine dependence.

Three studies of cocaine-abusing methadone-maintained

patients by Silverman et al. (1996, 1998, 1999) are

exceptions in attaining rates of abstinence that were

equivalent to those reported in primary cocaine depen-

dence (Higgins et al., 1991, 1993, 1994; Jones et al.,

2001; Chutuape et al., 1999; Silverman et al., 1996, 1998,1999, 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 main-

tenance. 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 Silvermanstudies. Finally, two studies examining CM with bupre-

norphine have had contrasting results. A study from

Vermont using CM in patients with opiate but no

concurrent cocaine dependence found excellent treat-

ment 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 buprenor-phine 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 com-

bined use and cocaine use, but not for opiate use. Future

studies should examine whether CM may havegreater 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 directlyor smaller more immediate reinforcements might im-

prove 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 con-

tingency was more effective with fluoxetine at 40 mg

than placebo. They suggest that the antidepressanteffects of the medication may be important to reverse

dysphoric symptoms and increase motivation for

change, but did not specifically examine whether reduc-

tions 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 thatthe 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 contin-gencies were not used. The high retention in the Bickel

study using contingencies with buprenorphine probably

was due to sample selection of primary opiate depen-

dence 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; 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 undemandingconditions 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

T. Kosten et al. / Drug and Alcohol Dependence 70 (2003) 315�/325322

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 125�/300

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

post-synaptic 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 stron-

ger 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).

Acknowledgements

Supported by the National Institute on Drug Abuse

grants R01-DA05626 (TRK), K05-DA0454 (TRK),P50-DA009250, and the Veterans Administration Men-

tal Illness Research, Education and Clinical Center

(MIRECC).

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