Desipramine, amantadine, or fluoxetine in buprenorphine-maintained cocaine users

Journal

of Substance

Pergamon

Abuse Treatment, Vol. 12, No. 6, pp. 423-428, 1995 Copyright 0 1995 Elsevirr Science Inc. Printed in rhe USA. All rightr reserved 0740.5472195 $9.50 + .OU

BRIEF REPORT

Desipramine, Amantadine, Buprenorphine-Maintained

or Fluoxetine in Cocaine Users

ALISON OLIVETO, PhD, THOMAS R. KOSTEN, MD, RICHARD SCHOTTENFELD, MD, JEAN FALCIONI, MA AND DOUGLAS Substance

Abuse Center,

Department

of Psychiatry,

Yale School

ZIEDONIS,

of Medicine,

34 Park

MD St., New Haven,

CT 06519

The clinical efficacy of promising cocaine anti-craving medications was examined in combination with buprenorphine. Twenty-one opioid-dependent cocaine abusers were enrolled in a double-blind, 12-week trial in which they received on a daily basis buprenorphine (8 mg, s.1.) plus either desipramine (150 mg, p.o.), amantadine (300 mg, p.o.), or fluoxetine (60 mg, p.0.). Urine samples and self-reported drug use were obtained l-3 times/week. The order of greatest patient retention across the 12 weeks was desipramine (83.3%) > amantadine (66.7%) > fluoxetine (20.0%). The desipramine and amantadine groups appeared to have greater increases in opioid- and cocainefree urines than the Juoxetine group. These results suggest that desipramine and amantadine may facilitate greater opioid and cocaine abstinence than fluoxetine. Abstract -

Keywords-

buprenorphine;

opioid

dependence;

cocaine

INTRODUCTION HAVING A HIGH ABUSE LIABILITY (Foltin & Fischman, 1991), is frequently used in combination with opioids (e.g., Kosten, Rounsaville, & Kleber, 1987). Moreover, cocaine use often increases in opioiddependent patients treated with the mu-opioid agonist methadone (Kosten, Kleber, & Morgan, 1989). Thus, it is important to discover effective pharmacotherapies that treat both opioid dependence and cocaine abuse. Recent work with the partial opioid agonist buprenorphine in cocaine-abusing opioid addicted individuals

This work was supported by grants DA05626 and DA06190 from the National Institute on Drug Abuse. A preliminary report of this work is published in NlDA Research Monograph Series, and a subset of this data are published in Am J Psychiatry 150:1755, 1993. Requests for reprints should be addressed to Alison Oliveto, PhD, Substance Abuse Center at CMHC, 34 Park St., S-106, New Haven, CT 06519.

March

20, 1995; Accepted

August

desipramine;

drug

interactions.

suggested that it may be associated with decreased cocaine use compared with methadone maintenance (Kosten et al., 1989), although this has not been replicated in double-blind comparisons of buprenorphine to methadone (Fudala, Johnson, & Jaffe, 1991; Kosten et al., 1993; Schottenfeld et al., 1994). These results indicate that it may be necessary to develop pharmacological augmentations to buprenorphine for treating cocaine-abusing opioid addicted individuals. To this end, this preliminary investigation was conducted to determine whether buprenorphine in combination with any of three medications (i.e., amantadine, desipramine, or fluoxetine) decreases opioid and cocaine use in cocaine-abusing opioid addicted individuals. These three medications were chosen because they previously have shown some efficacy in decreasing self-reported “craving” for cocaine; however, all have shown less efficacy in treating cocaine-abusing opioid addicted individuals on methadone maintenance (Bakti et al., 1991; Gawin et al., 1989; Kosten et al., 1992).

COCAINE,

Received

abuse;

2, 1995.

423

A. H. Oliveto et al.

424

METHOD Subjects Twenty-one male and female volunteers (ages 22-45) were recruited from a local methadone maintenance program (n = 2) or from the general Greater New Haven population (n = 19) after giving written informed consent to participate in a randomized clinical trial of opioid abuse pharmacotherapy. All patients had to meet the following criteria: (a) opioid dependence, as documented by current treatment in a methadone maintenance program or the precipitation of withdrawal upon administration of naloxone (0.8 mg, IM); (b) cocaine use, as documented by at least one positive cocaine urine and/or reported use of at least 14 g of cocaine over the 3-month period immediately preceding study entry; (c) no history of a psychotic episode; (d) no current alcohol or sedative physical dependence; (e) no current use of medications for psychiatric conditions; (f) women who have a negative pregnancy test and agree to effective birth control during their participation. Patients could not participate if they had (a) significant medical contra-indications to study participation (e.g., cerebral, renal, thyroid, hepatic, or cardiac pathology); (b) acute suicidality or severity of clinical condition such that inpatient treatment is indicated; (c) illiteracy and/or inability to comprehend the consent form or study procedures; (d) concurrent treatment with AZT or other medications for the treatment of AIDS. This study was approved by the Yale Human Investigations Committee. Of the 21 clients entered, 1 dropped out of the study within 1 week. His/her data will be excluded from all analyses. Three subjects who were administratively discharged from the study for reasons unrelated to their participation are not included in the retention analysis.

Medications The medications were buprenorphine hydrochloride, amantadine hydrochloride, desipramine hydrochloride, and fluoxetine hydrochloride. Buprenorphine was dissolved in 30% alcohol plus phosphate buffer and administered sublingually. To maintain the blind, the dosages of amantadine, desipramine, and fluoxetine were placed in size 00 blue opaque capsules with lactose filler.

Research Design The study consisted of a 12-week trial in which clients were randomly assigned to one of three medication groups in which they received open buprenorphine (BUP) at 8 mg/day, s.l., and one of the following: amantadine (AMA; 300 mg/day, p.0.); desipramine (DMI; 150 mg/day, p.0.); and fluoxetine (FLX; 60

mg/day, p.0.). The medication dosages were gradually increased to the maintenance dose over a 2-week period, starting at 2 mg of BUP, 100 mg of AMA, and 50 mg of DMI. Those in the FLX group received the maintenance dose immediately. Afterwards, patients who wished to continue were then switched directly from BUP to open methadone at 60 mg/day, p.o., which they received for an additional 12 weeks while continuing to receive the same study medication; these data are published elsewhere (see Oliveto, Kosten, Schottenfeld, & Ziedonis, 1993). All medications were administered under nursing supervision once daily (i.e., 7 days/wk). The principal investigator and the pharmacist were nonblind and held the code. Clients were inducted on to BUP over a 2-week period, such that they initially received a 2 mg dose/day. The dose was then increased gradually until clients received 8 mg/day by the end of week 2. Clients then were maintained on this dose for the next 10 weeks. Similarly, clients were inducted on to AMA or DMI over a l-week period, such that they initially received 100 (AMA) or 50 (DMI) mg/day; the dose was increased gradually over the first week until clients received either 300 or 150 mg/day and then were maintained on this dose for the next 11 weeks.

Experimental

Procedure

Clients first underwent a screening procedure, which included a brief psychiatric interview (see intake assessments below), physical examination, appropriate routine medical work-up, EKG, urine toxicology/screen, and, when appropriate, a pregnancy test. Clients then received a Narcan challenge (i.e., 0.8 mg of naloxone, IM) to verify opioid physical dependence, unless they were being transferred from the Methadone Maintenance Program. Immediately following the Narcan challenge, clients entered treatment and were administered the first dose of medication. Clients were treated with at least onceweekly group relapse prevention therapy in addition to the medication. Over the course of the study, subjects completed various self-reports on a weekly or monthly basis (see below). In addition, subjects submitted urine samples three times/week (MWF) to test for opioid and cocaine use. In order to continue their participation, clients could not miss completing weekly assessments or being medicated on more than two consecutive occasions. If subjects quit or were dropped from the study they underwent detoxification from the medication with an option to transfer to a naltrexone maintenance program. Those clients who successfully completed the study were given the option of participating in an outpatient naltrexone maintenance program, being followed on a drug-free basis after detoxification from opioids or entering the regular methadone maintenance program.

425

Buprenorphine Augmentation Assessments Intake assessments included the Addiction Severity Index (ASI), the Beck Depression Inventory (BDI), a Quantitative Cocaine Inventory (QCI), and an opiate withdrawal symptoms checklist. The ASI is a 140-item structured clinical interview used to provide a problem severity index covering six major areas (i.e., medical, legal, family-social, psychological, drug abuse, and employment) ( McLellan et al., 1980). Sociodemographic data are also collected on this form. This instrument has demonstrated good validity and reliability (Kosten, Rounsaville, & Kleber, 1983). The BDI, which consists of 13 items describing depressive symptoms that differ in degree of severity from 0 (nof at all) to 3 (extremely) (Beck, Ward, & Mendelson, 1961). The QCI lists questions concerning amount, frequency, route, and behavioral effects of cocaine use during the past week. The opioid intoxication/withdrawal symptoms checklist lists 43 phrases describing behavioral effects of opiate use and termination of use that are rated on a scale of 1 (not at all) to 4 (very W?UCh).

Weekly assessments included the opiate intoxication/withdrawal symptoms checklist, the QCI, a Drug Use Inventory, in which subjects reported the amount and frequency of other drugs used during the past week or month, and a Craving Scale, in which patients rated the intensity of their desire for cocaine at the time they completed the form as well as in the past week on a scale from 0 (none at all) to 24 (more than ever). In addition, the BDI was completed on a monthly basis. Urine samples were obtained thrice-weekly and tested for the presence of illicit opioids, cocaine, benzodiazepines, and their metabolites. Analyses were conducted using Abbott Diagnostics Radio Immunoassay Drug Detection System. A urine was rated positive for a given drug class if the quantity of drug or metabolite was 2 300 ng/ml (cocaine or benzodiazepines) or 2 200 ng/ml (opiates).

significant and marginally significant effects were inferred from ap I 0.05 and 0.05

RESULTS Subject characteristics were generally similar across groups (Table 1). Subjects (52.9% male; 5.9% Hispanic/94.1% White, 11.8% married/cohabiting, 35.3% employed full-time) had a mean age of 33.1 (1.4) years, and completed a mean of 11.6 (0.4) years of education. Subjects reported using heroin for a mean of 22.9 (2.8) days in the last month prior to study entry and on an average of 8.8 (1.5) years. Subjects reportedly used cocaine for a mean of 8.4 (2.5) days in the last month prior to study entry but differed by medication group in their lifetime use of cocaine, in that those in the DMI group reported significantly longer history of cocaine use than those in the FLX group (F = 5.45, p < 0.05; Duncan’s Multiple Range Test, p < 0.05). The order of greatest patient retention across the 12 weeks was DMI (83.3%) > AMA (66.7%) > FLX (20.0%). By week 7 of the study, three-fifths of the subjects in the FLX group and one-third in the AMA group had dropped out of the study (Figure 1). In the DMI group, one subject dropped out of the study by week 8. Patient retention, in terms of total number of weeks participated, did not significantly differ across medication groups. During week 1, the mean percentage of opioid-free

Patient

Retention

Data Analysis Data generally are expressed as mean (*SE) values or mean changes (weeks 3-12) from baseline (week 1) measurements. Retention data (total weeks participated) and interval subject characteristics data were entered into a one-way analysis of variance (ANOVA) with medication group (AMA, DMI, FLX) as the factor. For each subject, data from the maintenance phase (weeks 3-12) were averaged and entered into a repeated measures ANOVA with medication group and time (baseline vs. maintenance) as factors. Data during maintenance were also transformed into change from baseline scores and entered into an ANOVA with medication group as the factor. For all tests, statistically

0

1

2

3

4 5 Week

6 7 8 Number

9 101112

FIGURE 1. Subject retention in the 12-week trial. The percentage of subjects retained in the study is plotted as a function of week number for each medication group; that is, amantadine (AMA; n = 6), desipramine (DMI; II = 6), and fluoxetine (FLX;

n = 5).

426

A. H. Oliveto

et ul.

TABLE 1 Patient Characteristics of Each Medication Group; i.e., Amantadine (AMA, n = 5), Desipramine (DMI, n = 8), and Fluoxetine (FLX, n = 4) Medication Characteristic

Group

AMA

DMI

FLX

32.8 (2.8) 4Mll F 5w

32.8 (1.3) 4Ml4F 7WllB 118 cohab 12.2 (0.3) 518 unemp

34.2 (4.8) 1 MI3F 4w 114 married 11.8 (0.6) 214 unemp

9.2 20.5 11 .o 9.5

6.8 26.0 0.3 6.8

Demographics Age (yrs) Sex Race Marital status Education (yrs) Employment status

015 maricoh 10.4 (1.3) 11.5 unemp

Drug use history Heroin use (yrs) Heroin use (daysimo) Cocaine use (yrs) Cocaine use (daysimo)

Opioid-Negative

9.8 24.4 4.4 8.0

Urines

80

60

AMA

DMI

FLX

Cocaine-Negative

Urines

60 -

-40

’ AMA

DMI

Medication

FLX

Group

FIGURE 2. The mean change in percentage of opioid-free (top panel) and cocaine-free (bottom panel) urines during the last IO weeks (week 3-i 2) of the trial. Mean (?SE) change from week 1 data are plotted as a function of medication group for 5 (AMA), 8 (DMI), and 4 (FLX) subjects, respectively.

(2.1) (5.6) (1.7) (5.6)

(2.7) (6.0) (2.2) (4.1)

(3.1) (4.0) (0.2) (3.5)

urines in each group was 0.0 k 0.0 (DMI), 6.7 + 6.7 (AMA), and 8.3 f 8.3 (FLX). The mean percentage of cocaine-free urines was 16.7 & 10.5 (DMI), 20.0 f 12.2 (AMA), and 50.0 * 28.8 (FLX). After the first 2 weeks during which patients were stabilized on the medications, the percentage of opioid-free urines increased by a mean of 26.5 * 10.6 in the DMI group, 9.2 + 8.1 in the AMA group, and 7.3 ? 20.0 in the FLX group (Figure 2; top panel). The percentage of cocaine-free urines increased by a mean of 22.1 +- 10.4 and 12.8 t 17.8 in the DMI and AMA groups, respectively, and decreased by 13.9 + 13.9 in the FLX group (Figure 2; bottom panel). None of these differences were statistically significant. Self-report measures are shown in Table 2. Selfreported cocaine use in terms of the number of days, times, or dimes used did not differ across medication groups or over time. Craving for cocaine also did not differ. However, self-reported cocaine high decreased slightly but significantly from baseline during the maintenance phase (F = 5.8; p < 0.05). In addition, the amount of dollars spent on opiates significantly differed across medication groups (F = 4.02; p < 0.05) and also significantly decreased from baseline during the maintenance phase (F = 17.22; p = 0.001). Initially, self-reported opioid withdrawal symptom scores were similar across groups (Table 2); however, during the last 10 weeks of the study, scores decreased by 6.7 (4.3) and 7.5 (3.4) in the DMI and AMA groups, respectively, but showed a trend toward increasing by 6.7 (4.0) in the FLX group (med*timc trend, F= 2.75, p = 0.098). Regardless of medication group, scores on the BDI significantly decreased from baseline measures during maintenance (F = 9.88, p = 0.008).

Buprenorphine

427

Augmentation TABLE 2 Self-Report Data Medication

n

Measure

Phase

Group FLX

DMI

AMA

Mean

Cocaine

use (daysiwk)

17 17

Baseline Maintenance

2.4 1.2

(0.9) (0.6)

2.0 1.4

(0.5) (0.6)

1.5 1.2

(1.2) (0.9)

2.0 1.3

(0.4) (0.4)

Cocaine

use (times/wk)

17 17

Baseline Maintenance

6.7 2.3

(2.9) (1.6)

2.9 2.3

(1.2) (1.3)

2.9 1.9

(2.0) (1.6)

4.0 2.3

(1.1) (0.8)

Cocaine

use (dimesiwk)

14 14

Baseline Maintenance

5.2 2.2

(3.9) (1.6)

1 .2 1.0

(0.6) (0.4)

0.7 0.5

(0.7) (0.5)

2.5 1.3

(1.4) (0.6)

Cocaine

craving

17 17

Baseline Maintenance

7.6 4.3

(1.9) (2.3)

6.2 6.0

(1.7) (1.5)

4.4 4.2

(3.6) (2.6)

6.2 5.1

(1.2) (1 .l)

Cocaine

high (scale

12 12

Baseline Maintenance

4.4 3.8

(0.4) (0.7)

2.7 2.8

(0.8) (0.4)

5.0 3.1

(1.0) (0.9)

3.6 3.2

(0.5) (0.3)

17 17

Baseline Maintenance

(scale)

17 17

Baseline Maintenance

69.3 61.8

O-39)

15 15

Baseline Maintenance

9.2 4.8

Opiate

O-20)

O-l 0)

use (dollarsiwk)

Withdrawal Beck

(scale

score

score (scale

Values represent the mean (?SE). obtained during weeks 3-l 0.

Baseline

data were obtained

278 98

dunng

DISCUSSION These results suggest that the DMI group had the greatest retention and FLX the least. Although baseline rates differed somewhat, the DMI and AMA groups also appeared to show greater opioid and COCaine abstinence than the FLX group. In addition, opioid withdrawal ratings tended to decrease in the DMI and AMA groups but increase in the FLX group, suggesting that FLX may have less utility as an adjunctive medication for opioid/cocaine abuse than DMI or AMA. Interestingly, the quality of the cocaine high reportedly decreased over the course of the study regardless of medication group. This may be buprenorphineinduced. For instance, buprenorphine reportedly decreases cocaine self-administration in primates (Mello, Mendelson, Bree, & Lucas, 1989; Mello, 1991) and cocaine place-preference in rats (Kosten et al., 1991). In humans, however, the interactions between buprenorphine and cocaine seem more complex. For instance, acute doses of buprenorphine enhance the effects of cocaine (Foltin & Fischman, 1994; Rosen et al., 1993), but this buprenorphine-induced enhancement is attenuated within a few days of buprenorphine maintenance (Rosen et al., 1993). Thus, although these results suggest that cocaine’s effects are enhanced by acute exposure to buprenorphine, they may be attenuated on chronic exposure. Whether the decrease in depression scores is due to

118

(43)

23

(7)

(10.0) (7.4)

67.4 60.7

(5.6) (4.6)

70.5 77.2

(10.4) (10.8)

(3.0) (2.8)

5.8 4.2

(1.7) (1.4)

9.0 4.8

(3.3) (1.6)

(56) (48)

intake and week

1 of the study,

156 74

(26) (34)

whereas

174 57

(31) (17)

68.7 64.9

maintenance

(4.3) (4.1)

7.8 4.6

(1.4) (1.1)

data were

buprenorphine is also not clear. However, low doses (0.2 mg/day, s.1.) of buprenorphine have been shown to decrease depression ratings relative to placebo in non substance-abusing depressed individuals (Emrich, Vogt, & Herz, 1982), suggesting that the reduction in depression may be buprenorphine-related. Overall, these findings suggest that further study of buprenorphine maintenance with medications such as desipramine or amantadine for treating opioid and cocaine abuse is warranted. At present, a clinical trial is underway, in which the efficacy of desipramine in combination with either buprenorphine or methadone is examined in opioid-dependent cocaine abusers.

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Academy of Science, 398, 108-I 12. Foltin, R.W., & Fischman, M.W. (1991). Assessment of abuse liability of stimulant drugs in humans: A methodological survey.

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