Chronic disulfiram treatment effects on intranasal cocaine administration: Initial results

BRIEF REPORTS

Chronic Disulfiram Treatment Effects on Intranasal Cocaine Administration: Initial Results Elinore F. McCance-Katz, Thomas R. Kosten, and Peter Jatlow Background: Simultaneous abuse of cocaine and alcohol is common. Alcohol decreases negative stimulant effects and potentiates "high." Disulfiram (Antabuse) is being studied in outpatient trials as a cocaine pharmacotherapy with the rationale that inabili~ to modulate cocaine effects with alcohol may decrease cocaine use. Methods: We examined the interaction of disulfiram and cocaine in a randomized, double-blind, placebo-controlled study where subjects were chronically treated with disulfiram and then participated in intranasal cocaine administration studies. Results: Disulfiram 250 mg/day treatment significantly increased plasma cocaine concentrations (p = .013), heart rate (cocaine 1 mg/kg, p = .046), and systolic (cocaine 2 mg/kg p = .003) and diastolic (cocaine 2 mg/kg, p = .022) blood pressure. "High" and "nervous" ratings were nonsignificantly increased. Conclusions: The combination of "high" with increased anxie~ in the context of inabili~.' to lessen negative effects with alcohol may be an effective treatment in selected patients. The significant pharmacokinetic interaction must be considered in the decision regarding use of disu!~ram. Biol Psychiatry 1998;43:540-543 © 1998 Society of Biological Psychiato' Key Words: Cocaine, alcohol, disulfiram, Antabuse, pharmacotherapy, drug interaction

Introduction Cocaine abuse is a serious public health problem that has defied the development of an effective pharmacotherapy. The rate of comorbid cocaine-alcohol abuse is estimated to be as high as 62-90% (Weiss et al 1988; Grant and Harford 1990), and cocaine abusers frequently report that use of alcohol during a cocaine binge prolongs the euphorigenic properties of cocaine (the "high"), relieves paranoia and stimulation during the binge, and diminishes acute abstinence symptoms. Furthermore, simultaneous From the Veterans Affairs Medical Center, West Haven, Connecticut (EFMK, TRK); and Department of Psychiatry (EFMK, TRK, PJ) and Department of Laboratory Medicine (P J), Yale University School of Medicine, New Haven, Connecticut. Address reprint requests to Elinore F. McCance-Katz, MD, PhD, VA Connecticut Health Care System, West Haven Campus, Department of Psychiatry, 116-A, 950 Campbell Ave., West Haven, CT 06516. Received March 27, 1997; revised June 10, 1997; accepted July 23, 1997.

© 1998 Society of Biological Psychiatry

consumption of cocaine and alcohol results in formation of an active metabolite with cocaine like properties, cocaethylene, which could contribute to toxicity during a cocaine binge (McCance et al 1995). Therefore, we have examined the use of disulfiram (Antabuse) as a potential treatment for cocaine-dependent patients who also abuse alcohol. We report initial results of a double-blind, placebocontrolled, within-subjects study to determine the safety and potential efficacy of disulfiram treatment for cocaine dependence.

Methods and Materials Six volunteers meeting DSM-IV criteria for cocaine dependence and alcohol abuse or dependence participated [4 African-American, 2 Caucasian; 2 women; age 31.8 (0.6) years, mean (standard error)]. All gave written informed consent and resided on an inpatient research unit. Participants reported on here were a subset of a larger within-subjects, double-blind, placebocontrolled study (n -= 7) with random assignment to study medications in which subjects were treated chronically with each of three doses of disulfiram (0,250 rag/day or 500 rag/day) and then underwent cocaine administration studies. Because 2 subjects dropped out prior to completion, we report on the initial results of the 6 subjects who completed the disulfiram placebo and 250 rag/day arms of the study. Subjects received disulfiram 250 mg/day, or placebo dosed at 9 PM. After 3 days of disulfiram treatment (based on time necessary for disulfirarn to inhibit aldehyde dehydrogenase) (Helander and Carlsson 1990), subjects participated in cocaine (l mg/kg, 2 mg/kg, or placebo) administration sessions (one session daily for 3 days;). Disulfiram study drugs were separated by at least 5 days {washout period) based on the time needed for enzyme regeneration (Helander and Carlsson 1990). Intranasal cocaine administration sessions included physiological (heart rate, systolic and diastolic blood pressure) monitoring, blood sampling (via intravenous catheter), and observation of subjective effects using visual analog scales (Fischman et al 1983) at baseline and predetermined time points for 480 rain. Analysis of cocaine from plasma samples was conducted as previously described (Jatlow et al 1991). Pharmacokinetics parameters were calculated from cocaine concentrations as previously described (McCance-Katz et al 1993). Area under the curve (AUC) values were computed for each dependent cardiovascular and subjective measure under each of the six study session conditions and were analyzed within a two-factor repeated-measures analysis of variance (ANOVA). Results were considered statistically significant when p < .05 (two tailed). 0006-3223/98/519.00 Pit S0006-3223(97100506-4

Disulfiram Effects on Cocaine

BIOL PSYCHIATRY 1998;43:540-543

550-

•

500-

541

Cocaine 2mg,/kg(itl.) I)isulflritm2.50mg Cocaine 2mg/kg(i.n.) DisulRramplacebo

450 = 400-

Cocaine Img/kg (i,n.) Di~alfiram250mg

350-

Cocaine im~kg (i.n)

+

Di~ulf~amPl~.~bo

30025020()150-

Figure l. Mean plasma cocaine concentrations following administration of cocaine 1 rng/kg and 2 mg/kg over time after chronic treatment with disulfiram 250 rag/day or disulfiram placebo. i.n., intranasal.

10050-

0rF 0

10

I 60

I 90

I 120

I 180

I 240

i 300

I 360

I 420

480

T~e{~ns)

Results Disulfiram 250 mg/day, significantly increased cocaine concentrations relative to placebo (Figure 1). AUC for cocaine 1 mg/kg-disulfiram 250 mg/day, was 78,628 (14,187) ng • mirdmL and for cocaine 1 mg/kg alone was 25,464 (2,983) ng" min/mL (F = 14.1, df = 1,5p = .0131. AUC for cocaine 2 mg/kg-disulfiram 250 mg/day, was 219,267 (43,013) ng • min/mL, while cocaine 2 mg/kg "alone was 49,910 (9,529) ng" min/mL (IF = 15.5, df = 1,5 p -- .011). Elimination of half-life (tV2) was increased following disulfiram treatment [tV2 cocaine 1 mg/kgdisulfiram 250 mg/day, was 135 (18.21 rain, and cocaine 1 mg/kg alone was 83 (3.2) min (F = 9.9, df = 1 , 5 p = .026); tV2 cocaine 2 mg/kg-disulfiram 250 mg/day was 190 (26.2) rain, and cocaine 2 mg/kg alone was 89 (4.0) rain (F = 14.0, df = 1,5, p = .013)]. Disulfiram significantly increased heart rate following

cocaine administration (Table 1), with peak heart rates of 92-95 bpm observed 30--6(I rain following cocaine administration. Systolic and diastolic blood pressure significantly increased relative to cocaine alone administration only after administration of cocaine 2 mg/kg Disulfiram treatment increased ratings of "high" for both cocaine doses, but this approached statistical significance only for the cocaine 2 mg/kg dose (F = 6.0, df --: 1,5, p = .058) (Table 1). Disulfiram increased ratings of anxiety for cocaine 2 mg/kg, approaching statistical significance (F = 4.3, df = 1,5, p = .083) (Table 11.

Discussion Disulfiram 250 mg daily, a dose regularly used in the treatment of alcoholism, has significant effects on responses to acute intranasal cocaine administration. Disulfiram treatment significantly increased plasma cocaine

Table 1. Summary of Cardiovascular and Behavioral Data D S 2 5 0 rag/day vs. Pla

Variable

Cocaine ( m g / k g )

Heart rate (bpm • min) Systolic blood pressure ( m m H g • min) Diastolic blood pressure ( m m H g • min) " H i g h " ( m m - rain)

"Nervous" ( m m • rain)

AUC

mean (SE). DS, disulfiram; Pla, placebo.

2 5 0 mg

Placebo

F

p value

(9161

3 6 4 7 5 (1678)

6.9

.046

43323(15161

3 7 5 2 5 ( 14651

6.1

.057

61761 (1645)

59320 (1590)

65150(17361

5 9 5 1 4 ( 11338)

27.4

.003

33168(1650)

3 2 3 6 6 ( 13371

3 4 6 9 5 (16571

3 1 2 8 8 (14361

10.8

.022

6.0

.058

4.3

.083

40189

2633 (1216)

1596

(5(151

4187 ([366)

1819

(726)

(539)

581

(375)

2588(17141

509

(438)

539

ns ns ns ns

542

BIOL PSYCHIATRY 1998;43:540-543

concentration AUC and approximately doubled elimination half-life. Disulfiram inhibits both plasma and microsomal carboxylesterases and plasma cholinesterase (Faiman 1979), which are the primary pathways for cocaine metabolism (Benowitz 1993) and may explain the significant effect on cocaine pharmacokinetics. A similar effect on plasma cocaine concentration was found in our earlier pilot study (Hameedi et al 1995), but the design of this study better approximated outpatient treatment conditions and permitted fuller assessment of pharmacokinetics, and cardiovascular and subjective effects by increasing the observation period following cocaine administration. Following disulfiram treatment, cocaine significantly increased heart rate, and the high dose of cocaine significantly increased blood pressure. These indices remained elevated when plasma cocaine concentrations were declining at later time points and were greatest for cocaine 2 mg/kg. These findings are in contrast to those obtained when multiple doses of cocaine alone have been administered to human volunteers, where evidence for development of acute tolerance to cardiovascular effects was found (Fischman et al 1985; Ambre et al 1988; Foltin and Fischman 1991). While findings in this study remained in a medically safe range, there is potential for increased cocaine toxicity with disulfiram treatment. This should be an important consideration in determining whether disulfiram treatment is appropriate for a given patient. Behavioral responses to the disulfiram-cocaine combination provide an insight as to the possible basis for disulfiram as a treatment for cocaine dependence. Overall, cocaine "high" is somewhat greater with disulfiram, but this may be coupled with anxiety. The combination of "high" with anxiety may be unpleasant and less reinforcing, interrupting binge cocaine use in some who would usually consume alcohol to alleviate such effects, but would be unable to do so during disulfiram treatment. In this study, non-treatment-seeking, cocaine-dependent subjects were recruited for participation. At the conclusion of the study, as is our customary practice in these studies, all were offered follow-up treatment in an outpatient cocaine treatment program, and they were also given the option of electing continued treatment with disulfiram 250 mg/day, for 6 months at no charge if they thought it would help in cessation of their cocaine use. Five subjects elected outpatient treatment; however, all refused continued disulfiram treatment. Clinical interviews prior to discharge revealed that the primary reasons for not accepting disulfiram treatment included negative effects (e.g., anxiety) experienced following active disulfiram treatment and cocaine administration and lack of motivation to stop alcohol use. Disulfiram is being investigated in clinical settings as a treatment for cocaine-alcohol abuse. We reported an open

McCance-Katz et al

pilot study comparing disulfiram 250 rag/day, to naltrexone 50 mg/day, and found that disulfiram reduced both cocaine and alcohol use (Carroll et al 1993). Van Etten et al (1994) also reported that disulfiram 250 nag/day, decreased cocaine and alcohol use in their patient sample. Subsequently, our research group has conducted an outpatient, controlled, double-blind, randomized trial (n :-122), where disulfiram 250 mg/day, was administered in combination with psychotherapy for cocaine-dependent, alcohol-abusing patients, which confirms the benefits of this pharmacotherapy. Few adverse events were observed in this study (Carroll et al in press). Disulfiram may have potential as a treatment for cocaine-alcohol abuse, but could also increase the risk of toxicity as a consequence of its pharmacokinetic interaction with cocaine. In ongoing studies, we plan to determine whether lower doses of disulfiram might be more efficacious for treatment of cocaine-alcohol use disorders.

Supported in part by NIDA grants K20-DA00216 (EFMK). K02DA00tl2 (TRK), R29-DA09573, P50-DA04060, and NIH-M01RR00125 (General Clinical Research Center).

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Disulfiram Effects on Cocaine

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