A double-blind, placebo-controlled assessment of the safety of potential interactions between intravenous cocaine, ethanol, and oral disulfiram

Abstract

Background: A majority of cocaine addicts have a comorbid alcohol use disorder. Previous studies demonstrated efficacy of disulfiram in the treatment of cocaine dependence among patients with comorbid alcohol use disorder or opioid dependence. However, the cardiac risks of a disulfiram-ethanol reaction (DER) in individuals who drink, when coupled with the cardiac effects of cocaine, could result in significant toxicity or lethality due to the 3-way drug interaction.

Aims: This study examined the safety of combining cocaine (30 mg i.v.) and ethanol (0.4 g/kg i.v.) in disulfiram-treated (0, 250, and 500 mg/d, p.o.) cocaine-dependent research volunteers.

Results: The results showed that disulfiram did not enhance the cardiovascular effects of cocaine and may have reduced the subjective high from cocaine. In contrast, ethanol produced adverse ECG changes including QTc prolongation and a DER consisting of hypotension, tachycardia, nausea, and flushing in disulfiram-treated subjects. The severity of the DER was related to disulfiram dose and the trial with 500 mg/d was stopped prematurely due to safety concerns. The DER-related hypotension and tachycardia seen with ethanol infusion alone in disulfiram-treated subjects, was not exacerbated when combined with cocaine. In fact, cocaine tended to counteract the ethanol-related hypotension though it did exacerbate the tachycardia in two of seven subjects.

Conclusions: Though conclusions are limited by the moderate doses of cocaine, ethanol, and disulfiram tested, the data do suggest that the risks of the moderate use of cocaine and ethanol in individuals treated with moderate doses of disulfiram (≤ 250 mg/d) may not be as problematic as some may assume.

Figure 1

Study schematic describing the screening and baseline i.v. infusion conditions, 7 days of randomized oral treatment with disulfiram or placebo combined with four days of cocaine (or saline) and ethanol (or dextrose) infusion, and a two week safety follow-up period.

Figure 2

Diastolic Blood Pressures (mm Hg) observed on each infusion day before (Days -2 and -1) and after (Days 4–7) randomized treatment with disulfiram (250 mg/d) or placebo. The infusion conditions for each day are shown within each panel and their timing is marked by the two vertical lines. A 2 ml volume of cocaine (Coc: 30 mg) or saline was infused over 60 sec beginning at time 0. At +5 min, ethanol (Etoh) or dextrose infusions were begun. The ethanol dose was 0.4 g/kg and was delivered at the rate of 30 ml/min of a 10% solution in dextrose.

Figure 3

Heart Rates (beats per min) observed on each infusion day before (Days -2 and -1) and after (Days 4–7) randomized treatment with disulfiram (250 mg/d) or placebo. Other details are the same as in Fig.2.

Figure 4

Diastolic pressures (mmHg) and heart rates (beats per min) for the three subjects (#257, #333, and #335) treated with 500 mg/d disulfiram who received ethanol infusion on Day 6. Data shown are for the pre-randomization baseline ethanol infusion (Day -2: Sal+Etoh) and post-randomization control infusion (Day 4: Sal+Dextr), and ethanol infusions on Days 6 (Sal+Etoh) and 7 (Coc+Etoh). Note that only S#257 received infusions on Day 7 and that S#333 and #335 received rescue medication (+Dph=diphenhydramine and +PE=phenylephrine) on Day 6 due to DER. Other details are the same as in Fig.2.

Figure 5

Corrected QT (QTc) Intervals (msec) observed before (Pre) and after (Post) the i.v. cocaine(coc)/saline and ethanol(etoh)/dextrose infusions on Days 4–7 for subjects receiving placebo (n=8) or 250 mg/d disulfiram (n=7). * P indicates the significance of the Disulfiram vs. placebo difference in the Post-Pre changes in QTc.

Figure 6

Subject-rated “Feel Effects” on each infusion day before (Days -2 and -1) and after (Days 4–7) randomized treatment with disulfiram (250 mg/d) or placebo. Other details are the same as in Fig.2.