Compliance to supervised disulfiram therapy: a comparison of voluntary and court-ordered patients

We hypothesized that court mandate would significantly enhance compliance with supervised disulfiram therapy. We conducted a twelve-week prospective study of outpatient compliance with court-ordered, monitored disulfiram treatment as compared to voluntary, monitored treatment. The court ordered group (n=19) was significantly more compliant than the voluntary group (n=22). Legally mandated subjects attended an average of 87% (+/-21%) of scheduled visits, versus 42% (+/-35%) for the group without court order. Court mandate roughly doubles the compliance rate of monitored disulfiram therapy, effectively enhancing clinic attendance during the first twelve weeks of treatment.     

Disulfiram for the treatment of alcoholism. An evaluation in 128 men.

One hundred twenty-eight alcoholic men were assigned randomly to receive either a regular dose of disulfiram (250 mg), a pharmacologically inactive dose (1 mg), or no disulfiram. There were no statistically significant differences among the three treatment groups in total abstinence, percentage of drinking days, days worked, family stability (living with same relative), or percent of scheduled appointments kept. However, 21% of those who received the regular dose of disulfiram and 25% who received the pharmacologically inactive dose remained abstinent, whereas only 12% of those who received no disulfiram did so. These results indicate that disulfiram may be of limited value in the treatment of alcoholism, fear of the disulfiram-ethanol reaction is important in preventing drinking, and patients willing to take disulfiram are more likely to be abstinent if given the drug. We also found that complete abstinence correlated significantly with compliance and obtaining employment.     

Techniques to Enhance Compliance with Disulfiram

Pharmacodynamic benefits of disulfiram in the treatment of alcoholism have yet to be clearly demonstrated. Nevertheless, research does suggest that disulfiram may well have positive effects on drinking if medicational compliance procedures are employed. This paper reviews research on four strategies for enhancing disulfiram compliance: implants, incentives, contracts, and patient information. Generalizations about the strategies are drawn and needs for future research are briefly addressed.     

Disulfiram treatment for cocaine dependence in methadone-maintained opioid addicts

Aims: Cocaine use by patients on methadone maintenance treatment is a widespread problem and is associated with a poorer prognosis. Recent studies have evaluated disulfiram as a treatment for individuals with comorbid alcohol and cocaine abuse. We evaluated the efficacy of disulfiram for cocaine dependence, both with and without co-morbid alcohol abuse, in a group of methadone-maintained opioid addicts. Design: Randomized double-blind, placebo-controlled trial. Setting: Urban methadone maintenance clinic. Participants: Sixty-seven cocaine-dependent, methadone-maintained, opioid-dependent subjects (52% female; 51% Caucasian). Intervention: Study medication, either disulfiram or placebo, was placed directly in the methadone to ensure compliance for 12 weeks. Measurements: Primary outcome measures included weekly assessments of the frequency and quantity of drug and alcohol use, weekly urine toxicology screens and breathalyzer readings. Findings: Disulfiram treated subjects decreased the quantity and frequency of cocaine use significantly more than those treated with placebo. Alcohol use was minimal for all subjects regardless of the medication. Conclusions: Disulfiram may be an effective pharmacotherapy for cocaine abuse among methadone-maintained opioid addicts, even in those individuals without co-morbid alcohol abuse. Disulfiram inhibits dopamine beta-hydroxylase resulting in an excess of dopamine and decreased synthesis of norepinephrine. Since cocaine is a potent catecholamine re-uptake inhibitor, disulfiram may blunt cocaine craving or alter the "high", resulting in a decreased desire to use cocaine.     

Treatment of cocaine and alcohol dependence with psychotherapy and disulfiram

Aims. To evaluate disulfiram and three forms of manual guided psychotherapy for individuals with cocaine dependence and concurrent alcohol abuse or dependence. Design. Randomized controlled trial. Setting. Urban substance abuse treatment center. Participants. One hundred and twenty-two cocaine/alcohol abusers (27% female; 61% African-American or Hispanic). Interventions. One of five treatments delivered over 12 weeks: cognitive behavioral treatment (CBT) plus disulfiram; Twelve Step facilitation (TSF) plus disulfiram; clinical management (CM) plus disulfiram; CBT plus no medication; TSF plus no medication. Measurements. Duration of continuous abstinence from cocaine or alcohol; frequency and quantity of cocaine and alcohol use by week, verified by urine toxicology and breathalyzer screens. Findings. Disulfiram treatment was associated with significantly better retention in treatment, as well as longer duration of abstinence from alcohol and cocaine use. The two active psychotherapies (CBT and TSF) were associated with reduced cocaine use over time compared with supportive psychotherapy (CM). Cocaine and alcohol use were strongly related throughout treatment, particularly for subjects treated with disulfiram. Conclusions. For the large proportion of cocaine-dependent individuals who also abuse alcohol, disulfiram combined with outpatient psychotherapy may be a promising treatment strategy. This study underlines (a) the significance of alcohol use among treatment-seeking cocaine abusers, (b) the promise of the strategy of treating co-morbid disorders among drug-dependent individuals, and (c) the importance of combining psychotherapy and pharmacotherapy in the treatment of drug use disorders.     

Methods for Detecting Disulfiram in Biologic Fluids: Application in Studies of Compliance and Effect of Divalent Cations on Bioavailability

Studies regarding the efficacy of disulfiram in the treatment of alcoholism have not included a method of evaluating compliance to the prescribed regimen. This article outlines current methods used to detect disulfiram in blood, breath, and urine.     

One-year follow-up of disulfiram and psychotherapy for cocaine-alcohol users: sustained effects of treatment

Aim. To evaluate outcomes 1 year after cessation of treatment for cocaine- and alcohol-dependent individuals. Design. Randomized controlled trial. Setting. Urban substance abuse treatment center. Participants. Ninety-six of 122 subjects randomized to treatment. Interventions. One of five treatments delivered over 12 weeks. Cognitive-behavioral treatment (CBT) plus disulfiram; Twelve-Step facilitation (TSF) plus disulfiram; clinical management (CM) plus disulfiram; CBT without disulfiram; TSF without disulfiram. Measurements. Percentage of days of cocaine and alcohol use during follow-up, verified by urine toxicology screens and breathalyzer tests. Results. First, as a group, participants reported significant decreases in frequency of cocaine, but not alcohol, use after the end of treatment. Secondly, the main effects of disulfiram on cocaine and alcohol use were sustained during follow-up. Finally, initiation of abstinence for even brief periods of time within treatment was associated with significantly better outcome during follow-up. Conclusions. These findings support the efficacy of disulfiram with this challenging population and suggest that comparatively brief treatments that facilitate the initiation of abstinence may have long-term benefits.     

The efficacy of disulfiram for the treatment of alcohol use disorder

Background: Alcohol use disorders (AUD) involving hazardous, harmful, and addictive misuse of alcohol are widespread in most parts of the world. The aim of this study was to review the effect of disulfiram in the treatment of patients with AUD. The effect of disulfiram was evaluated according to the primary outcome of an intake of alcohol below 30 and 20 g/d for men and women, respectively, as well as secondary outcomes such as days until relapse, alcohol intake, and numbers of drinking days. Methods: A systematic review of the literature was conducted using MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials (CENTRAL). Results: Eleven randomized controlled trials were included with a total of 1,527 patients. They compared disulfiram treatment with placebo, none or other abstinence‐supportive treatments. Overall, 6 studies reported of a significant better effect on abstinence for patients treated with disulfiram. Six of 9 studies measuring secondary outcomes reported that patients treated with disulfiram had significantly more days until relapse and fewer drinking days, respectively. The quality of the included studies was moderate. Heterogeneity was significant in most of the meta‐analyses, but valid results were found regarding the effect of disulfiram versus placebo over 12 months and unsupervised disulfiram versus other or no treatment. The vast majority of significant studies were of shorter duration, while only 3 studies of 12 months were significant regarding more days until relapse and/or reduction in drinking days. Conclusions: Supervised treatment with disulfiram has some effect on short‐term abstinence and days until relapse as well as number of drinking days when compared with placebo, none, or other treatments for patients with alcohol dependency or abuse. Long‐term effect on abstinence has not been evaluated yet. However, there is a need for more homogeneous and high‐quality studies in the future regarding the efficacy of disulfiram.     

Fulminant hepatitis and fatal toxic epidermal necrolysis (Lyell disease) coincident with clarithromycin administration in an alcoholic patient receiving disulfiram therapy

Disulfiram is widely used in the treatment of chronic alcoholism. Adverse drug reactions with fatal outcome following disulfiram therapy are infrequent, and hepatic failure accounts for most of them. Since disulfiram is a cytochrome P450 (CYP450) enzyme system inhibitor, numerous interactions with several drugs metabolized in the liver have been reported. Like disulfiram, clarithromycin inhibits a CYP450 isoenzyme, but, despite its widespread use for the treatment of respiratory tract infections, no interactions with disulfiram have been described as yet. We report a case of fatal toxic epidermal necrolysis (Lyell disease) and fulminant hepatitis shortly after starting treatment with clarithromycin in a patient who was receiving disulfiram. This is the first case of such a severe dermatosis in a patient receiving either disulfiram or clarithromycin therapy. The temporal relationship between drug administration and clinical symptoms in this case suggests a probable interaction between the 2 drugs.     

A behavioral treatment of alcoholic methadone patients

Alcoholism is a frequent complication of methadone treatment and is one of the few behaviors found to correlate with methadone treatment failure. To eliminate drinking among severely alcoholic patients, we tested the efficacy of incorporating methadone into a behavioral contingency to reinforce disulfiram ingestion. Methadone was dispensed to alcoholic narcotic addicts contingent upon their ingesting disulfiram, and as a control patients were urged to take disulfiram but received methadone regardless of whether they took disulfiram. The results indicated that the reinforced disulfiram treatment was highly successful in controlling alcoholism. In addition, nonstatistically significant trends suggested that the reinforced disulfiram treatment resulted in a superior adjustment, as reflected in arrest rate, unemployment, and illicit drug use. There appeared to be no significant physiologic or behavioral adverse effects.     

Coadministration of disulfiram and lorazepam in the treatment of alcohol dependence and co-occurring anxiety disorder: an open-label pilot study

ABSTRACT

Background: Anxiety is common among persons with alcohol use disorder during early abstinence from alcohol. Although benzodiazepines are effective for short-term treatment of anxiety, they are rarely used beyond acute detoxification due to concerns about misuse or interactions with alcohol. Objectives: We conducted an open-label trial to explore the effects of coadministering lorazepam and disulfiram to alcohol-dependent patients with anxiety disorder symptoms. The rationale for this model is to minimize the risks of the benzodiazepine, while also potentially enhancing adherence to disulfiram. Methods: Forty-one participants with DSM-IV alcohol dependence who also met syndromal criteria for anxiety disorder with or without co-occurring major depressive syndrome initiated treatment with lorazepam (starting dose 0.5 mg three times daily) and disulfiram (starting dose 500 mg three times weekly). Participants received 16 weeks of monitored pharmacotherapy with manualized medical management. Results: Adherence to treatment decreased steadily with time (85.4% at 4 weeks, 36.6% at 16 weeks). Participants showed significant increases in percent abstinent days during treatment and at 24 weeks follow-up. Large reductions in anxiety, depression, and craving were observed during treatment, and improvement remained significant at 24 weeks. Duration of adherence with disulfiram strongly predicted abstinence at 16 weeks. There was no evidence of misuse of lorazepam or dose escalation during the study. Conclusion: Lorazepam can be safely used for short-term treatment of anxiety in combination with disulfiram treatment of alcohol use disorder. However, it is not clear that making lorazepam dispensing contingent on adherence to disulfiram enhances retention in disulfiram treatment.     

The impact of personality disorders on alcohol-use outcomes in a pharmacotherapy trial for alcohol dependence and comorbid Axis I disorders

Although antisocial and borderline personality disorders frequently co-occur with alcohol dependence and other Axis I disorders, their effect on alcohol use outcomes in context of pharmacotherapy remains unclear. Patients with Major Axis I disorders, including alcohol dependence, and diagnosis of antisocial (ASPD) or borderline personality disorder (BPD) were enrolled in a 12-week medication trial for treatment of their alcohol dependence. Everyone was randomized to one of four cells: naltrexone alone, placebo alone, open label disulfiram and naltrexone, or open label disulfiram and placebo. Outcome measures included scales for alcohol use and craving. Data were analyzed comparing patients with ASPD vs. those without, and patients with BPD vs. those without. Diagnosis of personality disorder did not adversely affect alcohol outcomes, and patients with ASPD or BPD did not have a poorer response to medication than patients without diagnosis of ASPD or BPD. The findings suggest that naltrexone and disulfiram can be safely and effectively used with patients who have comorbid diagnoses of Axis I and Axis II disorders.     

Monitoring Relapse Drinking During Disulfiram Therapy by Assay of Urinary 5-Hydroxytryptophol

Screening for recent alcohol use by testing urine for the ratio of 5-hydroxytryptophol (5HTOL) to 5-hydroxyindole-3-acetic acid (5HIAA) was performed in 10 methadone patients on disulfiram (Antabuse) maintenance therapy in an outpatient setting. Apart from alcohol ingestion, treatment with aldehyde dehydrogenase inhibitors such as disulfiram is the only known cause of an abnormally high 5HTOL/5HIAA ratio. After introduction of drug therapy, increased ratios were observed in all patients. The new higher level reached was relatively stable over time within the same patient but variable between patients. Four patients continued to consume alcohol, as evidenced by 5HTOL/5HIAA ratios well above the new individual plateau, while still taking 400 mg disulfiram 3 times per week under strict supervision. To try to achieve sobriety in two patients who drank frequently while on therapy, the disulfiram dose was doubled. Continued testing demonstrated this to increase the 5HTOL/5HIAA steady-state level further, and the absence of extreme values above this new baseline level indicated adherence to abstinence with possibly one single relapse. When disulfiram administration was discontinued, as planned, by five of the patients, four of them returned to drinking very soon. The present results show that during disulfiram maintenance the continuous inhibition of aldehyde dehydrogenase produces a new higher and dose-related 5HTOL to 5HIAA steady state level in urine, but relapse to drinking will still lead to further increased 5HTOL/5HIAA ratios. It is also suggested that an individual dose-titration regimen, whereby the disulfiram dose is raised gradually until 5HTOL/5HIAA testing indicates sobriety, will improve therapeutic effectiveness.     

Disulfiram treatment increases plasma and red blood cell acetaldehyde in abstinent alcoholics

BACKGROUND: Much of alcohol's toxicity is due to its product, acetaldehyde. The role of acetaldehyde derived from endogenous sources was assessed in alcoholic patients administered disulfiram, an inhibitor of aldehyde dehydrogenase. METHODS: The first part of the study included 23 subjects without biochemical or clinical evidence of chronic liver disease who were abstinent for 2 weeks; 11 patients were started on disulfiram (250 mg/day), whereas the other 12 were not given disulfiram and served as controls. The second part of the study included 13 alcoholic patients with clinical or pathological evidence of cirrhosis who also were administered disulfiram for 2 weeks. Plasma and red blood cell (RBC) acetaldehyde as well as serum transaminases were measured at baseline and after 1 and 2 weeks of treatment. RESULTS: In the disulfiram-treated group of alcoholics without known cirrhosis, RBC acetaldehyde levels increased from the pretreatment value of 2.98+/-0.18 microM to 4.14+/-0.33 microM after 1 week and to 4.14+/-0.26 microM after 2 weeks of treatment (p < 0.001). Compared with the pretreatment values (2.07+/-0.24 microM), plasma acetaldehyde levels also increased after 1 week (3.18+/-0.32 microM) and 2 weeks (3.15+/-0.26 microM) of disulfiram treatment (p < 0.001). There were no significant differences in sequential levels measured in either plasma or RBC acetaldehyde levels in patients who were not administered disulfiram. In the group of cirrhotic patients, the mean baseline RBC acetaldehyde value (3.60+/-0.22 microM) was significantly higher than in noncirrhotics. Disulfiram therapy increased the RBC acetaldehyde after 1 week (4.63+/-0.27 microM, p < 0.001) and 2 weeks of treatment (4.06+/-0.28 microM, p < 0.05). Compared with baseline values, plasma acetaldehyde levels were significantly higher after 1 week but not after 2 weeks of disulfiram. There were no significant differences among serum transaminases in alcoholics administered disulfiram, although three cirrhotic patients did have clinically significant elevations. CONCLUSIONS: In abstaining subjects given disulfiram, acetaldehyde concentrations increase, possibly due to diminished catabolism of endogenously generated acetaldehyde. Disulfiram should be given cautiously, especially in patients with cirrhosis.     

Supervised disulfiram in the treatment of alcohol use disorder: a commentary

Background: This commentary discusses the systematic review “The efficacy of disulfiram for the treatment of alcohol use disorder (AUD)” by Jørgensen and colleagues (2011, Alcohol Clin Exp Res DOI: 10.1111/j.1530‐0277.2011.01523.x ). The main focus of the commentary is on long‐term effects, long‐term use, and psychotherapeutic application of supervised disulfiram. Methods: A brief qualitative overview is given of previous and recent clinical studies on disulfiram in alcoholism treatment. Results: The alcohol deterrent disulfiram is an effective pharmacological adjunct to the treatment of AUD when it is administered as supervised low‐dose disulfiram and is integrated in comprehensive biopsychosocial alcoholism therapy. However, the assumed underlying psychological effects of psychotherapeutic disulfiram application have never been properly investigated. Prospective long‐term follow‐up studies are rare and suggest that long‐term effects of disulfiram are associated with long‐term use and/or integration of the medication in cognitive behavior therapy. Conclusions: Evidence from decades of research suggests psychological effects as principal mode of action of supervised disulfiram. Future randomized controlled trials are needed that investigate psychological actions and long‐term outcomes of this alcohol deterrent.     

Lack of toxicity from concomitant directly observed disulfiram and isoniazid-containing therapy for active tuberculosis.

We retrospectively evaluated the use of disulfiram among alcoholic patients being treated for active tuberculosis. There were 13 alcoholics treated with disulfiram, 105 alcoholics not on disulfiram, and 249 non-alcoholics. Rates of toxicity were higher among alcoholics than among non-alcoholics (58% vs. 32%), but there was no difference between alcoholics taking and those not taking disulfiram (61% vs. 57%). There were no neurological side effects in the disulfiram group. Disulfiram appeared to be safe when added to intermittent, directly observed isoniazid-containing tuberculosis treatment, and was useful in managing complications of alcohol abuse. However, the small number of patients on disulfiram limits the strength of this negative finding.     

Physicians' opinions about medications to treat alcoholism

Aims Medications play a limited role in the treatment of alcoholism. This paper examines physicians’ opinions about and use of two alcoholism medications currently approved in the US—disulfiram and naltrexone—and one alcoholism medication—acamprosate—that might be approved. Design A total of 1388 substance abuse specialist physicians who were members of the American Academy of Addiction Psychiatry or the American Society of Addiction Medicine completed a questionnaire in 2001 (65% response rate). Findings The average percentages of physicians’ patients with alcoholism who were prescribed the following medications were: 13% (naltrexone), 9% (disulfiram), 46% (antidepressants) and 11% (benzodiazepines). Almost all physicians had heard of naltrexone and disulfiram, but their self‐reported level of knowledge about these medications was lower than for antidepressants. Physicians estimated that naltrexone had a small‐to‐medium effect size, which was similar in magnitude to the effect size reported in recent meta‐analyses of randomized clinical trials. Physicians identified the following three courses of action as the most likely to result in greater use of medications to treat alcohol dependence: more research to develop new medications (33%), more education of physicians about existing medications (17%), and increased involvement of physicians in alcoholism treatment (17%). Conclusions Physicians’ low rate of use of naltrexone may reflect its small‐to‐medium effect size.     

SLC Neurotransmitter Transporters as Therapeutic Targets for Alcohol Use Disorder: A Narrative Review

Alcohol use disorder (AUD) is 1 of the most prevalent of all substance use disorders and contributes significantly to global disease burden. Despite its prevalence, <10% of individuals with AUD receive treatment. A significant barrier to receiving treatment is a lack of effective pharmacotherapies. While 3 medications have been approved by the FDA for AUD (disulfiram, acamprosate, naltrexone), their efficacy remains low. Furthermore, a number of undesirable side effects associated with these drugs further reduce patient compliance. Thus, research into new effective pharmacotherapies for AUD is warranted. Due to their involvement in regulating synaptic neurotransmitter levels, solute carrier (SLC) transporters could be targeted for developing effective treatment strategies for AUD. Indeed, a number of studies have shown beneficial reductions in alcohol consumption through the use of drugs that target transporters of dopamine, serotonin, glutamate, glycine, and GABA. The purpose of this narrative review is to summarize preclinical and clinical studies from the last 2 decades targeting SLC neurotransmitter transporters for the treatment of AUD. Limitations, as well as future directions for expanding this field, are also discussed.     

Disulfiram Treatment of Patients with Both Alcohol Dependence and Other Psychiatric Disorders: A Review

In treatment of alcohol dependence, disulfiram is most useful in conjunction with a structured, supervised, aftercare program. However, it has been reported to cause psychiatric side effects and to interact with various psychiatric medications. Many patients with alcohol dependence suffer from other psychiatric disorders and are treated with such psychiatric medications. This paper reviews the pertinent clinical pharmacology of disulfiram and the literature on potential psychiatric complications and drug interactions of disulfiram. At the usual dosage, about 250 mg/day, disulfiram does not appear to increase significantly the risk of psychiatric complications or of psychiatric drug interactions. Therefore, it can be considered a treatment option for patients with alcohol dependence and other psychiatric disorders.