Supervised Disulfiram as Adjunct to Psychotherapy in Alcoholism Treatment
Henning Krampe1,* and Hannelore Ehrenreich2
1Department of Anaesthesiology and Intensive Care Medicine, Charité – Universitätsmedizin Berlin, Campus Virchow-Klinikum and Campus Charité Mitte; Charitéplatz 1, D-10117 Berlin, Germany, 2Division of Clinical Neuroscience, Max Planck Institute of Ex- perimental Medicine, Hermann-Rein-Str. 3, D-37075 Göttingen, Germany
Abstract: Supervised intake of the alcohol deterrent (AD) disulfiram has proven to be an effective adjunct to biopsychosocial alcoholism therapy for more than 60 years. This article summarizes disulfiram literature between 1937 and 2000 and reviews 13 clinical trials of di- sulfiram in alcoholism treatment from the years 2000 to 2008. After giving an update of general safety issues and recent case reports con- cerning safety problems with disulfiram, we focus on the introduction of psychotherapeutic application of supervised disulfiram.
The results of our review show: (1) Disulfiram proved to be an effective therapeutic tool in all clinical studies published from 2000 to 2008. (2) Comparisons with other pharmacological agents – naltrexone, acamprosate, topiramate and gamma-hydroxybutyrate – indicate that disulfiram was equal in two trials but superior in the majority of trials. (3) Therapy programs that make use of the psychological ef- fects of supervised disulfiram have – independently of the dose – better results than programs that neglect psychological effects. As a con- sequence, we suggest that supervised low-dose disulfiram (not more than 100mg/d), will show highest success when it is carefully inte- grated into psychotherapeutic alcoholism therapy.
The major program of psychotherapy with disulfiram comprises the steps “Initial psychoeducation about the effect of disulfiram and its therapeutic implications”, “Advanced psychoeducation”, and “Disulfiram as coping skill and extension of repertoire of coping skills”. As psychological mechanisms of supervised disulfiram we suggest: (1) deterrence; (2) (auto)suggestion; (3) therapeutic ritual around (4) a frequently renewed active decision process; (5) continuous reinforcement of a sober lifestyle and development of new coping skills.
Keywords: Addiction, alcohol dependence, alcohol deterrents, alcoholism treatment, antabuse, disulfiram, pharmacotherapy, psychotherapy.
INTRODUCTION
Alcohol dependence is a frequent, chronic, relapsing and non- curable disease, characterized by a fluctuating and devastating course, an increased mortality and low long-term abstinence rates. It belongs to the most frequent psychiatric disorders and causes enormous societal costs [1-7]. Only comprehensive, integrated, structured and intensive long-term therapy with a strict abstinence orientation, followed by lifelong attending of check-up sessions and self-help group participation will guarantee long-term recovery [6, 8]. Supervised intake of the alcohol deterrent (AD) disulfiram has proven to be an effective adjunct to biopsychosocial alcoholism therapy for more than 60 years [9-14].
Tetraethylthiuram disulfide (disulfiram) was first developed in 1881 and used in industry to vulcanize rubber [for a historical review of disulfiram see Banys, 1988, 15]. By 1910, observations were made that rubber industry workers who were exposed to tetra- ethylthiuram disulfide experienced an aversive reaction after drink- ing alcohol, and in 1937, disulfiram’s potential to act as a medica- tion in alcoholism therapy was first discovered by the US-american plant physician Williams. He gave a very accurate and vivid de- scription of the so-called disulfiram ethanol reaction (DER) in a letter to JAMA [16]: “The laborers working with these chemicals, especially the ones who grind the finished products, find that they cannot drink alcohol in any form. Even beer will cause a flushing of the face and hands, with rapid pulse, and some of the men describe palpitations and a terrible fulness in the face, eyes and head. After a glass of beer (6 ounces) the blood pressure falls about 10 points, the pulse is slightly accelerated, and skin becomes flushed in the face and wrists. In fifteen minutes the blood pressure falls another 10 points, the heart is more rapid, and the patient
*Address correspondence to this author at the Department of Anaesthesiol- ogy and Intensive Care Medicine, Charité – Universitätsmedizin Berlin, Campus Virchow-Klinikum and Campus Charité Mitte; Charitéplatz 1, D- 10117 Berlin, Germany; Tel: + 49 30 450-531145; Fax: + 49 30 450- 531911; E-mail: [email protected]
complains of fulness of the head. There doesn’t seem to be any other effect of this chemical; men have worked here for years without any complaint other than their inability to drink. They have become involuntary total abstainers. I wonder if there is any other way to test toxicity. We have used a patch test on mice and fed it to mice without harm. If the chemical compound is not harmful to man, one wonders whether one has discovered the cure for alcoholism.” Independently from this early description of the DER, the Danish physicians Hald and Jacobsen discovered in 1945 by serendipity the alcohol-sensitizing effect of disulfiram. They drank wine at dinner after having ingested disulfiram when testing the medication as an agent against intestinal worms. By 1948, Hald and Jacobsen de- scribed the accumulation of acetaldehyde as the cause of DER, reported on preclinical studies and introduced together with Mart- ensen-Larsen disulfiram as a medication for alcohol dependent patients [17-19]. Since that time, disulfiram has not stopped to play a role in alcoholism therapy. However, when in the nineties of the last century, new pharmacological agents for the treatment of alco- hol dependence emerged, like naltrexone or acamprosate, disul- firam ran out of fashion and even received a reputation as obsolete medication that was only mentioned in reviews because of histori- cal reasons [e.g. 20-27]. Three essential developments led to a revival of disulfiram during the last years: (1) There is no evidence for a sufficient efficacy of a primarily pharmacotherapeutic treat- ment of alcoholism [28]. (2) Disulfiram has been found to be an effective pharmacological adjunct in the psychotherapeutic treat- ment of cocaine dependence [for review see 29-32]. (3) In recent clinical trials on alcoholism therapy disulfiram has proven more or at least as effective as the newer medications acamprosate, naltrex- one and topiramate [33-39; for review see 9, 40]. As a consequence, disulfiram has regained its status as an important psychopharmaco- logical agent for addiction therapy and its reappraisal is widely discussed in recent reviews: Whereas some authors regard it only as a second-line medication in relapse prevention [41], and others conclude that it constitutes a viable treatment with modest efficacy even though hampered by medication nonadherence [42-44], a third
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group of clinicians and scientists belief that it is among the most successful medications for alcohol dependence [9, 10, 45]. Re- cently, disulfiram has been discussed as a potential anticancer drug, and there are many new preclinical studies, as well as two ongoing clinical trials of disulfiram in cancer patients [46]. Thus, the knowl- edge that has been gathered on disulfiram in the addiction field continues to be contemporary and clinically relevant.
This paper gives an update on disulfiram in the addiction ther- apy of alcohol dependent patients. While previous reviews have emphasized the role of this drug as a pharmacological agent, this article introduces the practical steps of psychotherapeutic applica- tion of supervised disulfiram. For integration of a medication into psychosocial approach, knowledge of the state of research and clinical practice is prerequisite: This article starts with a review of recent clinical trials of disulfiram in alcoholism treatment, gives an introduction in general safety issues and an update of recent case reports concerning safety problems with disulfiram. We identified articles that have been published since the last review of disulfiram by Suh et al. [14] through a comprehensive search using MED- LINE, PsycINFO, and Current Contents [2000 –2009; keywords: disulfiram, antabuse, clinical trial, alcohol dependence, alcoholism, alcohol deterrents], as well as through references cited in research articles. This review does not include detailed discussions of either studies on disulfiram implants or oral disulfiram in the treatment of cocaine dependence. Comprehensive reviews on disulfiram im- plants can be found in Hughes & Cook [12] and Suh et al. [14]; the role of disulfiram as a pharmacological agent for cocaine depend- ence is discussed in Vocci & Elkashef [29], Preti [30], Karila et al. [31], Suh et al. [14], Weinshenker & Schroeder [32] and Malcolm et al. [47].
OUTCOME RESEARCH ON DISULFIRAM IN ALCOHO- LISM THERAPY
Disulfiram has been used in alcoholism therapy for more than 60 years, and previous literature is heterogeneous. Landmark trials differ considerably with regard to regimen, e.g. unsupervised disul- firam within a controlled blinded multicenter trial [e.g. 48], super- vised administration within a partially blinded study [e.g. 49], comparison of supervised and unsupervised disulfiram [e.g. 50] or supervised disulfiram as part of behavior therapy [e.g. 51-53]. The psychological effects of disulfiram like deterrence from drinking (see below for a more extensive description) may have differed among these studies due to the different way of explaining AD treatment and of managing intake [49-53], and it may even have disappeared when the majority of patients stopped taking disulfiram [48]. Despite the heterogeneity of literature, several excellent re- views were published at regular intervals during the last decades. They outlined the history of disulfiram treatment, summarized the state of clinical safety and efficacy studies of this drug, and de- scribed its clinical application [9, 11, 12, 14, 15, 54-61].
Previous meta-analyses did not distinguish between supervised and unsupervised disulfiram and reported moderate effect sizes [62, 63]. The recent meta-analysis of Berglund [40] included 641 ran- domized controlled trials and seven longitudinal prospective stud- ies. The outcome data of these studies were transformed to the effect size d that represents an estimation of standardized mean differences, making diverse drinking outcomes and other clinically relevant outcome data of different studies comparable with each other. This meta-analysis showed that unsupervised administration does not have any effect (d=0), whereas supervised disulfiram as an adjunct to psychotherapy is more effective (d=0.53) than naltrexone plus cognitive behaviour therapy (d=0.28) or acamprosate (d=0.26). This finding is reflected in two recent qualitative reviews: Brewer et al. [60] report that 17 out of 18 clinical studies on supervised disulfiram from 1966 to 1999 found positive outcomes. Impor- tantly, the outcome variables from some of these trials include not only drinking measures, but also clinically relevant variables like
number of arrests [64], treatment retention [65], work absenteeism [66] and postoperative complications [67]. Suh et al. [14] selected eight out of these 18 trials that addressed explicitly addiction ther- apy of alcohol dependent patients and showed high methodological quality (e.g. sample size, statistical comparison). The authors found positive outcomes of disulfiram in all eight studies and confirmed the conclusions drawn by Brewer et al. [60].
We reviewed 13 recent clinical trials of disulfiram in alcohol- ism therapy from 2000 to 2008 [13, 33-39, 68-73] that were not yet included in the reviews of Brewer et al. [60] and Suh et al. [14]. Our results are summarized in Table 1 and show: (1) Disulfiram proved to be an effective therapeutic tool in all studies. (2) Com- parisons with other pharmacological agents -naltrexone, acampro- sate, topiramate and gamma-hydroxybutyrate- indicate that disul- firam was equal in two trials [35, 36], but superior in the majority of trials [33, 34, 37, 38, 39]. (3) Therapy programs that make use of psychological effects of disulfiram [13, 33, 34, 37, 38, 68-70, 73]
have – independently of dose- better results concerning supervised disulfiram than programs that neglect psychological effects [35, 36]. As a consequence we suggest that current clinical application of disulfiram should make full use of psychotherapeutic mecha- nisms of low-dose disulfiram. However, as Fuller & Gordis (2004) point out, the assumed underlying effects of psychotherapeutic disulfiram application have never been properly investigated [74]. Therefore, further studies might explicitly focus on the subjective experience that AD intake causes in addicted patients. Randomized controlled trials might investigate the different ways of administra- tion, e.g. supervised low-dose versus supervised low-dose plus psychotherapeutic application of disulfiram.
Some authors mention medication nonadherence as one impor- tant argument against disulfiram’s effectiveness in clinical practice [42-44]. Interestingly, two studies investigated the subjective rea- sons of relapsed patients for having stopped disulfiram [75, 76]. Børup et al. studied 210 alcohol dependent patients who were re- admitted to a disulfiram treatment program after having voluntarily discontinued disulfiram therapy. They found that none of the pa- tients reported adverse events as a reason for stopping disulfiram intake. The most frequent arguments were the wish to drink alcohol (41%) and the feeling to be able to maintain abstinence without disulfiram (25%). These data are in line with the results of Liskow et al. who asked 187 inpatients of an alcoholism therapy center about their experiences with disulfiram. Patients’ most frequent reasons for stopping the medication intake were the desire to drink alcohol (34% to 48%) and the feeling that they did not need disul- firam any more (29% to 36 %), as compared to the low rate who gave side effects as a reason (5% to 18%). In other words, most patients do not stop disulfiram treatment because of adverse events but because of two core features of addiction, explicit or implicit desire to relapse and the idea to cope with the chronic disease with- out therapeutic help.
We are convinced that patients’ consideration to stop disulfiram does not reflect “classical nonadherence” to a pharmacological agent that would simply have to be accepted. In contrast, stopping disulfiram derives from the desire to drink alcohol. This situation actually offers a unique opportunity for psychotherapeutic action on core features of addiction, often overlooked in routine clinical care: Early signs of (threatening) relapse and the patients’ transient over- estimation of their self-capacity to control addiction. Thus, careful supervision of disulfiram intake may enable addiction therapists to identify acute high-risk situations for imminent relapse.
In order to support the patient in maintaining abstinence, con- temporary addiction treatment offers a plethora of effective thera- peutic elements. Individually tailored relapse prevention strategies comprise motivational interventions, supportive psychotherapy and application of therapeutic alliance, coping and problem-solving including functional analyses, psychoeducation, and restructuring of dysfunctional thinking. However, the concept of combining
Table 1. Recent Clinical Studies (2000-2009) on Disulfiram Treatment in Alcoholism Therapy
Authors Design Setting Patients, Diagnosis, Selection Criteria Treatment Conditions Supervision, Psychoeducation
Reported AE
Outcomes
Martin et al. (2003) (2004) Non-randomized prospec- tive observational study
Outpatient DSF clinic N= 41 patients with alcohol dependence or misuse;
n=19 with court-ordered DSF, n=22 with voluntary DSF; diagnosis according to DSM-IV SCID interview 1. Court ordered supervised DSF, 500 mg / thrice per week
2. Voluntary DSF, 500 mg /
thrice per week; treatment
duration not reported Explicit information of patients about mecha- nisms and side effects of DSF, written in- formed consent about DER
Supervision of DSF intake by clinic nurses 1 AE: elevated liver enzymes Positive alcohol breatha- lyzer results at week 12: no difference between groups (only 1 positive result in entire sample).
Compliance at week 12: court-ordered DSF (84%)> voluntary DSF (41%).
Compliance at month 15: court-ordered DSF (61%)> voluntary DSF (18%).
Martin et al. (2004) Retrospective chart review Outpatient DSF clinic N= 46 patients with alcohol dependence; n1= 26 patients with HCV(+), n2= 20
HCV (-) patients; inclusion of all HCV(+) patients of the clinic, random selection of HCV(-) patients as control group Supervised DFS over 12 months: 500 mg / thrice per week Explicit information of patients about mecha- nisms and side effects of DSF, written in- formed consent about DER
Supervision of DSF intake by clinic nurses
see outcomes AST elevation over baseline: HCV (+) (14) > HCV (-) (3).
Clinically relevant AST elevation: no difference between HCV (+) (3) and HCV (-) (2).
Clinically relevant ALT elevation: no difference between HCV (+) (1) and HCV (-) (1).
Mueser et al. (2003) Retrospective chart review Mental health center,
integrated treatment for patients with dual disorders N=33 patients with psy- chotic disorder and comor- bid AUD; diagnosis accord- ing to DSM-III-R or DSM- IV; inclusion of patients who were prescribed DSF and with chart data avail- able for at least 1 year DSF for an average of 2 years:
125 mg/d in 1 patient, 250 mg/d in 27 patients, 500 mg/d in 5 patients Supervision: daily=14, weekly=6,
biweekly=1, monthly=3, bimonthly= 8, none=5 7 patients with AE, e.g. upset stomach, skin rash, nausea, vomiting Remission of AUD at 3-year follow-up: 21 patients with remission of AUD for at least 1 year, 10 patients with 2-year remission of AUD
Nieder- hofer &
Staffen (2003) Randomized placebo- controlled, double-blind trial N= 26 adolescents (age 16 – 19 years), chronic or episodic alcohol depend- ence; diagnosis according to DSM-III 90 days of unsupervised treatment:
1. DSF: 200 mg / d 2. daily placebos No supervision, but compliance interview every 3rd day by “special interviewer” 1 AE in DSF, 1 in Placebo; type not reported Abstinence at day 90: DSF (7/13)> placebo (2/13); mean cumulative abstinence duration DSF (M 68.5
SD 37.5)> placebo (M 29.7 SD 19.0)
De Sousa &
De Sousa (2004)
Open-label, randomized trial Outpatient addiction treat-
ment clinic, explicit en- gagement of family mem- bers in supervised medica- tion administration and enhancing therapy compli- ance; voluntary group therapy
N=100 male patients with alcohol dependence; diagnosis according to DSM-IV, selection of patients without comorbid psychiatric disorder and with a family member to ensure treatment compli- ance and provide informa- tion at follow-up visits
12 months of treatment:
1.DSF: 250 mg / d
2.NTX: 50 mg / d
Explicit information of patients about mecha- nisms and side effects of study drugs
Supervision of daily drug intake by family member
AE: DSF
DSF (86%)>NTX (44%); GGT at month 12: DSF (M 85 U/l)< NTX (M 117
U/l); Craving at month 12: DSF> NTX
(Table 1) Contd..
Authors
Design Setting
Patients, Diagnosis, Selection Criteria
Treatment Conditions
Supervision, Psychoeducation
Reported AE
Outcomes
De Sousa &
De Sousa (2005)
Open-label, randomized trial Outpatient addiction treat-
ment clinic, explicit en- gagement of family mem- bers in supervised medica- tion administration and enhancing therapy compli- ance; voluntary group therapy
N=100 male patients with alcohol dependence; diagnosis according to DSM-IV, selection of patients without comorbid psychiatric disorder and with a family member to ensure treatment compli- ance and provide informa- tion at follow-up visits
8 months of treatment:
1.DSF: 250 mg / d
2.ACP: 1998 mg / d
Explicit information of patients about mecha- nisms and side effects of study drugs
Supervision of daily drug intake by family member
AE: DSF = ACP: nausea (4% vs 3%)
3.serious AE in DSF: polyneu- ropathy
Days to relapse: DSF (M 123 SD 19)> ACP (M 71 SD 27); abstinence at month 8: DSF (88%)>ACP (46%); GGT at month 8: DSF (M 111 U/l)> ACP (M 79 U/l); Craving at month 8: DSF>ACP
Petrakis
et al. (2005)
Multicenter randomized placebo-controlled trial
General clinic setting with psychiatric TAU including psychopharmacological medication for all patients
N=254 patients with psychiatric Axis I disorder and comorbid alcohol dependence; diagnosis according to DSM-IV SCID interview; selection of patients with stable psychi- atric symptoms and at least
3.days of alcohol absti- nence before randomization
12 weeks of treatment:
1.NTX alone: 50 mg / d
2.Placebo alone
3.Open-label DSF: 250 mg / d + blinded NTX: 50 mg /d
4.Open-label DSF: 250 mg /d +blinded pla- cebo
No supervision, but medication monitoring with Microelective events monitoring (MEMS) caps at each visit; additional weekly clinical management/
compliance enhance- ment therapy
14 serious AE: NTX: 1 death;
Placebo: 1 death, 1 drug overdose, 1 alcohol over- dose, 1 pneu- monia;
DSF+NTX: 2 cardiac events, 1 DER;
DSF+Placebo:
4.psychiatric hospitaliza- tions, 1 cardiac event, 1 neu- ropathy
Treatment retention: DSF+placebo (70%), NTX (66%) > NTX+DSF (51%);
Complete abstinence: 177/254 patients (69.7%);
Drinking outcomes (drink- ing days per week, days of abstinence): DSF+placebo, NTX>placebo; no advan- tages of DSF + NTX;
Reduction in GGT: DSF > NTX;
Reduction in craving: DSF> NTX
Krampe
et al. (2006)
Prospective 9-year observa- tional study
Highly structured setting of long-term outpatient addic- tion treatment including mandatory high-frequency therapeutic contacts, super- vised DSF, urinanalysis, aggressive aftercare
N=180 patients with chronic alcohol depend- ence; diagnosis according to DSM-IV, selection of
patients with domicile near- by, health insurance- covered treatment costs; exclusion of patients with dementia and amnesic syndrome.
Comprehensive, intensive outpatient program for 2 years: psycho- therapeutic application of supervised DSF, doses between 100 mg / d and 400 mg three times per week (Details table 2)
DSF intake always supervised by a team of rotating therapists who explicitly work out cognitive-behavioral application of DSF
7 AE: 5 sexual dysfunctions, 2 nausea
2 serious AE: 1 hepatitis, 1 allergic ec- zema;
Cumulative 9-year absti- nence probability: 52%; patients on sham-AD (S=.86) > patients on verum (S=.49); patients with long- term intake (S=.75) > patients who stopped AD between months 13 and 20 (S=.50).
Days of AD intake and subsequent abstinent days without AD: patients with detrimental lapse and with malignant relapse < patients with coped lapse.
Nava (2006)
Randomized, open-label trial; weekly examinations of vital signs, adjunctive CBT
N=86 alcohol-dependent patients; diagnosis accord- ing to DSM-IV; selection of patients with at least 2 weeks of alcohol abstinence and without comorbid psychiatric disorder
12 months of treatment:
1.GHB: 50 mg /
kg of body weight /d
2.NTX: 50 mg / d alone
3.DSF: 250 mg / d
Weekly administration of medication, supervi- sion of drug intakte by family member or friend
2 AE in GHB, 2 in NTX and 4
in DSF
No serious AE
No difference between treatments in drinking outcomes: GBH: 14% relapse, 14% non-abstinent, 7% dropout, 65% abstinent; NTX: 26% relapse, 18% non-abstinent, 7% dropout, 49% abstinent; DSF: 10% relapse, 22% non-abstinent,
12 % dropout, 40% abstinent
(Table 1) Contd..
Authors
Design Setting
Patients, Diagnosis, Selection Criteria
Treatment Conditions
Supervision, Psychoeducation
Reported
AE
Outcomes
Neto et al. (2007)
Prospective 6-months observational study
Outpatient addiction treatment clinic; supervised DSF, voluntary therapy sessions, AA atten- dance
N= 74 alcohol-dependent patients after discharge from inpatient detoxification; diagnosis according to DSM- IV; exclusion of patients who continued aftercare program in controlled environment
Comprehensive outpatient program for 6 months: supervised DSF of unknown dose, elements of CRA
Patients sign written consent to take supervised DSF; supervisors are significant others trusted by the
patient
Not reported 92% of patients prescribed DSF took it (55/60); abstinence probability: Patients on DSF longer than 121 days > patients on DSF less than 120 days; days of DSF intake: abstinent patients
(MD 180 range 15-150)>
relapsed patients (MD 111 range 1-180)
De Sousa et al. (2008)
Open-label, random- ized trial
Outpatient addiction treatment clinic, explicit engagement of family members in supervised medication administration and enhancing therapy compliance; voluntary group therapy
N=100 male patients with alcohol dependence; diagnosis according to DSM-IV, selection of patients without comorbid psychiatric disorder and with a family member to ensure treatment compliance and provide information at follow-up visits
9 months of treatment:
1.DSF: 250 mg / d
2.TPM: 50 mg /
3.times per day
Explicit information of patients about mechanisms and side effects of study drugs
Supervision of daily drug intake by family member
AE: DSF>TPM: nausea (4% vs 1%)
2 serious AE in DSF: polyneu- ropathy De Sousa Supervision of daily drug intake by family member No serious AE Laaksonen et al (2008) Rationale of the three different pharmaco-therapies discussed in therapeutic self-help booklets Serious AE: DSF: 1 traffic accident; ACP: 1 intoxication, Abbreviations: disulfiram and relapse prevention only works if therapists make full use of the psychological actions of this drug and start to disengage from the emphasis of its pharmacological effects including “medi- cation nonadherence”. For that it is necessary to administer disul- firam neither in an unsupervised nor in a supervised way without psychotherapy. We propose that disulfiram will show highest suc- cess when it is carefully integrated into psychotherapeutic alcohol- ism therapy. SAFETY OF DISULFIRAM IN ALCOHOLISM TREAT- MENT • Adverse Effects Table 2. Dose and Frequency of Supervised Disulfiram in the Treatment Periods of OLITA •Inpatient period: Detoxification mention prevalence rates of 1/10,000 to 1/25,000 without citing any original study as a reference. The estimated frequency of disul- firam-induced fatal hepatitis is 1 case in 30,000 patients treated per year [58]. Hepatitis may occur between 16 and 120 days after start- ing treatment with a peak frequency at 60 days [77]. Early diagno- sis and immediate cessation of disulfiram treatment usually leads to complete recovery (11). As an adjunct to psychotherapy plus disul- firam, patients should therefore have regular physical and blood- workups, e.g. every 2 weeks over the first 2 months of disulfiram treatment and at 6-12 weeks intervals thereafter. In the case of suspected liver reaction to the drug, an alternative AD, calcium carbimide, may be considered. However, even though hepatotoxic- ity is lower for calcium carbimide than for disulfiram, a hepatotoxic potential in susceptible people cannot be entirely excluded also for calcium carbimide [79]. As a consequence, a thorough survey of patients taking calcium carbimide is as necessary as in patients taking disulfiram. •DER •Contraindications liver cirrhosis), history of stroke, acute psychotic disorders, epilep- tic seizures, florid ulcers, rubber allergy, pregnancy, severe cogni- tive impairment precluding understanding the disulfiram effect, and alcohol use within 12 hours. Particularly in older people, the indica- tion and risk of disulfiram has to be carefully considered, and the disulfiram dose should be low (e.g. ti50mg/d). To our knowledge, indication, risk and dose of disulfiram in old people have not been systematically investigated in clinical studies. Thus our treatment suggestions for supervised disulfiram in older alcohol dependent patients are based on our own clinical long-term experience of treating patients with disulfiram. Older people profit from super- vised disulfiram as much as young people do but tend to have a more severe DER in case they drink and are generally at greater risk to have contraindications, e.g. severe cardiovascular disease. •Drug Interactions •Safety Issues in Long-Term Treatment with Disulfiram Studies on long-term use of disulfiram (i.e. ti 1 year) are sparse. patient after two weeks of treatment with 400mg, 3 times per week. Both patients were put on sham-AD. The liver values of the patient with hepatitis recovered within 4 weeks, and the allergic eczema of the second patient improved within 5 weeks. Adverse events com- prised complaints about sexual dysfunction (5 men) and nausea (1 woman, 1 man). Whereas adverse reactions showed remission in 5 patients, 2 men were put on reduced dose because of complaints of sexual dysfunction (1) and nausea (1) respectively. •Recent Case Reports •Disulfiram and Cancer three times in disulfiram literature: Chick [58] discussed two mor- tality studies on alcohol dependent patients with contradictory results [96, 97]. Schmidt & de Lint found that death rates from lung cancer were significantly lower in disulfiram users than in non- users [96]. Berglund reports that the rate of patients who were treated with disulfiram at the initial admission to hospital was sig- nificantly higher in those patients who died later from neoplasm (mainly lung cancer) than in those patients who died from other conditions [97]. Both studies lack essential data like rate, frequency and duration of disulfiram use, duration and amount of alcohol consumption, relapses, drinking on disulfiram and, importantly, severity of concomitant cigarette smoking. Taking into account that untreated alcohol use disorders increase the risk of cancer [e.g. 98, 99], no conclusion can be drawn about whether disulfiram causes any cancer risk in alcohol dependent patients. Nevertheless, when explaining the disulfiram effect to patients, therapists should always point out that alcohol consumption within 2 weeks after intake of disulfiram leads to an elevation of a dangerous and potentially life- threatening poison, acetaldehyde. The patients should be taught that even when no DER occurs, an increase in acetaldehyde is toxic and patients should maintain complete alcohol abstinence in order to protect their physical health. PSYCHOTHERAPEUTIC APPLICATION OF SUPERVISED DISULFIRAM IN COMPREHENSIVE, LONG-TERM OUT- PATIENT TREATMENT OF ALCOHOLISM later substituted by disulfiram. The OLITA 9-year follow-up study aimed at investigating the role of supervised AD in relapse preven- tion and as adjunct for maintenance of long-term abstinence in 180 chronic alcohol dependent patients [13]. Subsamples were com- pared regarding (1) sham-AD (n= 15) versus verum-AD (disul- firam/calcium carbimide) (n= 165); (2) alcohol relapse (n=72) versus long-term abstinence (n=108); (3) coped lapses (n=35) versus finally detrimental lapses (n=33) versus malignant relapses (n=39); (4) AD use for 13-20 months (n= 41) versus more than 20 months (n= 74). Regarding ADs the following parameters were assessed: Dose, duration of intake, contraindications, adverse ef- fects, substitution of disulfiram/calcium carbimide by sham-AD medication, individual reasons for stopping of AD intake, alcohol consumption within 14 days after last medication, experience and extent of DER. PSYCHOTHERAPEUTIC APPLICATION OF SUPERVISED DISULFIRAM: MAJOR PRACTICAL STEPS makes the so-called "disulfiram alcohol challenge" unnecessary and provides some kind of (auto)suggestion. During psychoeducation, the therapist dramatically outlines the danger of drinking alcohol Table 3. Basic Therapeutic Knowledge: Contraindications and Adverse Effects of Disulfiram under the influence of disulfiram and passes responsibility onto the patient, even asking for a promise to stop taking the medication before drinking. This information is followed by the supervised intake of the drug, establishing a therapeutic ritual. The patient is challenged each time to actively decide against alcohol and for sobriety in front of a witness. During this therapeutic ritual, the therapist praises the patient for taking disulfiram and for maintain- ing abstinence, thereby providing a continuous reinforcement of a sober lifestyle. Since drinking is no longer an option of problem- solving, one part of this new lifestyle is the development and train- ing of alternative coping skills. •Administration: Supervision of Low Dose Disulfiram Therapists have to keep in mind that ADs can be used with very •Basic Knowledge on Disulfiram and Disulfiram-Ethanol- Reaction (DER): Pharmacology and its Use in Psychoedu- cation disulfiram remit within some weeks. Male patients sometimes complain about sexual dysfunction, mainly erectile dysfunctions. However, until now there is no evidence that disulfiram causes sexual dysfunction and a placebo-controlled study on the side ef- fects of disulfiram even found a higher rate of erectile dysfunctions in the placebo group than in the disulfiram group [104]. In case of serious but less frequent side effects like skin complaints, hepatitis and polyneuropathy, disulfiram has to be stopped at once and symp- tomatic treatment has to be initiated (Table 3). Fig. (1). Pharmacological action of disulfiram. Fig. (2). Basic therapeutic knowledge: Intervention in case of Disulfiram-Ethanol-Reaction (DER). Fig. (2) summarizes the medical measures in case of DER. In case of mild reactions it is sufficient when the patient immediately stops drinking alcohol and is monitored over several hours in the addiction clinic. He should be instructed to rest in a room with fresh air and drink a lot of water. Blood pressure and heart frequency are to be measured regularly. In case of severe DER the patient has to be taken to the emergency department and the specific symptoms are to be treated. Because the disulfiram dose in psychotherapeutic application is low, the probability of an occurrence of a serious DER is low, provided that the patient has not taken additional disul- firam on own initiative. Within the 9 years of the OLITA study, approximately 50% of alcohol consumption happened within 1 to 7 days after the last disulfiram intake. Nevertheless, no patient expe- rienced a severe DER, and 42% of patients who drank after 1 week had no DER, 23% experienced a mild reaction and only 9% had a moderate reaction [13]. disulfiram may also be harmless. He teaches the patient that the human organism is able to react completely different in case of another relapse, meaning that in a future relapse situation, the body may react with a severe and dangerous DER. The patient should also be informed that apart from DER every elevation of acetalde- hyde in the body is a dangerous poisoning, potentially increasing the risk of cancer, that is to be avoided. •Initial Psychoeducation on Disulfiram alcohol consumption for 1 to 2 weeks after taking disulfiram and this cognitive-emotional conviction should be recallable at any time. The cognitive-emotional experience of alcohol intolerance is the basic fundament of the therapeutic effect of disulfiram. Thera- pists can have an impressive demonstration of both the resulting deterrence and protection effect when they ask about how patients feel and what they think after the ingestion of disulfiram. Often patients report that they experience a feeling of protection and safety that helps them to cope with high-risk situations. In parallel, they report that they develop real fear of alcohol and that they take explicitly care to avoid the consumption of smallest amounts of alcohol, e.g. in mustard and vinegar. Both experiences are essen- tially supportive for abstinence maintenance and should -without stressful dramatizing- be confirmed by the therapist. The psycho- education on disulfiram is considered to be successful when the patients are able to verbalize in their own words basic knowledge: •Advanced Psychoeducation Fig. (3). Psychotherapeutic application of supervised disulfiram I - Initial psychoeducation. Fig. (4). Psychotherapeutic application of supervised disulfiram II - advanced psychoeducation. The most common misunderstandings that therapists have to correct in advanced psychoeducation are: (1) Disulfiram is con- fused with anti-craving medications. (2) Patients are worried that they might develop DER without alcohol consumption. (3) Male patients are afraid of developing erectile dysfunction. •Disulfiram as Coping Skill and Extension of the Repertoire of Coping Skills Fig. (5). Psychotherapeutic application of supervised disulfiram III - Disulfiram as coping skill and extension of repertoire of coping skills. therapeutic success can only be maintained when the patient has sufficient routine in carrying out a broad spectrum of alternative skills. Effective measures of behavior therapy that will replace medication completely after at least 12 months of disulfiram treat- ment include individual relapse prevention plans, skills training to reject alcohol, problem solving strategies, communication training and cognitive restructuring. SUMMARY AND CONCLUSIONS REFERENCES [9]Brewer C. Supervised disulfiram is more effective in alcoholics than naltrexone or acamprosate -or even psychotherapy: how it works and why it matters. Adicciones 2005; 17(4): 285-96. [36]Nava F, Premi S, Manzato E, et al. Comparing treatments of alco- holism on craving and biochemical measures of alcohol consump- tions. J Psychoactive Drugs 2006; 38(3): 211-7. [63]Miller WR, Wilbourne PL. Mesa Grande: A methodological analy- sis of clinical trials of treatment for alcohol use disorders. Addic- tion 2002; 97(3): 265-77. [83]Altun G, Alter A, Erdogan O. Acute myocardial infarction due to disulfiram (Antabus)-Alcohol interaction. Cardiovasc Drugs Ther 2006; 20: 391-2. Received: April 26, 2010 Accepted: April 29, 2010
Days to relapse: DSF (M 133
SD 21)>TPM (M 79 SD 33); abstinence at month 9: DSF (90%)>TPM (56%); Craving at month 9: TPM
& De Sousa (2008)
Open-label, random- ized trial
Outpatient addiction treatment clinic, explicit engagement of family members in supervised medication administration and enhancing therapy compliance; voluntary group therapy
N=58 adolescent patients with alcohol dependence; diagnosis according to DSM-IV, selection of patients aged between 15 and 18 years, without comorbid psychiatric disorder, with a family member to ensure treatment compliance and provide information at follow-up visits
6 months of treatment:
1.DSF: 250 mg / d
2.NTX: 50 mg / d
Explicit information of patients about mechanisms and side effects of study drugs
AE in DSF: neuritis (3)
Days to relapse: DSF (M 84 SD 14)>NTX (M 51 SD 16);
Abstinence at month 6: DSF (79%)>NTX (52%);
Craving at month 9: DSF>NTX
Open-label, random- ized multi-center trial
Brief self-help manual according to cognitive behavioral therapy
N=243 patients with alcohol dependence; diagnosis according to ICD-10, selection of patients seeking outpatient treatment, without severe comorbid psychiatric disorder
3.months of super- vised treatment, 9 months of unsuper- vised treatment:
1.DSF: 100 to
200 mg / d or 400 mg /
twice weekly
2.NTX: 50 mg / d
3.ACP: 1998 mg / d
Supervision of drug intake by significant others trusted by the patient
AE: DSF=ACP= NTX
(31% vs 29% vs 40%)
1suicide,
2drowned
Drinking outcomes during 3 months of supervised medication: Days to first heavy drinking: DSF (M 47 SD 28)> NTX (M 22 SD 22), ACP (M 18 SD 22); weekly gram ethanol consumption: DSF (M 52 SD 91)< NTX (M 184 SD 174), ACP (M 203
SD 180); days to first drink: DSF (M 30 SD 28)> NTX (M 20 SD 20), ACP (M 11 SD 17); abstinent days / week: DSF (M 6
SD 1)> NTX (M 5 SD 2), ACP (M 5 SD 2). Drinking outcomes during 9 months of
unsupervised medication: Days to first heavy drinking: DSF (M 106 SD 17)= NTX (M 129 SD 22), ACP (M 111 SD 23); weekly gram ethanol consumption: DSF (M 109 SD 104)< NTX (M 229 SD 200), ACP (M 195 SD 148); abstinent days /
week: DSF (M 6 SD 1)> NTX (M 4 SD 2), ACP (M 4 SD 2)
AA: Alcoholics Anonymous; ACP: Acamprosate; AD: Alcohol deterrent; AE: Adverse Event; AUD: Alcohol Use Disorder; ALT: Alanine transaminase; AST: Aspartate transa- minase; CBT: Cognitive Behavioral therapy; CRA: Community Reinforcement Approach; DER: Disulfiram Ethanol Reaction; DSF: Disulfiram; GGT: Gamma-glutamyl trans- ferase; GHB: Gamma-hydroxybutyrate; HCV: Hepatitis C virus; M: Mean; MD: Median; NTX: Naltrexone; S: Survival probability; SCID: Structured Clinical Interview for DSM- IV; SD: Standard deviation; TAU: Treatment as usual; TPM: Topiramate; U/l: Units per liter; Vs: Versus
Taken at a dose of ti250mg/d disulfiram has been considered to be a safe and well-tolerated medication [11, 15, 47, 58, 77].
According to data from the Danish Committee on Adverse Drug Reactions from 1968 to 1991 the safety of disulfiram corre- sponds to an intermediate rate of adverse reactions with 1 per 200 to 2000 treatments per year, mainly related to the liver, nervous system and skin [77]. Malcom et al. [47] reviewed 5 randomized clinical trials on disulfiram in alcoholism treatment that were pub- lished between 1984 and 2008. The authors conclude that adverse reactions in the trials appear far less serious and less frequent than adverse events reported post marketing in textbooks or the package insert. Serious adverse events were noted in 4 recent randomized clinical trials: Polyneuropathy occurred in 3 out of 50 patients and
2out of 50 patients in the studies of De Sousa & De Sousa 2005 [34] and De Sousa et al. 2008 [38], respectively. In the trial of Petrakis et al. [35] 2 cardiac events and 1 DER were recorded in the treatment condition “Disulfiram plus Naltrexone” (n=65), as well as 4 psychiatric hospitalizations, 1 cardiac event and 1 neuropathy in the treatment condition “Disulfiram plus placebo” (n=66). The authors report that 2 of the nonfatal cardiac events occurred after patients had discontinued study medications for other reasons, and the other one in the context of heavy cocaine use. Out of the 4 patients with psychiatric hospitalizations, 3 completed the study. An elevation of alanine transaminase values >200 units/l was ob- served in 6 out of 78 subjects in the trial of Laaksonen et al. [39]. Values returned to normal in 2 to 3 weeks after dose reduction to 100mg/d in 3 subjects and discontinuation of disulfiram in the other
3patients.
The most frequent adverse effects at the dosage of ti250mg/d are less serious and include initial tiredness, sleepiness, headache, and an unpleasant breath odour (garlic-like taste, metallic taste). However, at dosages of ti500mg/d, serious adverse effects were reported like psychosis, confusional states, peripheral neuropathy, optic neuropathy and seizures [58]. These effects are dose-related and can be prevented by using a small dose of 100mg/d or even less. To prevent serious adverse events, low dosage should be the standard of disulfiram treatment. As an example, Table 2 shows dose and frequency of supervised disulfiram as a component of the 2-year treatment program OLITA (Outpatient Long-term Intensive Therapy for Alcoholics, see below for a comprehensive description of the program). For psychotherapeutic application of disulfiram it is essential to point out that there is no need to increase dosage in order to cause a DER. As will be explained below, disulfiram’s positive impact on alcohol abstinence is mainly caused by psycho- logical mechanisms, and there is no clear evidence that it requires experience of a DER.
A rare but serious adverse event that can even occur under low- dose disulfiram is hepatotoxicity [11, 58, 77]. The mechanism and exact frequency of disulfiram-induced hepatitis are not known. Data from the Danish Committee on Adverse Drug Reactions from 1978 to 1987 show that 35 of the 1188 reports of drug induced hepatic injury were linked to disulfiram, as were 5 of 52 drug-induced hepatitis fatalities [78]. In their recent review, Ritvo et al. [61]
2-3 weeks; daily individual sessions, 15min each. Supervised disulfiram, 100mg daily
•Outpatient period I: Intensive phase
3 months; daily individual sessions, 15min each. Supervised disulfiram, 100mg daily
•Outpatient period II: Stabilizing phase
3-4 months, according to individual need; 3 times a week in- dividual sessions, 15min each.
Supervised disulfiram, 400mg, 3 times a week
•Outpatient period III: Weaning-off phase
6 months; twice a week individual sessions, 30min each. Supervised disulfiram, 400mg, twice a week
•Outpatient period IV: Aftercare phase
12 months; once weekly group session; initially weekly indi- vidual sessions (30min) which are gradually reduced.
Supervised disulfiram, 400mg, once a week; tapering off between months 13 and 20, individual extension possible
Skin complaints are among the less serious adverse events of even low-dose disulfiram and include rashes, pruritus, and exfoliative dermatitis. They mostly show an early peak incidence after 7 days, but occurrence after longer treatment periods were reported [77].
The DER at a dose of ti250mg/d is mild and varies from a slight flush to nausea, headache, dizziness and tightness of the chest. As a consequence, deaths from a DER have not been reported in recent years. However, in the first 10 years following disulfiram’s intro- duction, doses of 1000-3000mg/d were employed, and DERs were fatal in some cases [e.g. 80, 81].
Contraindications of disulfiram are: Severe cardiovascular disease (e.g. coronary heart disease), end-stage liver disease (e.g.
Disulfiram can cause clinically important interactions with the elimination or pharmacodynamics of a number of other drugs: Amitriptyline, antipyrine, barbiturates, benzodiazepines such as chlordiazepoxide, diazepam, triazolam, caffeine, diphenylhydan- toin, imipramine, isoniazid, metronidazole, tranylcypromine, per- phenazine, phenytoin, rifampicin, theophylline, tricyclics, warfarin [15, 58].
Ojehagen et al. (1991) investigated 50 socially stable patients par- ticipating in a long-term but non-intensive outpatient treatment (19 sessions/2 years) with voluntary disulfiram intake of 400mg 3 times per week [82]. The authors did not report any adverse event. Impor- tantly, a favorable drinking outcome was noted in 75% of long-term and only 31% of short-term users. Mueser et al. (2003) conducted chart reviews on 33 patients with psychotic and comorbid alcohol use disorders that were on disulfiram for 2 years (125mg/d in 1 patient, 250mg/d in 27 patients and 500mg/d in 5 patients). Side effects were reported by 7 patients (21%) with upset stomach, skin rash, nausea and vomiting as the most common events [71]. Inter- estingly, during a 3-year follow-up, 21 patients experienced a re- mission of their alcohol use disorder for at least one year and 10 patients showed a 2-year remission [82]. Børup et al. reported data from 93 patients who had taken supervised disulfiram for at least 1 year at a dosage of 600-800mg twice weekly. Patients were moni- tored by standard laboratory blood and urine tests. None of these patients developed any clinically significant adverse effect [76]. In the 2-year OLITA program, disulfiram was normally tapered off between months 13 and 20 of therapy (therapy contacts, dose and frequency of disulfiram Table 2) [13]. When patients preferred to continue they were allowed to do so until feeling safe enough to stop. High-frequency therapy contacts and regular laboratory tests ensured a strict monitoring of adverse events: Blood samples were taken at least every 2 weeks during months 1-3, monthly during months 4-12, bimonthly until the end of therapy, as well as once to twice yearly after termination of OLITA. Urine specimens were collected daily (after every therapeutic contact) during months 1-3, three times a week during months 4-6, two times a week during months 7-12, at least weekly during months 13-24, as well as weekly to quarterly after termination of therapy. A total of 115 patients completed the first year of OLITA with continuous use of AD. Of these patients, 41 stopped AD (38 patients on verum and 3 on sham-AD) as scheduled between months 13 and 20, with an average duration of intake of 500 days (SD 69); 74 (63 on verum and 11 on sham-AD) wished to continue disulfiram after month 20, with an average duration of intake of 976 days (SD 416). During the first weeks of treatment 2 out of 180 patients experienced seri- ous adverse events, and 7 patients reported adverse events. One male patient developed acute hepatitis after 56 days with a dose of 400mg, 3 times per week. Allergic eczema occurred in 1 female
In the last years, 10 case reports recorded serious adverse reac- tions of disulfiram: Acute myocardial infarction in a 36-year old man with a history of chronic alcoholism and smoking after DER under 500mg disulfiram/d and the reported consumption of salad with fermented vinegar and the use of aftershave [83]; disulfiram- methylphenidate interaction causing an acute psychotic state under 400mg disulfiram/d and 36mg OROS-methylphenidate/d in a 33- year-old alcohol-abstinent man with a history of alcohol and other substance abuse since the age of 15 years [84]; manic episode with psychotic symptoms in a 34-year-old alcohol-abstinent man with alcohol abuse for 15 years after 2 weeks of 500-1500mg disul- firam/d [85]; punding in a 39-year-old alcohol-abstinent woman with alcohol dependence since age 26 after 4 months of 200mg disulfiram/d [86]; neuropathy in 2 alcohol-abstinent patients, a 31- year-old woman with alcohol misuse for over 5 years after 2 months of 250mg/d, and in a 27-year-old man with a history of seizures, personality disorder and alcohol abuse since the age of 24 years after 1 month of 1600mg/d [87]; manic episode with psy- chotic features in a 38-year-old alcohol-abstinent man with a his- tory of 20 years of alcohol abuse after 1 month of 200mg disul- firam/d and subsequent reduction of the dose to 200mg every other day [88]; a disulfiram reaction after 1 single dose of the antibiotic Ceftin (cefuroxime axetil; 250mg at 6pm) in an alcohol-abstinent patient taking 125mg disulfiram/d for 18 months [89]; delirium- associated DER in a 51-year-old woman with a history of alcohol dependence for 5 years and major depression for 3 months after 10 days of 250mg disulfiram/d and 2 days of additional 1 glass of alcoholic beverage [90]; transient optic and peripheral neuropathy in a 57-year-old alcohol-dependent man with a history of comorbid depression, cigarette smoking, hyperlipidaemia and gastroesophag- eal reflux disease who maintained alcohol abstinence for 3 years taking disulfiram of unknown dose [91]; dermatitis recall in a 43- year-old man with a history of nickel dermatitis and 15 years of alcohol dependence after 4 days of inpatient treatment with 750mg disulfiram/d [92]; significant hypotension and ST depression during DER that required treatment in the emergency department in a 27- year-old man who relapsed after 3 weeks of alcohol abstinence under an unknown dose of disulfiram for 2 weeks [93].
Malcom et al. (2008) state that it is difficult to disentangle adverse effects of disulfiram itself from DER or from medical and psychiatric complications and comorbidities occurring with alcohol dependence [47]. From our perspective, the best way to prevent serious adverse events comprises two strategies: (1) low dose disul- firam of not more than 100 mg/d, and sham AD for patients with ineligibility or after initial subjective or objective adverse events; (2) integration of supervised disulfiram in an intensive, comprehen- sive and structured biopsychosocial therapy program that ensures regular medical examination and blood tests, biochemical control of substance consumption, as well as long-term psychotherapeutic treatment to make full use of the psychological effects of the medi- cation [6].
Given the carcinogenicity of acetaldehyde [94, 95] the question arises whether taking a drug that leads to the accumulation of acet- aldehyde in case of alcohol consumption may increase the risk of cancer. To the best of our knowledge this issue was only addressed
In summary, low-dose disulfiram – in best case not more than 100mg/d – is a safe and well-tolerated medication. However, ad- verse events like hepatitis or skin complaints may even occur under low dose. In order to fulfil safety measures best possible, super- vised disulfiram treatment should always be initiated with a careful physical examination at the beginning of therapy including labora- tory tests for pregnancy, blood tests and electrocardiogram. Patients taking disulfiram should be in regular contact with a physician, at least monthly for the first 6 months of treatment. Regular physical check-up examinations and liver function tests at 2-week intervals for the first 2 months and at 2-3 months intervals thereafter are recommended. In addition, patients should be informed about symptoms and early signs of hepatotoxicity (e.g. fever, jaundice) so that they can immediately contact the doctor and stop disulfiram when adverse effects are noted.
Several conclusions can be drawn from 60 years of treatment research on disulfiram: Supervised disulfiram constitutes an effec- tive adjunct to alcoholism therapy. It has shown high clinical safety and stable psychological effects in various treatment studies: Tak- ing disulfiram at the patients’ own discretion yields hardly any positive results; however, supervised oral administration of disul- firam as one part of a comprehensive treatment program has benefi- cial effects which are mainly explained by a psychological action. The clinical approach of psychotherapeutic disulfiram application that we describe in this review is based on the experience made in the OLITA project. The results of this 9-year follow-up study of comprehensive biopsychosocial alcoholism therapy did not indicate any impact of pharmacological mechanisms but gave many hints on psychological processes underlying disulfiram treatment. OLITA is a systematic four-step biopsychosocial outpatient treatment pro- gram for chronic alcohol dependent patients aiming at immediate social re-integration and extending over 2 years [6, 13, 100-102]. In the OLITA pilot study, the ADs disulfiram and calcium carbimide were employed as central therapeutic elements. Patients who were ineligible for disulfiram or calcium carbimide (severe liver disease, cardiovascular disorders, allergy) obtained a sham-AD tablet (sham-alcohol deterrent). This sham-AD tablet was presented to the patient as “special antabuse”, lacking dangerous adverse effects with respect to his / her specific medical condition. For pragmatic reasons, calcium carbimide with its shorter duration of action (12- 24 hours) was used in therapeutic phases with daily contacts, and
The result showed that cumulative probability of not having relapsed was .52, and of not having consumed any alcohol .26. Alcohol consumption was defined as every intake of an alcoholic beverage, reaching from so-called “mini lapses” (one single swal- low by accident) over lapses (every re-emergence of drinking ex- ceeding one day but being coped with) to full-blown relapses. A relapse was interpreted as recurrence of an addictive drinking pat- tern with premature termination of treatment or cessation of post- treatment follow-up visits (patient breaks up contact and cannot be “reached” any more – malignant relapse). Remarkably, experience of a disulfiram ethanol reaction after alcohol consumption was rare, although more than 50% of the alcohol lapses occurred within 14 days after last AD intake. Patients on sham-AD (due to contraindi- cations to verum-AD) showed even higher cumulative abstinence probability than patients on verum (S=.86 versus S=.49, p=.03). Abstinent and relapsed patients did not differ with regard to dose and tolerability of the medication. Abstinent patients had longer duration of intake, stopped disulfiram according to the planned therapy phase, and had longer days of abstinence after cessation of disulfiram. Relapsed patients had shorter duration of intake, stopped disulfiram more often without giving any reason or re- lapsed without having quit AD. As a consequence they had a shorter duration of intake of AD and less abstinent days without AD (p<.001 for all differences). Patients with coped lapse did not differ from patients with detrimental lapse with regard to dose, reasons for stopping of AD, time between stopping of AD and first alcohol consumption, and experience of DER. Patients with malignant relapse, however, rejected AD intake without giving any reason and dropped out of treatment on own initiative (p<.001 for all differ- ences). Detrimental lapses and malignant relapses occurred earlier than successfully coped lapses (p<.001). Patients with detrimental lapse and with malignant relapse had fewer days of AD intake and less subsequent days without AD than patients with coped lapse (p<.001). Importantly, cumulative abstinence probability was S=.75 for patients with long-term intake compared to S=.50 for patients who stopped AD between months 13 and 20 (p<.001).
Taken together, our data imply a psychological rather than a pharmacological action of AD, showing that (1) the longer the AD intake the more likely is a patient to stay continuously abstinent even after termination of AD; (2) the dose of AD is as irrelevant as the experience of a disulfiram ethanol reaction for AD to be effec- tive; (3) sham-AD is as efficient as disulfiram/calcium carbimide, provided that its use is repeatedly explained and continuously guided and encouraged.
Before going into the detailed steps of psychotherapeutic use of disulfiram, we will introduce the assumptions on which our ap- proach is based. Repeated explanation of the action of disulfiram by the therapist followed by repetition of the acquired information by the patient, is a prerequisite for the deterrent effect of disulfiram,
We suggest that the psychological effects of disulfiram extend far beyond its pharmacological action. They comprise: (1) deter- rence; (2) (auto) suggestion; (3) therapeutic ritual around (4) a frequently renewed active decision process; (5) continuous rein- forcement of a sober lifestyle and development of new coping skills. Taken together, disulfiram may be seen as an important component on the way to a stepwise recovering self-control and / or as a special skill that the patient learns to use.
low doses without losing their efficacy. Thus prerequisite of super- vised disulfiram is an adequately low dosage (e.g. 100mg/d) and most importantly a proper administration of the medication. Disul- firam should always be administered in form of effervescent tablets which are available at 200mg and 400mg. Effervescent tablets are dissolved in water. As a consequence they have the crucial advan- tage that they cannot be hidden between the fingers or spit out after intake. Furthermore they appear to have a bioavailability up to three times higher than non-effervescent tablets [103]. For the admini- stration of 100mg, the 200mg tablets can be divided easily into two parts. Every therapeutic contact including a disulfiram administra- tion starts with the therapist putting an effervescent tablet into a glass and adding water. When the tablet has dissolved completely the patient drinks the fluid. In order to prevent that patients pour the dissolved disulfiram into the sink or a flower-pot, the therapist takes care not to let the patients alone in the room when they drink the medication. Thus disulfiram is always administered under strict supervision.
Therapists working with disulfiram need to have sufficient knowledge about safety issues, adverse effects and contraindica-
tions of this drug (Table 3). Most of the harmless side effects of
Therapists using disulfiram as a psychotherapeutic tool also need basic knowledge of pharmacology and how to proceed in case of DER (Figs. 1, 2). In humans, various liver enzyme systems metabolize alcohol to acetate. Alcohol dehydrogenases metabolize alcohol to acetaldehyde and aldehyde dehydrogenases convert acetaldehyde to acetate that finally enters the citric acid cycle (Fig. 1). Disulfiram and its active metabolic derivates irreversibly block
the conversion of acetaldehyde to acetate by disabling both cyto- plasmic and mitochondrial forms of aldehyde dehydrogenase (ALDH1 and ALDH2) [105, 106]. As a consequence, alcohol con- sumption after the intake of disulfiram leads to an accumulation of the toxic acetaldehyde in blood. The unpleasant symptoms of acet- aldehyde poisoning start as soon as 10 minutes after alcohol inges- tion. They are mainly caused by the vasodilatating effect of acetal- dehyde and are summarized with the term DER: A mild reaction consists of facial flushing and redness with sensation of warmth or heat (vasodilatation in the face and neck), sweating and mild head- ache; moderate levels of intensity include dizziness, tightness in the chest, nausea, palpitation, dyspnea, tachycardia, and hypo-
/hypertension. Severe reactions may occur and comprise vomiting, respiratory depression, cardiovascular collapse, shock, arrhythmias, myocardial infarction, sudden cardiac arrest, unconsciousness, epileptic seizures, convulsions, and death.
Even though DER with a disulfiram dose of 100mg/d is consid- ered to be mild, therapists should not make the mistake to trivialize the intensity of DER when they perform the psychoeducation with the patient. Each DER and even putative DER (e.g. after consump- tion of one alcohol-containing Easter egg) that a patient describes should be discussed with him as a serious event and potentially dangerous poisoning. This event is to be treated with the adequate medical carefulness: Making sure that the patient stops alcohol consumption, monitoring of the patient in the clinic, repeated con- trol of blood pressure and heart frequency. The patient is only allowed to resume disulfiram intake when blood and breathalyzer tests have confirmed that he is again totally alcohol abstinent for at least 12 hours. During such a crisis intervention with an uncompli- cated DER and in the following therapy sessions, therapist and patient discuss about what it means that the patient experienced no serious DER. The therapist attributes the absence of a serious DER to "having been lucky" and points out that having experienced a mild reaction is no guaranty that future alcohol consumption under
Because inhibition of aldehyde dehydrogenases by disulfiram is irreversible, the DER after alcohol consumption will only disappear when the body has produced a sufficient amount of new aldehyde dehydrogenase after stopping disulfiram intake. This takes up to 1 week and some patients report that they experienced a DER 2 weeks after the last intake of disulfiram. As a consequence, patients should be asked to wait at least 2 weeks after the last disulfiram ingestion, if they want to resume alcohol consumption.
The major program of psychotherapy with disulfiram comprises the steps "Initial psychoeducation about the effect of disulfiram and its therapeutic implications" (Fig. 3), "Advanced psychoeducation" (Fig. 4) and "Disulfiram as coping skill and extension of repertoire of coping skills" (Fig. 5).
During the first psychoeducation sessions the therapist explains with an easy-to-understand-language the effect, the pharmacology and therapeutic application of disulfiram (Fig. 3). It is not important that the patients rehearse all pharmacological details by heart. The essential point is that they develop an active and vivid feeling and belief that they have acquired transient alcohol intolerance after taking disulfiram. Patients should intensively and emotionally experience the knowledge that they are physically unable to tolerate
(1)How the medication works, (2) how long it works, (3) which mild adverse effects may occur, (4) that there are essentially no clinically relevant pharmacological effects unless the patient drinks alcohol, (5) how and with which symptoms DER would occur in case of drinking alcohol.
After having explained the disulfiram effect in the first sessions, the therapist asks patients repeatedly during the following weeks and months to explain in their own words why they are taking the medication (Fig 4). In most cases patients cannot reproduce all important aspects of disulfiram medication, motivating them to keep practicing. Thus, advanced psychoeducation is not limited to the beginning of therapy but should be repeated at regular intervals during the complete therapy process.
Two simple interventions are helpful to rectify the confusion with anti-craving medication and the irrational fear of a DER with- out drinking alcohol: The pharmacological effects of disulfiram are discussed repeatedly. In addition, patients perform structured self- observation as homework. The results of self-monitoring, e.g. no DER under strict alcohol abstinence, or fluctuations in alcohol craving during the course of a day, are discussed in the therapy sessions. Here, typical interventions of cognitive therapy are ap- plied to lead the patient to "guided discovery", e.g. naïve questions about situation, thoughts, emotions, physical sensations, actions and behavior, and most importantly, the consequences that patients can draw from their self-monitoring.
Particularly the fear of erectile dysfunction can cause more serious therapeutic problems because many chronic alcohol de- pendent male patients suffer indeed from sexual problems, and erectile dysfunction is mentioned in some countries as potential side effect in the information sheet of disulfiram. Therapeutic interven- tions are oriented to the traditional biopsychosocial treatment of sexual dysfunction and comprise: Clarifying whether the patient is worried to develop erectile dysfunction or whether he is suffering from dysfunction; exploration whether the patient attributes a pre- existing problem to the intake of disulfiram; discussion of the state of research on the association between sexual dysfunction and chronic alcoholism. Patients should be informed about prevalence, etiology and course of sexual dysfunction in alcohol dependence, and they should be told that there is no evidence from clinical trials
that disulfiram causes any sexual problems. Subsequent examina- tions should include a comprehensive sexual history and find out to which extent the sexual dysfunction might be influenced by psy- chogenic factors, as well as endocrinological and neurological sequelae of alcohol consumption or other medical factors. Inde- pendently from any specific details of the treatment of the erectile dysfunction, therapists should (1) clearly emphasize that total alco- hol abstinence is prerequisite to support recovery of sexual func- tioning, (2) that the recovering process may take several months, and (3) that disulfiram intake is among the most successful methods of relapse prevention.
As a consequence of the combination of psychoeducation and skills training, the patient will regard alcohol consumption no longer as a meaningful alternative of problem solving. He or she has intentionally acquired alcohol intolerance and therefore the intake of disulfiram establishes one of the most important coping skills to prevent relapse during early abstinence.
However, maintenance of alcohol abstinence is not only charac- terized by the fact that the patient does not drink any more but also by the fact that he or she is taking alternative actions instead of drinking. As a consequence, the therapy sessions following psycho- education are used to support any behavior that supports abstinence in both daily life and high risk situations (Fig. 5). This is performed by (1) the patients' self observation of alternative activities, (2) discussion and role playing of alternative activities in therapy ses- sions, (3) the patients' explicit behavior testing of the coping skills in real life, (4) judging and finally training of those actions that are the most promising for the individual patient. On the long run,
When the status of disulfiram in contemporary addiction ther- apy was put up for discussion during the last years, Fuller and Gordis [11] asked the question "Does disulfiram still have a role in alcoholism treatment?" and concluded that "the answer is a quali- fied yes" provided that disulfiram is given under supervision of a therapist. This conclusion is confirmed by the reviews of Brewer et al. [60] and Suh et al. [14], and, most importantly, by the recent meta-analysis of Berglund [40].
In this article, we review 13 recent clinical trials of disulfiram in alcoholism therapy from 2000 to 2008 and conclude that, compared with other medications, disulfiram is the most effective pharmacol- ogical adjunct to psychotherapy in alcoholism treatment. We found that therapy programs that make use of psychological effects of disulfiram have - independently of dose - better results than pro- grams that neglect psychological effects. Thus, we propose that disulfiram will show highest success when it is carefully integrated into psychotherapeutic alcoholism therapy. Because dosage seems to play only a minor role, it should be kept low. Concerning safety issues of disulfiram, we conclude that the best way to prevent seri- ous adverse events comprises two strategies: (1) low dose disul- firam of not more than 100 mg/d, and sham AD for patients with ineligibility or after initial subjective or objective adverse events;
(2)integration of supervised disulfiram in an intensive, comprehen- sive, and structured biopsychosocial therapy program.
Psychotherapeutic application of supervised disulfiram can easily be implemented in clinical practice of routine therapy pro- grams of outpatient alcoholism clinics. It is surprising that the assumed psychological mechanisms of this approach are derived from clinical experience but that there are no studies on them. From the perspective of 60 years of research on disulfiram the time has come for treatment studies that investigate these psychological mechanisms.
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