Aversion therapy

One of the earliest forms of treatment conducted within this model was called aversion therapy. The idea was to pair drug use with a really nasty consequence... 

Historically, the treatment of alcohol use disorders with medication has focused on the management of withdrawal from the alcohol. In recent years, medication has also been used in an attempt to prevent relapse in alcohol-dependent patients. The treatment of alcohol withdrawal, known as detoxification, by definition uses replacement medications that, like alcohol, act on the GABA receptor. These medications (i.e., barbiturates and benzodiazepines) are cross-tolerant with alcohol and therefore are useful for detoxification. By contrast, a wide variety of theoretical approaches have been used to reduce the likelihood of relapse. This includes aversion therapy and anticraving therapies using reward substitutes and interference approaches. Finally, medications to treat comorbid psychiatric illness, in particular, depression, have also been used in attempts to reduce the likelihood of relapse. 

Disulfiram (Antabuse). Disnlfiram is the only medication specifically approved by the FDA as an aversion therapy for snbstance abnse, specifically alcohol abnse or dependence. Disnlfiram s mechanism of action is qnite simple it is an inhibitor of alcohol dehydrogenase, the major enzyme responsible for the metabolism. Inhibiting this enzyme resnlts in the accnmnlation of acetylaldehyde. Acetylaldehyde is primarily responsible for many of the nnmistakable symptoms of a hangover, and when it accnmnlates in the presence of disnlfiram, it produces a constellation of very nncomfortable physical symptoms. 

The aversive agents diminish substance use by producing an aversive reaction when a specihc illicit substance is consumed. For example, disulfiram (Antabuse) prevents the breakdown of acetaldehyde, a toxic metabolite of alcohol, producing a noxious reaction when alcohol is consumed. While aversive agents have been in existence for decades, studies of their effectiveness in adults have produced mixed results (Kaminer, 1994b Garbutt et al., 1999). Likewise, there is only one published case report on the use of aversive therapy for pediatric SUD. Myers and associates (1994) reported on the use of disulfiram (Antabuse) for two teens with alcohol dependence. Both patients were briefly abstinent, but then became noncompliant and quickly relapsed. 

Wilson, T. G. 1978. "Alcoholism and Aversion Therapy Issues, Ethics, and Evidence." In Behavioral Approaches to Alcoholism, edited by G. Allen Marlatt and P. E. Nathan. New Brunswick Rutgers University Center on Alcohol Studies. 

During the next several weeks these symptoms would periodically reoccur. One day, the two collaborators met in the hall and, during the course of their discussion, discovered that they had been having the same symptoms. Comparing notes, they realized that the only common denominator was alcohol. Subsequent studies confirmed that the problem was caused by a drug-alcohol interaction. Eventually, disulfiram was introduced clinically as aversion therapy in alcoholics. Its mechanism... 

Disulfiram is an aversive therapy that works by inhibiting acetaldehyde dehydrogenase. Interactions between disulfiram and alcohol can result in potentially severe reactions, such as myocardial infarction, congestive heart failure, respiratory depression and death. Patients taking disulfiram should be warned of the possible presence of alcohol in liquid medicines, tonics, foods and even in toiletries and mouthwashes. Patient adherence to disulfiram is poor and there is a lack of strong evidence for its effectiveness, thus it is not routinely recommended. 

Complaints of weakness, tenderness, and stiffness of skeletal muscles, especially in the neck and shoulder, are common. Following emetine aversion therapy for alcohol abuse, muscle weakness and pathological changes in muscle biopsy specimens have been described (SED-11, 594). 

Acetaldehyde causes nausea, vomiting, and va.saldehyde dehydrogenase, allowing acetaldehyde to accumulate. 

Cyanamide also acts as a potent inhibitor of the enzyme aldehyde dehydrogenase, which results in a disulfiram-like reaction in individuals concomitantly exposed to alcohol. Potentiated by the ingestion of alcohol, the accumulation of acetaldehyde in the body presents as a syndrome of vasodilation characterized by facial flushing, headache, nausea, vomiting, difficulty in breathing, sweating, chest pain, hypotension, weakness, blurred vision, and confusion. Calcium cyanamide has been used in aversion therapy for alcoholism. 

Prodrugs can be used to give a slow release of drugs which would be too toxic to give directly. Propiolaldehyde is useful in the aversion therapy of alcohol, but is not used itself since it is an irritant. However, the prodrug pargylene can be converted to propiolaldehyde by enzymes in the liver (Fig. 8.19). 

Amino-l,2,4-triazole and diethyldithiocarba-mate are mechanism-based inactivators. The latter is of interest in that the oxidized form, disul-firam (Antabuse ), is an aldehyde dehydrogenase inhibitor used in patients in alcohol aversion therapy. Many of the early animal and human studies on interactions of ethanol and disulfiram with various chemicals can now be rationalized in the context of P450 2E1 (refs [668], [669]). 

Pargylene (3.45) is used in the aversion therapy of alcoholism to inhibit aldehyde dehydrogenase and so cause a highly unpleasant concentration of acetaldehyde to build up in the bloodstream. Pargylene does not have this effect directly, but only after the liver e.r. has metabolized it to propiolaldehyde (3.46) which is the true drug (Shirota, DeMaster and Nagasawa, 1979). 

In5>ortantly, disulfiram (DSF) which is an oxidized form of diethyldithiocarbamate (deDTC), Scheme 4, was found to induce dramatic increases in apoptosis in a number of melanoma cell lines.(id) As shown in Figure 4, melanoma cells in culture are much more sensitive to DSF than those of normal melanocytes (MC) or prostate cancer (Du 145). This is significant as DSF has been used for fifty years as the main conq>onent of alcohol-aversion therapy approved by the FDA.(57) The use of DSF in clinical treatment of melanoma is currently being investigated in a phase I trial.(5 )... 

Of course, these symptoms can also be cured by ethanol itself and relapse is common in the first few months after withdrawal. To help avoid relapse, acamprosate, a weak NMDA antagonist, is sometimes used. This drug appears to help diminish fedings of craving. Naltrexone, an opioid receptor antagonist, can block reward pathways that are activated by alcohol and so break the fink between alcohol and its reinfordng effects. An alternative approach of aversion therapy is provided by the dmg disulfiram. 

---