Chemical Aversive Conditioning for Alcoholism

Number: 0896

Policy

Aetna considers aversive conditioning for alcoholism experimental and investigational due to insufficient evidence in the peer-reviewed literature.

Background

Chemical aversion therapy is a behavior modification technique that is used in the treatment of alcoholism by facilitating alcohol abstinence through the development of conditioned aversions to the taste, smell, and sight of alcohol beverages. Aversive conditioning involves pairing alcohol with unpleasant symptoms (e.g., nausea) which have been induced by one of several chemical agents. While a number of drugs have been employed in chemical aversion therapy, the three most commonly used are emetine, apomorphine, and lithium.  However, it should be noted that these agents are not FDA approved specifically for chemical aversive conditioning for alcoholism (CMS, 2015).

Smith et al (1990) conducted a study of a multimodal inpatient program that used aversion therapy as a treatment component. A sample of 200 patients who had been completed treatment for alcoholism were recruited and a final sample of one hundred sixty (80%) were located. A minimum of 13 months had elapsed since treatment (mean 20.5 months) and abstinence status was determined for the first 12 months since treatment, the entire elapsed time since treatment (range 13 to 25 months, mean 20.5 months), and "current abstinence" (last 6 months). Results showed an abstinence rate for the first 12 months of 71.3%; 65% for the total period since treatment  (mean 20.5 months), and the current abstinence rate was 78.1The authors suggested that a multimodal alcoholism treatment program utilizing aversion conditioning is at least as acceptable to patients as counseling centered programs and can be expected to yield favorable abstinence rates.  However, replication of these findings in a controlled clinical trial would strengthen the weight of evidence.

Smith et al (1991) evaluated 249 patients who were treated for alcoholism in an inpatient multimodal treatment program that included aversion therapy.  They were matched on 17 baseline variables post hoc with patients from a national treatment outcome registry who received inpatient treatment that emphasized individual and group counseling as the primary therapeutic elements but did not include aversion therapy for alcohol. Data on 6- and 12-month abstinence rates from alcohol and all mood-altering chemicals was collected. The authors reported results including a statistically significant difference in the patients treated with aversion therapy compared with the matched patients.  The patients treated with aversion therapy for alcohol had higher alcohol abstinence rates at 6 and 12 months (p less than 0.01) and abstinence rates from all mood-altering chemicals were higher in the aversion group at 6 months (p less than 0.05) but not at 12 months.  Treatment groups in 6-month alcohol abstinence rates were found to have the largest differences for males (p less than 0.001), those over 35 (p less than 0.001), daily drinkers (p less than 0.001), and those with alcohol-related work performance problems (p less than 0.05).  Again, while encouraging, this study design is not a randomized controlled clinical trial to evaluate the effectiveness of chemical aversive conditioning for alcoholism. 

Frawley et al (1992) studied 214 randomly selected patients treated with aversion therapy for cocaine dependence in four chemical dependency units operated by Schick Shadel Hospitals.  Of these, 156 were followed up 12 to 20 months post-treatment (average 15.2 months). One-year total abstinence from alcohol was 54% for those receiving aversion for both alcohol and cocaine and 77% for those receiving aversion for alcohol, cocaine, and marijuana. Current abstinence from alcohol at follow-up was 68% and 81%, respectively. Results showed that 1 year total abstinence from marijuana was 42% for those treated with aversion for cocaine and marijuana and 64% for those treated with aversion for alcohol, cocaine, and marijuana while current abstinence at follow-up from marijuana was 61% and 81%, respectively. The results illustrated that total abstinence from cocaine for the group overall was 53% at one year post-treatment, current abstinence of at least 6 months at follow-up was 68.6%, while those treated with aversion for cocaine alone had a one-year abstinence of 39% and a current abstinence of 62.4%. Study participants treated with aversion for alcohol and cocaine had a one-year total abstinence from cocaine of 69% and a current abstinence of 76%. Those treating with aversion for cocaine and marijuana had a one-year total abstinence from cocaine of 50% and a current abstinence of 65%. Those treating with aversion for alcohol, cocaine, and marijuana had a one-year total abstinence from cocaine of 73% and a current abstinence of 73%. The authors noted that the use of aversion therapy for both alcohol and cocaine in alcoholics who were also using cocaine was associated with higher total abstinence rates (88% vs. 55%) from cocaine when compared with alcoholics who used cocaine but received no aversion as part of their program. They further noted that the conclusion is tentative since the follow-up rate in this study was lower than that of the previous study (64% vs. 84%) and that being around other users accounted for 49% of relapse situations while family/work stress was associated with relapse in 33% of cases and unpleasant feelings in 24% of cases. The use of both reinforcement treatments and the use of support following treatment were associated with improved abstinence rates from cocaine while those patients who reported losing all urges for cocaine after treatment had a total abstinence from cocaine of 90%, those who reported losing all the uncontrollable urges had a total abstinence of 64%, and those who reported still having the urge reported only 33% total abstinence from cocaine.

Smith et al (1997) reported on 249 patients who were treated for alcoholism in an inpatient multimodal treatment program that included aversion therapy and were matched post hoc on 17 baseline variables with patients from a national treatment outcome registry. The latter patients received inpatient treatment that emphasized individual and group counseling as the primary therapeutic elements but did not include aversion therapy for alcohol. Six- and 12-month abstinence rates from alcohol and all mood-altering chemicals were reported and the patients treated with aversion therapy for alcohol had higher alcohol abstinence rates at 6 and 12 months (p < 0.01). The abstinence rates from all mood-altering chemicals were significantly higher in the aversion group at 6 months (p < 0.05) but not at 12 months. It should be noted that these comparisons pooled faradic aversion and chemical aversion results. In order to determine whether or not the faradic aversion gave comparable results to the chemical aversion, the two groups were separately analyzed and no significant differences in outcome was found.

Diana et al (2008) reported that ethyl alcohol (EtOH), the main psychoactive ingredient of alcoholic drinks, is widely considered responsible for alcohol abuse and alcoholism through its positive motivational properties, which depend at least partially on the activation of the mesolimbic dopaminergic system.  They further noted that acetaldehyde (ACD), EtOH's first metabolite, has been classically considered aversive and useful in the pharmacologic therapy of alcoholics.  The authors illustrated that EtOH-derived ACD is necessary for EtOH-induced place preference, a preclinical test with high predictive validity for reward liability and that ACD is essential for EtOH-increased microdialysate dopamine (DA) levels in the nucleus accumbens (NAcc), and that this effect is mimicked by ACD administration to the intraventral tegmental area (VTA). The authors state that these results provide in vivo and in vitro evidence for a key role of ACD in EtOH motivational properties and its activation of the mesolimbic DA system. They further note that these observations suggest that ACD would oppose its well-known peripherally originating aversive properties by increasing VTA DA neuronal activity. These findings could help in devising new effective pharmacologic therapies in alcoholism.

Cassiaglia et al (2013) reported that people at high risk for alcoholism show deficits in aversive learning, as indicated by impaired electrodermal responses during fear conditioning, a basic form of associative learning that depends on the amygdala. They also state that positive family history of alcohol dependence has been related to decreased amygdala responses during emotional processing.  This study reported that reduced amygdala activity during the acquisition of conditioned fear in healthy carriers of a risk variant for alcoholism (rs2072450) in the NR2A subunit-containing N-methyl-d-aspartate (NMDA)-receptor. The authors note that results indicate that rs2072450 might confer risk for alcohol dependence through deficient fear acquisition indexed by a diminished amygdala response during aversive learning, and provide a neural basis for a weak behavioral inhibition previously documented in individuals at high risk for alcohol dependence.

Kim et al (2014) noted that episodes of alcohol consumption produce use-limiting aversive effects as well as use-promoting euphoric effects and that the brain regions associated with the reward circuit in patients with alcohol dependence show signs of conditioning for alcohol craving. Kim et al (2014) also note that brain structures in the medial temporal region are known to be crucial for aversive conditioning.  This study was conducted to compare differences in patterns of brain activation in response to cues that induce cravings versus aversion in alcohol dependence in 38 alcohol dependent and 26 healthy volunteers who were administered cue reactivity tasks while undergoing functional magnetic resonance imaging (fMRI) to examine brain response to craving-inducing cues (CIC) and aversion-inducing cues (AIC). The authors found that the right medial frontal gyrus (right orbitofrontal cortex) during CIC was greater in alcohol dependent study participants than in healthy volunteers. Participants in the alcohol dependence group displayed less activation in the right amygdala and the right middle temporal gyrus during AIC than did the healthy volunteers and brain reactivity within the right medial frontal gyrus in response to CIC was positively correlated with the scores of alcohol dependent participants on the Korean Alcohol Urge Questionnaire (AUQ-K) and the Michigan Alcohol Screening Test (MAST). Reactivity within the amygdala in response to AIC was negatively correlated with AUQ-K scores among alcohol dependent patients.  The authors concluded that the dysfunction of the orbitofrontal cortex that results from repeated exposure to alcohol accounts for craving and relapse in alcohol dependent subjects. Additionally, alcohol dependent subjects seem to be less sensitive to cues related to aversive consequences of alcohol overuse in comparison with healthy individuals.

The U.S. Centers for Medicare and Medicaid Services (CMS) have published a National Coverage Determination (NCD) stating that chemical aversion therapy for alcoholism may be an effective component of certain alcoholism treatment programs, particularly as part of multi-modality treatment programs which include other behavioral techniques and therapies, such as psychotherapy and thus do cover chemical aversion therapy. However, the NCD also notes that “[h]owever, since chemical aversion therapy is a demanding therapy which may not be appropriate for all Medicare beneficiaries needing treatment for alcoholism, a physician should certify to the appropriateness of chemical aversion therapy in the individual case.”

The above policy is based on the following references: