Alcohol dependence is associated with much human misery throughout the world. By exploring the effects of alcohol on the brain, researchers have produced medicines to help improve the lives of sufferers and those around them.
Alcohol dependence is the severe form of alcoholism, characterised by speciﬁc deviant behaviours associated with prolonged consumption of excessive amounts of alcohol. It is considered a chronic illness of undetermined aetiology, with recognisable symptoms and signs in proportion to its severity. Consumption of large amounts of alcohol causes signiﬁcant clinical toxicity and tissue damage, physical dependence, and a dangerous withdrawal syndrome. The terms alcohol dependence and alcoholism also have a severe impact on the lives of alcoholics and their families. Eventually, drunkenness may lead to failed relationships as well as job loss due to absenteeism from work and a range of other problems. The most common forms of organ damage are cirrhosis, peripheral neuropathy, brain damage, and cardiomyopathy, often accompanied by arrhythmias. Gastritis is common, and pancreatitis may also develop.
Alcohol dependence is among the most common psychiatric disorders in the population: lifetime prevalence is around ten per cent. It is more common in men, but it is increasing in women. In Europe, the female to male ratio has narrowed to 1:3. Serious drinking often starts in adolescence; nearly half of all alcoholics develop ﬁrst symptoms between 15 and 19 years of age. Alcohol dependence often goes undiagnosed. This can lead to missed information about the medical and psychiatric conditions involved, drug interactions, and lost opportunities for prevention, e.g. during pregnancy to prevent the damaging effects of alcohol on the foetus.
There is an enormous cost associated with the abuse of alcohol. In its World Health Report of 2001, the WHO estimates that alcohol contributes to 1.5 percent of all deaths worldwide (750,000 people a year). In their report, the authors also mention that ﬁve per cent of all deaths involving people between the age of 5 and 29 worldwide can be attributed to alcohol. They conclude that the global burden of alcohol is actually greater than that of tobacco in terms of the loss of years of life, as the major health problems associated with smoking tend to emerge in later years.
Alcohol dependence is familial; an important risk factor for developing the disease is to have an alcoholic parent. Also, a genetic predisposition underlies alcoholism, particularly in the more severe form. The major genes that have so far been identiﬁed are protective against alcoholism; approximately 50 per cent of Southeast Asians have genetic variants of alcohol metabolising enzymes such that after drinking only small amounts, they experience tachycardia, nausea, and headaches as a result of the accumulation of the toxic metabolite acetaldehyde. These unpleasant effects act as a natural deterrent.
The cornerstones of treatment are behavioural approaches such as those offered by Alcoholics Anonymous, cognitive behaviour therapy and motivational enhancement therapy. Complementing these approaches, pharmacological treatments for alcoholism are being used. Medications are used to attain speciﬁc clinical goals such as promoting abstinence or reducing heavy drinking. They can help patients achieve these goals by reducing their desire for alcohol, reducing the rewarding effects of alcohol, or reducing protracted withdrawal symptoms. Adherence to the treatment is the most important predictor for successful pharmaceutical treatment of alcohol dependence. Treatment has to take into account both detoxiﬁcation and withdrawal. First, alcohol is withdrawn and the patients’ behaviour has to be changed to achieve sobriety.
The oldest therapeutic agent, acetaldehyde-dehydrogenase (ADH) inhibitor, was introduced as early as 1952 as an aversive therapy for alcohol dependence. The ADH inhibitor leads to increased levels of acetaldehyde, which is a toxic intermediate. Patients who take the medicine and drink alcohol will experience hypotension, nausea, vomiting, flushing, headache, and possibly palpitations and convulsions or even death. The molecule works most effectively in patients who adhere to the treatment, and patients who relapse on the medication tend to drink signiﬁcantly less, but there is only minimal evidence that it facilitates abstinence.
Another form of treatment consists of using a beta-endorphin inhibitor or opioid antagonist. The compound acts on receptors in the central brain by blocking the effects of endogenous opioids which increase after alcohol consumption. It is being used in early problem drinkers in targeted situations perceived as posing a high risk. Targeted opioid antagonist therapy combined with brief psychotherapeutic management has become an important strategy for reducing excessive alcohol use. The product has a well documented efﬁcacy, at least in the initial three months of treatment, and is easy to take on a once-daily basis.
A benzamide derivative with an inhibiting effect on dopamine-2 receptors – usually prescribed to treat patients with Parkinson’s disease who present with therapy induced movement disorders – is used in the long-term management of alcoholics of anxious or depressive temperament.
A structural analogue of gamma-amino butyric acid (GABA) has been used for almost 20 years in reducing both drinking frequency and cumulative drinking days. Chronic exposure to alcohol causes a decrease in the inhibitory GABA system and a corresponding increase in the activity of the excitatory glutamate system in the brain. The compound is thought to enhance GABA transmission by increasing the number of sites for GABA uptake. It also interferes with the action of glutamate, such as n-methyl-d-aspartate (NMDA)-receptors, thus restoring glutamatergic-mediated inhibitory and excitatory neurotransmission. The compound appears to have a prolonged action for up to a year after therapy has ceased, but compliance with a medication requiring three times a day administration is often difﬁcult.
The optimal duration of the latter two treatments has not been established, but six months should be considered a minimum duration of treatment, and 12 months more desirable.
In case of alcohol withdrawal, fluid balance must be maintained and large doses of vitamin C and B-complex vitamins, particularly thiamine, are given promptly. Some medicines frequently used to treat alcohol withdrawal are similar to alcohol in their effects; tranquillisers are the mainstay of therapy.
Data from recent studies suggest several further effective approaches using medicines may be available for treating alcohol dependence. The combination of an opioid antagonist and a GABA analogue may hinder relapse and promote abstinence. Another opioid antagonist found to be effective has a longer half-life, but the dose and optimal duration of therapy have not yet been established. So far, this compound has been used to treat alcohol dependence only in research settings.
An antiemetic selective serotonin 5-HT3-receptor antagonist has been shown to have a beneﬁcial effect on early-onset alcohol dependence, presumably by modulating dopamine release in dopamine pathways of the midbrain. In early-onset alcoholics, this compound appears to be a promising approach to reduce alcohol use.
New research shows that an antiepileptic thought to have multiple mechanisms of action, including enhanced GABA inhibition, may prove useful in signiﬁcantly reducing drinking days. The researchers suggest that the molecule stops the rewarding effects of alcohol which encourage its abuse, by reducing dopamine release, thus facilitating the action of GABA and inhibiting glutamate function. More generally, the results indicate that a different approach to treating alcohol dependence by using products for each stage of treatment would be useful – such as initiation of abstinence, treatment of withdrawal symptoms and long-term maintenance of abstinence.
The pharmacology of serotonin and its many receptors has been found to contribute to alcohol use in animals. 5-HT1A receptors may be associated with alcohol consumption and the development of tolerance, 5-HT2 receptors have been found to contribute to reward, and 5-HT3 receptors are linked to the development of reinforcement through synaptic projections on the dopamine system in the midbrain. Results of clinical trials using selective serotonin reuptake inhibitors (SSRIs) have been mixed. However, recent research suggests that subtypes of alcoholics may beneﬁt from this form of therapy.
Given the extent of the involvement of dopamine in motivation, reward, and reinforcement, dopamine antagonists are logical areas for further study. Antipsychotic medication has demonstrated various degrees of usefulness in reducing alcohol consumption or increasing abstinence. To date, the use of these medicines has been limited by their side-effect proﬁles. Dopamine’s importance in the addiction process suggests a need for further studies using dopamine antagonist medications with more modest side effect proﬁles.
There are still unanswered questions about the treatments for alcohol dependence, but research to address them is underway. Outstanding points include the effectiveness of medicines between different patient populations or in combination with other medicines or psychosocial therapy and the optimum dose and length of treatment. The next few years should provide key answers for the treatment of the alcohol dependent patient.