Antakson in the treatment of patients with alcoholism
A.G. Goffman, A.Yu. Magalif
, T.A. Kozhinova, I.V. Yashkina FGU Moscow NIIP Roszdrav “Psychiatry and psychopharmacotherapy” No. 5 / 2008
After the discovery of the opioid system at the end of the 20th century, the role of opioid receptors in the pathogenesis of not only drug addiction, but also alcoholism was established. In experiments on animals and in the study of patients with alcoholism, it was found that the activity of opioid receptors significantly affects ethanol consumption. It is known that substances capable of binding to opioid receptors with a high degree of affinity—opioid receptor ligands—modulate the functioning of the latter. There are endogenous (produced in the body) and exogenous ligands of opioid receptors. Several dozen endogenous ligands that are pentapeptides have been described. These include enkephalins and endorphins. Exogenous ligands are of plant origin or are synthetic substitutes for morphine. The best known are morphine, diacetylmorphine (heroin), acetylmorphine, as well as methadone, fentanyl and other drugs.
The opioid system in the human body functions in such a way that endogenous ligands, by binding to opioid receptors, change the content of intracellular messengers. The effects of opioid receptors are modulated through g proteins. There are 5 types of opioid receptors. The functions of m-, k- and d-receptors have been most studied. They are located in different parts of the brain, as well as in the duodenum, stomach, spinal cord, placenta, and immune cells. These receptors cause analgesia, regulate mood, affect cognitive functions, memory, sense of smell, gastrointestinal motility, and blood pressure. They inhibit the activity of the respiratory and cardiovascular centers, regulate eating behavior, thermoregulation, the synthesis of a number of hormones, and inhibit the release of the antidiuretic hormone, dopamine.
Of particular importance is that opioid receptor ligands have potent analgesic activity and alter the emotional perception of pain. At the same time, they depress breathing, suppress the activity of the cough center, have a pronounced hypnotic effect, and increase the tone of the bladder and intestines. The greatest analgesic effect is exerted by m-agonists – ligands that act predominantly on m-receptors. It is known that the more pronounced m-agonist properties are, the faster a pathological addiction to a drug or drug is formed.
When opium addiction develops, the number of receptors, the affinity of receptors for ligands, and the properties of signal transduction systems change. The properties of opioid receptors vary depending on the type of drug.
In the development of alcoholism, genetic defects of opioid receptors are considered important [1–8].
In the pathogenesis of the development of alcohol dependence, a major role is played by disruption of the interaction of endogenous opiates and the catecholamine system, primarily the dopamine system [3–5].
Since the opiate system was given particular importance in the regulation of emotions and desires, efforts were made to create drugs that block the action of drugs that affect opiate receptors. It was assumed that blocking opioid receptors with a non-addictive drug would lead to the disappearance of the euphoria that appears after taking opium-type drugs. In this way, it was supposed to eliminate the consequences of taking opiates and make their consumption pointless by patients.
First, naloxone was synthesized, with the help of which it was possible to remove patients from a state of deep morphine intoxication. Then naltrexone was synthesized, which is a direct antagonist of opiates, has long-term antagonistic activity, does not cause pathological addiction and is well tolerated.
Initially, naltrexone began to be used to treat patients with opium addiction (abuse of opium, morphine, codeine, heroin, acetylmorphine). The drug was prescribed to patients after withdrawal symptoms had stopped (not earlier than 5–9 days after the last drug intake). The course of treatment could last for many months. This helped prolong remissions. Many patients tried to test the effectiveness of naltrexone treatment and were convinced that euphoria did not occur after taking an average dose of the drug, but in the case of taking very large doses of opium or heroin, a narcotic state with respiratory arrest developed.
Since alcoholism and opium addiction have some common pathogenetic mechanisms, attempts have begun to use naltrexone to treat patients suffering from alcohol dependence.
The results of studies carried out in different countries [9–12] showed that naltrexone in the treatment of patients with alcoholism is a fairly effective drug. In the process of daily use of naltrexone, the dosage of alcohol consumed was reduced, the intensity of the pathological desire for intoxication decreased, and some patients subsequently completely stopped drinking alcohol. It was also noted that the effect of anti-alcohol therapy increased if daily intake of Antaxon was combined with psychotherapeutic influence.
Similar results were recorded by domestic researchers [2, 13–22].
To date, judging by the information accumulated on the Internet, approximately 1000 studies have been carried out on the treatment of patients with alcoholism using naltrexone. Many studies have been published comparing the effectiveness of naltrexone and other drugs. Interest in the use of naltrexone as a treatment for patients with alcoholism has not waned until recently [23–36].
Thus, R. Leeman et al. noted that naltrexone reduces alcohol consumption in heavy drinking at a young age. K.Richardson et al. found that naltrexone has the greatest effect when the craving for alcoholic intoxication is particularly intense; it is more effective than acamprosate.
Approximately equal effectiveness of naltrexone and topiramate in the treatment of heavy drinking was established by G. Florez et al.
In a double-blind, placebo-controlled study, H. Pettinati et al. found that combinations of disulfiram with naltrexone were much more effective than placebo.
A randomized multicenter study compared the effectiveness of disulfiram, naltrexone and acamprosate (E. Laaksonen et al.). The authors concluded that all three drugs, when used with short-term cognitive behavioral therapy, significantly reduced alcohol consumption.
S. Rosner et al. conducted a meta-analysis of a comparative study of the effectiveness of the glutamate receptor antagonist acamprosate and naltrexone. Naltrexone has been found to be most effective in preventing heavy drinking.
A similar meta-analysis of works devoted to the comparative effectiveness of naltrexone and acamprosate was carried out by H. Kranzler and J. Van Kirk. Both drugs are effective in reducing the severity of alcohol abuse.
A systematic study of the literature on the effectiveness and dangers of using naltrexone and acamprosate for 1990–2002 was carried out by C. Bouza et al. They concluded that both drugs were effective in treating alcoholism in adults. Naltrexone is more indicated for the purpose of controlling alcohol consumption.
A study of the effectiveness of naltrexone administered in injection form was carried out by P. Manelli et al. The introduction of an injectable drug ensures a more constant level of its concentration in the body. The effectiveness of the technique allowed the authors to suggest the advisability of using injectable naltrexone to treat patients suffering from other types of addiction.
SD'Malley et al. found that injectable naltrexone increases the duration of abstinence in heavy drinking.
A systematic review of the literature by the Cochrane Library concluded that naltrexone reduces the intensity of cravings. It is more effective than nalmefene, also an opioid receptor blocker, and much more effective than placebo. However, it is not known how long naltrexone treatment should last.
B. Johnson studied the effects of three injectable forms of naltrexone and established the advantages of the injectable drug compared to its oral form.
According to D. Davidson et al., when treating with naltrexone, it is very important to achieve compliance between the doctor and the patient, especially in the second phase of treatment.
E.Barrios de Tomasi, J.Jnares-Gonzares assign a very significant role to the opiate system in the pathogenesis of alcoholism. They consider the effectiveness of naltrexone in the treatment of patients with alcoholism to be undoubted and believe that d- and m-receptors modulate alcohol consumption to the greatest extent.
In order to establish the effectiveness of treating patients with alcoholism with an opiate receptor blocker, an open, standardized clinical trial of the drug Antaxon was conducted on a sample of 20 patients (18 men and 2 women) randomized by age and basic anamnestic indicators (18 men and 2 women) who were diagnosed with alcohol dependence of stages II and III.
Antaxon (generic name “naltrexone”) is produced by the Italian company “Zambon”; in 1998 the drug was registered in Russia. Antaxone is a pure, competitive opioid receptor antagonist, has no agonist properties, has a more intense effect on opioid receptors than naloxone, and has a longer duration of action. Antakson binds to opioid receptors of all types and prevents or eliminates the action of endogenous and exogenous ligands of opioid receptors for one day. The drug is metabolized in the liver to form pharmacologically active metabolites. The average half-life of Antaxon from the body is 4 hours, and its main metabolite, 6-b-naltrexone, is 13 hours. This explains the ability of the drug to accumulate.
Antaxon has found wide application in the treatment of patients with opium addiction and heroin addiction. Maintenance therapy with Antaxon has shown that when taking the drug daily, euphoria and analgesia caused by opium drugs do not occur. It was also found that with long-term use of Antaxon, the craving for the drug is reduced and it is possible to prolong remission and minimize the number of breakdowns and relapses. The drug is well tolerated and does not cause addiction or pathological addiction.
The objectives of the study were to establish the effectiveness of Antaxon in the treatment of patients with alcoholism during the period of therapeutic remission. Such indicators as reduction of affective, neurosis- and psychopathic-like disorders, manifestations of primary pathological attraction to alcoholic intoxication were taken into account. To standardize the study, we used individual registration cards reflecting the dynamics of affective and other psychopathological disorders, cards of general clinical impressions, and cards of the therapeutic effectiveness of the drug. The patients' condition was assessed on days 1–3 and 7, then after 2, 4, 6 and 8 weeks of therapy. The study was stopped if the patient refused treatment, there was no therapeutic effect, or the patient's condition worsened.
Antakson was prescribed as monotherapy at a dose of 50 mg/day daily throughout the study period. All patients gave voluntary consent to treatment with the drug. No special types of psychotherapy were used. All patients were on outpatient treatment, i.e. in conditions of free access to alcoholic beverages.
Characteristics of the examined patients
The average age of the patients was 41.3 years. In 18 observations, stage II alcohol dependence was diagnosed, in 1 observation – stage II–III, in 1 observation – stage III. 47% of patients had secondary or special secondary education, 53% had higher education. At the time of the examination, 13% of patients were not working. 27% of patients were engaged in mental labor, 60% in physical labor. 53% of patients had their own families.
The average duration of the disease was 8.7±0.3 years (from 4 to 10 years). The progression of the course of alcoholism (the rapidity of formation of withdrawal syndrome and pathological desire for intoxication from the onset of alcohol abuse) was low (more than 8 years) in 40% of patients, medium in 33% (from 5 to 8 years), and high in 27% (up to 5 years). A constant, continuous form of alcohol consumption was noted in 13% of patients, pseudo-binge drinking - in 74%, dipsomanic (in the form of binges preceded by mood disorders) - in 13%.
53% of patients had liver pathology (mainly as a result of alcohol abuse), 40% had arterial hypertension (mainly hypertension), 1 patient was diagnosed with alcoholic encephalopathy and polyneuropathy.
The majority (80%) of patients had conflicting family relationships, 73% had professional and administrative violations, and 60% had serious economic problems caused by drunkenness and dismissal from work.
In most cases, the course of alcoholism was in remission. Complete therapeutic remissions occurred in 67% of patients, in 60% of them the duration of remissions (therapeutic and spontaneous) exceeded 12 months, the average duration of remissions was 1.47±0.56 years.
results
In the post-withdrawal period, subdepressive melancholy or anxiety-melancholy disorders persisted for several days in 90% of observations; manifestations of dysphoria were noted in 2 observations.
The criteria for the effectiveness of Antaxon therapy were considered to be indicators of positive dynamics of psychopathological disorders and manifestations of pathological desire for intoxication. These data are reflected in table. 12.
As follows from these tables, a unidirectional positive trend in all indicators was observed. By the 3rd week of treatment, asthenic and affective disorders were reduced in 90% of patients, and night sleep was normalized. Irritability, short temper, and anger persisted longer. From the indicators in table. 2 it follows that the leading manifestations of the primary pathological craving for alcohol during the period of remission weakened and completely disappeared unevenly. Affective and vegetative disorders, which are usually considered as equivalent to a pathological desire for intoxication, disappeared quite quickly. Sleep disorders with “alcoholic” dream content also quickly disappeared. The ideational components of the desire for intoxication disappeared gradually, over the course of 3–4 weeks. By the beginning of the 2nd month of treatment with Antaxon, the condition of almost all patients had improved significantly. Only 2 patients dropped out of the study. One patient interrupted treatment due to a business trip, another 1 patient due to lack of therapeutic effect. No side effects have been identified. The therapeutic effect was considered significant (complete or almost complete remission) in 85% of patients, a moderate effect was noted in 2 patients.
In some observations, patients stopped drinking alcohol immediately after starting treatment. In other cases, a gradual decrease in the dosage of alcohol consumed was observed. In one observation, a patient who refused treatment and was constantly in a state of more or less deep intoxication, gradually began to drink smaller and smaller doses of alcohol and then stopped drinking completely.
After the end of the study, an attempt was made to treat patients with schizotypal disorder (low-progressive schizophrenia) combined with alcoholism with Antaxon. Patients sought help due to drunkenness and were treated mainly in drug treatment institutions. Of the 10 patients with a combined course of two diseases, 8 showed a positive effect in the form of stopping alcohol consumption or a significant reduction in its daily dosage. It is possible that the effectiveness of treatment could be greater if the administration of Antaxon to these patients was combined with the administration of antidepressants and antipsychotics.
Thus, a clinical study of the effectiveness of Antaxon showed that it can be recommended as an anti-relapse agent in the complex therapy of patients with alcohol dependence. Antaxon is one of the few drugs that reduces the intensity of the desire for intoxication. The drug is compatible with other medications, which potentially increases the effectiveness of therapy.
Antakson can be prescribed to all patients with alcoholism, regardless of the severity of the condition and the duration of alcohol abuse. Special indications for treatment with Antaxon are the following: 1) continuous consumption of alcohol, which interferes with seeking medical help; 2) a very intense desire for intoxication, which cannot be eliminated by other means; 3) periodic, regularly occurring exacerbation of the desire for intoxication, the occurrence of which cannot be prevented by any of the known methods.
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