Mental and behavioral disorders due to use of alcohol. Alcohol dependence syndrome: clinical guidelines

List of Abbreviations

AWS – alcohol withdrawal syndrome

BP – blood pressure

ALT – alanine aminotransferase

ALDH – aldehyde dehydrogenase

AST – aspartate aminotransferase

WHO – World Health Organization

GABA – gamma-aminobutyric acid

Gamma-GT – gamma-glutamyltransferase

DA – dopamine

VLEL – vital and essential drugs

TRP – treatment and rehabilitation program

MP – medicinal product

Russian Ministry of Health – Ministry of Health of the Russian Federation

ICD-10 – International Statistical Classification of Diseases and Related Health Problems, Tenth Revision

ADR – adverse drug reactions

AC – alcohol craving (pathological craving for alcohol)

PT – psychotherapy

ADS – alcohol dependence syndrome

SSRIs – Selective Serotonin Reuptake Inhibitors

LCE – level of confidence of evidence

LoR – level of recommendation

RR – respiratory rate

HR – heart rate

CDT – carbohydrate-deficient transferrin

MCV – erythrocyte mean corpuscular volume

Terms and Definitions

Alcohol withdrawal syndrome is a complex of autonomic, somatic, neurological, and mental disorders occurring in patients with dependence syndrome upon complete cessation of alcohol intake or reduction of its dose after repeated, usually prolonged, and/or high-dose use.

Alcoholic personality deterioration is a psychopathological syndrome manifested by progressive emotional coarsening, intellectual and volitional decline with a narrowing of the range of interests and leveling of personal characteristics.

Antidepressants (Greek *anti-* "against" + Latin *depressus* "pressed down, dejected")

– a group of medicines that improve the condition of patients with various mental disorders accompanied by depression. In accordance with the

Anatomical Therapeutic Chemical (ATC) classification recommended by the WHO, the following groups of antidepressants are distinguished: non-selective monoamine reuptake inhibitors; selective serotonin reuptake inhibitors; non-selective monoamine oxidase inhibitors; type A monoamine oxidase inhibitors; other antidepressants.

Antiepileptics – a group of medications used to relieve seizures of any origin. In accordance with the Anatomical Therapeutic Chemical (ATC) classification recommended by the WHO, the following groups of antiepileptics are distinguished: carboxamide derivatives, fatty acid derivatives, other antiepileptics. Some of these medications have the ability to stabilize mood, prevent or mitigate and shorten relapses of affective disorders. Synonym: anticonvulsants.

Antipsychotics – a group of medicines that exert a diverse, predominantly inhibitory effect on higher nervous activity, emotional state, and behavior without impairing consciousness. In accordance with the Anatomical Therapeutic Chemical (ATC) classification recommended by the WHO, the following groups of antipsychotics are distinguished: aliphatic phenothiazine derivatives; piperazine phenothiazine derivatives; piperidine phenothiazine derivatives; thioxanthene derivatives; butyrophenone derivatives; indole derivatives; diphenylbutylpiperidine derivatives; benzamides; other antipsychotics.

Compliance (from English compliance, "consent, conformity") – the patient's voluntary adherence to the prescribed treatment regimen; synonym: treatment adherence.

Opioid receptor modulator – a selective opioid receptor ligand exhibiting antagonist properties at µ- and δ-receptors and partial agonist properties at κ-receptors.

Adverse drug reaction (Eng. – adverse reaction) – any untoward and harmful reaction in a human organism that occurs with the use of a medicinal product in recommended doses for prophylaxis, treatment, and diagnostics, or for the modification of a physiological function, and for which a causal relationship with the medicinal product is established.

Rehabilitation (from Latin rehabilitation, "restoration of rights") – a comprehensive, targeted use of medical, social, educational, and occupational measures aimed at adapting the patient to activity at the highest possible level for them (WHO definition, 1995).

Sensitizing agents (Latin *sensibilis* "sensitive") – in addictology, this is a group of medicines that sharply increase the body's sensitivity to alcoholic beverages and cause physical alcohol intolerance.

Alcohol craving (psychological dependence) (Eng. – alcohol craving) – a nosologically specific psychopathological disorder characteristic of dependence diseases, clinically manifested by ideational (thought-related), behavioral, affective (emotional), vegetative, and sensory disturbances. Diagnostic criteria for alcohol craving include: a strong desire or compulsion to take alcohol, loss of quantitative and situational control, and continued alcohol use despite clear harmful consequences, with awareness of the link between use and consequences.

Specific medicines – medicines which, in accordance with the Anatomical Therapeutic Chemical (ATC) classification recommended by the WHO, belong to the group "N07B Drugs used in addictive disorders". This group is a miscellaneous one, including drugs of various pharmacotherapeutic groups and mechanisms of action, in particular: disulfiram – an acetaldehyde dehydrogenase inhibitor; naltrexone**

– an opioid receptor antagonist; nalmefene – an opioid system modulator.

Tolerance (Latin *tolerantia* "endurance, ability to bear")

– a progressive weakening of the desired psychotropic effect of alcohol (euphoria, calming, relaxation, etc.), which forces the patient to increase doses and frequency of alcohol-containing beverage intake. This is based on the physiological mechanism of the body's adaptation to the toxic effect of alcohol. Cross-tolerance

– the development of tolerance to a substance to which an individual has not been previously exposed, as a result of alcohol intake.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Alcohol dependence syndrome (hereinafter – ADS)

– a combination of physiological, behavioral, and cognitive phenomena in which alcohol use takes a leading place in the patient's value system.

ADS has characteristic features of development, course, and outcomes, which are determined by persistent somatoneurological disorders, mental degradation, and the presence of social problems.

Synonyms: alcoholism, alcohol addiction, alcohol dependence.

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

ADS develops under the influence of a complex of biological (genetic, neurophysiological, biochemical), personality-psychological (character traits, personality disorders), and social-environmental (micro- and macrosocial) factors, the specific weight of each of which in the genesis of the disease is unique for an individual clinical case [1-3].

A high risk of ADS development is associated with the mesolimbic dopamine neurotransmitter system, which is called the brain reward system (internal reinforcement system) [2; 4].

The brain reward system is responsible for the subjective assessment of "pleasure" and is the neurobiological substrate of goal-directed behavior. The ability of alcohol to induce immediate and intense dopamine (hereinafter – DA) release in the reward system leads to strong excitation of the latter and is accompanied by positively colored emotional experiences. This determines the high hedonic potential of alcohol. The positive motivation towards alcohol intake formed in this process promotes its further use and the development of pathological alcohol craving (hereinafter – PAC). PAC, acting as a kind of "parasite" of the reinforcement system, uses the powerful mechanisms of this system for its own development and maintenance. Currently, the dopamine hypothesis described above is the main one explaining the pathogenesis of ADS [4-6].

According to the dopamine hypothesis, a single intake of alcohol significantly increases the concentration of free DA. Systematic alcohol intake leads to functional depletion of the dopamine neurotransmitter system: with chronic use of high doses of alcohol, the DA concentration decreases. The latter circumstance triggers the mechanism for forming a new, higher level of activity of the dopamine neurotransmitter system and accelerating the metabolic turnover of DA. As a result, the DA synthesis and utilization systems become unbalanced, where its excess becomes constant [4]. The new dysfunctional state is caused both by disorders of the dopamine neurotransmitter system itself and by the resulting imbalance in the systems modulating it (peptide modulation), activating it (glutamate), and inhibiting it (gamma-aminobutyric acid (hereinafter – GABA)), as well as impaired reactivity of neurohumoral systems [2; 4; 7].

This is how the "vicious circle" of DA metabolism in the brain reinforcement system is formed.

This new functional state (new metabolic level) of the dopamine neurotransmitter system no longer depends on alcohol intake and has the capacity for long-term persistence. In the absence of alcohol intake, not only does the pathophysiological "vicious circle" fail to fade, but on the contrary, the body's self-regulation is aimed at recreating this circle. This state is the biological manifestation of established ADS. With the development of ADS, the vital needs of the body give way to the need for new intakes of alcohol [2; 7-8].

There are also other hypotheses of the pathogenesis of AUD, in which the endogenous opioid and GABA-glutamatergic systems of the brain play leading roles. Thus, the opioid redundancy hypothesis suggests a biological predisposition to excessive alcohol consumption, as well as the dependence of this phenomenon on increased activity of the endogenous opioid system. When alcohol is consumed, this system is activated, which, in turn, has a decisive effect on excessive alcohol consumption. The opioid "compensation" hypothesis suggests the biological determinism of AUD, but clarifies that it is associated with insufficient activity of the endogenous opioid system. As a result, alcohol compensates for the deficiency of the endogenous opioid system, which ultimately also leads to excessive alcohol consumption. The opioid alcohol-sensitivity hypothesis suggests that an initially low or high level of endogenous opioid activity is not associated with alcohol consumption. The development of AUD occurs due to an increase in the activity of this system that arises upon alcohol consumption and the formation of a positive reinforcing effect of alcohol intake, which again ultimately leads to its excessive consumption [2; 7-8].

The GABA and glutamate system is also of great importance for the development of the primary effects of alcohol in the central nervous system and the possible mechanisms of formation, development, and maintenance of AUD. It is hypothesized that the effect of alcohol on glutamate-mediated neurotransmission and mechanisms of synaptic plasticity in the structures of the mesolimbic system is crucial for assessing the novelty and importance of a stimulus and may serve as the basis for the molecular mechanism of AUD development [2; 7-8].

1.3 Epidemiology of the Disease or Condition

AUD is a major medical and social problem. According to medical statistics, up to 2% of the global population suffer from alcohol abuse or dependence [2; 9].

In 2022, specialized institutions of the Russian Ministry of Health registered 1,131,911 patients with AUD, or 772.9 per 100,000 population, which accounted for 64.7% of the total dispensary caseload and 0.77% of the total population. Compared to 2021, this dispensary caseload decreased by 2.3%. Among patients with AUD, the 40-59 age group predominated, accounting for 51.8% in both 2021 and 2022. The 20-39 age group accounted for 30.7% of patients in 2022, and the group aged 60 and older accounted for 17.4%. In 2022, 9 pediatric patients with AUD under the age of 14 and 132 adolescent patients with AUD aged 15-17 were registered, accounting for 0.03% of the child population and 1.7% of the adolescent population, respectively [10-11].

Patients with AUD also predominate among those seeking specialized care for the first time compared to other substance use disorders. Thus, in 2022, 53,347 patients with AUD sought addiction treatment for the first time in their lives in the Russian Federation (2021: 53,544). The incidence rate of primary AUD in 2022 was 36.4 per 100,000 population (in 2021: 36.8 per 100,000 population). The decrease in primary AUD incidence in 2022 compared to the 2021 level was 0.4% [10].

The hospitalization rate for patients with AUD in Russia in 2022 was 218.2 per 100,000 population, which is 4% higher than in 2021 (209.5 per 100,000 population). By this indicator, patients with AUD significantly exceed other substance use disorders [10].

Despite the characteristic predominance of patients with AUD among the addiction caseload in Russia, over the past 10 years there has been a decline in indicators related to AUD incidence and prevalence [10].

1.4 Features of Coding the Disease or Condition

The International Classification of Diseases, 10th Revision (hereinafter referred to as ICD-10) provides coding for the type of psychoactive substance (hereinafter referred to as PAS) used, the stage of the disorder, and the current nature of the dependence syndrome [12].

F10.2xx – mental and behavioural disorders due to use of alcohol, dependence syndrome

The current nature of AUD is specified by the fifth character:

F10.20.. – currently abstinent

F10.21.. – currently abstinent, but in an environment that restricts use (hospital, prison, etc.)

F10.22.. – currently under clinical supervision on maintenance or replacement therapy

F10.23.. – currently abstinent, but on treatment with aversive or blocking drugs

F10.24.. – currently drinking (active dependence)

F10.25.. – continuous use

F10.26.. – episodic use

F10.29.. – episodic use, unspecified

The stage of AUD is specified by the sixth character:

F10.2x1.. – initial (first) stage

F10.2x2.. – middle (second) stage

F10.2x3.. – terminal (third) stage

F10.2x9.. – stage unknown

1.5 Classification of the disease or condition

There is no unified classification of clinical variants of AUD. Various national classifications exist in different countries. The international classification of diseases developed by the WHO is adapted to international national taxonomies in most countries [13-14].

ICD-10 identifies three stages of AUD [12]:

- initial (first);

- middle (second);

- terminal (third)/

The stages are conventional reference points that help determine a patient's position on the path from the onset of the disease to its outcome. The three stages correspond to three cardinal clinical syndromes of AUD: PAS craving, alcohol withdrawal, and alcoholic degradation, which sequentially complement the clinical picture of the disease as it progresses. Staging allows the symptoms of AUD to be viewed in interconnection and over time, and clinical syndromes to be used as diagnostic criteria.

The dynamics of AUD is also expressed by the rate of symptom development – the progre­dience of the disorder. To assess progredience, the period from the onset of regular alcohol consumption to the development of alcohol withdrawal syndrome (hereinafter referred to as AWS) is used as a guide. There are three degrees of disease progredience [13]:

- high – up to 3 years in men, up to 2 years in women;

- medium – from 3 to 12 years in men; from 2 to 7 years in women;

- low – over 12 years in men; over 7 years in women.

According to the pattern, the following forms of alcohol consumption are distinguished [13-14]:

- continuous – daily or almost daily alcohol consumption;

- periodic – periods of daily alcohol intake alternate with more or less prolonged intervals when the patient does not consume alcohol or consumes it occasionally, in small doses and without loss of control;

- intermittent – against the background of continuous alcohol consumption, there are periods of escalation with maximum doses of alcohol intake.

Depending on the role of genetic factors, two variants of the course of AUD are distinguished [13-14]:

- exoformic variant (Th. Babor type A; C. Cloninger type I), characterized by late onset, low hereditary loading, presence of therapeutic and spontaneous remissions, influence of situational factors on the occurrence of relapses, and social preservation;

- endoformic variant (Th. Babor type B; C. Cloninger type II) with high hereditary loading for AUD, pathological premorbid profile, early onset of the disorder, strong PAS craving independent of external factors, remitting-free course, observed predominantly in men.

1.6 Clinical presentation of the disease or condition

The main clinical signs of the initial (first) stage of AUD are [12-16]:

1) Formation of primary PAS craving – the appearance of an intense desire or sense of compulsive urge to consume alcohol;

2) Altered reactivity to alcohol – a 2-3 fold increase in alcohol tolerance, as former doses no longer cause euphoria; extinction of the protective gag reflex; decrease in quantitative and situational control over alcohol consumption (the ability to control the onset, termination, or dose: alcohol is consumed in larger amounts and over a longer period than intended);

3) Altered intoxication pattern – a gradual reduction of the euphoria phase; the occurrence of partial amnestic forms of intoxication with forgetting of events that occurred during intoxication, especially when consuming maximum doses of alcohol for a given patient;

4) Change in the pattern of alcohol consumption with a transition from episodic to regular intake of alcohol-containing beverages.

At the middle (second) stage of AUD, in addition to the aggravation of the signs noted in the initial stage, AWS additionally develops. The main clinical signs of the middle (second) stage of AUD are [12-16]:

1) Fully formed primary PAS craving, losing its connection with psychologically understandable motives and dominating among the patient's behavioral motives;

2) Altered reactivity to alcohol – a 5-6 fold increase in alcohol tolerance, reaching a maximum (plateau) of tolerance and maintaining it for a number of years; loss of the protective gag reflex; loss of quantitative and situational control over alcohol consumption;

3) Changes in the clinical picture of intoxication: a substantial decrease in the euphoria stage; the appearance of altered forms of intoxication accompanied by motor restlessness, disinhibition, and aggressiveness; the occurrence of severe degrees of intoxication; the predominance of amnestic forms of intoxication;

4) Development of alcohol withdrawal syndrome (AWS), which becomes more severe and complex as the disease progresses, with the addition of seizures, psychoses, and reversible psycho-organic disorders;

5) Establishment of a "habitual" pattern of alcohol consumption—constant, intermittent, or periodic (binge drinking);

6) Alcoholic personality changes: signs of moral and ethical coarsening with blunting of higher emotions and enhancement of lower emotions; accentuation of premorbid character traits; intellectual and amnestic decline with impaired attention, memory, and difficulties in acquiring new knowledge and skills.

The main clinical signs of the terminal (third) stage of alcohol dependence syndrome (ADS) are [12-16]:

1) Primary craving for alcohol, acquiring a compulsive character with alcohol consumption in any setting;

2) Changes in reactivity to alcohol: decreased alcohol tolerance, initially for single doses and then for daily consumption, with a transition to weaker alcoholic beverages or surrogates; the occurrence of vomiting, initially at the end of a binge and after severe intoxication, and subsequently even after consuming small doses of alcohol;

3) Changes in the clinical picture of intoxication: absent or weakly expressed euphoria; decreased severity of disinhibition and aggressiveness; rapid onset of stupor and soporous phenomena with the consumption of relatively small amounts of alcohol;

4) AWS, rapidly occurring after cessation of alcohol intake, accompanied by pronounced somatovegetative, neurological, and refractory psycho-organic disorders;

5) Change in the pattern of alcohol consumption, transitioning either to continuous use with low tolerance or to true binges;

6) Alcoholic personality degradation: distinct signs of moral and ethical decline and "moral coarsening" with blunting of higher and enhancement of lower emotions; intellectual and amnestic decline to the degree of dementia;

7) Appearance of residual mental disorders, including chronic (prolonged, protracted) forms of psychoses and late-onset mental disorders;

8) General decrepitude, similar to premature aging; concomitant persistent somatoneurological disorders: polyneuropathy, cerebellar disorders, characteristic lesions of the heart, liver, and other organs and systems, which cause premature death of the patient.

Features of ADS in adolescents include: lack of clarity in the development stereotype of the main syndromes, reflecting the mental characteristics of puberty; initially weakened or absent quantitative control; a tendency toward a malignant course in the presence of unfavorable premorbid factors (epileptiform or unstable personality type, high genetic predisposition), rapid development of craving for alcohol (with an underdeveloped ideational component); poor insight into the disease; atypical forms of intoxication are characteristic in the early stages. The main manifestations of ADS may regress if alcohol consumption is discontinued [14-15].

2. Diagnostics, medical indications and contraindications for diagnostic methods

Clinical diagnostics, consisting of collecting complaints, anamnesis, and analyzing the obtained data, is of primary importance in diagnosing ADS. Other diagnostic methods play a secondary role.

Criteria for establishing the diagnosis of the disease/condition:

A diagnosis of ADS can be established if 3 or more of the following criteria have been present at some time during the preceding year [12]:

– a strong desire or sense of compulsion to take alcohol;

– impaired capacity to control substance-use in terms of its onset, termination, or levels of use, as evidenced by alcohol being taken in larger amounts or over a longer period than intended, persistent desire or unsuccessful efforts to cut down or control alcohol use;

– a physiological withdrawal state (withdrawal syndrome) when alcohol use has ceased or been reduced, as evidenced by the characteristic withdrawal syndrome for alcohol, or by use of the same (or a closely related) substance with the intention of relieving or avoiding withdrawal symptoms;

– evidence of tolerance, such that a increased doses of alcohol are required in order to achieve intoxication or desired effects, or a markedly blunted effect with chronic use of the same dose;

– preoccupation with alcohol use, manifested by the fact that important alternative pleasures or interests are wholly or partly abandoned because of alcohol use, or a great deal of time is spent in activities necessary to obtain, use, or recover from the effects of alcohol;

– continued alcohol use despite clear evidence of overtly harmful consequences, as evidenced by chronic use when the nature and extent of the harm are or may be known.

2.1 Complaints and Anamnesis

In some cases, a patient with ADS may have no complaints; therefore, the physician needs to purposefully inquire about the quantity, frequency, pattern, typical conditions and circumstances of alcohol consumption, as well as subjectively perceived benefits and/or negative consequences associated with alcohol use.

Comments: The main characteristic of ADS is the desire (often strong, sometimes irresistible) to consume alcohol—craving for alcohol. This desire is manifested by a combination of affective, ideational, behavioral, cognitive, and somatic phenomena and occupies a paramount place in the individual's value system. Alcohol consumption continues despite clear harmful consequences for the health and social well-being of the consumer and despite possible condemnation or prosecution by society. The behavior of an alcohol-dependent individual is determined by the desire to constantly or periodically consume alcohol in order to experience the sought-after sensations and/or relieve mental or physical discomfort (including that associated with cessation of use) [12]. Subjective awareness of the craving for alcohol most often occurs during attempts by the dependent individual to stop or limit its use.

An additional source of information can be family members, medical records, etc. Differential diagnosis between ADS and harmful alcohol use is required when identifying such anamnestic facts as: family or occupational dysfunction; offenses related to alcohol use; problems with mood, sleep, or sexual functioning; target-organ damage, or specific symptom patterns, such as anxiety, elevated blood pressure (hereinafter referred to as BP), or headaches after every weekend [17].

2.2 Physical Examination

Physical examination findings are not specific for ADS. A medical examination is an important adjunct to clinical diagnostics, allowing the determination of the clinical and dynamic features of the disease and establishing guidelines for assessing the severity of the condition [2; 13].

Comments: Physical and neurological examinations are performed before starting therapy and during the course of treatment. For example, the middle stage of AUD may be characterized by somatovegetative disorders such as elevated blood pressure, frequent fluctuations in blood pressure, arrhythmias, changes in heart rate (hereinafter referred to as HR) and respiratory rate (hereinafter referred to as RR), and potential neurological disorders such as transient tremor or nystagmus. In the terminal stage, neurological disorders may become overt: pronounced tremor, gait disturbances, ataxia, sensory disturbances, and other manifestations of peripheral polyneuropathy. The same applies to somatic manifestations of the disease: hepatomegaly and liver tenderness may also be signs of chronic high-dose alcohol consumption [2; 13].

2.3 Laboratory Diagnostics

Laboratory test data are used to complement clinical diagnosis, providing an objective assessment of the patient's general condition, confirming chronic high-dose alcohol consumption, and monitoring remission. Laboratory diagnostics can be useful when the clinician suspects that the patient is significantly underreporting the extent of alcohol misuse, including due to comorbid mental illness or cognitive decline; for the timely detection of alcohol-induced target organ damage; and for making decisions regarding the setting and tactics of medical care to prevent potential complications [2; 13; 17].

To achieve these objectives, current practice involves analyzing indirect biomarkers that increase either in response to prolonged systematic and/or excessive alcohol consumption, such as carbohydrate-deficient transferrin (hereinafter – CDT) and mean corpuscular volume (hereinafter – MCV); or reflect target organ damage resulting from chronic high-dose alcohol consumption, such as gamma-glutamyl transferase (hereinafter – gamma-GT), aspartate aminotransferase (hereinafter – AST), and alanine aminotransferase (hereinafter – ALT) [2; 13; 17].

Diagnostic accuracy increases when investigating a specific combination of multiple indirect biomarkers: exceeding the normal values of each biomarker in such combinations will indicate chronic high-dose alcohol consumption [17-20].

• It is important to remember that laboratory diagnostics only helps identify individuals who misuse alcohol, rather than establish a diagnosis of AUD per se [2; 13]. It is recommended that adult patients with suspected AUD undergo blood testing for indirect biomarkers in unclear diagnostic cases to confirm chronic high-dose alcohol consumption using one of the following combinations: qualitative and quantitative determination of carbohydrate-deficient transferrin (CDT) in blood serum by capillary electrophoresis + determination of blood gamma-glutamyl transferase activity, or qualitative and quantitative determination of carbohydrate-deficient transferrin (CDT) in blood serum by capillary electrophoresis + determination of erythrocyte size [18-21].

Leveled for Reliability of Recommendations (LRR) BLevel of Evidence (LoE) 2Level of Reliability of Recommendations B (Level of Evidence 2).

Comments: Chronic alcohol consumption does not have a precise definition in either legislative acts or medical reference books. This definition encompasses various patterns of systematic alcohol intake, ranging from risky use to established alcohol dependence [22]. According to the WHO, heavy episodic drinking is defined as the intake of ≥ 5 standard drinks (60 g of pure ethanol) during an alcohol binge [23-24].

Daily consumption of at least 60 g of pure ethanol per day reliably causes an increase in indirect biomarkers: CDT within 7-10 days, gamma-GT within 3-6 weeks, and MCV within 1 month. According to several researchers, a "positive test" that allows considering an elevation in an individual biomarker's values as a result of alcohol misuse is >1.7% for CDT; >80 IU/L for men and >50 IU/L for women, or ≥30% above the upper limit of normal for gamma-GT; and >96 femtoliters for mean corpuscular volume (MCV) [2; 18-21].

As is well known, elevated levels of indirect biomarkers are associated not only with chronic high-dose alcohol consumption by the patient; their non-specific elevation can be the result of various somatic, endocrine, or oncological diseases, pregnancy, the use of certain medications, etc. This circumstance explains why the sensitivity and specificity parameters of individually considered indirect biomarkers are moderate and vary over a wide range. It has been established that the combination of elevated blood levels of both CDT and gamma-GT or MCV provides the highest diagnostic sensitivity/specificity (60-90%/80-95% for CDT+gamma-GT and 60-95%/80-95% for CDT+MCV) and correlation with actual alcohol consumption volumes [17-18; 20].

When evaluating laboratory data, it is important to consider the presence of comorbid conditions or medication use that may affect biomarker levels.

Comments: A CDT level exceeding 1.7% is regarded as an indicator of alcohol misuse. Upon cessation of alcohol intake, elevated CDT levels persist for up to 2 weeks, after which values normalize. In individuals who do not consume alcohol, the serum CDT content ranges from 0.3% to 0.7%. With irregular and/or minor alcohol consumption, CDT levels do not exceed 1.2%. The range of 1.3%-1.6% is termed the "grey zone" and requires a repeat CDT test in 3-4 weeks [2; 18; 25; 27].

1. general general-medical blood biochemistry (testing blood total protein levels, gamma-glutamyltransferase activity, alanine aminotransferase activity, aspartate aminotransferase activity, total bilirubin, free (unconjugated) bilirubin, albumin, glucose, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, urea, and creatinine in the blood);

2. complete blood count (red blood cells, platelets, hemoglobin, white blood cells), differential leukocyte count (leukocyte formula), and erythrocyte sedimentation rate;

3. complete (clinical) urinalysis (visual urine examination (color, transparency), urine specific gravity (relative density), urine protein, urine glucose, urine bilirubin, urobilinogen, ketone bodies, and detection of salts, cellular elements, and casts in the urine).

LeR CLoE 5Level of Evidence Recommendations C (Level of Data Validity 5).

Comments: Performing routine laboratory tests is important to determine the current general somatic health status, rule out potential acute conditions requiring specialized medical care, and monitor possible complications during the treatment process.

2.4 Instrumental Diagnostics

The utility of instrumental diagnostics in AUD is limited due to the absence of specific physical signs characteristic of this disease.

To diagnose pathology comorbid with AUD, the involvement of other specialists is required. In specific clinical situations and according to indications, instrumental diagnostic methods are prescribed: comprehensive ultrasound examination of internal organs, electroencephalography, echoencephalography, skull radiography in one or more projections, targeted chest radiography, etc. [2; 13].

Comments: Alcoholic cardiomyopathy (alcoholic heart disease, alcoholic myocardial injury, toxic dilated cardiomyopathy), secondary hypertension, rhythm disturbances in alcoholic heart disease, and conduction abnormalities in patients with AUD necessitate careful monitoring of cardiac activity.

2.5 Other Procedures

Comments: Psychodiagnostic evaluation is adjunctive in nature; its value increases when compared with the results of clinical observation and individual instrumental examinations (e.g., electroencephalography). The results of psychodiagnostic evaluation help determine the optimal scope and format of subsequent psychotherapeutic interventions. The psychodiagnostic program depends on the clinical situation. For example, in patients with comorbid central nervous system organic disorders or schizophrenia, the main focus is on identifying features of thought disorders and performance characteristics; in amnestic syndrome or dementia, the focus is on neuropsychological tests and tasks identifying impairments in writing, calculation, praxis, etc. Follow-up assessments conducted during treatment make it possible to objectively evaluate the impact of ongoing therapy and rehabilitation [2; 13].

Comments: Assessing the severity of a patient's condition makes it possible to make balanced and rational decisions regarding not only the setting of medical care, but also therapeutic measures [2; 13].

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

Alcohol use disorder (AUD) therapy is a multi-stage, comprehensive, individualized, and long-term process. AUD is a chronic disease with a relapsing course, making long-term maintenance therapy mandatory. It can be carried out for several years. The decision to adjust maintenance therapy is made individually, taking into account the patient's current condition, the severity of psychoactive substance (PAS) craving, as well as comorbid pathology (personality disorders, endogenous disease, exogenous-organic disease, etc.), if any [2; 13; 17].

Any therapeutic interventions must pursue clear objectives, have specific tactics, and conclude with an evaluation of their effectiveness [2; 30].

Treatment objectives:

1) relapse prevention and maintenance of remission (sobriety);

2) management of PAS craving syndrome to enable psychotherapy and rehabilitation;

3) prevention of complications from alcohol use (therapy for somatoneurological pathology characteristic of AUD is performed as indicated);

4) relief of other psychopathological disorders, if present (e.g., comorbid pathology).

Treatment strategy: comprehensive pharmacotherapy and psychotherapeutic treatment.

Treatment efficacy criterion: stabilization of the patient's psychophysical state.

3.1. Pharmacotherapy

3.1.1. Specific medicines

Disulfiram

Comments: Disulfiram belongs to the so-called sensitizing agents. In AUD therapy, they are the drugs of choice at the stage of establishing remission. The term "sensitizing" in relation to AUD therapy is conventional. Sensitization in the narrow sense of the word is the body's hypersensitivity to a foreign substance. When the body interacts with this substance, a specific reaction occurs, the severity of which depends on the concentration of this substance. The essence of sensitizing therapy for AUD is based on the use of agents that sharply increase the body's sensitivity to alcoholic beverages. These include disulfiram, cyanamide, and certain other medicinal products (hereinafter – MPs). All of them, to one degree or another, create physical intolerance to alcohol associated with the disruption of its metabolism and the appearance in the blood of toxic products of its incomplete breakdown, creating a "chemical barrier" ("metabolic blockade") to further alcohol consumption. In cases where the patient has an internal commitment to sobriety and external social control, in the absence of contraindications, sensitizing MPs provide significant assistance in establishing and maintaining remission.

Disulfiram blocks aldehyde dehydrogenase (hereinafter – ALDH), an enzyme involved in the biotransformation of ethanol and the conversion of toxic acetaldehyde into non-toxic carbon dioxide and water [35]. When using disulfiram, ethanol consumption becomes physically impossible due to the occurrence of extremely unpleasant, health-threatening conditions associated with the accumulation of acetaldehyde. 5–10 minutes after alcohol consumption, patients taking disulfiram experience a feeling of warmth, followed by facial and bodily flushing caused by vasodilation. All of this is accompanied by a throbbing headache, sweating, dry mouth, nausea, vomiting, dizziness, and weakness. In more severe cases, chest pain, shortness of breath, marked hypotension, and confusion are possible. Deaths resulting from the intake of more than 500 mg of disulfiram have been reported [36]. Cases of disulfiram overdose have been described, manifesting as delirium with prominent hallucinations, tachycardia, and hypertension. After symptoms disappear, patients typically feel exhausted and fall asleep, after which they fully recover. The disulfiram-alcohol reaction lasts from half an hour to 2 hours. The duration and severity of symptoms depend both on the dose of disulfiram and the amount of alcohol consumed. The threshold level of alcohol sufficient to trigger a reaction is approximately equivalent to 7 ml of 100% ethanol [13]. There is evidence that 5 g of alcohol is sufficient for a disulfiram-alcohol reaction to develop [37]. After taking disulfiram, hypersensitivity to ethanol persists for 6–14 days, during which time a sufficient number of new ALDH molecules are synthesized.

Disulfiram is prescribed only after alcohol withdrawal syndrome (AWS) has been managed. The average maintenance dose of the drug is 250 mg daily; morning administration is preferred when it is easier to abstain from alcohol. If the drug causes drowsiness, it is better to take it at bedtime. The safest and most effective dose of the drug has not been established. Doses exceeding 250 mg cause side effects such as fatigue, metallic taste in the mouth, bad breath, impotence (rarely), polyneuropathy, toxic psychosis, and toxic hepatitis (extremely rarely) [36]. The prescription of such doses is inexpedient. The dose may be reduced to 125 mg if side effects preclude the use of higher doses. Once the dose is selected, the dosing regimen must be strictly followed. A complete (clinical) blood count and liver function assessment should be performed every 3–6 months. Since disulfiram has a teratogenic effect, it should not be prescribed to pregnant women [17]. It is not recommended to prescribe the drug to patients unmotivated to completely abstain from alcohol [36].

The results of large multicenter and randomized controlled trials have indicated the limited "usefulness" of disulfiram associated with patient non-compliance. Only supervision of drug administration and psychotherapeutic intervention can significantly increase the effectiveness of therapy [2; 17; 38].

In Russia, only oral tablets of disulfiram are registered; the use of any other dosage forms of the drug is prohibited [39-40].

Comments: Randomized comparative studies have shown that the use of #disulfiram in adolescents aged 15–18 years (the symbol # designates medicinal products whose prescription and use do not comply with the instructions for use) at a maintenance dose of 125–250 mg daily reduced disease relapse and increased the number of days of alcohol abstinence. The authors emphasized that the effectiveness of the drug depended on supervision of its administration: #disulfiram was most effective in adolescents with high motivation for sobriety, as well as those under the regular supervision of relatives and/or a specialist [41-42].

Cyanamide

Comments: Cyanamide also belongs to MPs whose mechanism of action is associated with ALDH blockade. According to comparative studies, cyanamide has a more favorable safety profile compared to disulfiram [43].

Cyanamide is prescribed only after relief of alcohol withdrawal syndrome (AWS) at a dose of 12 to 25 drops (36–75 mg) twice daily at 12-hour intervals. Cyanamide has a more specific mechanism of action as it affects only ALDH (disulfiram also blocks β-dopamine beta-hydroxylase). The course of treatment is 3–6 months or longer [43–44].

Naltrexone** (the symbol ** denotes medicines included in the Vital and Essential Drugs List)

Comments: According to the pharmaco-therapeutic group, naltrexone** is an opioid receptor antagonist. The main effect of opioid receptor antagonists in the treatment of patients with AUD is a reduction in alcohol-induced euphoria. As a consequence, alcohol craving weakens, alcohol consumption decreases, and the frequency of relapses is reduced.

The efficacy of naltrexone** in the treatment of AUD has been demonstrated in numerous randomized controlled trials: opioid receptor antagonists reliably reduce the euphorigenic effect of alcohol and selectively affect alcohol craving [30; 33; 46].

The initial oral dose of naltrexone** is 25 mg for the first 4–5 days, then 50 mg per day [34]. The duration of therapy is at least 3 months [17; 47]. At therapeutic doses in patients free of opioids in their system, naltrexone** generally does not cause serious side effects. The efficacy of therapy increases when combined with psychotherapy [36; 38; 47].

Extended-release formulations of naltrexone** solve the most complex problems of maintaining compliance and retaining the patient in the therapeutic program. Naltrexone** powder for extended-release intramuscular suspension 380 mg is administered once a month, its duration of action is 4 weeks, and it has a relatively smooth pharmacokinetic profile with little to no daily fluctuations [48–53].

To date, a relatively large number of randomized controlled trials of the intramuscular form of naltrexone** have been conducted [49–50]. It has been shown that patients receiving the extended-release suspension experienced a marked decrease in the number of heavy drinking episodes compared to those receiving placebo—by more than 25%, as well as a 15% reduction in gamma-glutamyl transferase (GGT) levels. This decrease in GGT levels is a logical and expected fact: the absence (or reduction) of continuous alcohol intoxication has a beneficial effect on the patient's health (physical functioning). Side effects occurred in at least 10% of patients receiving long-acting naltrexone**. The most frequent among these were nausea, headache, and fatigue. In approximately 95% of cases, nausea was mild, and the vast majority of such episodes were observed during the first month of treatment. Some patients reported pain at the injection site [17; 51].

The duration of treatment is 3 to 6 months, after which the question of potentially extending drug administration is decided [36; 52–53]. Complete abstinence from alcohol is the goal of treatment with extended-release naltrexone**, but it should not be put forward as an absolute requirement; if the patient agrees to treatment but continues to drink periodically, this does not mean that treatment should be stopped: some patients, especially initially, respond to naltrexone** not by cessation, but merely by a reduction in alcohol intake. Based on experience with the drug in patients with opioid dependence syndrome, long-term naltrexone** treatment (1 year or more) can be safe [13; 36].

Comments: Randomized comparative studies have shown that the use of naltrexone** in adolescents aged 15–18 years at a dose of 50 mg per day reduced alcohol craving, but its effect on the relapse rate of the disease and alcohol consumption was insufficient without concomitant psychotherapeutic support [41–42]. Nalmefene

Comments: According to its pharmaco-therapeutic group, nalmefene is an opioid system modulator. Since the end of the 20th century, a number of foreign countries have been actively introducing the tactics of "controlled" drinking (reduced drinking) into the treatment of patients with alcohol use disorders, since even a small reduction in the amount of alcohol consumed has a beneficial effect on human health. Methods have been developed for training patients to reduce alcohol consumption to a moderate level in order to improve the quality and duration of life and restore their social adaptation. Such tactics have made it possible to increase the reach of addiction care, extending it to patients who did not want to maintain complete sobriety and for whom reducing alcohol consumption was the ultimate goal of treatment. In Russia, the tactic of reducing alcohol consumption is infrequently used and is considered as an alternative or complement to treatment focused on complete abstinence, where "controlled drinking" serves as an intermediate goal on the path to alcohol abstinence.

Within the framework of the strategy to reduce alcohol consumption, the prescription of nalmefene is recommended for patients who are at high risk of alcohol misuse and are not motivated to achieve immediate abstinence from alcohol. Nalmefene administration should be combined with psychosocial support aimed at maintaining adherence to treatment. Nalmefene is used on an as-needed basis: on days when, in the patient's opinion, the probability of alcohol consumption is high, 1 tablet at a dose of 18 mg is taken 1–2 hours before the anticipated intake. The maximum daily dose is 18 mg. The physician should monthly assess the patient's progress in reducing alcohol consumption, general condition, therapy adherence, and identify side effects to determine the efficacy and expediency of continuing nalmefene therapy. The duration of therapy should not exceed 12 months [17; 33; 54–57].

Comments: A comparative study showed that the use of #nalmefene in adolescents at a dose of 18 mg per day, combined with psychosocial interventions aimed at lifestyle modification, contributed to a reduction in alcohol consumption [42].

3.1.2. Other medicines

Antidepressants

Comments: It should be understood that affective disorders, predominantly of the depressive spectrum, are manifestations of psychological alcohol craving (PAC) and typically lie on "its facade" [2; 64]. Antidepressants are used to relieve these disorders via the so-called anti-craving mechanism of action [2; 14; 64-65]. The latter is associated with the complex effect of antidepressants on serotonergic and dopaminergic neurotransmission. Differentiating manifestations of affective (typically depressive) pathology from a comorbid mental disorder is possible only on the basis of a syndromal approach. There is evidence that the reduction effect on PAC occurs within the very first days of antidepressant intake, sometimes 1–1.5 weeks before their antidepressant effect develops [63-65]. In other words, the suppression of PAC can be quite an independent property of theirs, alongside the main one—the antidepressant effect [13]. Indications for prescribing antidepressants include: depressed mood, anxiety, dysphoria, emotional lability, sleep disorders manifested by difficulty falling asleep and heavy awakenings, or early morning and/or frequent night awakenings with the inability to fall back asleep [13-14; 64-66].

Based on the results of clinical studies, it was concluded that treatment with selective serotonin reuptake inhibitors (hereinafter referred to as SSRIs) in patients with alcohol use disorder (AUD) after detoxification reduces the desire to drink alcohol and lessens symptoms of alcohol-related anxiety and depression [59].

The efficacy of #fluoxetine** as an agent reducing alcohol consumption and affecting PAC in adults has been demonstrated in several studies [67-69]. Various doses of the drug were evaluated, but the recommended dose is 20 mg daily with a possible subsequent increase to 40 mg daily, once a day, in the morning [67; 69].

#Citalopram also reduced PAC in adult patients; its efficacy has been demonstrated in several studies in comparison with placebo and other SSRIs [63-65]. The recommended doses of the drug are 20-40 mg daily [72].

#Sertraline** has shown efficacy in reducing PAC in adults at a dose of 200 mg daily [73].

#Fluvoxamine is also effectively used to reduce PAC in adult patients with AUD [66; 74]. #Fluvoxamine is prescribed in a dose of 50 to 200 mg daily, 1-2 times in the evening [66].

The efficacy of antidepressant use largely depends on the course type of AUD. For example, it has been shown that in severe courses of AUD (endoform variant, type B according to Th. Babor; type II according to C. Cloninger), characterized by early onset, burdened family history, impulsive/antisocial personality traits, and others, the prescription of antidepressants may worsen outcomes and is therefore not recommended [59]. In a milder course of AUD (exoform variant, type A according to Th. Babor; type I according to C. Cloninger), the prescription of antidepressants may be justified and effective [58]. High efficacy of #sertraline** was demonstrated in a double-blind placebo-controlled study: the drug reduced alcohol consumption in adult patients specifically with type A AUD [75].

When adult patients present with depressive disorders within the structure of PAC, other antidepressants are used: #mirtazapine at a dose of 30 mg daily [76]; #trazodone at a dose of 50-150 mg daily, in the evening before bedtime [13; 58-62; 77]. The duration of treatment is at least 1 month [13; 58-62; 77].

Comments: In adult patients with AUD and comorbid affective disorders, the inclusion of antidepressants in the therapy contributes both to the reduction of depressive, anxiety, or mixed disorders and to a decrease in the level of PAC [81-83]. Antidepressants are used both as monotherapy and in combination with other drugs [13; 63-65]. In the presence of comorbid pathology, antidepressants are used for their direct indications: in the treatment of depressions of various etiologies; conditions accompanied by anxiety; obsessive-compulsive disorders; panic disorders; generalized anxiety disorder; post-traumatic stress disorders.

High proven efficacy regarding comorbid affective (depressive and anxiety) disorders in adult patients diagnosed with AUD is demonstrated by: sertraline**, fluvoxamine, fluoxetine**, paroxetine** [59; 78].

Trazodone [78; 84] and mirtazapine [78] have a lower level of evidence.

Amitriptyline** and mianserin are also used in addiction treatment practice [13; 64].

A justified method for prescribing antidepressants is starting therapy with low doses followed by their gradual increase to optimal therapeutic doses. An exception is made for SSRI antidepressants, which are prescribed immediately at therapeutically adequate doses. Dose selection is individual. If there is no positive clinical effect within the first 3-4 weeks of therapy, substituting the prescribed antidepressant with a drug having a different mechanism of action is indicated. Antidepressant treatment is long-term, lasting at least 3-6 months. Discontinuation of medications, as well as their initiation, is carried out gradually [13; 64].

• The recommended dose of fluvoxamine is 50-200 mg once daily, in the evening; fluoxetine** – 20-60 mg daily; sertraline** – 50-200 mg daily; paroxetine** – 10-50 mg daily; citalopram – 10-40 mg daily; escitalopram – 10-20 mg daily; trazodone – 75-150 mg daily; mirtazapine – 15-45 mg daily; amitriptyline** – 75-200 mg daily; mianserin – 60-90 mg daily [13; 59; 64; 78-84].

• It is recommended that adolescents diagnosed with AUD and comorbid depressive and anxiety disorders of non-alcoholic origin be prescribed medications from the "Antidepressants" group to relieve manifestations of depression and anxiety, provided there are no contraindications to specific drugs in accordance with the instructions [85].

Leveled for Reliability of Recommendations (LRR) BLevel of Evidence (LoE) 2Level of Reliability of Recommendations B (Level of Evidence 2).

Comments: An analytical review of 15 studies reporting on the treatment outcomes of adolescents with co-occurring depression and substance use disorders (specifically alcohol) showed that the use of antidepressants can be effective. Most frequently in adolescents (aged 12-15 years), #fluoxetine** was used at a dose of 20 mg/day [85].

Antiepileptic drugs

Comments: Antiepileptic drugs in AUD are typically used at the stage of relapse prevention and stabilizing therapy to manage PAC exacerbations when the clinical picture is dominated by affective disturbances such as internal tension, dysphoria, irritability, and anhedonia [13; 63-64; 86-92].

The pathogenetic rationale for using antiepileptic drugs to suppress primary PAC can be the "kindling" concept, which boils down to the emergence of epileptiform activity in the limbic brain structures following repeated alcohol excesses; initially, this activity is temporary in nature and then stabilizes ("chronic epileptogenesis") [63-64]. Its very localization causes various mental pathologies colored by emotional and autonomic disorders.

This theory is also not contradicted by another one related to the thymoleptic/mood-stabilizing action of antiepileptic drugs. The mood-stabilizing effect of these agents is associated with their impact on the GABAergic system: antiepileptic drugs reduce GABA metabolism in the brain. GABA, in turn, acts as a presynaptic modulator of dopaminergic neurons, causing a decrease in DA concentration in presynaptic formations [13]. Studies have shown that antiepileptic drugs have a significant effect on reducing the risk of disease relapse and also decrease the amount of alcohol consumed in the event of its resumption [87; 91].

To suppress PAC and associated affective pathology in adult patients, #carbamazepine** and #valproic acid** are most frequently used [63-64].

#Carbamazepine** has demonstrated efficacy in reducing AUD symptoms (extending the period of abstinence, reducing heavy drinking days, and decreasing the amount of alcohol consumed) at a dose of 600–800 mg per day [86–87].

#Oxcarbazepine** has demonstrated efficacy in reducing AUD symptoms (extending the period of abstinence and decreasing the amount of alcohol consumed) in adults at doses ranging from 600–900 mg (low dose) to 1500–1800 mg per day (high dose) [87].

#Valproic acid** has demonstrated efficacy in reducing AUD symptoms and stabilizing mood (extending the period of abstinence, reducing heavy drinking days, and decreasing the amount of alcohol consumed) at a dose of 450–900 mg per day [88].

The recommended doses of #lamotrigine for adults range from 200 to 300 mg per day [87; 89].

Studies in adult populations have also shown the efficacy of #gabapentin (600, 900, or 1800 mg) [87; 92] and #topiramate** (75–300 mg) [87; 89], although their use in the treatment of AUD remains controversial [17; 36; 64].

In many studies, antiepileptic drugs have shown efficacy as agents that reduce AUD symptoms, prolong remission, and decrease the amount of alcohol consumed in the event of a relapse in patients with AUD [87]. However, to date, there is no conclusive evidence supporting the efficacy of this drug class in the treatment of AUD [86]. It should be emphasized that due to conflicting study results, clinicians must evaluate the risk-benefit ratio for each individual case when prescribing antiepileptic drugs [91].

Antipsychotics

Comments: Antipsychotics are used to relieve intense affect, psychopath-like (behavioral) disorders, psychomotor excitation, agitation, aggressiveness, and impulsive behavior when acute AUD symptoms occur.

It should be noted that most adult patients with AUD tolerate antipsychotic therapy relatively well. This is due to the use of low to moderate doses necessary to achieve a therapeutic effect, as well as short courses of therapy (on average 2–3 weeks, not exceeding 4–6 weeks).

By mechanism of action, antipsychotics exert a blocking effect on dopamine receptors, which accounts for their positive therapeutic impact on psychopathological symptoms: "psychotic" charge, tension, and affective rigidity observed during the activation of AUD symptoms. The use of antipsychotics in addiction medicine allows for the rapid relief of conditions accompanied by psychomotor excitation, agitation, and aggressive behavior [13; 63–64].

Antipsychotics are used only under strict indications, as they are not primary agents for the treatment of AUD [13].

Antipsychotics are used as symptomatic therapy for appropriate indications. During exacerbations of AUD symptoms, when the clinical picture includes restlessness, psychomotor excitation, agitation, sleep disturbances, agitated anxiety, and behavioral disorders such as aggression or hyperactivity, adult patients are prescribed: haloperidol** – 1.5–20 mg per day in 2–3 divided doses orally or intramuscularly [13; 93]; #zuclopenthixol** – 25–100 mg per day in 1–2 divided doses orally or 50–150 mg once daily intramuscularly [13–14]; chlorprothixene – 15–150 mg per day orally in 2–3 divided doses depending on specific indications [13–14]; chlorpromazine** – 25–100 mg per day orally in 2–4 divided doses, or once daily intramuscularly [13–14]; #risperidone** – 2–4 mg per day orally in 1–2 divided doses [13–14].

During exacerbations of AUD symptoms, when psychomotor excitation, agitation, anxiety, and persistent insomnia predominate in the clinical picture of adult patients, the following are used: levomepromazine** – 25–200 mg per day 1–3 times a day orally or once daily intramuscularly [13–14]; #quetiapine** – 25–50–200 mg per day orally [13; 95; 97].

When the clinical picture of an AUD exacerbation involves pathological motivations, cathymic formations, attitudinal forms of behavior, and overvalued ideas about the "benefits of alcohol," adult patients are effectively treated with: #perphenazine** – 8–30 mg per day orally in 2–4 divided doses [13–14]; #trifluoperazine** – 10–15 mg per day orally [13–14].

In the presence of neurosis-like disorders and behavioral disorders associated with explosiveness, hysteria, and emotional disinhibition, adults are prescribed thioridazine** – starting at 50–150 mg per day [13–14].

For anxiety states, psychomotor excitation, aggressive or dangerous impulsive behavior, periciazine** is used as an adjunctive medication for short-term treatment in adult patients at 10–30 mg per day orally [13–14]. It should be noted that the dosing regimen varies significantly depending on the patient's condition. Doses must be selected individually. Treatment should start with low doses, which can then be gradually increased. The minimum effective dose should always be used.

For anxious-depressive states, restlessness, excitation, and other symptoms and signs related to emotional state, sleep disturbances, neuroses, and neurosis-like conditions with hypochondriacal, vegetative, cenestopathic, and phobic disorders, adult patients are prescribed alimemazine. To achieve a vegetative-stabilizing effect – 15–60 mg per day; to achieve an anxiolytic effect – 20–60 mg per day; to achieve a hypnotic effect – 5–10 mg once [13; 98].

The dosing regimen for antipsychotics varies significantly depending on indications and the patient's condition [13].

Antipsychotics should be prescribed for a limited time, as their long-term use leads to debilitating states of lethargy and subdepression [2; 13; 64].

Comments: For a certain proportion of adolescents, pharmacological treatment is an important component, despite the fact that most drugs used to treat AUD are recommended for individuals over 18 years of age. Any medications are prescribed only after a risk-benefit assessment [13–14].

Comments: Antiepileptic drugs represent a pathogenetically targeted therapy in cases where AUD in adolescents develops against the background of residual organic brain syndrome. It manifests with polymorphic clinical symptoms: paroxysmal disorders (dysphoria, migraine-like paroxysms, parasomnias, tics, stuttering, enuresis, etc.), cerebasthenic disorders (cephalgia, weather sensitivity, poor tolerance to heat, transport, etc.), and affective disorders (irritable weakness, grumbling, tearful anger, protest reactions, and verbal aggression). All these disorders have a borderline relationship with epilepsy, and the prescription of antiepileptic drugs is aimed at destabilizing the pathological system arising from the epileptization of brain structures [99].

The prescription of #carbamazepine** is preferred when a frontotemporal partial epileptic focus is identified; the prescription of #valproic acid** is preferred in the presence of primarily generalized pathological activity (according to electroencephalography) [99].

3.2 Psychotherapy

Psychotherapy (hereinafter referred to as PT) for alcohol use disorders (AUD) is a targeted professional assistance aimed at modifying and restoring the healthy state of the organism through psychological means, designed to eliminate personal, affective, behavioral, and other disorders, optimize the patient's interpersonal relationships, strengthen motivation to participate in the treatment program, promote abstinence from alcohol, and facilitate social and professional reintegration [100-102].

PT is an essential part of any therapeutic program for AUD. Psychotherapeutic interventions directly alter the psychological and social factors associated with alcohol abuse and significantly enhance the efficacy of pharmacotherapy [100-102].

The goal of PT is to motivate the patient for treatment and rehabilitation, foster alcohol abstinence, and achieve sustained remission.

The objectives of PT include: motivating the patient for treatment; correcting and/or compensating for impaired mental functions; developing and enhancing skills in emotional self-regulation, relaxation, stress coping, and relapse prevention; building self-control skills, voluntary inhibition of impulsive behavior, and correcting hyperbolic discounting of consequences; modifying internal and external (including familial) factors that stimulate addictive behavior.

From the very first contact with an alcohol-dependent patient, it is important to consider the development of key nonspecific therapeutic factors of PT [103]:

- psychotherapeutic relationship: therapeutic alliance; empathy, congruence, and unconditional positive regard; analysis of transference and countertransference reactions;

- feedback (provided to and received from the patient);

- expectation effect (placebo effect);

- group dynamics (group cohesion).

Criteria for PT efficacy:

1) cessation of alcohol intake;

2) establishment of therapeutic remission;

3) established compliance with pharmacotherapy;

4) retention of the patient in the treatment, including rehabilitation, program;

5) improvement in quality of life, including mental state and family functioning;

6) patient satisfaction with the resolution of addressed problems.

Comments: When selecting specific methods of PT, four main groups of factors are taken into account: (1) patient factors (diagnosis and disease severity; presence of comorbid psychiatric pathology; stage of motivation; individual capabilities and personality traits; patient's ability to accept a particular PT concept); (2) goal-setting factors (targets, goals, and objectives of PT); (3) professional competence in a given psychotherapy method; (4) organizational factors.

All PT methods with established (proven) efficacy possess therapeutic potential, but incorporating as many methods as possible—or even all available ones—into each patient's treatment program is not advisable [13].

PT methods make it possible to develop anti-relapse skills, skills in emotional self-regulation, relaxation, and stress coping, correct and/or compensate for impaired executive functions, and strengthen motivation and compliance with the ongoing treatment, including pharmacotherapy.

Methods with proven efficacy include:

– person-centered psychotherapy [106-107];

– motivational interviewing and motivational psychotherapy [108-110];

– cognitive-behavioral psychotherapy [111-113].

The following methods also demonstrate high efficacy:

– situational control therapy (contingency contracts; reward reinforcement) [114-116];

– relapse prevention [117-119];

– development of emotional self-regulation, relaxation, and stress-coping skills [117; 120];

– family psychotherapy (various modalities) [121-122].

The aforementioned interventions can be administered in individual, couple (family work), and group formats. For patients under the age of 18, the emphasis is placed on psychosocial and family therapy [13-14].

PT methods with uncertain efficacy may be used as auxiliary measures, provided they belong to professional and ethical methods of psychotherapy.

3.3. Assessment of treatment efficacy and safety

Comments: The efficacy of combination treatment is assessed based on the dynamics of psychopathological, somatovegetative, and neurological disorders in patients with AUD [2; 13].

Criterion for pharmacotherapy efficacy: stabilization of the patient's psychophysical state [2; 13].

Criterion for PT efficacy: patient retention in the treatment program and consent to continue treatment [2; 13].

Comments: The safety and tolerability of therapy are evaluated throughout its course based on the frequency of onset and development of ADRs.

ADRs are recorded based on:

– spontaneous patient reports;

– physical examination and clinically significant changes in vital signs (blood pressure, heart rate, respiratory rate, body temperature) from baseline values;

– clinically significant deviations of laboratory test results and instrumental diagnostic methods from baseline values.

The causal relationship between ADRs and medicinal products is assessed using the Naranjo algorithm (Appendix G1) [124]. If an ADR occurs, the physician must document their actions in the primary medical documentation, for example, prescribe additional medications (which ones, at what dosage, for what period), etc., and also complete the "Notification of an Adverse Reaction or Lack of Therapeutic Effect of a Medicinal Product" form and submit it to Roszdravnadzor [123].

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Rehabilitation of a patient diagnosed with AUD is a combination of medical, psychological, and social (public and intersectoral) measures carried out with the aim of achieving the maximum possible compensation or restoration of impaired/lost bodily functions and the social adaptation of the patient. According to the conclusion of the WHO Expert Committee on Medical Rehabilitation, this concept is defined as "the combined and coordinated use of medical and social measures, education, and vocational training or retraining aimed at ensuring the patient achieves the highest possible level of functional activity" [2].

Rehabilitation aims to preserve the positive outcomes achieved during prior treatment through the restoration (development) of the normative personal and social status of an AUD patient by maintaining sobriety, further correcting and developing their personal, intellectual, moral, emotional, and creative potential [2; 13; 125-127].

The strategic goals of rehabilitation in patients with AUD are [2]:

1) safe cessation of alcohol consumption and maintenance of a sober lifestyle;

2) achievement of premorbid personal and/or social status;

3) creation of an adaptive social environment, primarily to prevent access to alcohol and prevent relapses.

The pragmatic goals of rehabilitation are:

1) formation of conscious and stable patient motivation (set) for alcohol abstinence and participation in the treatment and rehabilitation program (hereinafter referred to as TRP);

2) implementation of therapeutic measures aimed at arresting mental and behavioral disorders caused by alcohol consumption and preventing disease relapses;

3) treatment of existing somatic and neurological disorders and diseases;

4) correction of the patient's personality structure and provision of conditions for positive personal development;

5) correction of family relationships;

6) enhancement of the patient's level of social functioning (with the involvement of family and community resources);

7) achievement of actual social engagement: study, work.

One of the problems complicating the rehabilitation process in patients with AUD is that a number of psychological functions necessary for the full restoration of normative personal and social status are severely impaired in them [126]. Nevertheless, these functions can be restored to a normative level as a result of completing a TRP or compensated for through the development of other functions and the formation of entirely new skills and abilities. Therefore, when designing a rehabilitation program, it is necessary to consider not only the rehabilitation aspect but also the habilitation aspect of rehabilitation [2; 13].

The MRP includes three stages: restorative (pre-rehabilitation), medical rehabilitation, and preventive (post-rehabilitation). Medical rehabilitation also takes place in three stages: adaptation, integration, and stabilization.

Comments: Rehabilitation of patients with alcohol dependence syndrome (ADS) requires a sufficient duration of therapeutic measures and continuity between inpatient and outpatient care [13; 128-129]. Diverse efforts are needed targeting various spheres of patient functioning: psychological, occupational, familial, social, and recreational. Accordingly, the following areas of rehabilitation are distinguished: medical care (provision of necessary medical assistance for ADS treatment and existing somatic issues; therapy for comorbid mental disorders); organizational measures (creation of a structured therapeutic environment); psychological and psychotherapeutic measures (cognitive rehabilitation, psychotherapeutic and psychological correction of personal, familial, and social functioning; motivation and compliance maintenance); participation in the 12-step program; social and pedagogical measures (stimulation of physical activity, formation, development, and enhancement of self-care and social communication skills; occupational therapy); and social support [2; 13; 130].

5. Prevention and Dispensary Observation

Once ADS is established, tertiary (modification) prevention becomes of paramount importance. It is primarily medical and individualized, targeted at individuals with established ADS, and aimed at preventing further disease progression, reducing harmful consequences, and preventing relapse.

Dispensary monitoring is carried out in accordance with the Procedure for Dispensary Monitoring of Persons with Mental and/or Behavioral Disorders Associated with Psychoactive Substance Use [131].

6. Organization of Medical Care

ADS therapy can be provided in inpatient settings (including day hospitals) and outpatient settings. There is continuity of care between the inpatient and outpatient units of addiction treatment services [2].

Comments: A provisional diagnosis of ADS is established within the first 24 hours based on clinical examination data. The definitive diagnosis is established within 3–7 days based on clinical examination data, instrumental and laboratory test results, and dynamic observation [13; 131].

The inpatient treatment course continues until the patient's psychophysical state stabilizes, which implies a reduction in the clinical manifestations of psychoactive substance withdrawal and existing somatoneurological disorders. The duration of inpatient treatment is, on average, 14–21 days [2; 13]. The duration of outpatient treatment and monitoring is determined by the procedure for providing medical care in the profile of "psychiatry-addiction" and the procedure for dispensary monitoring of persons with mental and (or) behavioral disorders associated with psychoactive substance use [131].

6.1. Indications for hospitalization:

• exacerbation of craving for alcohol and/or other psychopathological disorders after the relief of alcohol withdrawal syndrome (AWS);

• need for special research methods to perform differential diagnosis;

• lack of clinical effect from ongoing ADS therapy in outpatient settings and day hospitals.

6.2. Indications for outpatient treatment:

• exacerbation of craving for alcohol and/or other psychopathological disorders without prior relapse of remission.

6.3. Indications for discharge:

• elimination of manifestations of psychoactive substance use and/or other psychopathological disorders.

6.4. Referral for rehabilitation:

• all patients diagnosed with ADS who have received inpatient and/or outpatient addiction treatment are referred for further rehabilitation with the aim of stabilizing remission [2; 13; 125; 127].

Optimal patient routing algorithm during sequential rehabilitation stages:

1) Treatment of mental and behavioral disorders due to alcohol use: emergency addiction treatment department or addiction department of an addiction hospital (dispensary).

2) Inpatient rehabilitation: medical rehabilitation department of an addiction hospital (dispensary) or addiction rehabilitation center.

3) Outpatient rehabilitation: medical rehabilitation department (day addiction hospital or addiction department of an addiction dispensary (hospital)).

4) Dispensary monitoring by the district addiction psychiatrist [131].

7. Additional Information

No additional information available.

Criteria for Evaluating the Quality of Medical Care

Quality of care criteria for specialized medical care provided to adults and children with ADS (ICD-10 code: F10.2)

References

Appendix A1. Working Group Composition

Co-Chairs:

Klimenko, Tatyana Valentinovna, MD, Prof.

Krupitsky, Evgeny Mikhailovich, MD, Prof.

Masyakin Anton Valerievich, MD, Associate Professor.

Secretary:

Gubanov, Georgy Alexandrovich

Working Group Members:

Agibalova, Tatyana Vasilyevna, MD

Arkus, Maxim Leonidovich, PhD

Buzik Oleg Zhanovich, Doctor of Medical Sciences

Korchagina, Galina Alexandrovna, MD, Prof.

Ilyuk Ruslan Dmitrievich, D.Sc. in Medicine

Lobacheva Anna Stanislavovna, Ph.D. in Medicine

Mikhailov Mikhail Albertovich, D.Sc. in Medicine

Nadezhdin Alexey Valentinovich, Ph.D. in Medicine

Poplevchenkov Konstantin Nikolaevich, Ph.D. in Medicine

Rybakova Ksenia Valeryevna, D.Sc. in Medicine

Authors:

1. Vinnikova Maria Alekseevna, Doctor of Medical Sciences, Professor. Russian Society of Psychiatrists.

2. Nenastyeva Anna Yuryevna, Candidate of Medical Sciences. Russian Society of Psychiatrists.

3. Utkin Sergey Ionovich, Candidate of Medical Sciences. Russian Society of Psychiatrists. Federation of Anesthesiologists and Reanimatologists.

Conflict of interest: none

All members of the working group have confirmed the absence of financial support / conflicts of interest that need to be disclosed.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience of these clinical guidelines:

1. Psychiatrist-addictologist

2. District psychiatrist-narcologist

3. Adolescent psychiatrist

4. Psychiatrist

5. District psychiatrist

6. Psychotherapist

7. Medical psychologist

The following information resources were used in the development of these clinical guidelines:

• Order of the Russian Ministry of Health dated February 28, 2019, No. 103n (as amended on June 23, 2020) "On approval of the procedure and timelines for the development of clinical guidelines, their revision, the standard form of clinical guidelines and requirements for their structure, composition and scientific validity of the information included in clinical guidelines" (with amendments and additions that entered into force on August 4, 2020).

• Analysis of scientific literature sources and other data, as well as internet resources over the past 10 years:

  - domestic: medical guidelines, scientific publications in periodicals, e-library scientific electronic library, State Register of Medicines, Register of Medicines, Federal State Statistics Service of the Russian Federation;

  - foreign: Cochrane Library, Medline, MedScape, PubMed, National Institute on Alcohol Abuse and Alcoholism (NIAAA), Substance Abuse and Mental Health Services Administration (SAMHSA), European Monitoring Centre for Drugs and Drug Addiction (EMCDDA)

  - Regulatory documents of the Government of the Russian Federation and the Ministry of Health of the Russian Federation.

Rating schemes for assessing the levels of evidence certainty (1, 2, 3, 4, 5) and the levels of recommendation consensus (A, B, C) were used in the development of these clinical guidelines.

Appendix A2.1 – Levels of Evidence (LoE) Grading Scale for diagnostic methods (diagnostic interventions)

Appendix A2.2 – Levels of Evidence (LoE) Grading Scale for prevention, treatment, and rehabilitation methods (preventive, therapeutic, and rehabilitative interventions)

Appendix A2.3 – Grades of Recommendation (GoR) Scale for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitative interventions)

Appendix A2.4 – Rating scheme for the grades of recommendation (GoR) for therapeutic, rehabilitative, and preventive interventions

Procedure for updating clinical guidelines.

The update mechanism for clinical guidelines provides for their systematic updating at least once every three years, as well as upon the emergence of new evidence-based data regarding the diagnosis, treatment, prevention, and rehabilitation of alcohol dependence syndrome, or when justified additions/comments to previously approved clinical guidelines become available, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

1. Order of the Russian Ministry of Health dated December 30, 2015 No. 1034n «On approval of the Procedure for the provision of medical care in the profile "psychiatry-narcology" and the Procedure for dispensary observation of persons with mental disorders and (or) behavioral disorders associated with the use of psychoactive substances» (with amendments and addenda).

2. Order of the Russian Ministry of Health No. 299n dated May 17, 2016 «On approval of the standard of primary health care for dependence syndrome caused by the use of psychoactive substances» (Registered with the Russian Ministry of Justice on June 15, 2016 No. 42534).

3. Order of the Russian Ministry of Health No. 302n dated May 17, 2016 «On approval of the standard of specialized medical care for dependence syndrome caused by the use of psychoactive substances» (Registered with the Russian Ministry of Justice on June 15, 2016 No. 42536).

4. Order of the Federal Service for Surveillance in Healthcare No. 1071 dated February 15, 2017 «On approval of the Procedure for Pharmacovigilance» (with amendments and additions).

5. Order of the Russian Ministry of Health No. 103n dated February 28, 2019 (as amended on June 23, 2020) «On approval of the procedure and deadlines for the development of clinical guidelines, their revision, the standard form of clinical guidelines and requirements for their structure, composition, and scientific validity of the information included in clinical guidelines» (with amendments and additions that entered into force on August 4, 2020).

Appendix B. Physician Action Algorithms

Appendix C. Patient Information

What is alcoholism

From a medical standpoint, alcoholism is a chronic, progressive disease caused by the effect of alcohol as a narcotic substance. This disease has characteristic manifestations, clinical course, and outcomes, leading to persistent somatoneurological disorders (diseases of internal organs and the nervous system) and mental degradation (intellectual decline, dementia).

Main manifestations of alcoholism, features of the course and development of this disease.

1. Occasional drinking, episodic drinking.

Very often, when a doctor asks a patient, «How do you consume alcohol?», the answer is: «Moderately, like everyone else, on holidays». Later, in the course of the conversation, everything naturally falls into place; nevertheless, one needs to clearly understand the gradation and difference between moderate, ordinary alcohol consumption and habitual or everyday drinking. Despite all the relativity of the concept of «moderate» alcohol consumption, it is characterized by certain signs:

1. Alcoholic beverages are consumed rarely – no more than once a month, in small doses that do not cause any noticeable intoxication;

2. With moderate alcohol consumption, control over the amount of alcohol consumed is completely preserved, as is a critical assessment of one's behavior, and no noticeable motor disorders are observed;

3. Alcoholic beverages are consumed only during non-working hours and in an appropriate situation.

Alcohol abuse generally begins with accidental or episodic drinking. In such cases, doses of alcoholic beverages that cause a pronounced state of intoxication are consumed, but this happens episodically, and during periods of abstinence, there is no craving for alcohol. Already at this stage, one can notice that a person gradually develops a bodily adaptation to alcohol, meaning that previous doses no longer cause noticeable intoxication, and therefore the drinker begins to increase the doses to achieve the desired effect. If signs of transition to alcohol abuse are detected, it is necessary to consult a specialist. Alcohol consumption in adolescence is also a reason to see a doctor.

2. Systematic alcohol abuse.

Habitual or episodic drinking is followed by systematic drinking, during which the core manifestations of alcoholism develop. At this stage, drinking becomes more frequent, occurring for virtually any reason, significant or insignificant. It becomes very difficult for a person to abstain from alcoholic beverages, and they begin actively seeking reasons to drink. During periods of forced abstinence from alcohol (family troubles, lack of money, work, etc.), such individuals experience mood disorders, a feeling that something is missing, and that "something is not right." However, the person already knows "their remedy": another drink relieves all these unpleasant sensations. Alcohol is generally consumed at least 1–2 times a week, and in some cases daily. However, at this stage, control over the amount of alcohol consumed is still retained. Nevertheless, an increase in the volume of alcohol consumed is already clearly evident. At the same time, protective reflexes disappear: whereas previously a person would drink a large dose of alcohol and might vomit, now vomiting disappears. It should be noted that even a very large dose, which would normally cause severe intoxication, does not induce vomiting. Simply put, the body tires of fighting, and the disease begins to take over. If such a situation arises, it can serve as a reason to consult specialists. It is better to prevent the progression of the disease in a timely manner than to fight its manifestations for the rest of one's life.

3. Initial (First) Stage of Alcoholism.

A) An increase in single and daily doses of alcohol required to achieve intoxication is the earliest and most common sign of alcohol tolerance and the development of the disease.

B) The next sign of the disease is the development of a pathological craving for alcohol, in other words, the formation of psychological dependence. The craving for alcohol may be expressed more or less distinctly. Often, the desire to drink is rather obsessive in nature, distracting the person from work and channeling their energy into satisfying this desire. Thus, drinking turns into the primary interest in life. Characteristically, the sick person now strives to drink despite all opposing factors: lack of money, family conflicts, trouble at work, etc. Once the craving for alcohol has formed, the patient characteristically does not want to resist it, or if they do want to, they are usually no longer able to cope with it without medical assistance.

C) Another important sign of the disease is the loss of control over the amount consumed. After the first drink, the desire to drink more sharply intensifies, and a peculiar "greed for alcohol" appears. Therefore, the drinker continues to drink until deep intoxication sets in. Thus, the person loses the ability to "drink moderately like everyone else." You can say goodbye to this myth and wish forever. That's it!

It should always be remembered that the loss of control over drinking does NOT disappear even after many years of abstinence from alcohol. This is precisely why it is impossible to transition to "moderate" drinking after treatment and abstinence, and any attempt to resume alcohol consumption inevitably leads to a relapse ("slip") into alcoholism. Of course, you can deny the loss of control, claim that you "can not drink," that you were "forced to drink," or find any other excuse for your disease and drinking. The choice is yours.

D) The next sign of the disease, which is a consequence of the two previous ones, is a change in the character of intoxication. Memory lapses regarding the end of the intoxication typically appear. In addition, pronounced intoxication may be accompanied by malice, aggressiveness, and quarrelsomeness. After sobering up, a person may not remember how they got home, how they argued with their wife or neighbors, how they fought with a neighbor on the landing, or who took all the money out of their pockets. They may genuinely believe they could not have behaved the way they are told they did. They might even think they are being falsely accused.

All of the above signs characterize the initial, first, or "preclinical" stage of alcoholism. The term "preclinical" is due to the fact that not all signs of the disease are bright and distinct. Unfortunately, patients in this stage generally do not consult doctors, do not consider themselves alcohol-dependent, excuse themselves with the notorious "I drink like everyone else," and do not wish to undergo treatment. Nevertheless, the presence of these signs indicates the need to consult a specialist.

4. Advanced (Second) Stage of Alcoholism.

At this stage, the core symptoms of the disease develop. Joining all the above manifestations are:

A) Alcohol withdrawal syndrome (hangover, the desire for a "hair of the dog" to improve physical condition). Hangover symptoms are caused no longer so much by alcohol itself as by the products of its incomplete breakdown formed in the body. Withdrawal syndrome also develops insidiously, gradually, not all at once. In the early stages of withdrawal syndrome development, the need for a morning drink arises only after consuming large doses of alcohol. With further alcohol abuse, the need to relieve the hangover arises even after small amounts consumed. Clinically, in the first stage, withdrawal syndrome manifests as headache, weakness, malaise, nausea, sometimes vomiting, tremors in the hands and body, and cardiac arrhythmias. Subsequently, mental disorders join in: the patient suffers from insomnia, develops anxiety, cannot find a place to rest, may experience causeless bursts of irritability and anger, while sweating and tremors persist—in a word, "a wretched state of mind." Another important fact: whereas previously a "hangover" lasted only a few hours, in more advanced stages it lasts already 2–7 days or even longer.

The development of alcohol withdrawal syndrome indicates that irreversible changes regarding alcohol have occurred in the body. Once arisen, alcohol withdrawal syndrome does not disappear even after many years of abstinence from alcohol. It can only become more severe. This largely determines the medical tactics: to achieve complete abstinence from alcohol, and to exclude the consumption of any alcoholic beverages for the rest of one's life.

B) Constant, intermittent, and binge drinking is one of the manifestations of the disease, during which, so to speak, the most habitual rhythm of alcohol abuse is formed.

The constant form is characterized by prolonged alcohol abuse lasting weeks and months. This does not mean that there are no breaks in this form, but they are rare, short-lived, and generally caused by extraordinary situations (e.g., somatic diseases, hard or shift work, etc.).

The second form—intermittent drinking—has the following character: against the background of multi-week or multi-month drinking, periods of its sharp intensification arise. At the end of such a "binge," there may be short (1–3 days) breaks associated with bodily exhaustion and intolerance to alcohol. Then the severity of these phenomena decreases again. A period begins when the patient drinks relatively moderately, followed by a "binge" similar to the one described above.

The third form is binge drinking. Alcohol is consumed regularly for several days or weeks. Then "lucid intervals" follow. Their duration varies—from 7–10 days to several weeks or even months. After the end of the "binge," a sharply pronounced withdrawal syndrome is observed, often accompanied by mental disorders in the form of insomnia, depressed mood, feelings of guilt, anxiety, unmotivated fears, etc.

C) Personality changes (alcoholic degradation). Now, that is, in the second stage, the dependent person displays traits of "moral coarsening," and their "character spoils": the person is deceitful, boasts of non-existent victories and feats, becomes rude, unceremonious, selfish, and cynical. Disregarding the interests of the family, the patient shows extreme persistence in demanding and acquiring money for alcohol, and loses the sense of tact. The emotional sphere also suffers: causeless mood swings appear—from causeless gaiety, sociability, and optimism to gloominess, depression, malice, and irritability. Crude humor appears—a tendency toward flat, vulgar jokes. And the saddest thing about this is that the patient themselves generally does not notice it. Those around them suffer. A decline in intellect and memory may also occur: attention worsens, the ability to memorize decreases, and acquiring new knowledge and skills is also difficult, etc.

D) The development of alcoholic psychoses (delirium tremens) is possible.

The presence of these signs indicates the need to consult a specialist for treatment.

5. Terminal (Third) Stage of Alcoholism.

At this, one might say, final stage of alcoholism, marked physical exhaustion sets in. Alcohol tolerance drops sharply, and intoxication occurs after only a small amount of alcohol (vodka, wine, beer, etc.). The dependent individual is constantly intoxicated and experiences an irresistible urge and craving for alcohol—reaching for the next dose with trembling hands, begging, and humiliating themselves. There are very few "sober days", which occur only when the patient is unable to obtain alcoholic beverages. Severe mental disorders develop, up to and including psychoses. The capacity for productive labor is lost. The patient is no longer able to work, loses their professional skills, and leads a parasitic lifestyle. Needless to say, spiritual interests and family bonds are lost. The patient becomes a heavy burden to those around them. At this final stage, damage to internal organs and the nervous system—caused by prolonged alcohol intoxication, including severe conditions such as paralysis, cirrhosis, dementia, and others—is most pronounced.

The described course of the disease is caused by the effect of alcohol primarily on the central nervous system, where alcoholism gradually leads to brain shrinkage due to damage and death of nerve cells. Simultaneously, pathological changes in the liver, gastrointestinal tract, heart, and reproductive system develop and progressively worsen. Personality disintegration and physical debility are the inevitable outcomes of alcoholism.

An afflicted person needs treatment, and the earlier it is started, the better. However, much depends on how much the patient themselves understands that they are ill. It is precisely the awareness and admission of one's illness that is the first step toward recovery. And this first step is usually always the hardest.

Somatic complications of alcoholism

Ethyl alcohol is a universal poison. There is not a single cell in the human body that alcohol does not damage upon penetrating it. All organs are affected, but certain tissues (such as nervous tissue) are destroyed to a greater extent because alcohol penetrates them more easily, and the cells of these systems are not adapted to process harmful substances.

Damage to the digestive system

Changes begin right in the oral cavity, where alcohol suppresses secretion and increases saliva viscosity. An alcoholic's teeth are destroyed for many reasons—immune suppression, poor diet, and lack of personal hygiene.

Due to the suppression of defense mechanisms, esophagitis develops. The swallowing process is disrupted—food begins to reflux from the stomach back into the esophagus. Heartburn and vomiting are inevitable companions of the dependent individual. With prolonged ethanol intake, the veins of the esophagus dilate, their walls thin out, and a point comes when the veins rupture during vomiting, leading to severe hemorrhage. Only emergency surgery can save the patient in this case. However, death usually occurs before the patient can be delivered to a surgeon.

In alcoholism, gastric juice secretion decreases, the protective mucus barrier of the stomach walls undergoes changes, and an inflammatory process (gastritis) develops. The result is the death of gastric cells, impaired digestion, malabsorption of nutrients, gastric bleeding, the development of gastric ulcers, and gastric cancer. Changes in the stomach are detected in 95% of patients with alcoholism.

With systematic alcohol consumption, the movement of food masses through the intestines slows down. Ulcers form on the intestinal walls. The absorption of beneficial substances and the excretion of harmful ones are impaired, and metabolism is disrupted.

Beneficial microorganisms—the inhabitants of the intestine that produce B vitamins—die. That is, gradually, upon the depletion of the vitamin reserve (B vitamin storage), avitaminosis sets in. And it is precisely avitaminosis that is the primary cause of severe neurological complications of alcoholism. The absorption of all trace elements whose metabolism involves vitamins is impaired, and protein loss occurs.

Simultaneously, harmful intestinal microorganisms proliferate, utilizing beneficial food nutrients for nourishment and poisoning the body with their metabolic waste products. Alcoholic enteritis (inflammation of the intestine) develops, with diarrhea (loose stools) as its main manifestation. Systematic alcohol consumption exhausts the secretory processes of the pancreas. Secretory cells are replaced by supportive tissue, leaving fewer and fewer functioning cells. Acute or subacute pancreatitis develops. As is well known, the pancreas produces insulin—the hormone responsible for sugar metabolism in the human body. Its production naturally decreases in alcoholism. First, a condition occurs that doctors call "impaired glucose tolerance", and then—acquired diabetes mellitus.

Alcoholic liver disease is a multistage process. In the first stage, because the liver cannot cope with processing toxins, it undergoes compensatory enlargement. Then, cells constantly neutralizing ethanol and its metabolites die from overwork, and their place is taken by adipose tissue (alcoholic fatty liver disease). Against the background of fatty degeneration of the liver, alcoholic hepatitis (inflammation of liver cells) develops. In terms of tissue changes, manifestations, and consequences, alcoholic hepatitis is indistinguishable from viral hepatitis. Gradually, necrosis (cell death) occurs in certain areas of the liver. From this point on, liver disease becomes irreversible, meaning that even if alcohol consumption ceases, liver cells will not regenerate.

Alcoholic liver cirrhosis, the 3rd stage of alcoholic liver disease, can be characterized as follows. After the bulk of liver cells die, nodules begin to form from the remaining cells, representing chaotically arranged, non-functioning liver cells. The liver becomes bumpy and decreases in size. The nodules compress the hepatic veins, and systemic blood circulation is disrupted. The veins of the esophagus, stomach, and intestines dilate compensatorily. Alcoholics diagnosed with liver cirrhosis die quickly due to poisoning by harmful substances that are no longer utilized by the liver; patients frequently die from hemorrhages of dilated veins. Large liver nodules (if the patient lives that long) develop into cancerous tumors (hepatocellular carcinoma). Tumors develop due to the direct toxic effect of alcohol and immunodeficiency.

Cardiovascular system damage.

Alcoholic heart disease develops as a result of the direct action of alcohol and acetaldehyde (an alcohol breakdown product), profound structural remodeling, and physicochemical disorders. With systematic alcohol consumption, myocardial (heart muscle) contractility and performance decrease. Heart cells swell and are destroyed, the number of cell nuclei decreases, the structure of muscle fibers is disrupted, cell membranes loosen and break down, and protein synthesis in heart cells is impaired. Subsequently, dystrophy and necrosis (death) of heart cells are detected.

Patients with alcoholism exhibit the entire spectrum of conduction and excitability disorders. Atrioventricular block, pre-excitation syndrome of the ventricles, and intraventricular conduction block are the most common.

Alcoholic heart damage is complicated by hypertension and vascular atherosclerosis.

Blood pressure levels in individuals who abuse alcohol are initially higher (by 10–15%) than in abstainers. This places an additional burden on the heart.

The concept of the "alcoholic heart" exists. This term denotes the typical appearance of an alcoholic's heart observed at autopsy. Heart size is increased due to cavity enlargement and proliferation of connective tissue (non-functional muscular tissue, but connective tissue). Cessation of alcohol consumption in the compensated stage halts toxic myocardial damage. If the damaging factor persists, decompensation develops. The strength and speed of heart contractions decrease, leading to heart failure: edema of all organs. Recovery at this stage of alcoholic heart disease is impossible.

Immune system damage.

Systematic alcohol abuse causes a decrease in phagocytosis. Phagocytosis is one of the body's most crucial anti-infective defense mechanisms, used to destroy microbes as well as altered, dangerous cells. The protective function of blood proteins is suppressed. The level of lysozyme decreases—a protein found in many human secretions (saliva, tears, tissues of various organs, skeletal muscles) capable of exerting an antimicrobial effect and breaking down microbial cell walls. The number of lymphocytes (immune cells) decreases. This is caused both by the direct toxic effect of ethanol on the bone marrow, where lymphocytes are produced, and by liver dysfunction. Impaired immunity leads to the formation of persistent foci of chronic infection. Alcoholics suffer from infectious diseases (pneumonia, abscesses, etc.) more often than abstainers. However, the primary danger to the body comes from antibodies directed against its own normal cells (autoantibodies), which begin to be synthesized under the influence of alcohol. In particular, every second patient exhibits autoantibodies targeting the liver, and every fourth targeting the spleen. Autoantibodies to brain tissue also exist.

Nervous system involvement

Alcoholism manifests with a multitude of neurological symptoms based on metabolic disorders in nervous tissue, neuronal death, increased intracranial pressure, and destruction of nerve trunk sheaths.

Systematic alcohol consumption leads to premature aging and disability. The life expectancy of individuals prone to heavy drinking is 15–20 years shorter than the statistical average. The leading causes of death among alcohol abusers are accidents and trauma. Patients with alcoholism typically die not from alcohol-related disease itself, but from comorbid conditions developing due to suppressed immunity, liver damage, and cardiovascular pathology.

Alcoholic degradation develops in the late stages of alcoholism. It is characterized by persistent memory and intellectual decline, emotional coarsening, ethical deterioration, loss of insight into alcohol abuse and overall condition, diminished capacity for systematic labor, and usually the loss of former social standing. There are 3 types of degradation. Let us examine them.

Degradation with passivity: the patient is lethargic, passive, uninitiative, and loses former interests. Even among drinking companions, they remain a passive witness to events; any activity arises only when it comes to acquiring alcoholic beverages. Such patients are prone to a dependent lifestyle.

Degradation with psychopathic-like symptoms: the patient exhibits increased irritability, proneness to anger, temper tantrums, and depression. Such patients are overtly cynical, intolerant of contradiction, aggressive, or conversely, cowardly, sycophantic, and deceitful.

Degradation with euphoria: the patient's state is dominated by a carefree, complacent mood with a sharp decrease in insight regarding their behavior and situation. Excessive frankness in communication with others, a joking tone, and an abundance of clichés and stereotypical trite jokes are characteristic. The alcoholic humor described in alcoholism is most pronounced in these patients. It is "impossible to awaken either pride, self-esteem, or a sense of dignity" in these patients.

The described complications of alcoholism are typical of advanced disease. They are difficult to treat. Prevention is also difficult but possible—one must timely consult a specialist who will help achieve cessation of alcohol intake.

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

G1. Naranjo Algorithm

Russian Title: Naranjo Algorithm for Assessing Causality of Adverse Drug Reactions (ADRs)

Original title: Naranjo algorithm

Source (official developer website, validated publication): Naranjo C.A., Busto U., Sellers E.M., et al. A method for estimating the probability of adverse drug reactions. Clinical Pharmacology and Therapeutics. 1981; 30(2):239-245. DOI: 10.1038/clpt.1981.154

Type (underline): rating scale; index; questionnaire; other (specify):_____________

Purpose: The Naranjo algorithm is used to assess the probability of a relationship between a drug and an adverse drug reaction. When determining the degree of certainty of the "drug–ADR" relationship, this questionnaire is focused on obtaining specific answers scored in points. A certain number of points corresponds to a specific degree of probability.

Content (template):

Categories of the probability of the ADR-drug causal relationship according to the Naranjo scale based on answers to 10 questions are determined as: