Mental and behavioral disorders due to use of alcohol. Alcohol withdrawal syndrome (alcohol withdrawal state): clinical guidelines

List of Abbreviations

AWS – alcohol withdrawal syndrome (alcohol withdrawal state)

ALT – alanine aminotransferase

AST – aspartate aminotransferase

ATC – anatomical therapeutic chemical

GABA – gamma-aminobutyric acid

Gamma-GT – gamma-glutamyl transferase

VLEL – vital and essential drugs

ABDS – acid-base balance status

Med – medication

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 reaction

psychoactive substance – psychoactive substance

AC – alcohol craving (pathological craving for alcohol)

PNS – peripheral nervous system

РКИ – randomized controlled trial

ADS – alcohol dependence syndrome

LCE – level of confidence of evidence

GRS – grade of recommendation strength

CNS – central nervous system

BE – base excess (deficit)

CIWA-Ar – Clinical Institute Withdrawal Assessment for Alcohol scale, Revised

HCO₃ – standard bicarbonate

pCO₂ – partial pressure of carbon dioxide (CO₂) in equilibrium with H₂CO₃ in whole blood

pH (power hydrogen) – ratio of acidic and alkaline elements in a liquid, the negative decadic logarithm of H⁺ ion concentration in a liquid medium

pO₂ – partial pressure of oxygen (O₂) in whole blood

RASS – Richmond Agitation-Sedation Scale

Terms and Definitions

Antioxidants (Eng. – antioxidants) – medicinal products belonging to various pharmacological groups, capable of inhibiting free radical processes in the human body through various means: from simple scavenging of free radicals to complex chain interactions with them, reducing their toxicity or shortening their lifespan. They possess a broad spectrum of action, including detoxifying, antidotal, general tonic, stimulating, metabolic, and other effects.

Benzodiazepines (Eng. – benzodiazepines) – a group of medicinal products belonging to anxiolytics by pharmacological action. They possess a broad spectrum of pharmacological effects, including anxiolytic, sedative, hypnotic, myorelaxant, anticonvulsant, amnestic, and others. Syn.: benzodiazepine derivatives.

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.

Cross-tolerance (Eng. – cross-tolerance) – the development of tolerance to a substance to which an individual has not been previously exposed, as a result of the administration of another substance. Both substances typically, but not necessarily, share a similar pharmacological action.

Hangover syndrome (Eng. – hangover) – a state developing after the termination of alcohol intoxication, regardless of the severity and duration of the latter. Symptoms may also occur in healthy individuals after the consumption of large doses of alcohol.

Alcohol dependence syndrome (Eng. – alcohol dependence syndrome) – a combination of physiological, behavioral, and cognitive phenomena in which alcohol use takes on a much higher priority for a given individual than other behaviors that once had greater value. A central characteristic of the dependence syndrome is the desire (often strong, sometimes overpowering) to take alcohol. It is a chronic, progressive disease caused by the action of alcohol as a narcotic substance. It has its characteristic symptoms, specific features of development and course, and defined outcomes.

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.

Tolerance (Lat. – tolerantia, "endurance, capacity to endure") – a progressive diminution of the desired psychotropic effect of alcohol (euphoria, sedation, relaxation, etc.), which compels the patient to increase doses and frequency of alcohol consumption. It is based on the physiological mechanism of the body's adaptation to the toxic effects of alcohol.

Tremor (Lat. – tremor, "shaking") – rhythmic, rapid, involuntary contractions of the muscles of the trunk or extremities.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Alcohol withdrawal syndrome (alcohol withdrawal state, hereinafter referred to as AWS; Eng. – alcohol withdrawal) is a complex of vegetative, somatic, neurological, and psychiatric disorders occurring in patients with dependence syndrome upon complete cessation of alcohol intake or reduction of its dose following repeated, usually prolonged, and/or high-dose consumption. AWS develops several hours after the cessation of alcohol use and, if uncomplicated, resolves within 2–5 days. AWS may be complicated by major convulsive seizures and/or psychosis.

Synonyms: alcohol withdrawal syndrome, withdrawal state caused by alcohol use.

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

A single intake of alcohol activates the brain reward system (internal reinforcement system, reward system) and thereby induces positive emotions. With frequent alcohol consumption, this system becomes less sensitive to the effects of alcohol. Alcohol, initially consumed for its pleasurable effects, is subsequently used, at least in part, to escape the unpleasant effects of withdrawal (negative reinforcement). Consequently, motivation for natural rewards decreases, while motivation for alcohol consumption significantly increases. The pathway leading from the pleasure of intoxication to dependence appears to pass through phenomena associated with automatism. Behavior initially motivated by a goal (consuming alcohol to become more uninhibited, social, euphoric) subsequently becomes a habit. The brain reward system is dopaminergic. Alcohol increases the activity of dopamine neurons in the ventral tegmental area both directly and indirectly—via increasing the activity of the gamma-aminobutyric acid (hereinafter – GABA) system and the release of endogenous opioids. During the development of alcohol dependence syndrome (hereinafter – ADS), the activity of neural networks playing a role in mood changes, including stress reactivity (amygdala and hypothalamus) and interoception (insula and cingulate cortex), is altered. Several neurotransmitter systems are involved in these processes, including glutamatergic, GABAergic, noradrenergic, corticotropin-releasing factor, and opioid systems. An important role in the development of AWS is played by long-term synaptic plasticity impairment caused by chronic alcohol use, i.e., alteration (increase or decrease) of transmission efficiency in specific synapses. Glutamatergic and GABAergic neurotransmitter systems are predominantly involved in these processes. AWS is associated with increased release of corticotropin-releasing factor in the central nucleus of the amygdala, which also leads to the activation of stress-reactive systems and alteration of emotional background. In addition to catecholamines, GABA, and glutamate, neuropeptide systems (dynorphin, neuropeptide Y, nociceptin, vasopressin), endocannabinoids, and possibly others are involved in the development of AWS [1; 2].

1.3 Epidemiology of the Disease or Condition

An idea of the prevalence of AWS can be formed based on the overall prevalence of alcohol dependence syndrome (hereinafter – ADS), as AWS is its obligatory and integral part. It is considered that AWS is the most frequent reason for seeking specialized medical care; however, it should be noted that exact epidemiological data are lacking. In 2021, specialized institutions of the Russian Ministry of Health registered 1,159,031 patients with ADS, or 791.4 per 100,000 population, which accounted for 65.3% of the total dispensary cohort and 0.79% of the total population [3].

1.4 Features of Coding the Disease or Condition

[1]

F10.3xx – Alcohol withdrawal state (alcohol withdrawal syndrome)

AWS is part of ADS and is coded independently when the withdrawal syndrome is the direct reason for seeking care from a medical specialist due to pronounced severity of disorders.

The diagnosis of AWS is specified by the fifth character, indicating the presence or absence of complications:

F10.30...uncomplicated

F10.31...with seizures

F10.39...NOS (not otherwise specified)

[1] Mental and behavioural disorders (F00 - F99). (Class V of ICD-10, adapted for use in the Russian Federation). Edited by Kazakovtsev B.A., Holland V.B. – Moscow: Russian Ministry of Health, 1998. – 512 p.

1.5 Classification of the disease or condition

Depending on the severity of clinical manifestations, alcohol withdrawal syndrome (AWS) is divided into three severity grades: mild, moderate, and severe [4; 5]. The severity of AWS is objectified using an alcohol withdrawal assessment scale: the Clinical Institute Withdrawal Assessment for Alcohol scale, Revised (hereinafter referred to as CIWA-Ar) [5].

1.6 Clinical presentation of the disease or condition

AWS is a severe psychophysical condition that occurs exclusively in patients with alcohol dependence syndrome (ADS). AWS includes numerous somatovegetative, neurological, and psychopathological disorders. Somatovegetative and neurological disorders, such as headache, dizziness, asthenia, feeling of malaise, thirst, coated tongue, nausea, abdominal bloating, diarrhea, increased blood pressure (hereinafter referred to as BP), tachycardia, discomfort or pain in the cardiac region, and hyperhidrosis, are non-specific, meaning they can be observed in other conditions and diseases associated with intoxication [4; 5].

AWS should be distinguished from a post-intoxication (hangover) state. The main distinction is the presence of signs of secondary pathological craving for alcohol (hereinafter referred to as PCA). These signs are nosologically specific and, accordingly, characteristic only of patients with established ADS, exacerbating under the influence of alcohol intoxication. These signs include a strong desire to consume alcohol (to relieve hangover), accompanied by psychopathological disorders in the form of internal tension, irritability, dysphoria, depression, etc. [5].

An intermediate position between nosologically specific and non-specific disorders is occupied by disturbances caused by the impact of chronic high-dose alcohol consumption on the central nervous system (hereinafter referred to as the CNS), i.e., relatively specific to patients with ADS. Among them are intermittent, superficial, anxious sleep; vivid, restless, frightening dreams; ideas of reference and guilt; hyperacusis; isolated auditory and visual illusions; hypnagogic hallucinations; coarse tremor of the entire body or hands, eyelids, tongue; nystagmus, sweating, tachycardia, convulsive seizures, etc. [5].

AWS is always accompanied by the appearance or worsening of pre-existing cognitive impairments, with attention, memory, and the speed of intellectual processes being affected [4].

Thus, AWS consists mainly of two parts: nosologically specific signs of PCA and non-specific/low-specificity signs resulting from the toxic effects of alcohol. The combination of nosologically specific and non-specific signs determines the individual clinical features of AWS in a given patient [5].

The course and severity of clinical manifestations of AWS depend on the following factors: duration and stage of ADS; alcohol tolerance; duration of prior alcohol consumption; premorbid personality traits; and the patient's current somatic and neurological status [4; 5].

Individuals under the age of 18 are characterized by the absence of pronounced somatoneurological manifestations in the structure of AWS and a short duration of its course. Autonomic, asthenic, somnipathic, and depressive-dysphoric manifestations predominate [5].

2. Diagnostics, medical indications and contraindications for diagnostic methods

Clinical diagnosis, consisting of collecting complaints, medical history, and analyzing the obtained data, is of primary importance in diagnosing AWS. Other diagnostic methods play a secondary role [5-9].

Criteria for establishing the disease/condition diagnosis: the diagnosis of AWS can be established in the presence of [7]:

1. Clear evidence of recent cessation or reduction of alcohol intake following prolonged and/or high-dose use.

2. Presence of symptoms from the following list:

• desire to consume alcohol;

• tremor of the tongue, eyelids, or outstretched hands;

• sweating;

• nausea or vomiting;

• feeling of malaise or weakness;

• tachycardia or arterial hypertension;

• psychomotor agitation;

• headache;

• anxiety;

• insomnia;

• feeling of malaise or weakness;

• episodic visual, tactile, or auditory hallucinations or illusions;

• major convulsive seizures;

• depressive and dysphoric disorders.

3. The existing symptoms are not attributable to a medical disorder unrelated to alcohol use and are not better explained by another mental or behavioral disorder.

2.1 Complaints and Anamnesis

Comments: In addition to data on frequent and/or heavy alcohol use, the diagnosis of AWS requires a temporal relationship between the cessation (or reduction) of alcohol use and the onset of symptoms. When symptoms that may resemble withdrawal appear, for example, 2 weeks after complete cessation of alcohol use, the diagnosis of AWS becomes untenable [6].

Comments: The scale includes 10 frequent symptoms of AWS (Appendix G). Assessing patients using the scale takes about 5 minutes. Scores from 0 to 8 indicate no or mild AWS severity, which generally does not require active medical intervention; scores of 9–15 indicate moderate severity; scores of 16 and above indicate severe AWS and impending delirium [12].

The scale is a tool for objectifying the severity of AWS over time and can therefore be effectively used to adjust therapy. The persistence of high CIWA-Ar scores despite adequate doses of benzodiazepine derivatives indicates the presence of concurrent organic pathology in the patient [13].

2.2 Physical Examination

Physical examination findings are non-specific in AWS; they provide guidance in determining the severity of the patient's condition.

Comments: Somatic and neurological examinations are performed before starting therapy and during the course of treatment. Monitoring the patient's condition over time is important for the timely diagnosis of potential somatic and neurological complications.

2.3 Laboratory Diagnostics

1. general clinical biochemical blood test (determination of total blood protein, gamma-glutamyl transferase (hereinafter referred to as gamma-GT) activity, alanine aminotransferase (hereinafter referred to as ALT) activity, aspartate aminotransferase (hereinafter referred to as AST) activity, total blood bilirubin, free (unconjugated) blood bilirubin, blood albumin, blood glucose, blood cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, blood urea, and blood creatinine);

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

3. general urinalysis (visual assessment of color, transparency, determination of specific gravity (relative density), protein, glucose, bilirubin, urobilinogen, detection of ketone bodies, salts, cellular elements, casts).

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

Comments: Laboratory diagnostics in addition to classical clinical examination allows for an objective assessment of the patient's current condition, ruling out acute conditions requiring specialized medical care and latent organ pathology [8]. Routine laboratory tests in most cases allow for indirect confirmation of chronic heavy alcohol consumption: the levels of indirect biomarkers—AST, ALT, and gamma-GT—increase in response to a higher frequency and dose of alcohol intake. Indirect biomarkers have a relatively wide range of sensitivity/specificity. Specifically, AST has a sensitivity/specificity of 20–80%/50–95%; ALT, 18–58%/50–57%; and gamma-GT, 40–60%/80–90% [15; 19]. Therefore, to specifically confirm the alcoholic nature of organ damage, they are frequently used in combination [29; 30].

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: from risky drinking to established alcohol dependence [8].

Comments: Prolonged alcohol intake leads to ABB disorders and water-electrolyte imbalances. Blood ABB in AWS is characterized by a tendency toward metabolic acidosis, frequently combined with respiratory alkalosis. Furthermore, patients with AWS exhibit a tendency toward major blood electrolyte deficiencies: hyponatremia, hypokalemia, hypomagnesemia, and hypocalcemia. Severe water-electrolyte and ABB disorders can lead to arrhythmias, tissue hypoxia, and other life-threatening conditions. Additional tests (indicated above in the guideline statement) are performed to diagnose existing disorders [8; 31; 32].

2.4 Instrumental Diagnostics

The utility of instrumental diagnostics in AWS is limited due to the absence of specific signs characteristic of AWS.

Diagnosing comorbid pathology associated with AWS requires the involvement of other specialists. In a specific clinical situation and according to indications, instrumental diagnostic methods are prescribed: comprehensive ultrasound examination of internal organs, electroencephalography, echoencephalography, whole skull radiography in one or more projections, targeted chest radiography, etc. [5; 8].

Comments: Cardiac conduction disorders and arrhythmias are characteristic of patients with AWS, necessitating careful monitoring of cardiac activity [8].

2.5 Other Procedures

Comments: Assessing the severity of AWS enables well-founded and rational decisions regarding the setting of medical care and therapeutic interventions.

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

3.1. Drug therapy

Comments: AWS is invariably accompanied by water-electrolyte and ABB imbalances. In mild AWS, correction is generally performed by administering fluids and oral rehydration salt formulas [8].

Moderate and severe AWS generally require infusion therapy. In the presence of pathological changes in the heart, lungs, liver, and kidneys, the infusion volume may be restricted. Infusion therapy should be continued until complete correction of water-electrolyte and ABB disorders [8].

In severe AWS accompanied by vomiting, diarrhea, and hyperthermia, the degree of hypovolemia may increase and lead to hypovoclemic shock [41; 42]. In addition, severe AWS is frequently accompanied by a decrease in total blood plasma protein and albumin levels, leading to a decrease in oncotic pressure and fluid redistribution into the interstitial space [43]; therefore, correction of hypovolemia is one of the primary therapeutic goals [44].

Since infusion therapy itself can significantly affect the electrolyte balance and blood ABB, composition-balanced polyionic buffered solutions must be used. Modern balanced infusion solutions containing metabolizable organic acid anions (acetate, citrate, malate), such as: potassium chloride + calcium chloride + magnesium chloride + sodium acetate + sodium chloride + malic acid**[1]; dextrose + potassium chloride + magnesium chloride + sodium acetate + sodium gluconate + sodium chloride; potassium chloride + sodium acetate + sodium chloride**; #[2]meglumine sodium succinate** can be administered intravenously for various water-electrolyte and ABB disorders under the monitoring of diuresis, electrolyte levels, and blood ABB values. Average infusion volumes range from 400–3000 ml/day at a rate of no more than 500 ml/hour [8]. #Meglumine sodium succinate** is prescribed at a dose of 400 ml once daily for 7 days, according to the manufacturer's recommendations [45].

Comments: Benzodiazepine derivatives are currently the "gold standard" for AWS treatment; they are the only class of medicinal products (hereinafter referred to as MPs) whose efficacy has been proven both in treating AWS and in preventing the development of its severe forms and complications [12].

The therapeutic effect is mediated through the GABAergic mechanism: benzodiazepine derivatives exert a stimulating effect on the "benzodiazepine" site of GABA receptors, which regulate the influx of chloride ions through their channels into cells, and restore the hyperpolarization of GABAergic neuron membranes, resulting in the disappearance of tremor, tachycardia, hyperhidrosis, anxiety, seizures, etc. [49].

Currently, there are 2 main meta-analyses on the treatment of AWS [50, 51]. They concluded that benzodiazepines are the drugs of choice based on the assessment of the development of severe forms and complications (delirium and seizures), as well as adverse effects of the prescribed therapy and the duration of AWS. A meta-analysis comparing benzodiazepines with placebo or an active control drug included 11 trials involving a total of 1,286 patients [50]. The results demonstrated that the administration of benzodiazepines (compared to placebo) leads to a clinically significant reduction in symptoms within two days [50].

Further studies focusing on benzodiazepine therapy for AWS emphasized the selection of the preferred administration regimen for this drug class. Long-acting benzodiazepine derivatives with active metabolites are preferred as they contribute to a smoother onset of the clinical effect. Diazepam is the most commonly used drug in this group. A safer approach is symptom-triggered administration of benzodiazepine derivatives—providing patients with the necessary therapy only when they actually need it. This dosing regimen is preferred for patients with a low risk of AWS complications: it shortens the duration of detoxification and reduces the risk of adverse events. The use of benzodiazepine derivatives is recommended when CIWA-Ar scores exceed 8 [52]. When applying this approach, the patient's condition should be regularly assessed using the CIWA-Ar scale: if the CIWA-Ar score is > 8–10 points, the patient is administered 5–10 mg of diazepam**. For patients with a CIWA-Ar score of 16 or higher, the assessment interval should be 10–15 minutes, and benzodiazepines should be administered intravenously. At 10–15 points on the CIWA-Ar scale, patient evaluations are performed hourly. As the patient's condition stabilizes, the assessment interval is increased to 4–6 hours [12]. A disadvantage of symptom-triggered therapy is the impossibility of effectively using the CIWA-Ar rating scale in certain patients with severe AWS, including those requiring endotracheal intubation and mechanical ventilation. For these patients, the Richmond Agitation-Sedation Scale (RASS), which is suitable for intensive care settings, is used [5].

Another approach is the administration of fixed doses of benzodiazepine derivatives sufficient to alleviate AWS symptoms, with their gradual tapering over several days. This approach is applicable for outpatient treatment of AWS when continuous medical observation and assessment of the patient's condition using the CIWA-Ar scale are not feasible. Fixed doses are also used in inpatient settings in cases of a high risk of severe complications, such as delirium or seizures. In inpatient settings, 24-hour monitoring of the clinical condition is recommended to avoid excessive sedation or respiratory depression. A single dose of diazepam** is 5–10 mg intravenously or intramuscularly. The drug is administered in 4 divided doses over 2–3 days, followed by a 25% dose reduction from the fourth to the seventh days. Additional administration of diazepam** is recommended for severe AWS if the effect is insufficient. The maximum daily dose of diazepam** is 60 mg [11; 53; 54]

Chlordiazepoxide is administered orally. The average daily dose is 30–100 mg, divided into 4 doses. The maximum daily dose of chlordiazepoxide is 200 mg [5; 28].

Oxazepam** is administered orally at a dose of 10 to 30 mg, 3–4 times a day [5; 28].

Lorazepam** is administered orally at a dose of 2 to 10 mg, divided into 3 doses per day [5; 28].

Tofisopam is administered orally at a dose of 150 to 300 mg, divided into 3 doses per day [5; 28].

In elderly patients or patients with severe hepatic impairment, the use of short-acting benzodiazepine derivatives (lorazepam**, oxazepam**) is preferable to prevent respiratory depression [5].

Comments: Bromdihydrochlorphenylbenzodiazepine** is used as part of combination therapy for AWS and can be administered orally, intravenously, or intramuscularly. Intramuscularly or intravenously, 0.5 mg (0.5–1 ml of a 0.1% solution) is prescribed once daily. Orally, it is prescribed at 2–5 mg per day. The average daily dose is 1.5–5 mg, divided into 2–3 doses, usually 0.5–1 mg in the morning and afternoon and up to 2.5 mg at bedtime. The maximum daily dose of bromdihydrochlorphenylbenzodiazepine** is 10 mg [5; 8; 28].

Comments: Barbiturates and their derivatives are prescribed in cases where benzodiazepine derivatives are ineffective or insufficient for correcting sleep disorders, anxiety, fear, psychomotor agitation, and for preventing and treating seizure disorders, which is typically observed in severe AWS. Drugs in this group have a narrower therapeutic index. Because they have a greater potential to depress the central nervous system, they should be used with extreme caution [57].

Despite the fact that barbiturates and their derivatives have a narrower "therapeutic window" compared to benzodiazepine derivatives, these drugs are nevertheless widely used in the treatment of severe AWS and AWS complications. The inclusion of barbiturates and their derivatives in therapeutic regimens enhances the efficacy of benzodiazepine derivatives [56; 58]. For the treatment of AWS as part of combination products, #phenobarbital** is most commonly used at a dose of 100–200 mg [5, 59].

The dosing regimen is selected individually for each patient; as a rule, the plasma concentration of #phenobarbital** should be 15–40 mcg/ml (65–170 mcmol/l). The maximum daily dose is 500 mg.

Comments: Antiepileptic drugs (anticonvulsants) in certain clinical situations (individual intolerance or development of paradoxical (atypical) reactions to benzodiazepine derivatives, established epilepsy, or a history of seizures) can serve as an alternative to benzodiazepine derivatives. The use of antiepileptic drugs reduces the likelihood of seizure syndrome and pathological craving for alcohol during AWS, while they possess a low addictive potential. In addition, drugs of this group are effectively used to correct affective symptoms in AWS, including lowered mood, irritability, and anxiety. As a rule, antiepileptic drugs cause sedation less frequently compared to benzodiazepine derivatives. Clinical studies have shown that the use of these agents is quite effective for AWS. The most commonly used drugs in this group are carbamazepine** and #valproic acid**. The recommended dose of carbamazepine** is 600–1200 mg on the first day, gradually tapering to 200 mg by days 5–9 of AWS [5; 11; 54; 60]. Doses of #valproic acid** are selected individually, as the effective dose depends on body weight and the drug formulation. The recommended dose is 750–900 mg per day [5].

A number of studies have demonstrated the efficacy of #gabapentin in mild to moderate AWS. The drug is prescribed at an initial dose of 600 mg, titrated up to 1600 mg per day for the entire duration of AWS [60].

Antiepileptic drugs are generally used as adjunctive therapy for AWS when basic treatment (infusion therapy, benzodiazepine derivatives, barbiturates and their derivatives, vitamins) is insufficient [5; 8; 60].

Comments: In the treatment of AWS, vitamins that are involved in the formation of enzymes and coenzymes promoting redox processes in the body, influencing tissue respiration, carbohydrate metabolism, as well as the activity of the central and peripheral nervous systems, are traditionally used. Vitamins are administered parenterally during the first few days of AWS, usually as part of infusion therapy (it should be remembered that according to the instructions, parenteral forms of #thiamine** are administered exclusively intramuscularly), followed by oral administration [6].

Chronic alcohol use leads to B-vitamin deficiency, particularly #thiamine**. #Thiamine** hypovitaminosis leads to impaired nerve conduction in the central and peripheral nervous systems, followed by the development of Wernicke-Korsakoff syndrome and polyneuropathy. This vitamin must be administered at a dose of 100 to 500 mg/day for 3–4 days to prevent neurological complications, especially encephalopathy [5; 6; 11, 61]. Subsequent oral administration of thiamine** is continued until AWS is resolved. It should be emphasized that glucose causes thiamine** depletion, increasing the risk of encephalopathy [6; 11].

Comments: Drugs with antioxidant activity (antioxidants) are widely used in the treatment of AWS to mitigate the effects of chronic high-dose alcohol consumption, despite belonging to different anatomical, therapeutic, and chemical (ATC) classification groups. These medications are used to normalize acid-base balance and blood gas composition, eliminate tissue hypoxia, and increase the resistance of tissues and organs to the toxic effects of ethanol metabolites. They have a beneficial effect on autonomic and hemodynamic disorders in AWS and accelerate detoxification [8; 11; 28; 33; 34; 62-65]. The most frequently used drugs are listed below. Ethylmethylhydroxypyridine succinate** (ATC group "Other drugs for the treatment of nervous system diseases") is administered parenterally at 200 to 500 mg 2–3 times a day, and orally at 125 to 250 mg 3 times a day. In uncomplicated AWS, the drug can be used from the first day as an intravenous infusion at average therapeutic doses of 300 mg per day [62]. #Metadoxine (ATC group "Drugs used in alcohol dependence") is administered parenterally at 300–900 mg/day, and orally at 500–1000 mg/day [5; 8]. In uncomplicated AWS, it is used at doses of 900 mg twice a day diluted in 500 ml of 0.9% sodium chloride** [63; 64]. #Inosine+Meglumine+Methionine+Nicotinamide+Succinic acid** (ATC group "Drugs for the treatment of liver diseases") is administered parenterally for AWS of varying severity at 800 ml/day (400 ml twice a day, morning and afternoon) [65]. #Inosine+Nicotinamide+Riboflavin+Succinic acid** (ATC group "Other drugs for the treatment of nervous system diseases") is recommended from the moment patients are admitted to the clinic, administered as an intravenous infusion of 10.0 ml in 400 ml of 0.9% sodium chloride** twice a day for 5 days [66].

3.2. Psychotherapy

In acute conditions such as AWS, psychotherapeutic treatment is severely limited because patients are not fully able to utilize the offered psychotherapeutic interventions. The main objective of psychotherapeutic intervention during this period is to engage the patient and retain them in a treatment program that is not limited to the management of AWS. It is necessary to inform the patient about further treatment for alcohol use disorders (AUD).

During this period, it is relevant to conduct family clinical and psychological counseling for the patient's family members in order to inform them about the chronic nature of AUD, possible strategies and tactics for patient treatment, and to train family members in motivation skills to encourage the patient to continue treatment and rehabilitation after AWS resolution [68; 69].

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 diagnosed with AWS [5; 8].

Criterion for the efficacy of drug treatment: stabilization of the patient's psychophysical state [5; 8].

Comments: The safety and tolerability of therapy are assessed throughout its course by the incidence and development of adverse events (hereinafter referred to as AEs).

AEs are recorded according to:

– 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 AEs and drugs is assessed using the Naranjo algorithm (Appendix G) [71]. If an AE occurs, the physician must record their actions in the primary medical documentation, for example, prescribing additional drugs (which ones, at what dose, for what period), etc., and fill out the appropriate form[3]

[1] ** – this symbol indicates medicinal products included in the VLED (Vital and Essential Drugs) list.

[2] # – this symbol indicates medicinal products whose prescription and use are off-label.

[3] http: //www.rosminzdravnadzor.ru/medicines/monitor_bezopasnosti/

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Rehabilitation measures begin after the resolution of AWS symptoms and are carried out in accordance with the Clinical Guidelines for the treatment of AUD.

5. Prevention and Dispensary Observation

Dispensary observation is carried out in accordance with the Procedure for Dispensary Observation of Individuals with Mental Disorders and/or Behavioral Disorders Associated with Psychoactive Substance Use [5; 8; 72].

Once AWS is established, tertiary (modification) prevention becomes of paramount importance. It is primarily medical and individual in nature, targeted at individuals with established AUD, and aimed at preventing the further progression of the disease, reducing harmful consequences, and preventing relapse.

6. Organization of Medical Care

AWS therapy can be carried out in inpatient settings (including day hospitals) and outpatient settings. The course of treatment averages up to 10 days [5; 8; 28; 34; 36].

Comments: A provisional diagnosis of AWS 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 [72].

6.1. Indications for hospitalization:

• Moderate to severe AWS;

• AWS with seizures;

• Lack of clinical response to therapy administered in outpatient and day hospital settings⁶.

6.2. Indications for outpatient treatment:

• Mild AWS.

6.3. Indications for discharge:

Discharge of a patient diagnosed with AWS is carried out after the resolution of AWS symptoms. The resolution of AWS symptoms is objectified using the CIWA-Ar scale: the total score should range from 0 to 8.

7. Additional Information

No additional information available.

Criteria for Evaluating the Quality of Medical Care

Quality criteria for specialized medical care provided to adult patients with AWS (ICD-10 code: F10.3)

References

Appendix A1. Working Group Composition

Co-Chairs:

Klimenko, Tatyana Valentinovna, MD, Prof.

Krupitsky, Evgeny Mikhailovich, MD, Prof.

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. Association of Narcologists of Russia (Professional community of narcologists). National Narcological Society.

2. Nenastyeva Anna Yuryevna, Candidate of Medical Sciences. National Narcological Society. 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 working group members confirmed the absence of financial support/conflict of interest that needs to be disclosed.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience of these clinical guidelines:

1. Psychiatrist-narcologist

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: guidelines for physicians, 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 mechanism for updating clinical guidelines provides for their systematic revision at least once every three years, as well as upon the emergence of new evidence-based medicine data on the diagnosis, treatment, prevention, and rehabilitation of substance use disorders (SUD), and in the presence of justified additions/comments to previously approved clinical guidelines, 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 dated September 4, 2012 No. 124n «On approval of the standard of primary health care for withdrawal state caused by the use of psychoactive substances» (Registered with the Ministry of Justice of Russia on December 17, 2012 No. 26151).

3. Order of the Russian Ministry of Health dated September 4, 2012 No. 135n «On approval of the standard of specialized medical care for withdrawal state caused by the use of psychoactive substances» (Registered with the Ministry of Justice of Russia on December 19, 2012 No. 26193).

4. 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, standard form of clinical guidelines and requirements for their structure, composition and scientific validity of information included in clinical guidelines» (with amendments and addenda that entered into force on August 4, 2020).

Appendix B. Physician Action Algorithms

Appendix C. Patient Information

F10.3xx ALCOHOL WITHDRAWAL STATE.

Alcohol withdrawal syndrome is a potentially life-threatening condition. Alcohol withdrawal develops in stage II alcoholism. It occurs in individuals with alcoholism when they drink for several weeks, months, or years and then abruptly stop or significantly reduce their usual alcohol intake. The manifestations of alcohol withdrawal are associated with alcohol breakdown products formed in the body. This condition is life-threatening and sometimes results in severe somatoneurological disorders or death. Naturally, recovery from this severe condition and normalization of physical and mental status require time and specialized treatment.

The withdrawal state develops insidiously, gradually, and not immediately. It appears several hours after the cessation of alcohol intake. Initially, it manifests as headache, weakness, malaise, nausea, sometimes vomiting, tremors in the hands and body, and palpitations. Subsequently, other disorders join, including psychiatric ones: insomnia develops, anxiety arises, the patient cannot find a place for themselves, unmotivated outbursts of irritability and anger may occur, while sweating and tremor persist; in a word, "the soul feels troubled." Another important fact: whereas previously the hangover lasted only a few hours, in more advanced stages it lasts 2–7 days or even longer.

There is a danger that the alcohol withdrawal state may worsen at any moment. The most dangerous period in this regard is the 2nd–3rd day of its course. There is a high probability of developing delirium tremens (alcohol delirium), as well as other severe psychiatric disorders with hallucinations, delusions, and seizures. When alcohol withdrawal develops, the best option for the patient is to consult a physician, even if the manifestations are mild. Seeing a doctor is especially important if there are heart or liver diseases, or a predisposition to seizures.

Indications for hospitalization

Indications for hospitalization include moderate and severe conditions, as determined by the physician during the initial patient consultation; pronounced somatoneurological pathology, comorbid somatic pathology (liver, kidney, heart diseases, various nutritional disorders, etc.), a history of traumatic brain injury, and any other conditions assessed by the physician as clinically significant.

Treatment of alcohol withdrawal syndrome

If the manifestations of alcohol withdrawal are mild, treatment can be carried out on an outpatient basis, especially if close relatives are ready to help the person overcome this condition.

Inpatient treatment is required when a moderate to severe withdrawal state develops.

Treatment includes the following goals:

1) correction of water-electrolyte and acid-base balance disorders, and hypovitaminosis (infusion detoxification therapy);

2) monitoring of vital functions (symptomatic therapy aimed at normalizing the work of the heart, kidneys, gastrointestinal tract, lungs, and brain);

3) relief of psychiatric disorders (therapy for anxiety and sleep disorders);

4) prevention of complications;

5) preparation of the patient for further long-term therapy of alcohol dependence.

Prevention of alcohol withdrawal syndrome

Successful treatment of alcohol withdrawal does not solve the underlying problem—the presence of alcohol dependence. Overcoming alcohol dependence requires long-term comprehensive therapy. If a person realizes that they have alcohol dependence and wishes to address the problem, they should seek medical help at an appropriate facility or consult their attending physician.

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

Appendix G1. Clinical Institute Withdrawal Assessment-Alcohol, revised scale (CIWA-Ar)

Russian title: Clinical Institute Withdrawal Assessment for Alcohol scale

Original title: Clinical Institute Withdrawal Assessment-Alcohol, revised scale (CIWA-Ar)

Source (official developer website, validation publication): Sullivan J.T., Sykora K., Schneiderman J., Naranjo C.A., Sellers E.M. Assessment of Alcohol Withdrawal: the revised clinical institute withdrawal assessment for alcohol scale (CIWA-Ar) // British Journal of Addiction. 1989; 84: 1353-1357.

http://citeseerx.ist.psu.edu/viewdoc/download?doi=10.1.1.489.341&rep=rep1&type=pdf

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

Purpose: The CIWA-Ar scale is used to identify and interpret a patient's symptoms of alcohol withdrawal syndrome. When using the scale, the severity of various somatic and psychiatric symptoms of alcohol withdrawal is assessed, corresponding to a specific number of points, which are then summed. The maximum possible score is 67. It is considered that patients with a score greater than 8 require treatment using active pharmacotherapy methods, and their condition should be assessed every 2 hours. Patients with a score of less than 8 do not require active treatment.

Content (template):

Date__________________ Time_______________

Key (interpretation):

Notes: The CIWA-Ar scale can only be used if the patient is able to communicate.

Appendix G2. Richmond Agitation-Sedation Scale (RASS)

Russian name: Richmond Agitation-Sedation Scale.

Original name: The Richmond Agitation-Sedation Scale (RASS).

Source (official developer website, validation publication): Sessler C.N., Gosnell M.S., Grap M.J., Brophy G.M., O’Neal P.V., Keane K.A., Tesoro E.P., Elswick R.K. The Richmond Agitation-Sedation Scale: validity and reliability in adult intensive care unit patients. Am. J. Respir. Crit. Care Med. 2002; 166 (10):1338– 1344.

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

Purpose: The scale is used to describe the degree of a patient's psychomotor agitation or the depth of sedation. It is widely used in patients undergoing mechanical ventilation to prevent or correct insufficient sedative effects of drugs. The scale allows evaluation of the effectiveness of therapy. The scale is easy to use; it allows assessment of the patient's condition within 30–60 seconds using three consecutive steps: observation, response to auditory stimulation, and response to physical stimulation. The use of RASS may be difficult in patients with severe hearing and visual impairments.

Content (template):

Key (interpretation):

RASS Assessment Procedure

1. Patient observation

- If the patient is alert, calm, and attentive – 0 points.

- If the patient exhibits behaviors characterized by restlessness or anxiety – score from +1 to +4 points using the criteria listed in the description.

2. If the patient is somnolent, ask them in a loud voice, calling them by name, to open their eyes and look at you. Repeat this several times if necessary. Ask the patient to maintain eye contact.

- If eye contact is established with the patient and maintained for more than 10 seconds – score -1 point.

- If eye contact is established with the patient, but not maintained for 10 seconds – score -2 points.

- If the patient makes any movement in response to voice, excluding eye contact – score -3 points.

3. If patient does not respond to voice, physically stimulate patient by shaking shoulder and/or rubbing sternum.

- If the patient responds with any movement to physical stimulation – score -4 points.

- If the patient does not respond to voice or physical stimulation – score -5 points.

Appendix G3. Naranjo Algorithm

Russian title: Naranjo algorithm for assessing the causal relationship "adverse drug reactions (hereinafter – ADR) – drug"

Original title: Naranjo algorithm

Source (official developer website, validation 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):

Key (interpretation):

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