Mental and behavioral disorders due to psychoactive substance use. Psychoactive substance withdrawal state (withdrawal syndrome) (excluding alcohol and nicotine): Clinical Guidelines

List of Abbreviations

BP – blood pressure

ALT – alanine aminotransferase

AST – aspartate aminotransferase

ATC – Anatomical Therapeutic Chemical classification

ANS – autonomic nervous system

WHO – World Health Organization

GABA – gamma-aminobutyric acid

Gamma-GT – gamma-glutamyl transferase

Brain – brain

DA – dopamine

GI – gastrointestinal tract

VLEL – vital and essential drugs

CA – catecholamines

CT – clinical trials

ABDS – acid-base balance status

Med – medication

LSD – lysergic acid diethylamide

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

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

NA – noradrenaline

NSAIDs – non-steroidal anti-inflammatory drugs (M01A – anti-inflammatory and antirheumatic products, non-steroids)

ADR – adverse drug reaction

AE – adverse event

psychoactive substance – psychoactive substance

CUD – pathological craving for drugs

PNS – peripheral nervous system

DS – dependence syndrome

WD – withdrawal syndrome

SED/HYP – sedatives or hypnotics

LCE – level of confidence of evidence

GRS – grade of recommendation strength

cAMP – Cyclic adenosine monophosphate

CNS – central nervous system

HR – heart rate

BE – base excess (deficit)

COWS – Clinical Opiate Withdrawal Scale

HCO₃ – standard bicarbonate

MDMA – methylenedioxymethamphetamine (ecstasy)

MDA – methylenedioxyamphetamine

pCO₂ – partial pressure of carbon dioxide (H₂CO₃+CO₂) in blood under physiological conditions

pH (potential of hydrogen) – ratio of acidic to alkaline elements in a liquid, negative decadal logarithm of H⁺ concentration in a liquid medium

pO₂ – partial pressure of oxygen in whole blood

5-HT (5-hydroxytryptamine) – 5-hydroxytryptamine, serotonin receptor

Terms and Definitions

Mydriasis (Lat. – mydriasis) – pupil dilation greater than 4 mm.

Miosis (Lat. – miosis) – pupil constriction less than 2 mm.

Adverse drug reaction (Eng. – adverse reaction) – any noxious and unintended response to a medicinal product occurring at doses normally used in humans for the prophylaxis, diagnosis or therapy of disease or for the modification of physiological function, 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 previously been exposed, as a result of taking another substance. Both substances typically, but not necessarily, share a similar pharmacological action.

Psychoactive substance dependence syndrome (Eng. – dependence syndrome) – a cluster of physiological, behavioural, and cognitive phenomena in which the use of a psychoactive substance takes on a much higher priority for a given individual than other behaviours that once had greater value. A central descriptive characteristic of the dependence syndrome is the desire (often strong, sometimes overpowering) to take psychoactive drugs. It has characteristic symptoms, specific developmental and clinical patterns, and defined outcomes.

Pathological craving syndrome (psychological dependence) (Eng. – craving) – a nosologically specific psychopathological disorder characteristic of addiction disorders, clinically manifested by ideational (thought), behavioural, affective (emotional), vegetative, and sensory disturbances. Diagnostic criteria for psychoactive substance craving syndrome include: a strong desire or sense of compulsion to take the substance, loss of control over use (quantitative and situational), and persisting with substance use despite clear harmful consequences while being aware of the connection between use and its consequences.

Tolerance (Lat. – tolerantia, "endurance, capacity to bear") – a progressive decrease in the desired psychotropic effect of a psychoactive substance (euphoria, calming, relaxation, etc.), which drives the patient to increase the dose and frequency of administration of the substance.

Tremor (Lat. – tremor, "shivering") – rhythmic, involuntary, rapid contractions of trunk or limb muscles.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Withdrawal syndrome (Eng. – withdrawal) – a group of symptoms of variable clustering and severity occurring in patients with dependence syndrome (hereinafter – DS) upon complete cessation or reduction of the dose of a psychoactive substance (hereinafter – PAS) after repeated, usually prolonged and/or high-dose use. The onset and course of the withdrawal syndrome (hereinafter – WS) are time-limited and correspond to the type of PAS and the dose immediately preceding abstinence. An exception is hallucinogen dependence syndrome, for which WS is not characteristic [1].

Synonyms: withdrawal syndrome, abstinence syndrome, abstinence state induced by PAS use.

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

As a result of systematically repeated PAS intoxication, mechanisms restoring disrupted homeostasis are activated in the brain (hereinafter – Br): through functional reorganization of neurotransmitter systems, a new adaptation is established, which underlies DS [2-3]. It has been proven that this mechanism is unified across different PAS, primarily involving: 1) catecholaminergic (dopaminergic), 2) endogenous opioid, 3) GABAergic (GABA – gamma-aminobutyric acid), 4) glutamatergic, 5) NMDA, 6) endogenous cannabinoid systems [2; 4-7]. At the same time, there are certain specific features in the involvement of these systems in dependence on different classes of PAS. Upon cessation of PAS use, the balance is disrupted again, manifesting as toxicogenic WS symptoms that are opposite to the pharmacological effects of PAS [2; 4; 7].

Prolonged PAS use causes depletion of components within these neurotransmitter systems with a compensatory increase in their synthesis activity and inhibition of degradation enzymes (monoamine oxidase and dopamine beta-hydroxylase). Abrupt cessation of PAS intake leads to a suspension of catecholamine (hereinafter – CA) release from stores, but their biosynthesis remains enhanced, contributing to the accumulation of neurotransmitters, especially within brain tissue. General symptoms across WS of different PAS reflect the primary pathogenetic link, while differences in WS that confer specificity are determined by the varying spectrum of action of individual PAS. Noradrenergic (hereinafter – NA) and serotonergic neurotransmitter systems are more heavily involved in maintaining vegetative-somatic symptoms, whereas dopaminergic systems are involved in maintaining psychopathological symptoms of WS across different PAS [2; 4; 7].

The pathogenesis of opioid withdrawal is based on a sudden weakening of opioidergic transmission, which immediately triggers adaptive reorganizations of associated catecholaminergic, glutamatergic, GABAergic, and cholinergic neurotransmitter systems, alongside enhanced activation of brain regions that were suppressed during the action of opioid agonists. A key role in the pathogenesis of opioid withdrawal is played by disruptions in the interaction between the opioid and noradrenergic systems within the locus coeruleus. During the development of WS, activation of cAMP and protein kinase A occurs, the inhibitory effect on the locus coeruleus ceases, leading to increased activity and elevated release of NA from the locus coeruleus, which clinically manifests as WS symptoms – lacrimation, tachycardia, mydriasis, anxiety, muscle pain, diarrhea, and agitation [3].

In cannabinoid withdrawal, the primary role belongs to cannabinoid receptors, which are distributed unevenly across different brain regions. Most of them are located in the basal ganglia, hippocampus, and cerebral cortex [2; 4; 7].

The pathogenesis of withdrawal from sedatives or hypnotics (hereinafter – S/H) is similar to that of alcohol withdrawal and is likewise associated with effects on systems 1–4 (see information above) [2; 4; 7].

The pathogenesis of hallucinogen withdrawal is related to impaired serotonergic transmission. Hallucinogens share a structural similarity with serotonin. The intensity of hallucinogenic action correlates with the degree of affinity for the postsynaptic 5-HT2 receptor. Hallucinogens are capable of suppressing the spontaneous activity of serotonergic neurons themselves. Consequently, the neurotransmitter level in the central nervous system (hereinafter – CNS) not only fails to decrease but, on the contrary, increases significantly. As a result, a shift occurs in the balance between inhibitory and excitatory processes within the serotonergic system itself [2; 4; 7].

The mechanism of action of inhalants and the pathogenetic links of inhalant dependence syndrome are not yet fully understood. There are indications that the action of certain inhalants resembles the effects of ethanol. These are based on the stimulation of GABA [8] and glycine A1 receptors, as well as the inhibition of N-methyl-D-aspartate receptors, leading to CNS depression [9].

From a clinical perspective, each receptor can be viewed as the target of a single neurotransmitter. Therefore, the differential diagnosis of WS is built upon understanding the role of each neurotransmitter [2].

1.3 Epidemiology of the Disease or Condition

Withdrawal syndrome is the most frequent reason for seeking specialized medical care, and therefore its prevalence is estimated based on the overall prevalence of PAS dependence syndrome. Worldwide, approximately 36.3 million people (~ 0.7% of the global population aged 15–64) suffer from drug use disorders and require treatment [10]. In Russia, 229,743 patients with drug dependence syndrome were registered in 2022, or 157.8 per 100,000 population, which is a 1.2% increase compared to the previous year. Inpatient care was sought by 62,328 patients in 2022, or 42.8 per 100,000 population, representing an 8.4% increase compared to the previous year [11].

1.4 Features of Coding the Disease or Condition

Withdrawal syndrome is part of dependence syndrome and is coded independently when it is the direct reason for consulting a medical specialist due to marked severity of disorders [1].

F1x.3x – Withdrawal state

The type of psychoactive substance (PAS) used is specified by the third character. In cases where patients use more than one type of PAS, the disorder diagnosis should be established with respect to the specific PAS or class of substances that led to the existing disorder. In case of doubt, the disorder is coded according to the substance or its type whose abuse occurred most frequently, particularly in cases of continuous or daily use. Only in cases where the PAS intake pattern is chaotic and undefined, or if the consequences of using various PAS are inextricably mixed, should code F19 be used (Table 1).

Table 1. ICD-10 diagnosis formalization

The presence or absence of withdrawal complications is specified by the fifth character:

F1x.30: uncomplicated

F1x.31: with seizures

F1х.39: NOS (not otherwise specified)

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

1.5 Classification of the disease or condition

Depending on the severity of clinical manifestations, four severity grades of withdrawal are distinguished: mild, moderate, moderately severe, and severe. In most cases, such assessment is subjective. The exception is opioid withdrawal, the severity of which is objectively assessed using the Clinical Opiate Withdrawal Scale (hereinafter referred to as COWS) [12].

1.6 Clinical presentation of the disease or condition

The clinical picture of PAS withdrawal includes [2; 7]:

1) toxicogenic symptoms represented by nonspecific post-intoxication disorders such as headache, malaise, weakness, feeling of discomfort, etc. These symptoms are typically diametrically opposed to the direct pharmacological effect of the consumed PAS (for example, opioids have an analgesic effect; pain will develop during withdrawal);

2) nosologically specific addictive symptoms represented by pathological craving for the PAS—a strong desire to use the substance—as well as psychopathological disorders in the form of internal tension, irritability, dysphoria, depressed mood, etc.;

3) signs of exacerbation of various latent pathologies—cerebral organic insufficiency, liver dysfunction, etc., associated both with concomitant diseases and accumulated somatic consequences resulting from systematic PAS intoxication [2; 7].

2. Diagnostics, medical indications and contraindications for diagnostic methods

Clinical diagnostics, consisting of collecting complaints, anamnesis, and analyzing the data obtained, is of primary importance in diagnosing withdrawal. Other types of diagnostics play a secondary role [2; 7; 13; 14].

Criteria for diagnosing the disease/condition. A withdrawal diagnosis can be established in the presence of [1]:

1. objective data on recent cessation of use or reduction of PAS doses after prolonged use and/or in high doses;

2. symptoms and signs corresponding to the known characteristics of the withdrawal state for the specific substance or substances;

3. the existing symptoms are not due to a medical disorder unrelated to PAS use and cannot be better explained by another mental or behavioral disorder.

2.1 Complaints and Anamnesis

Opioid withdrawal (F11.3)

— strong desire to take opioids;

— rhinorrhea or sneezing;

— lacrimation;

— muscle aches or cramps;

— abdominal cramps, nausea, or vomiting;

— diarrhea;

— pupil dilation (mydriasis);

— goosebumps (piloerection), periodic chills;

— tachycardia or arterial hypertension;

— yawning;

— restless sleep;

— dysphoria.

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

Comments: In opioid use disorder, withdrawal develops rapidly: the first signs of withdrawal appear within just 2–4 weeks of systematic use [7].

Opioid withdrawal develops 6–24 hours after the last drug use. The time of withdrawal onset depends on the type of opioid (when using street methadone, the onset of withdrawal is delayed by 2–5 days) or on impurities included in the drug (benzodiazepine derivatives, antihistamines delay the onset of the first signs of withdrawal and prolong its duration). Pain syndrome has a relatively specific character in opioid withdrawal [2].

Patients with opioid withdrawal generally do not hide their conscious, often irresistible craving for the drug. They are frequently unmanageable and unpredictable, and the risk of aggressive actions, including auto-aggression, increases [2; 7].

Withdrawal is severe in patients with a long-term, continuous pattern of methadone use, less often heroin (more than 3–4 years), long disease duration (more than 10 years), and concomitant somatic and neurological diseases. In these cases, patients additionally exhibit: akathisia, hyperthermia, lability of blood pressure (hereinafter referred to as BP) and heart rate (hereinafter referred to as HR), anxiety, a sense of fear, and insomnia [2; 7].

The development of delirious states and seizure syndrome is not typical for opioid withdrawal. If these complications do develop, it is extremely rare—upon the use of opioid receptor blockers (antagonists) (naltrexone**), certain comorbid pathology, or combined use of other PAS [2; 7].

In the case of too early use of opioid receptor antagonists (naltrexone**, naloxone**, and nalmefene) or partial agonists (buprenorphine**) when full opioid receptor agonists are still circulating in the human body, precipitated opioid withdrawal develops. Precipitated opioid withdrawal is characterized by an abrupt onset, short duration, and more pronounced symptoms [3].

Cannabinoid withdrawal (F12.3)

— desire to take cannabinoids;

— asthenia, apathy, hypobulia;

— depressed mood;

— anxiety, irritability;

— tremor and muscle aches.

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

Comments: The development of withdrawal with systematic regular cannabinoid use takes at least 2–3 years. Withdrawal develops 4–5 hours after the last drug use, peaking on days 3–5. The duration of withdrawal averages 14 days [2; 7; 15].

At the initial stage, withdrawal is represented predominantly by an asthenic symptom complex with phenomena of affective lability and increased fatigability. Drowsiness and sluggishness during the day are noted, with sleep-onset insomnia in the evening. Autonomic reactions are diverse: constricting, sometimes pulsating headaches, stabbing pain in the heart and stomach areas, palpitations, hypertension, increased and labile pulse, persistent red dermographism, and hyperhidrosis. Neurologically, tremor, hyperactive tendon reflexes, and twitching of individual muscle fascicles are detected. A decrease in appetite is noted. The main symptoms are irritability, persistent headaches, and decreased performance. When using cannabis products with a low tetrahydrocannabinol content, the clinical picture of withdrawal is limited to mild asthenic disorders.

As the disease worsens and progresses, the clinical picture of withdrawal also becomes more complex. Asthenic symptoms are replaced by asthenodepressive ones; severe mood disorders, indifference, apathy, depression, and oppressive melancholy with a painful feeling of chest tightness and vague abdominal sensations may be observed. Intractable insomnia develops. Thoughts about the futility of one's future, disbelief in the possibility of stopping drug use and treatment success are accompanied by feelings of worthlessness and suicidal statements. Suicide attempts are more often demonstrative, but can also be genuine. The appearance of anxiety in the clinical picture of withdrawal indicates the possibility of developing abstinence psychosis. Subsequently, senestopathies and paresthesias may join. Complaints of unpleasant, distressing sensations of numbness and coldness in the extremities, a feeling of chest tightness, and abdominal cramps prevail. Tingling, burning, and crawling sensations appear on the skin in various parts of the body. All this is accompanied by itching predominantly localized in the extremities and the scalp. At the stage of fully developed withdrawal, dysphoric symptoms become characteristic for patients: irritation, anger, aggression [2; 7; 15; 16].

Sedative or hypnotic withdrawal (F13.3)

- desire to use sedatives/hypnotics;

- tremor of outstretched fingers, tongue, or eyelids;

- nausea or vomiting;

- tachycardia, postural hypotension, headache (symptoms of autonomic nervous system (hereinafter – ANS) hyperactivity);

- psychomotor agitation;

- insomnia;

- feeling of malaise or weakness;

- episodic visual, tactile, auditory hallucinations or illusions;

- paranoid mindset;

- major convulsive seizures;

- dysphoria.

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

Comments: WS develops after 4–6 months of regular sedative/hypnotic use. When exceeding therapeutic doses, WS may manifest earlier. Discontinuation of high doses of psychoactive substances (PAS) is typically accompanied by the development of epileptic seizures and psychosis, making sedative/hypnotic WS life-threatening. If sedatives/hypnotics were taken in therapeutic doses, but for a prolonged period, convulsions and psychosis usually do not develop.

The onset and duration of WS depend on the half-life of the consumed PAS. Substances belonging to the barbituric acid derivative group are more addictive [2; 7; 14].

Barbiturate WS has a phased course with a regular buildup of symptoms, reaching a peak on days 3–4, and the possible development of complications on days 3–8 of PAS discontinuation in the form of major convulsive seizures or psychoses. Abstinent barbiturate psychoses are most commonly represented by delirium, which is clinically similar to alcohol withdrawal delirium. Unlike the latter, there is a greater severity of anxiety, tension, irritability, and a higher proportion of auditory hallucinations. Vivid fantastic visual hallucinations are rare. The duration of barbiturate psychosis ranges from 2–3 days to 2 weeks. Hallucinatory-paranoid psychoses are rare. The duration of WS due to barbiturate use can average 4 weeks. If psychotic symptoms do not develop, a turning point in the course of WS can be observed by days 10–14, when the patient's appetite returns [2; 7; 14].

There is a structural and dynamic similarity between barbiturate WS and benzodiazepine WS. The differences lie in the severity of symptoms and their duration. The risk of developing benzodiazepine WS increases sharply with prolonged (>6 months) use or intake of excessively high doses. In some cases, convulsive seizures or acute psychosis may develop. The duration of WS is 2–3 weeks. Manifestations such as pronounced craving for PAS, emotional lability, fatigue, disrupted sleep rhythm, and insomnia may last up to 1–2 months [7; 14]. In recent years, the list of substances capable of causing habituation, dependence, and WS has expanded [17–18].

Cocaine and other stimulant WS, including caffeine** (F14.3 and F15.3)

— disturbed mood: depression and/or anhedonia (obligate sign);

— strong desire to use cocaine, other stimulants, including caffeine**;

— apathy and asthenia;

— psychomotor retardation or agitation;

— deep sleep, close to lethargic;

— increased appetite;

— insomnia or hypersomnia;

— bizarre or unpleasant dreams.

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

Comments: Cocaine WS occurs 24 hours after last drug use. Uncomplicated WS reaches maximum severity on days 3–4. Acute manifestations resolve within 10–14 days; in severe cases, symptoms persist for up to 1 month.

The clinical presentation of WS is predominantly depressive-dysphoric disorders, against which ideas of reference and persecution, suicidal thoughts, as well as delirium or acute paranoid state may occur, lasting from 3 to 15 days [2; 7; 14]. Patients clearly experience the inadequacy of their own existence, hopelessness, a sense of inner emptiness, and joylessness. At the same time, the craving for the drug has a clear psychopathological structure in the form of persistent anhedonic depression. The craving often becomes irresistible, leading to relapse. A feature of cocaine WS is the alternation of periods of remission and exacerbation of symptoms. During remission, sleep improves, and the craving for cocaine weakens. This state is replaced by a new attack of dysphoria, anxiety, irritability, and an intense need for cocaine [2; 7; 14].

Amphetamine WS occurs 12–24 hours after their last use, reaching maximum severity on days 2–4. A characteristic sign of stimulant WS is severe depressive disorders. At the peak of WS, delirium-like or acute paranoid psychosis with speech and motor agitation may develop. Chronic amphetamine psychoses occur, lasting from 2–3 weeks to several months.

Neurologically, stimulant WS manifests as impaired coordination of movements, fascicular twitches of individual muscle groups of the face and tongue, miosis, sluggish pupillary reaction to light, and nystagmus. Muscle tone is decreased. Tendon reflexes are increased.

The duration of stimulant WS is 7–14 days, in severe cases up to 1 month. Ephedrine derivative WS (ephedrone, pervitin) has the most severe course [2; 7; 14].

Caffeine** WS is a rare phenomenon in addiction medicine. Systematic use of caffeine** in high doses (exceeding 250 mg/day) contributes to the development of caffeine addiction. High doses of caffeine** are considered to be 5–10 g/day [19–21].

The development of WS directly depends on the half-life of caffeine** in the body, which is 4–6 hours. After this period, headaches, insomnia, and nightmares appear. Some patients experience convulsive twitching of the calf muscles, tremor of the tongue and fingers, and cardiac rhythm disturbances accompanied by anxiety and fear. A distinct feature of caffeine** WS is a pulsating headache that intensifies with physical, verbal, or even facial expression activity [20; 21].

Hallucinogen WS (F16.3)

WS is not characteristic of hallucinogen use disorders. Manifestations are vague, poorly differentiated, non-specific, and diagnostic criteria for the condition have not been established [1]. Hallucinogen WS is also not addressed in the International Classification of Diseases for Mortality and Morbidity Statistics (ICD-11) and the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) [19].

In chronic intoxication with dissociative anesthetics (phencyclidine, ketamine**, and some others), serotonergic hallucinogens (LSD, psilocybin, salvinorin, and some others), and methylamphetamines (MDA, MDMA, and some others), moderate autonomic dysfunction, somatic discomfort in the form of dull, mild aches without clear localization, and depressive-asthenic symptoms occur on days 1–2 of withdrawal. The duration of these disorders is also relatively short—up to 10–14 days [2; 7; 14].

With the use of anticholinergic hallucinogens (scopolamine, atropine**, cyclodol, tropicamide**, cyclopentolate), WS develops after 1.5–2 years of their systematic use in high doses. It develops, on average, one day after cessation of intake. It manifests as psychopathological, neurological, and somatovegetative disorders. Psychopathological disorders at the initial stage are represented by astheno-depressive symptoms, which progress during the course of WS. At the peak, pronounced dysphoria, irritability, and malice join [14].

Neurological and autonomic disorders manifest as generalized body tremor, increased skeletal muscle tone, and progressive stiffness of movement. Painful sensations in the back muscles, convulsive twitches of individual muscle groups, involuntary limb movements, and a mask-like face are characteristic. The disorders persist for 1 to 2 weeks, and the regression of symptoms also occurs via the astheno-depressive symptom complex. Tremor, muscle hypertonia, and increased tendon reflexes may persist for 1.5–2 months. Complications (epileptiform seizures, delirium) may develop, especially in the presence of congenital or acquired organic brain damage [14].

Volatile solvent WS (F18.3)

— dysphoria, irritability, anger;

— difficulty concentrating;

— increased appetite;

— anxiety;

— akathisia;

— depressed mood;

— insomnia.

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

Comments: Withdrawal syndrome develops after 6–12 months of systematic use of volatile solvents (inhalants). Considering the age factor (inhalant use is typical for children and adolescents), its manifestations are often mistaken for neurocirculatory dystonia. Although the withdrawal syndrome is mild and masked by age-related ANS dysfunction, its abstinence-related nature is confirmed by an intense craving for inhalants and the immediate restoration of psychophysical well-being upon their intake.

Behavioral and affective disorders occupy a leading place in the structure of withdrawal syndrome, presented by dysphoria, irritability, depressive, and hypochondriacal manifestations. Autonomic disorders are polymorphic and mild.

The dynamics of withdrawal syndrome development are as follows. A day after the last psychoactive substance intake, depression, irritability, and sleep disturbances appear. Appetite decreases, thirst develops, patients experience an aversion to inhalants, and a dull, diffuse headache troubles them. On days 2–3, these disorders are joined by unpleasant sensations in various parts of the body, especially in the chest, sore throat, difficulty inhaling, and a feeling of air hunger. Complaints of nausea, pain in the epigastrium and the right iliac region, and sometimes vomiting appear. Loose stools may occur 3–6 times a day. Hyperhidrosis, blood pressure fluctuations, tachycardia, and cardiac arrhythmia take place. Neurological disorders include coarse-amplitude tremor of the fingers and eyelids. At night, muscle pain and convulsive twitches in the lower extremities occur. Irritability intensifies, malice appears, and dysphoric outbursts become frequent. On days 5–7, the tension is replaced by asthenodepressive symptoms. Somatic disorders resolve by the end of the 1st week, and mental disorders by the beginning of the 3rd week of abstinence. In severe cases, withdrawal syndrome can be complicated by the development of delirium, lasting from several hours to 3 days and proceeding with illusions, true visual, and auditory hallucinations. On average, the duration of volatile solvent withdrawal syndrome is about 2 weeks [2; 7; 14].

2.2 Physical Examination

Physical examination data are non-specific for psychoactive substance withdrawal syndrome; they provide guidelines for determining the severity of the patient's condition [2; 7].

Comments: Somatic and neurological examinations are performed before starting therapy and during the course of treatment. Monitoring the patient's condition dynamically is important for the timely diagnosis of potential somatic and neurological pathology [2; 7; 22–24].

2.3 Laboratory Diagnostics

1. general general-therapeutic biochemical blood test (investigation of total blood protein level, determination of gamma-glutamyl transferase activity in the blood (hereinafter – gamma-GT), determination of alanine aminotransferase activity in the blood (hereinafter – ALT), determination of aspartate aminotransferase activity in the blood (hereinafter – AST), investigation of total blood bilirubin level, investigation of free (unconjugated) blood bilirubin level, investigation of blood albumin level, investigation of blood glucose level, investigation of blood cholesterol level, investigation of high-density lipoprotein blood cholesterol level, investigation of low-density lipoprotein cholesterol level, investigation of high-density lipoprotein cholesterol level, investigation of blood urea level, investigation of blood creatinine level);

2. complete blood count (investigation of red blood cell count, platelet count, white blood cell count, total hemoglobin level, differential white blood cell count (leukocyte formula), erythrocyte sedimentation rate);

3. urinalysis (visual urine examination, determination of urine specific gravity (relative density), determination of urine protein, investigation of urine glucose level, investigation of urine bilirubin level, determination of urobilinogen in urine, detection of ketone bodies in urine).

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

Comments: Carrying out laboratory diagnostics in addition to the classical clinical examination makes it possible to objectively assess the patient's current condition, exclude acute conditions requiring specialized medical care, and hidden organ pathology [2; 7; 22–24].

Comments: Prolonged use of psychoactive substances, most notably methadone, psychoactive substances, anticholinergic drugs, leads to the development of acid-base balance disorders and water-electrolyte disturbances. Severe water-electrolyte and blood acid-base balance disorders can lead to arrhythmias, tissue hypoxia, and other life-threatening conditions. Additional tests (specified above in the recommendation statement) are carried out to diagnose existing disorders [26].

2.4 Instrumental Diagnostics

The possibilities of using instrumental diagnostics are limited, as there are no specific signs characteristic only of psychoactive substance withdrawal syndrome.

To diagnose pathology concomitant with psychoactive substance withdrawal syndrome, the involvement of other specialists is necessary. In a specific clinical situation and in accordance with indications, instrumental diagnostic methods are prescribed: ultrasound examination of internal organs, electroencephalography, echoencephalography, radiography of the entire skull in one or more projections, targeted chest radiography, etc. [2; 7].

2.5 Other Procedures

Comments: Assessing the severity of psychoactive substance withdrawal syndrome makes it possible to make balanced and rational decisions regarding the conditions of medical care provision and therapeutic measures [2; 7; 22–24].

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

3.1. Drug therapy

Comments: In severe withdrawal syndrome, the type of psychoactive substance used is of secondary importance; infusion therapy is aimed to a greater extent at maintaining and stabilizing homeostasis, improving blood rheology and microcirculation, the disturbances of which are associated with escalating endotoxicosis [27–29].

Since infusion therapy itself can significantly affect the electrolyte balance and acid-base status (ABS) of the blood, balanced polyionic buffered solutions should 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**; dextrose + potassium chloride + magnesium chloride + sodium acetate + sodium gluconate + sodium chloride; potassium chloride + sodium acetate + sodium chloride**, #meglumine sodium succinate** can be administered IV for various water-electrolyte and ABS disorders under the control of diuresis, electrolyte levels, and blood ABS values. Average volumes of infusion solutions range from 400 to 3000 ml per day at a rate of no more than 500 ml per hour [2; 7].

Management of opioid withdrawal syndrome (F11.3)

Comments: #Clonidine** is a postsynaptic alpha-2 adrenergic receptor agonist of the inhibitory structures of the central nervous system (CNS). The drug has been used for the treatment of opioid withdrawal since 1978 [29]. #Clonidine** is an agent that reduces sympathetic hyperstimulation during opioid withdrawal. The drug acts on the CNS and the peripheral autonomic nervous system (ANS), reducing the endogenous release of adrenaline and noradrenaline, which are present in excess during opioid withdrawal. The central adrenergic system is closely linked to dopamine and the endogenous opioid system; therefore, #clonidine** exerts a normalizing effect on catecholaminergic neurotransmission. Essentially, the use of this drug is pathogenetic therapy [2; 7; 23-25; 29; 32-35].

The treatment method using #clonidine** is considered a variant of rapid detoxification [33]. It is performed in a hospital setting. Selecting the starting dose of #clonidine** is a crucial step determining the effectiveness of the chosen treatment regimen. In this case, the following rule should be followed: an individualized effective dose is selected that is capable of stopping opioid withdrawal with a minimum of adverse events (hereinafter referred to as AEs). Attention should be paid to the development of such AEs as decreased blood pressure (BP), dizziness, and myasthenia gravis. If blood pressure drops below 90/60 mmHg, the dose of #clonidine** is reduced [28; 29].

The minimum dose of #clonidine** is 0.15 mg. Daily dosages of the drug, divided into 3-4 doses, should not exceed 0.9-1.35 mg orally. The maximum doses of the drug are usually applied during the period of greatest severity of opioid withdrawal manifestations (days 2 to 4), after which the doses are gradually reduced and discontinued by days 7 to 10 [34].

#Clonidine** exhibits pronounced efficacy regarding somatovegetative disorders, while its effect on psychopathological and algic disorders of opioid withdrawal is less pronounced. The drug has no effect on neurological symptoms. Potential AEs of the drug include dry mouth and marked sedation [7; 28; 29; 32].

Comments: According to a number of clinical trials (hereinafter referred to as CTs), the protocol for managing opioid withdrawal based on #pregabalin** demonstrated better treatment tolerability due to a less pronounced central depressant effect and asthenia compared to the clonidine protocol [35]. #Pregabalin** for opioid withdrawal is prescribed in doses ranging from 150 to 600 mg per day [36-37].

Given that the data from conducted CTs are encouraging, the risks of developing dependence on the drug itself should nonetheless be taken into account [38-40].

Comments: Tramadol** is an agonist of mu-, delta-, and kappa-opioid receptors in the CNS and also selectively inhibits the neuronal reuptake of serotonin and noradrenaline [41-44]. In the first days of withdrawal with severe pain syndrome, the drug is administered intramuscularly, followed by oral administration. The daily dose of tramadol** should not exceed 600 mg. The dose of the drug is gradually reduced as the intensity of the pain syndrome decreases [2; 7; 41].

The use of tramadol** in the treatment of opioid withdrawal is associated with certain difficulties. Tolerance to the drug develops quite rapidly in patients, and adverse events may occur. In the latter case, it is necessary to reduce the daily dose of tramadol** while simultaneously prescribing a non-steroidal anti-inflammatory drug (hereinafter referred to as NSAID) in the absence of medical contraindications to the latter. Additionally, tramadol** enhances and potentiates the effects of medicinal products (hereinafter referred to as MPs) of other groups (antipsychotics, benzodiazepine derivatives, barbiturates and their derivatives, and other CNS depressants); therefore, when prescribing combination therapy, special attention must be paid to selecting adequate drug doses to avoid complications [2; 7; 41-45].

Comments: The World Health Organization (hereinafter referred to as WHO) has developed a method for pain relief using readily available means, presented as a simple and clear scheme known as the "WHO analgesic ladder" [46]. In narcological practice, NSAID doses are generally used at medium to high therapeutic levels [2; 24; 47; 48]. When NSAIDs are used for a short period, the likelihood of developing AEs is low; however, the use of high doses of these drugs in patients with a history of gastrointestinal disorders, peptic ulcer disease, renal failure, as well as in elderly patients, is undesirable [49].

The following drugs are used to relieve pain associated with opioid withdrawal: ketorolac** at a dose of up to 90 mg per day [46]; #lornoxicam at a dose of up to 16 mg per day (up to 24 mg on the first day) [48]; ibuprofen** at a dose of up to 1200 mg per day [2; 7].

Comments: One of the indications for the use of xenon is the treatment of pain syndrome. Xenon is an active NMDA receptor antagonist, exhibits pronounced analgesic, anxiolytic, and mood-stabilizing effects, and has demonstrated high efficacy even as monotherapy for opioid withdrawal (heroin and methadone) [51]. Xenon is administered by inhalation in a mixture with oxygen at 15-25% of the gas mixture volume; its application requires special equipment, which limits the widespread use of this MP in narcological practice. Being a xenobiotic, xenon does not participate in biochemical reactions and is excreted from the body unchanged, which explains the absence of medical contraindications to its use in therapeutic (subnarcotic) doses and AEs following its administration [51]. Its use is also limited by its high cost; nevertheless, in certain cases (intolerance to other MPs, presence of severe comorbid conditions), its use is fully justified [50].

Comments: The prescription of antipsychotics is in some cases part of adjuvant therapy (some antipsychotics have analgesic properties, which contributes to the qualitative reduction of pain disorders within the structure of opioid withdrawal syndrome and fully complies with WHO guidelines for the management of pain disorders), and in other cases refers to symptomatic therapy (manifestations such as anxious agitation, psychopathy-like behavior, psychomotor agitation, suicidal ideation, and aggression are merely symptoms of drug craving, yet require the prescription of medications with an appropriate spectrum of activity).

In cases of severe pain disorders unresponsive to the aforementioned drug groups, severe insomnia, psychomotor agitation, or behavioral disorders accompanying drug craving, antipsychotics are prescribed [53]. Drugs with a predominant sedative effect are preferred, since sufficient sedation during withdrawal is a necessary condition rather than an adverse event [2].

The use of antipsychotics during opioid withdrawal is pathogenetically oriented treatment based on the mechanism of action of this group of drugs on dopamine (DA) receptors (blockade of D2 and D4 DA receptors ensures a decrease in DA levels in the body, which are elevated during withdrawal, thereby reducing psychopathological symptoms). Attention should be paid to dose selection, which is always individualized [2; 22-24; 54].

Currently, atypical antipsychotics are preferred in addiction treatment practice as drugs with a better safety profile. The atypical antipsychotic tiapride exhibits sedative, anticonvulsant, antipsychotic, and analgesic effects [54]. The medication helps reduce and often relieve irritability, hot temper, depressed mood, and anxiety, and improves sleep, which indicates a reduction in the severity of pathological drug craving (hereinafter referred to as PDC) [2; 7]. The main indications for prescribing tiapride are psychomotor agitation, behavioral disorders with agitation, and aggressiveness. In isolated cases, the drug causes mild neuroleptic syndrome, which is relieved either by reducing the dosage or by adding corrective agents to the treatment regimen. The average daily doses of tiapride in opioid withdrawal are 400-600 mg [22-24; 54].

There is evidence regarding the efficacy of #quetiapine** in opioid withdrawal. The drug promotes the reduction of pathological craving for opioids, relieves anxiety, and diminishes pain manifestations. The drug is prescribed at 25-50 mg every 4 hours when complaints of psychoactive substance craving or any other withdrawal symptoms occur. The maximum daily dose of #quetiapine** was 200 mg [55].

In severe behavioral disorders, states of agitation, increased anxiety, hostility, and aggressiveness, zuclopenthixol** has demonstrated efficacy in daily doses ranging from 25 to 150 mg [54].

In the presence of depressive states, anxiety, tension, restlessness, insomnia, sleep disturbances, and pain within the structure of withdrawal, chlorprothixene is used in daily doses of up to 500 mg divided into 2-3 doses [2; 22-24].

As symptomatic therapy for relevant indications during withdrawal, other antipsychotics may also be used, such as periciazine**, chlorpromazine** (indications: anxiety state, psychomotor agitation, aggressive or dangerous impulsive behavior), levomepromazine** (indications: agitation, anxiety state, psychomotor agitation, pain syndrome, persistent insomnia), haloperidol** (indications: psychomotor agitation, aggression), #risperidone** (indications: aggressive behavior) [2; 22-24]. #Risperidone** is prescribed at doses of 2-4 mg per day.

It should be emphasized that all the above psychopathological disorders are manifestations of the syndrome of pathological craving for psychoactive substances, and the prescription of antipsychotics in this case is symptomatic [2; 7].

The list of medications used is extensive, but to date there remains a deficit of comparative clinical trials that would allow definitive conclusions regarding the efficacy and safety of using antipsychotic drugs in the treatment of not only opioid withdrawal, but also withdrawal from other psychoactive substances.

Comments: The following drugs are most frequently used in the treatment of opioid withdrawal: diazepam**, bromdihydrochlorophenylbenzodiazepine** in doses determined by the drug instructions. A single dose of diazepam** is 5-10 mg intravenously or intramuscularly. The maximum daily dose of diazepam** is 60 mg.

Bromdihydrochlorophenylbenzodiazepine** can be administered orally, intravenously, or intramuscularly. Intramuscularly or intravenously, it is prescribed at 0.5-1 mg 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 night. The maximum daily dose of bromdihydrochlorophenylbenzodiazepine** is 10 mg [2; 7; 22; 56].

Management of Cannabinoid Withdrawal (F12.3)

There are no specific medications for the treatment of cannabinoid withdrawal; therapy is symptomatic [57].

Comments: It was established that #gabapentin at a daily dose of 1200 mg significantly reduces the manifestations of cannabinoid withdrawal [58]. Nevertheless, this single observation requires additional confirmation in clinical practice.

Comments: A conducted comparative clinical trial showed that compared to placebo, #quetiapine** at a dose of 200 mg per day improved sleep quality, increased caloric intake, and reduced weight loss [59]. Nevertheless, this observation requires additional confirmation in clinical practice.

Management of Sedative/Hypnotic Withdrawal (F13.3)

Comments: A specific feature of benzodiazepine withdrawal therapy is the substitution of the drug to which the patient has developed dependence with an approved medication of similar action, followed by its gradual, step-by-step withdrawal [60; 63; 65].

Comments: A specific feature of barbiturate withdrawal therapy is the substitution of the drug to which the patient has developed dependence with an approved medication of similar action, followed by its gradual, step-by-step withdrawal [60; 65].

Comments: Few clinical trials have demonstrated the efficacy of high doses of benzodiazepine derivatives [66-67]. If ineffective, combining them with barbiturates and their derivatives or antipsychotics is recommended [67].

Management of Cocaine and Other Stimulant Withdrawal, Including Caffeine** (F14.3, F15.3)

There are no specific medications for the treatment of cocaine and other stimulant withdrawal, including caffeine**; therapy is symptomatic [68-69].

Comments: The following drugs are most commonly used in therapy: diazepam**, bromdihydrochlorophenylbenzodiazepine** in doses specified in the drug instructions [2; 7]. Benzodiazepine derivatives can be useful in the combination therapy of withdrawal state due to cocaine and other stimulants if depressive disorders and/or anxiety predominate in the clinical picture [68].

Comments: To date, there is a shortage of comparative clinical trials that would allow definitive conclusions regarding the efficacy and safety of antipsychotics in the treatment of psychoactive substance withdrawal states. Antipsychotics are used symptomatically when the clinical picture features psychomotor agitation, aggressiveness, worsening of dysphoric symptoms, or potential for impulsive actions, when the action of benzodiazepine derivatives proves insufficient. It should be understood that, as a rule, these symptoms are a manifestation of protracted withdrawal syndrome. The drugs used are the same as in the treatment of opioid withdrawal state (see information above). Whenever possible, atypical antipsychotics should be preferred [2; 7].

Treatment of withdrawal state due to volatile solvents (F18.3)

Withdrawal state from volatile solvents can be severe, as there is a high incidence of somatic and neurological complications whose pathogenetic mechanism involves toxigenic symptoms or the exacerbation of latent pathology. These include gross neurological disorders as well as damage to internal organs—the heart, kidneys, lungs, liver, and pancreas [2; 7; 14].

There is no universal detoxification protocol [70]. Treatment approaches and drug groups used are identical to those for alcohol withdrawal state and withdrawal state due to stimulants and other psychostimulants [2, 22, 60]. Treatment is carried out symptomatically in accordance with medical indications. Basic approaches include infusion therapy and the prescription of anxiolytics, barbiturates and their derivatives. Antiepileptics and antipsychotics are prescribed according to indications, with caution, and taking into account the patient's age (substance dependence on inhalants is predominantly a condition of adolescence) [2; 7; 60].

Treatment of withdrawal state due to multiple psychoactive substance use (F19.3)

In modern clinical practice, withdrawal states resulting from the use of multiple psychoactive substances are quite common; consequently, the clinical picture of the withdrawal state appears variegated, heterogeneous, and mixed. In such cases, therapeutic tactics are determined based on the prevailing clinical symptoms using the recommended treatment protocol for each psychoactive substance, either simultaneously or sequentially [1; 60; 71].

3.2. Psychotherapy

In acute conditions, such as a withdrawal state, the use of psychotherapeutic treatment is severely limited, as patients are unable to fully utilize the proposed psychotherapeutic interventions. The main objective of psychotherapeutic intervention during this period is to engage the patient and retain them in the treatment program, which is not limited to the management of the withdrawal state. It is necessary to inform the patient about further treatment of substance dependence.

During this period, family counseling / psychotherapy for the patient's family members is relevant in order to inform them about the chronic nature of substance dependence, possible treatment strategies and tactics, and to train them in skills of family motivation for patients to continue treatment and rehabilitation after withdrawal management [72-74].

3.3. Assessment of treatment efficacy and safety

Comments: Assessment of the efficacy of combination treatment is carried out based on the dynamics of psychopathological, somatovegetative, and neurological disorders in patients diagnosed with withdrawal state [2; 7].

Criterion for the efficacy of drug treatment: stabilization of the patient's psychophysical state [2; 7].

Comments: Assessment of the safety and tolerability of therapy is carried out throughout its course based on the frequency of occurrence and development of adverse events.

Adverse events 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 and instrumental diagnostic parameters from baseline values.

The causal relationship between the adverse event (AE) and the drug is assessed using the Naranjo algorithm (Appendix G) [75]. If an AE occurs, the physician must document their actions in the primary medical records (e.g., prescribing additional drugs, specifying the drug, dose, and duration), and complete the appropriate reporting form.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Rehabilitation measures begin after the withdrawal symptoms (WS) are relieved and are carried out in accordance with the Clinical Guidelines for the treatment of substance use disorders (SUD).

5. Prevention and Dispensary Observation

Dispanserny observation (routine clinical monitoring) 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.

Once WS is established, tertiary (modification) prevention becomes of primary importance. It is predominantly medical and individual, targets individuals with established SUD, and aims to prevent further disease progression, reduce harmful consequences, and prevent relapse [2].

6. Organization of Medical Care

Therapy for psychoactive substance withdrawal syndrome can be provided in inpatient settings (including day care facilities) and outpatient settings. The course of treatment averages up to 10 days [2; 7; 28; 60].

Comments: A preliminary diagnosis of withdrawal syndrome 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, results of instrumental and laboratory tests, and dynamic monitoring [2].

6.1. Indications for hospitalization:

• Moderate and severe psychoactive substance withdrawal syndrome;

• Psychoactive substance withdrawal syndrome with seizures;

• Lack of clinical response to ongoing therapy in outpatient and day care settings.

6.2. Indications for outpatient treatment:

• Mild psychoactive substance withdrawal syndrome.

6.3. Indications for discharge:

• Discharge of the patient with a diagnosis of psychoactive substance withdrawal syndrome is carried out after the resolution of withdrawal symptoms.

7. Additional Information

No additional information available.

Criteria for Evaluating the Quality of Medical Care

Criteria for assessing the quality of specialized medical care for adults and children with psychoactive substance withdrawal syndrome (excluding alcohol and nicotine) (ICD-10 code: F11.3, F12.3, F13.3, F14.3, F15.3, F16.3, F18.3, F19.3)

References

Appendix A1. Working Group Composition

Co-Chairs:

Klimenko, Tatyana Valentinovna, MD, Prof.

Krupitsky, Evgeny Mikhailovich, MD, Prof.

Masyakin Anton Valeryevich, Doctor of Medical Sciences, Associate Professor

Secretary:

Gubanov, Georgy Alexandrovich

Working Group Members:

Agibalova, Tatyana Vasilyevna, MD

Arkus, Maxim Leonidovich, PhD

Buzik Oleg Zhanovich, Doctor of Medical Sciences, Professor

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-narcologist

2. District psychiatrist-narcologist

3. Psychotherapist

4. 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: guides for physicians, scientific publications in periodicals, e-library scientific electronic library, State Register of Medicines, Register of Medicines of Russia, 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 - Scale for assessing levels of evidence (LE) for diagnostic methods (diagnostic interventions)

Appendix A2.2 - Scale for assessing levels of evidence (LE) for prevention, treatment, and rehabilitation methods (preventive, therapeutic, and rehabilitative interventions)

Appendix A2.3 – Grading of recommendations assessment, development and evaluation (GRADE) for prevention, diagnostic, treatment and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitative interventions)

Appendix A2.4 – Rating scheme for the strength of recommendations (SoR) 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 No. 1034n dated December 30, 2015 (as amended on June 7, 2022) "On Approval of the Procedure for Providing Medical Care in the Profile 'Psychiatry-Narcology' and the Procedure for Dispensary Observation of Persons with Mental Disorders and (or) Behavioral Disorders Associated with Psychoactive Substance Use" (with amendments and additions that entered into force on August 1, 2022).

2. Order of the Russian Ministry of Health No. 124n dated September 4, 2012 "On Approval of the Standard of Primary Health Care for Withdrawal State Caused by Psychoactive Substance Use" (Registered with the Russian Ministry of Justice on December 17, 2012, No. 26151).

3. Order of the Russian Ministry of Health No. 135n dated September 4, 2012 "On Approval of the Standard of Specialized Medical Care for Withdrawal State Caused by Psychoactive Substance Use" (Registered with the Russian Ministry of Justice on December 19, 2012, No. 26193).

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 Terms for the Development of Clinical Guidelines, Their Revision, the Standard Form of Clinical Guidelines and Requirements for Their Structure, Composition, and Scientific Validity of 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

F11.3 OPIOID WITHDRAWAL STATE

The onset of a withdrawal state ("craving" / "cold turkey") in opioid addiction indicates the formation of a qualitatively new stage of the disease—the second (moderate) stage of opioid dependence. The withdrawal syndrome develops approximately 2 weeks to 1.5 months after the onset of regular opioid use.

The withdrawal syndrome occurs after discontinuation of the drug or a sharp decrease in its dose, on average, after 6–24 hours. The time of development of the withdrawal syndrome depends on the type of opioid used; for example, methadone use is characterized by a delayed onset of withdrawal.

The main clinical manifestations of the withdrawal syndrome include autonomic, pain, and psychological disorders. Autonomic manifestations include: yawning, lacrimation, rhinorrhea and nasal congestion with frequent sneezing, diarrhea, mydriasis, fever, tachycardia, elevated blood pressure, sweating, chills, piloerection ("goosebumps"). In the initial stages of dependence, when pain disorders may be mild or absent, patients often mistake this condition for influenza or ARVI. Frequently, the initial manifestation of withdrawal consists of psychological disorders: tension, a sense of discomfort, anxiety, irritability, and sullenness, accompanied by general malaise and physical weakness. Sleep disturbances, up to complete insomnia, appear within 1 day after drug discontinuation and are characterized by persistence and resistance to treatment.

Within the structure of opioid withdrawal, pain disorders are among the most critical and are the most severely experienced by patients. Hence the slang term for opioid withdrawal—"lomka" (withdrawal/breakdown). On the second day after the last drug intake, muscular and joint pains appear in the extremities, back, and sometimes throughout the body, having a twisting character. Abdominal pain and diarrhea are common. Pain disorders are pronounced and subjectively extremely distressing and agonizing. The craving for the drug is conscious, often irresistible, and cannot be concealed. Behavior becomes uncontrollable and aggressive: the opioid withdrawal state accounts for the highest number of offenses, and the risk of suicide increases. The withdrawal syndrome reaches its maximum severity on days 2–3; its duration depends on the type of drug, the duration of the disease, and the treatment administered. 50

Acute disorders in heroin addiction rarely last longer than 5–10 days with treatment.

Treatment

When a withdrawal syndrome develops, the best option for the patient is to consult a physician, even if the manifestations of the condition are mild. Principles and approaches to treatment are identical for all types of dependence. Patient treatment must be prolonged and comprehensive, comprising several stages.

Stage 1: treatment of "lomka". At this stage, the drug is eliminated from the body, and all existing symptoms are alleviated. Currently, there are many good methods and medications that help relieve patient suffering. The main task of this stage is to relieve pain and restore vital body functions.

Stage 2: treatment of "craving", maintenance therapy.

At this stage, specific medications are used to relieve tension, improve mood, and stabilize sleep. Important attention is also paid to the condition of and, if necessary, the treatment of internal organs, especially the liver, kidneys, and brain.

Psychotherapy is administered at this stage, and psychologists are involved in the work. Stages 1 and 2 take place in an inpatient setting.

The main task of Stage 3 is to adapt the patient to normal life; it is called the rehabilitation stage. This is a very long stage of treatment; the longer it is, the better the outcome.

Prevention

For patients with opioid addiction, specific therapeutic methods aimed at maintaining sobriety exist, such as the use of opioid receptor blockers—their presence in the body protects the patient from the effects of drugs; methods and medications aimed at treating hepatitis C and other consequences of addiction are actively being developed. The use of each of these methods must be strictly individual and carried out under medical supervision.

F12.3 CANNABINOID WITHDRAWAL STATE

Cannabinoid withdrawal syndrome occurs, on average, 2–3 years after the onset of use of this group of drugs. Depressive disorders predominate in the withdrawal syndrome: fatigue, asthenia, irritability, malice, dysphoria, and insomnia. Hand tremors, sweating, nausea, and vomiting may be observed. In some cases, intense anxiety predominates during the withdrawal period—a state similar to panic reactions. Suicidal attempts are possible. Sometimes difficult-to-bear, strange (cenestopathic) sensations are noted in various parts of the body: chest tightness, labored breathing, unpleasant sensations in the cardiac region, a feeling of constriction and compression in the temporal region. Craving for the drug can vary in severity. The withdrawal syndrome reaches its peak on days 3–5, and its duration averages 7 days.

Treatment

When a withdrawal syndrome develops, the best option for the patient is to consult a physician, even if the existing disturbances are mild. Principles and approaches to treatment are identical for all types of dependence (see opioid withdrawal syndrome). There is no specific treatment for cannabinoid withdrawal syndrome.

Prevention

It should be understood that chronic use of cannabinoids (marijuana, hashish) leads to personality changes in patients. Patients develop an amotivational syndrome, in which loss of interests, decreased energy, passivity, and lack of ambitions predominate. Patients neglect all their responsibilities. Chronic intoxication with cannabis preparations leads to impairments in memory and attention, and may also serve as a trigger for the development of schizophrenia in individuals with a corresponding predisposition. Massive cannabinoid use can lead to psychosis with a late (delayed) onset, resembling similar states seen with hallucinogens. The main means of prevention is maintaining a healthy, sober lifestyle.

F13.3 SEDATIVE OR HYPNOTIC WITHDRAWAL STATE

The onset of the withdrawal syndrome depends on the half-life of the ingested substance. As a rule, the withdrawal syndrome occurs on days 1–2 after the last substance intake, reaches its maximum on days 1–2, and lasts for at least 1 week. Clinically, the withdrawal syndrome manifests as: pronounced tremor of outstretched fingers, tongue tip, or eyelids, nausea or vomiting, tachycardia, blood pressure fluctuations, headaches, insomnia, psychomotor agitation, convulsive seizures, and the possible appearance of visual, tactile, or auditory hallucinations (illusions), suspicion, and tension (delusional alertness).

Treatment

When withdrawal syndrome develops, the best course of action for the patient is to consult a physician, even if the symptoms are mild. Treatment of withdrawal syndrome by physicians involves a gradual reduction of the substance dose. Treatment must be carried out in a hospital setting.

Prevention

Chronic intoxication with sedatives and hypnotics leads to pronounced and persistent somatic, neurological, and psychiatric changes. Increased fatigue, exhaustion of attention, and a decline in quick-wittedness are noted. As the duration of sedative use increases, slowness, withdrawal, and depression appear, often alternating with outbursts of anger and rage. Swallowing disorders, handwriting deterioration, sluggish facial expressions, muscle weakness, and impaired fine motor skills and gait are revealed. Progressive cognitive decline leads to loss of working capacity and disability. The mortality rate is quite high. Causes of death include suicide, accidents while intoxicated, and overdoses. In any case of mood and sleep disturbances, to avoid the development of the aforementioned complications, consulting a doctor is recommended. Self-treatment is categorically dangerous.

F14.3 COCAINE WITHDRAWAL SYNDROME,

F15.3 WITHDRAWAL SYNDROME FROM OTHER STIMULANTS, INCLUDING CAFFEINE**

Withdrawal syndrome occurs 12–24 hours after the last use of amphetamines, with disorders reaching maximum severity on days 2–4. Withdrawal syndrome is characterized by fatigue, a feeling of being beaten down, lethargy, and sleep disturbances—insomnia or hypersomnia with nightmares. Irritability, malice, and hysterical reactions with a tendency toward self-harm are frequently noted. Marked dysphoria may be accompanied by ideas of self-blame and suicidal attempts. Isolated ideas of reference and persecution may occur. Acute manifestations of withdrawal syndrome disappear within 7–14 days, and in severe cases, persist for up to 1 month. During stimulant withdrawal, psychoses with speech and motor agitation lasting from 2–3 weeks to several months may be observed.

Following this period, a period of chronic dysphoria (irritability) and anhedonia (reduced or lost ability to experience pleasure and joy) typically begins. A distinct sense of the meaninglessness of one's own existence, hopelessness, a feeling of inner emptiness, joylessness, etc., appears. At the same time, the craving for the drug manifests as a persistent and pronounced lowering of mood, and the craving often becomes irresistible, leading to the resumption of substance use.

Treatment

When withdrawal syndrome develops, the best course of action for the patient is to consult a physician, even if the symptoms are mild. There are no specific therapeutic agents for the withdrawal syndrome of cocaine and other stimulants. The principles and approaches to treatment for all types of addiction are the same (see opioid withdrawal syndrome). The main objective of therapy is to prevent the development of psychiatric complications.

Prevention

All psychostimulants, excluding caffeine**, have an extremely high addictive potential. Addictive potential (the ability to cause dependence) depends on many factors: the type of drug, the method of administration, dose, etc. This form of substance use disorder is characterized by the rapid development of psychological dependence, the development of psychoses (hallucinations and delusions), and the formation of dementia. Thus, the main means of prevention is maintaining a healthy, sober lifestyle.

F16.3 HALLUCINOGEN WITHDRAWAL SYNDROME

According to most researchers, withdrawal syndrome does not occur with the use of LSD, psilocybin, mescaline, ketamine**, or phencyclidine. With prolonged systematic use of these substances, the following may be observed: sleep disturbances, blood pressure fluctuations, and general discomfort lasting 7–10 days, transitioning into a state characterized by pronounced weakness, increased fatigue, and a loss of initiative.

Treatment

Specific therapy does not exist. The principles and approaches to treatment for all types of addiction are the same (see opioid withdrawal syndrome). When dependence develops, the best option for the patient is to consult a physician.

Prevention

The consequences of hallucinogen use manifest as psychic dullness ("psychic deafness") or psychoses with rich symptomatology, observed even long after the last intake of these substances.

According to various sources, recurrences of hallucinations occur in 16–57% of LSD users as a result of triggering factors: stressful situations, the use of another psychoactive substance (e.g., alcohol), or the development of some disease.

In some cases, hallucinogens provoke the development of a mental illness—schizophrenia; it is impossible to predict or prevent its development. In this regard, even a single intake of hallucinogens can be dangerous. Given the unpredictability of the consequences of hallucinogen use, the best means of prevention is maintaining a healthy, sober lifestyle.

F18.3 VOLATILE SOLVENT WITHDRAWAL SYNDROME

Volatile solvent withdrawal syndrome occurs 6–12 months after the onset of use and 1–3 days after the last use of these substances. It manifests as lethargy, malaise, bodily discomfort, headache, sweating, dizziness, nausea, poor sleep, depressed mood, and irritability. These symptoms resemble manifestations of vegetative-vascular dystonia. On days 5–7, depressive symptoms join in. On days 4–5, withdrawal syndrome may be complicated by the development of acute psychosis lasting from a few hours to 3 days—with illusions or visual and auditory hallucinations. The duration of withdrawal syndrome is about 2 weeks.

Treatment

When withdrawal syndrome develops, the best course of action for the patient is to consult a physician, even if the symptoms are mild. In terms of therapeutic approaches, it is similar to the treatment of alcohol withdrawal syndrome.

Prevention

The use of inhalants leads to pronounced disorders of the nervous system. Polyneuropathy is frequently encountered, manifesting as reduced sensitivity and unpleasant sensations in the hands and feet, "sock" and "glove" numbness, decreased muscle strength, and blood supply disorders. Toxic damage to nerve endings in the brain leads to visual impairment up to blindness, as well as noise (ringing, buzzing, whistling) in the ears and hearing loss. Severe, rapidly progressive personality changes are observed, memory and intellect decline, and behavioral disorders (psychopath-like behavior) are characteristic. Disorders of the cardiovascular, respiratory, and urinary systems also occur.

Considering the age factor (addiction develops primarily in children and adolescents), primary prevention measures originating from the family are crucial in preventing the development of dependence.

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

G1. Clinical Opioid Withdrawal Scale (COWS)

Russian title: Clinical Opiate Withdrawal Scale.

Original title: The Clinical Opiate Withdrawal Scale (COWS).

Source (official developers' website, validation publication): Wesson D.R., Ling W. The Clinical Opiate Withdrawal Scale (COWS) Journal of Psychoactive Drugs, 2003. Vol. 35(2): 253-259. doi: 10.1080/02791072.2003.10400007.

Guidelines for the pharmacological treatment of opioid dependence with psychosocial support.

http://rcn.kg/uploads/files/WHO_Opioid_dependence_Russian.pdf.

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

Purpose: The COWS scale is used to measure the severity of opioid withdrawal symptoms in a patient. When using the scale, the severity of various somatic and psychological symptoms of opioid withdrawal is assessed, corresponding to a specific number of points, which are then summed. The maximum possible score is 48.

Content (template):

Key (interpretation):

G2. Naranjo Algorithm

Russian title: Naranjo algorithm for assessing the causal relationship "adverse drug reactions (hereinafter referred to as - ADR) - drug"

Original title: Naranjo algorithm

Source (official developer website, validation publication): Naranjo S.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. This questionnaire is designed to obtain specific answers scored in points when determining the degree of certainty of the "drug - ADR" relationship. A specific number of points corresponds to a specific degree of certainty.

Content (template):

Key (interpretation):

The categories of certainty for the "ADR - drug" relationship according to the Naranjo scale based on the 10 questions are determined as follows: