Mental and behavioural disorders due to psychoactive substance use. Psychoactive substance dependence syndrome (excluding alcohol and nicotine): clinical guidelines

List of Abbreviations

BP – blood pressure

WHO – World Health Organization

HIV – human immunodeficiency virus

HPLC – high-performance liquid chromatography

GABA – gamma-aminobutyric acid

GC – gas chromatography

DA – dopamine

VLEL – vital and essential drugs

ICA – immunochemical assay

TRP – treatment and rehabilitation program

MP – medicinal product

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

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

MS – mass spectrometry

NDC – narcological dispensary

AE – adverse event

psychoactive substance – psychoactive substance

CUD – pathological craving for drugs

PT – psychotherapy

DS – dependence syndrome

H&S – hypnotics and sedatives

WD – withdrawal syndrome

CVS – cardiovascular system

RPL – rehabilitation potential level

RR – respiratory rate

HR – heart rate

Terms and Definitions

Antidepressants (from Greek anti- "against" + Latin depressus "pressed down, dejected") are a group of medications that predominantly affect pathologically lowered mood or depressive affect. They do not cause mood elevation in healthy individuals. In accordance with the Anatomical Therapeutic Chemical (ATC) classification recommended by the WHO, the following groups of antidepressants are distinguished: non-selective monoamine reuptake inhibitors; selective serotonin reuptake inhibitors; non-selective monoamine oxidase inhibitors; monoamine oxidase A inhibitors; other antidepressants.

Antipsychotics – a group of medications capable of reducing psychotic symptoms and psychomotor agitation. They have a predominantly depressant effect on higher nervous activity, emotional state, and behavior without impairing consciousness. In accordance with the Anatomical Therapeutic Chemical (ATC) classification recommended by the WHO, the following groups of antipsychotics are distinguished: aliphatic, piperazine, and piperidine phenothiazine derivatives; thioxanthene derivatives; butyrophenone derivatives; indole derivatives, diphenylbutylpiperidine derivatives; benzamides; other antipsychotics.

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

Brief intervention – a specific therapeutic strategy aimed at helping an individual stop or reduce psychoactive substance (PAS) use. It is a short interview consisting of assessing the level of PAS use, providing information on the negative health consequences of excessive PAS use, discussing factors that stimulate and inhibit PAS use, and finding factors that promote abstinence.

Adverse drug reaction – any untoward and harmful medical occurrence that arises during the use of a medicinal product at recommended doses for prophylaxis, treatment, and diagnostics or for modifying a physiological function, and for which a causal relationship with the medicinal product is established.

Cross-tolerance – a phenomenon in which the intake of one substance leads to the development of tolerance to another substance to which the individual has not been previously exposed. Both substances typically, but not necessarily, share a similar pharmacological action.

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

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

Withdrawal syndrome – a complex of autonomic, somatic, neurological, and psychiatric disorders occurring in patients with dependence syndrome upon complete cessation of PAS intake or reduction of its dose after repeated, usually prolonged, and/or high-dose use.

Pathological craving syndrome (English: craving) is a nosologically specific psychopathological disorder for addiction disorders, clinically manifesting as ideational (thought), behavioral, affective (emotional), autonomic, and sensory disorders. Diagnostic criteria for pathological craving syndrome include: a strong desire or necessity to take PAS, loss of quantitative and situational control, continued substance use despite obvious harmful consequences while aware of the link between use and consequences. Pathological craving for PAS forms the basis of psychological and physical dependence.

Tolerance (from Latin tolerantia, "endurance, ability to tolerate") – a progressive weakening of the desired psychotropic effect of PAS (euphoria, sedation, relaxation, etc.), which forces the patient to increase doses and frequency of PAS intake. It is based on the physiological mechanism of the body's adaptation to the toxic effects of PAS.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Dependence syndrome (English: dependence syndrome; hereinafter – DS) is a combination of physiological, behavioral, and cognitive phenomena in which psychoactive substance (hereinafter – PAS) use takes a leading place in the patient's value system [1].

The main characteristics of DS are: a desire (often strong, sometimes irresistible) to take PAS; difficulties in controlling use and persistent continued use of PAS despite harmful consequences; preference for PAS use to the detriment of other activities and fulfillment of obligations; an increase in the tolerable limits of PAS use; the formation of a withdrawal state. DS can manifest in relation to a specific substance (e.g., diazepam**), a class of substances (e.g., opioid drugs), or a broader spectrum of various PAS [1-3].

Synonyms: drug addiction, narcotic dependence, substance abuse.

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

The neurophysiological mechanisms underlying the development of substance dependence (SD) from various psychoactive substances (PAS) upon their exogenous administration are essentially identical. They are based in the stem and limbic structures of the brain, where the reinforcement system is located [2-5]. This system participates in ensuring the emotional state, mood, motivational sphere, psychophysical tone, overall human behavior, and environmental adaptation. PAS exposure leads to excitation of the reinforcement system, most commonly due to the additional release of the neurotransmitter dopamine (hereinafter – DA) from storage sites or direct stimulation of postsynaptic dopamine receptors. Such excitation is accompanied by positively valenced emotional experiences. Free DA is subjected to metabolic enzymes and is rapidly degraded. Part of the free mediator is returned to storage via the reuptake mechanism, while additional DA release causes a compensatory decrease in dopamine receptor sensitivity. Repeated PAS intake leads to depletion of DA stores, which, together with reduced dopamine receptor sensitivity, causes insufficiently pronounced excitation of the reinforcement system upon normal impulse input. Psychophysiologically, this manifests in humans as lowered mood, feelings of sluggishness, weakness, experiences of boredom, and emotional distress. PAS intake against this background once again causes additional DA release from storage, which temporarily compensates for its deficit in the synaptic cleft and normalizes the activity of the brain's limbic structures. This process is accompanied by a subjective sense of improvement, emotional and psychic arousal, etc. However, free DA is rapidly degraded again, leading to a further decline in its levels, worsening psychoemotional state, and, consequently, the drive to use PAS again. This vicious circle underlies the formation of psychological dependence on PAS. The described mechanisms are leading ones, but they are also accompanied by many other disorders of neurochemical processes, brain functions, and behavior [2-5].

With prolonged PAS use, a DA deficiency can develop, potentially threatening the organism's viability. The compensatory mechanisms for this phenomenon include enhanced DA synthesis and suppression of the activity of its metabolic enzymes, primarily monoamine oxidase and dopamine-β-hydroxylase. As a result, an imbalance occurs in the DA synthesis and utilization systems, where its excess becomes constant, forming a "vicious circle" of DA metabolism in the brain's reinforcement system. This state is the biological manifestation of established SD [2].

Each PAS has its own pharmacological spectrum of action. Therefore, in the pathogenesis of SD, in addition to the dopamine system, the following neurotransmitter systems are involved: the endogenous opioid system; the GABAergic system (GABA – gamma-aminobutyric acid); the N-methyl-D-aspartate system; the system of endogenous cannabinoid receptor ligands (anandamide and palmitoylethanolamide); and the serotonergic system [2-7].

1.3 Epidemiology of the Disease or Condition

Worldwide, approximately 38.6 million people (~ 0.7% of the global population aged 15-64 years) suffer from PAS-related disorders and require treatment [8]. In Russia in 2022, there were 229,743 registered patients with drug-related SD, or 157.8 per 100,000 population, which is a 1.2% increase compared to the previous year. Inpatient care was sought in 2022 by 62,328 patients, or 42.8 per 100,000 population, an 8.4% increase compared to the previous year. In 2022, 13,967 patients with substance use disorders sought addiction treatment for the first time in their lives, or 9.6 per 100,000 population, a 1.1% increase compared to the previous year [9].

1.4 Features of Coding the Disease or Condition

The International Classification of Diseases, 10th Revision (hereinafter – ICD-10) provides coding for the type of PAS used, the stage of the disease, and the current character of the SD [1].

F1x.2xx – Dependence syndrome

The type of PAS used is specified by the third character. In cases of chaotic PAS intake where the consequences of use are clinically indistinguishable, code F19 should be used (Table 1).

Table 1. ICD-10 diagnosis formalization

The character of SD currently is specified by the fifth character:

F1x.20х – currently abstinent

F1x.21х – currently abstinent, but in an environment that restricts use (hospital, prison, other)

F1x.22х – currently under clinical supervision on maintenance or replacement therapy

F1x.23х – currently abstinent, but on treatment with aversive or blocking drugs

F1x.24х – currently using (active dependence)

F1x.25х – continuous (constant) use

F1x.26х – episodic use

F1x.29х – episodic use, NOS (not otherwise specified)

The stage of SD is specified by the sixth character:

F1x.2x1 – initial (first) stage

F1x.2x2 – middle (second) stage

F1x.2x3 – terminal (third) stage

F1x.2x9 – stage unknown

The diagnosis of "Drug addiction" (Narkomaniya) is established only if the PAS is included in the "List of narcotic drugs, psychotropic substances, and their precursors subject to control in the Russian Federation (Schedules 1, 2, 3)" [2,3]. That is, in cases of SD from sedatives or hypnotics (F13), stimulants (F15), hallucinogens (F16), inhalants (F18), or multiple psychoactive substances (F19), the Russian letter "H" is placed in the disorder code if the PAS is in the "List...", and the Russian letter "T" is placed if the PAS is not in the "List...". In the latter case, the disorder is classified as "substance abuse" (toksikomaniya). These letters are placed at the end of the code [1, Appendix A3].

1.5 Classification of the disease or condition

There is no unified classification of clinical variants of SD. Various national classifications exist in each country. The international classification of diseases developed by the WHO is adapted to international national systematics in most countries [1-3].

ICD-10 distinguishes three stages of SD: initial (first), middle (second), and terminal (third). The stages are conventional benchmarks helping to determine the patient's position on the path from the onset of the disease to its outcome. The three stages correspond to the three cardinal clinical syndromes of SD: pathological craving for PAS

(hereinafter – PCP), PAS withdrawal syndrome (WS), and psychic degradation, which sequentially complement the clinical picture of the disease as it develops. Staging allows the symptoms of SD to be viewed in interconnection and over time, and enables the use of clinical syndromes as diagnostic criteria [2].

By pattern, consumption is divided into: continuous (daily or almost daily), episodic (periods of daily PAS intake alternating with more or less prolonged intervals when the patient does not use PAS or uses it episodically in small doses), and mixed (against a background of continuous use – periods of PAS intake in maximum doses) PAS use [2].

1.6 Clinical presentation of the disease or condition

Formation of the initial stage of SUD is indicated by: 1) a strong desire or sense of a hard-to-overcome urge to use psychoactive substances; a reduced ability to control substance use: its onset, termination, or dose, as evidenced by use of the substance in larger amounts and over a longer period than intended, unsuccessful attempts or a persistent desire to cut down or control substance use; 2) increased tolerance to the effects of psychoactive substances, manifested by the need for a markedly increased dose to achieve intoxication or the desired effect, or by markedly diminished effect with continued use of the same dose of the substance; 3) continued use of psychoactive substances despite clear evidence of harmful consequences, as evidenced by chronic substance use with actual or presumed awareness of the nature and extent of the harm.

During the formation of the middle stage of SD, in addition to the signs indicated above, at least 1 of the 2 remaining criteria is additionally present: 1) WS or withdrawal state, occurring when PAS use is reduced or stopped, as evidenced by the complex of disorders characteristic of that substance or the use of the same (or a closely related) substance to relieve or avoid WS; 2) preoccupation with PAS use, manifested by the total or partial abandonment of other important alternative pleasures and interests because of substance use, or by a great deal of time spent in activities necessary to obtain, use, and recover from the effects of the substance.

In the terminal stage of substance use disorder (SUD), the following features appear: 1) signs of residual and late-onset psychiatric disorders; 2) increased tolerance to psychoactive substances (PAS) may be replaced by a tendency towards its decrease. In the terminal stage of SUD, persistent somatoneurological disorders and social problems are generally identified [1-3].

2. Diagnostics, medical indications and contraindications for diagnostic methods

Criteria for establishing the diagnosis of the disease/condition:

A diagnosis of SUD can be established if 3 or more of the following criteria have been present during a specific period over the course of a year [1]:

– a strong desire or sense of compulsion to take the PAS;

– a diminished ability to control PAS use in terms of its onset, termination, or dose, as evidenced by taking the PAS in larger amounts and over a longer period than intended, unsuccessful efforts or a persistent desire to cut down or control PAS use;

– withdrawal state (WS) occurring when PAS use is sharply reduced or ceased, as evidenced by the characteristic syndrome for the specific PAS or its use (or a similar substance) to relieve or avoid WS;

– increased tolerance to the effects of the PAS, manifested by the need for markedly increased doses to achieve intoxication or the desired effect, or by a markedly diminished effect with continued use of the same dose of the PAS;

– preoccupation with PAS use, manifested by giving up or reducing important alternative pleasures or interests because of PAS use, or spending a great deal of time in activities necessary to obtain, use, or recover from the effects of the PAS;

– continued PAS use despite clear evidence of harmful consequences, as evidenced by chronic use with actual or presumed awareness of the nature and extent of the harm.

2.1 Complaints and Anamnesis

In some cases, patients with SUD may present without complaints; therefore, the physician must purposefully inquire about the quantity, frequency, pattern, typical conditions, and circumstances of PAS use, as well as subjectively perceived benefits and/or negative consequences associated with PAS use.

Identification of the PAS used is carried out based on the patient's own report, analysis of urine, blood, and other biological materials, or other data (possession of drugs by the patient, identification of clinical signs, reports from informed third-party sources). It is always desirable to have such data from more than one source [2-3].

– craving for opioids, and related mood, sleep, and behavioral disturbances;

– toxic damage to the liver, cardiovascular system (hereinafter referred to as the CVS), and other organs and systems, viral hepatitis, human immunodeficiency virus (hereinafter referred to as HIV).

– decreased mental performance, diminished sense of duty, blunting of higher emotions (sense of conscience, duty, care, compassion, etc.) and enhancement of lower ones (selfishness, irritability, love of pleasure, parasitic tendencies, etc.) [1-3; 10-12].

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

Comments: The disease develops rapidly, in a short timeframe. It is often impossible to trace the transition from episodic use to systematic intake. The timeframe for the development of WS is also very short; accordingly, the middle and terminal stages of the disease develop quickly, when somatoneurological complications join. Since opioids are predominantly used parenterally, complications are often associated not only with the toxic effects of the drugs themselves, but also with the presence of impurities and a high likelihood of infection with hepatitis B, C, and HIV [1-3; 10-12].

– craving for cannabinoids, and related mood, sleep, and behavioral disturbances;

– apathy, passivity, reduced drive, inability to engage in activities requiring concentration and attention, decreased intellectual abilities, memory impairment (amotivational syndrome) [1-3; 10-12].

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

Comments: There are distinctive features in the development and dynamics of cannabinoid SUD:

1) The rate of disease progression is slow: the speed of physical dependence (WS) development from the onset of regular use is 8 years or more. Episodic (irregular) cannabinoid use can be quite prolonged, lasting several years.

2) Psychiatric signs of SUD predominate over physical ones.

3) Cannabinoid users frequently begin abusing other PAS (opioids, stimulants, alcohol).

Tolerance during systematic cannabinoid use increases slowly. Signs of its increase include: cannabis is smoked without tobacco admixture, smoking frequency increases, and preference is given to preparations with a higher drug content (hashish, high-potency hybrid cannabis strains, synthetic cannabinoids).

The terminal (third) stage of cannabinoid SUD is rare and may occur 10 or more years after systematic cannabinoid abuse. Lung and cardiovascular diseases and cognitive decline are characteristic. Tolerance decreases compared to the plateau observed in the middle stage, and the drug exerts a predominantly tonic effect.

Psychoses with schizophreniform hallucinatory-delusional symptoms are frequent, both at the peak of intoxication and during WS.

Changes in the moral, intellectual, volitional, and affective spheres are described within the structure of the amotivational syndrome. Amotivational syndrome manifests as apathy, passivity, reduced drive, and inability to engage in activities requiring concentration and attention. Intellectual abilities decline, memory weakens, and mental and physical exhaustion are constant. Patients become sluggish, passive, apathetic, withdrawn, and gloomy.

People who use cannabis may experience brief acute anxiety states, sometimes accompanied by paranoid ideas [1-3; 10-12].

– craving for SHDs, and related mood, sleep, and behavioral disturbances;

– impaired motor coordination, decreased or absent reflexes, acrocyanosis;

– decreased intellectual abilities, memory impairment [1-3; 10-12].

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

Comments: SHDs causing SUD include benzodiazepine derivatives and barbiturates. Most of these agents are medicinal products (hereinafter referred to as MPs). The addictogenic potential of agents from these two groups is higher when the elimination half-life of the drug is shorter [1-3; 10-12]. In recent years, the list of substances capable of causing dependence and SUD has expanded [3; 13-14]. SHDs are extremely heterogeneous regarding their ability to cause toxic effects; barbiturates and GHB precursors are the most dangerous in this regard, while GHB itself is non-toxic. SUD from these substances is often accompanied by the development of delirium, psychotic disorders, psychoorganic syndrome, and severe somatic pathology affecting the liver, heart, lungs, and kidneys [13-14].

– craving for cocaine or other stimulants, including caffeine, and related mood, sleep, and behavioral disturbances;

– intellectual-mnestic decline, affective lability, frequent depressive-dysphoric reactions [1-3; 10-12].

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

Comments: Features of cocaine and other stimulant SUD include rapid development of psychological dependence, mildly expressed physical dependence symptoms, and a predominance of the periodic pattern of drug use.

The formation of cyclicity indicates an already established SUD. Due to this specific disease course, the period of use with harmful consequences and the first (initial) stage of SUD proceed rapidly, and it is often impossible to trace the transition from the initial stage to the middle stage. High doses of cocaine and other stimulants can lead to the development of psychotic disorders with predominantly hallucinatory-delusional symptoms [1-3; 11-12].

Since the 2000s, there has been a rapid worldwide increase in the prevalence of new synthetic stimulants—amphetamine and methamphetamine derivatives. These psychoactive substances (PAS) are characterized by longer-lasting effects and high addiction potential. Overdose cases, which are dangerous due to the development of somatic complications (myocardial infarctions, strokes, rhabdomyolysis), are much more frequently observed in individuals dependent on these substances. Furthermore, psychotic disorders are significantly more common compared to consumers of "classical" stimulants [15-16].

SUD related to caffeine is diagnosed quite rarely. If it does develop, it does so over a long period; its main manifestations (compulsive drug craving, withdrawal symptoms, tolerance dynamics) do not reach a severe degree, nor do the medical and social consequences [2-3].

– craving for hallucinogens, and related disturbances in mood, sleep, and behavior;

– worsening of intellectual and mnestic decline following each episode of psychosis [1-3; 11-12].

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

Comments: Hallucinogens differ from other PAS in that their addictive action is based on the ability to induce psychotic states, the psychopathological structure of which may manifest as delirious, oneiric, or hallucinatory-paranoid syndrome.

The development of SUD differs somewhat from other types of PAS. Psychological dependence can develop rapidly—after just a few episodic trials (e.g., phencyclidine)—or it may take quite a long time to form, with episodic use lasting for years (lysergic acid diethylamide – LSD). With the use of certain plant-based serotonergic hallucinogens (psilocybin, mescaline), the development of SUD has not been described.

Withdrawal syndrome (WS) resulting from hallucinogen use manifests as mild somato-vegetative and asthenic disorders: general malaise, weakness, hand tremor, paresthesias, and depressed mood.

Many individuals who use hallucinogens episodically stop taking them on their own; accordingly, they do not develop SUD.

However, some individuals develop SUD with all its inherent symptom complexes: the formation of psychological and physical dependence, increasing tolerance, the establishment of a specific pattern of use (periodic or continuous), as well as medical and social consequences [1-3; 11-12].

A special place among drugs with hallucinogenic effects is occupied by centrally acting anticholinergics (N04A: Anticholinergic agents). These include medications such as trihexyphenidyl (tablets), cyclopentolate (eye drops), and tropicamide** (eye drops). A single dose of the listed anticholinergics (intranasally, intravenously, or orally) leads to the development of delirium, while systematic intoxication leads to impairments in memory, intellect, cardiac rhythm, as well as neurological and somatic disorders, including extremely severe ones. This group is heterogeneous—for instance, trihexyphenidyl is capable of inducing SUD fairly quickly; some researchers estimate its addiction potential to be close to that of phencyclidine [17]. Cyclopentolate and tropicamide**, as a rule, are used alongside PAS of other groups—most often opioids, but cases of chronic abuse of these agents when the primary drug is unobtainable are also known [18-20].

A number of medicinal products with anticholinergic effects also possess addiction potential: tricyclic antidepressants, diphenhydramine**, promethazine, chloropyramine**, and clemastine [17].

In recent years, there has been an increase in the prevalence of new designer hallucinogenic PAS [21].

Cases of serotonin syndrome development upon their intake have been described [22].

– craving for inhalants, and related disturbances in mood, sleep, and behavior;

– intellectual and mnestic decline [1-3; 11-12; 23].

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

Comments: There are 4 categories of inhalants: volatile solvents (paint thinners and removers, dry cleaning fluids, degreasers, gasoline, glues, correction fluids, and felt-tip markers), aerosols (spray paints, deodorants and hairsprays, fabric protectors, etc.), gases (medical anesthetics, propane-butane mixtures, refrigerants), and nitrites (volatile liquids with psychoactive effects—"poppers") [17; 24].

Initially, the inhalation of solvent vapors occurs within a peer group. The phase of episodic use lasts from 1 to 6 months, less frequently up to 1 year. If inhalations continue, systematic use is formed: inhalants are inhaled first 3-4 times a week, then daily, sometimes several times a day. The transition from episodic to escalating systematic use indicates the development of psychological dependence, i.e., compulsive drug craving. Another sign of established psychological dependence is the transition from group inhalant use to solitary use. Tolerance to inhalants is difficult to establish. An increase in tolerance is indicated by more frequent inhalation bouts (initially once a week, then 3-4 times a week, and later daily); a 4- to 5-fold increase in the amount of solvent inhaled compared to the initial amount. Tolerance also depends on the method of inhalation and the individual's vital capacity of the lungs.

In inhalant-related SUD, toxic encephalopathy with signs of cerebral atrophy develops rapidly, already by the middle stage. Polyneuropathy is frequently encountered, manifesting as reduced sensitivity, diminished reflexes, paresthesias of the hands and feet, "sock-and-glove" numbness, combined with muscular hypotrophy and acrohyperhidrosis. Toxic damage to nerve cells in the central nervous system leads to visual impairment up to blindness, as well as hearing disorders. With systematic inhalant intoxication, cardiac arrhythmias occur in the form of supraventricular tachycardia and ventricular extrasystoles. Signs of toxic renal injury are detected primarily by laboratory methods: azotemia, urine turbidity, symptoms of toxic glomerulonephritis, where patients frequently complain of lower back pain. Toxic liver damage manifests as pain in the hypochondrium, nausea, vomiting, low-grade fever, and frequently jaundice of the skin [1-3; 11-12].

– craving for multiple PAS, and related disturbances in mood, sleep, and behavior [1-3; 10-12].

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

Comments: Clinical manifestations of SUD depend on the predominant PAS. Encephalopathies are frequent, and dementia syndrome with neurological disorders develops early [2-34; 11-12].

2.2 Physical Examination

Physical examination findings are non-specific in SUD. Medical examination is an important adjunct to clinical diagnosis, allowing for the determination of the clinical and dynamic features of the disease and providing benchmarks for assessing the severity of the patient's condition [2-3].

Comments: Physical and neurological examinations are performed prior to the initiation of therapy and throughout the course of treatment. For example, in opioid-related SUD, the patient exhibits intravenous injection scars along superficial veins; in cocaine-related SUD, manifestations of chronic rhinitis; with the use of hepatotoxic PAS, enlargement of the liver, etc., all of which combined serve as evidence of systematic PAS use [2-3].

2.3 Laboratory Diagnostics

Laboratory test data are used to complement clinical diagnosis and allow an objective assessment of the patient's general condition, confirmation of systematic psychoactive substance (PAS) use or absence of PAS in the body, and monitoring of remission status. Laboratory diagnostics can be useful when the clinician suspects that the patient significantly underestimates the extent of PAS abuse, including due to comorbid mental illness or cognitive decline; for the timely detection of target-organ damage caused by PAS; and for making decisions regarding the settings and tactics of medical care to prevent the development of potential complications [2-3; 25].

Laboratory diagnostics for PAS use two main types of testing: immunochemical assay (hereinafter referred to as ICA) and gas chromatography (hereinafter referred to as GC), mass spectrometry (hereinafter referred to as MS), or high-performance liquid chromatography (hereinafter referred to as HPLC) [25-33].

Comments: ICA is most commonly used for initial screening due to its simplicity and cost-effectiveness.

The accuracy of ICA testing varies, being highest for cannabis and cocaine, and lower for opioids and psychostimulants. Each PAS has its own detection window in urine via ICA [2; 28] (Table 3)

Table 2 - PAS detection using ICA

In foreign practice, due to the widespread use of numerous semi-synthetic and synthetic morphine derivatives, an expanded panel is used to detect opioids, including not only major morphine metabolites but also frequently used PAS and medicinal products such as fentanyl, hydrocodone, methadone, oxycodone, buprenorphine, and tramadol** [30-33].

Modern designer drugs (synthetic cannabinoids, stimulants, and hallucinogens) are not detected by ICA [26].

Comments: Chromatography is used in complex diagnostic cases, to confirm ICA results, and to obtain highly accurate results. Chromatographic methods are highly accurate, but more expensive, technically complex, and time-consuming. Positive ICA results should be followed by confirmatory testing using GC/MS or HPLC [25-33].

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

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

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

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

Comments: Performing routine laboratory tests is important for determining general somatic health status, ruling out acute conditions requiring specialized medical care, and monitoring potential complications during treatment [2-3].

2.4 Instrumental Diagnostics

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

To diagnose pathology comorbid with PUD, other specialists must be involved. Instrumental diagnostic methods are prescribed according to clinical indications: comprehensive ultrasound examination of internal organs, electroencephalography, echoencephalography, skull radiography in one or more projections, targeted chest X-ray, etc. [2-3].

2.5 Other Procedures

Comments: Psychodiagnostic evaluation is auxiliary in nature; its value increases when compared with the results of clinical observation and specific instrumental studies (e.g., electroencephalography). The results of psychodiagnostic evaluation help determine the optimal scope and format of subsequent psychotherapeutic interventions.

Comments: Assessing the severity of the patient's condition makes it possible to make well-founded and rational decisions regarding both the settings of medical care and therapeutic measures [2-3].

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

PUD therapy is a multi-stage, comprehensive, individualized, and prolonged process. PUD is a chronic disease with a relapsing course, therefore long-term maintenance therapy is mandatory and may be carried out for several years. The decision to adjust maintenance therapy is made individually, taking into account the patient's current condition, the intensity of PAS cravings, and comorbid pathology (personality disorders, endogenous disease, exogenous-organic disease, etc.), if present [2-3; 34-35].

Any therapeutic interventions must pursue clear objectives, follow a defined strategy, and conclude with an evaluation of their efficacy [34].

Treatment objectives:

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

2) relief of withdrawal syndrome to enable psychotherapy and rehabilitation;

3) prevention of complications from PAS use (treatment of somatoneurological consequences of long-term PAS use is performed as indicated);

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

Treatment strategy: comprehensive pharmacotherapy and psychotherapeutic treatment.

Criterion for treatment efficacy: stabilization of the patient's psychophysical state and abstinence from PAS [2-3; 34-35].

3.1. Pharmacotherapy

Comments: Opioid receptor antagonists have been used in the treatment of opioid use disorder for over 40 years with quite successful outcomes. According to a systematic review [36], international guidelines for the treatment of opioid dependence [37-38], as well as domestic studies [39-45], the use of various forms of naltrexone** (oral form, intramuscular injection form) showed a significant reduction in heroin use. The main achieved results were retention in the treatment program and a decrease in relapse frequency. An important conclusion from the conducted studies was that naltrexone** is recognized as an effective drug for the treatment of patients with high motivation for abstinence [36]. Naltrexone** is well tolerated, has no addictive potential, and tolerance to its blocking effect does not develop [41].

Naltrexone treatment** is initiated after the patient has abstained from opioids for 7–10 days, provided there are no signs of opioid withdrawal syndrome. Abstinence is verified by laboratory urinalysis for opioid content. In addition, a provocative naloxone test is mandatory**: the patient is administered 0.2–0.4 mg of #naloxone** intravenously over 5 minutes or as a subcutaneous or intramuscular injection. If there is no reaction to the administration of #naloxone** within 15–30 minutes, a second dose of 0.4 mg IV or 0.4–0.8 mg SC is administered [2–3]. The test is considered positive if signs of opioid withdrawal appear. The naloxone test is not performed in patients with signs of opioid withdrawal or when opioids are detected in the urine [2–3]. Naltrexone therapy** should be initiated only with a negative provocative #naloxone** test. The starting dose is 25 mg of naltrexone** orally. The next day, naltrexone** is prescribed at 50 mg every 24 hours (this drug dose is sufficient to block the effects of parenterally administered opioids, e.g., 25 mg of heroin) [2; 37–39]. Alternatively, a regimen is possible in which naltrexone** is prescribed at a dose of 100 mg every 2 days or 150 mg every 3 days. Oral naltrexone** is a fairly effective agent for stabilizing remission in patients with opioid use disorders, provided that family members monitor treatment adherence (compliance) [41].

Long-acting injectable dosage forms can significantly improve outcomes in the treatment of opioid use disorder by increasing compliance [40-42]. The long-acting injectable naltrexone** formulation of 380 mg is administered intramuscularly once a month (every 4 weeks). Clinical studies have confirmed the efficacy of the prolonged formulation in terms of abstinence from opioids, craving for their use, and the general health status of patients when taken for 6 months [42]. Increasing the duration of a course of treatment with the long-acting injectable naltrexone** formulation of 380 mg up to 1.5 years did not reduce its efficacy and revealed no safety issues. During long-term therapy with the prolonged formulation of the drug, no serious adverse events (hereinafter referred to as AEs) were registered, and the overall incidence of AEs was low. Due to the high probability of disease relapse after completion of therapy, the course of treatment for patients with opioid use disorder must be prolonged [45].

Comments: Initially, the efficacy of #disulfiram was evaluated in cases of comorbid alcohol and cocaine dependence. These studies showed high efficacy of #disulfiram, although it was believed that the results reflected efficacy regarding alcohol use disorder [46]. Later studies demonstrated the effective impact of #disulfiram on maintaining remission in isolated cocaine use disorder: the use of #disulfiram combined with psychotherapeutic methods reduced cocaine use, leading to the conclusion that the drug can be effective in cocaine use disorder [47-48]. Studies have shown that #disulfiram reduces the positive reinforcing effects of cocaine use [48]. Currently, there are two theories explaining this effect of the drug. The first is based on the assumption that by inhibiting dopamine beta-hydroxylase, the enzyme catalyzing the conversion of dopamine to norepinephrine, disulfiram leads to increased dopamine concentrations in peripheral and central noradrenergic neurons, which in turn causes increased anxiety and agitation when using cocaine and other stimulants. The second explains the reduction in the subjective effects of cocaine through the effect of #disulfiram on the serotonergic system. It is known that cocaine blocks serotonin reuptake, leading to an increased concentration of serotonin in the synaptic cleft. #Disulfiram can inhibit the conversion of serotonin to its main metabolite, 5-hydroxyindoleacetic acid, by inhibiting aldehyde dehydrogenase, which leads to increased production of another serotonin metabolite, 5-hydroxytryptophol. Elevated levels of the latter are associated with a number of side effects, including headache, fatigue, and diarrhea. The psychological and physiological effects of 5-hydroxytryptophol negatively affect the perception of cocaine's effects and contribute to a significant decrease in euphoria from its intake [48].

To reduce the positive effects of intravenous cocaine administered at a dose of 0.25 mg/kg, #disulfiram is recommended at a dose of 62.5 mg daily; for intravenous cocaine doses ranging from 0.5 to 1 mg/kg, the #disulfiram dose should be 250 mg daily; for 2 mg/kg of intravenous cocaine, 500 mg daily [48].

Comments: Currently, polysen-substance use disorders (SUD) involving multiple psychoactive substances (PAS), where the clinical picture is variegated, heterogeneous, and mixed, are widely prevalent in clinical practice. In such cases, therapeutic tactics are determined based on the prevailing symptoms, using the recommended treatment protocol for each PAS either simultaneously or sequentially [2-3; 47; 49-51]. Naltrexone** is used for relapse prevention in both opioid and alcohol SUD. Disulfiram at a dose of 250 mg daily is used for relapse prevention in alcohol SUD. In established opioid and alcohol SUD, relapses of remission most frequently occur with the resumption of use of one of the PAS; for example, a return to opioid use occurs when the patient is in a state of alcohol intoxication, and vice versa. Therefore, in such clinical situations, the use of naltrexone** together with #disulfiram is a justified strategy [47; 49-51].

Comments: Studies have shown that patients with co-occurring cocaine and alcohol dependence achieve abstinence from these PAS while taking naltrexone** and #disulfiram [52]. The recommended dose of naltrexone** is 100 mg orally per day, and for #disulfiram, 250 mg orally per day [49; 52].

Comments: Antiepileptic drugs (anticonvulsants) in PAS SUD are generally used at the stage of anti-relapse and stabilizing therapy to arrest exacerbations of drug craving, when affective disorders in the form of internal tension, dysphoria, irritability, and anhedonia predominate in the clinical picture [2-3; 34; 47]. The mood-stabilizing effect of these agents is associated with their action on the GABAergic system: anticonvulsants reduce GABA metabolism in the brain. GABA, in turn, acts as a presynaptic modulator of dopaminergic neurons, causing a decrease in DA concentration in presynaptic formations [2-3].

Studies have shown that anticonvulsants have an effect on reducing the risk of disease relapse and also decrease the amount of PAS consumed in the event of resumed use [47; 51; 53-56].

Clinical studies have demonstrated the efficacy of:

#Topiramate** at a dose of up to 300 mg per day regarding the maintenance of sobriety and cessation of cocaine use in dependent patients who took the drug for 2 months [53];

#Lamotrigine at a dose of 200–400 mg per day regarding the reduction in the amount of cocaine used in dependent patients who took the drug for 10 weeks [54];

#Valproic acid** at a dose of up to 500–2500 mg per day regarding the reduction in the amount of stimulants used and the maintenance of sobriety in dependent patients who took the drug for 3 months [55]. At a dose of 1500 mg per day, #valproic acid** preparations were effective in suppressing pathological craving for cannabinoids in dependent patients who took the drug for 2 months [56].

#Carbamazepine** is used to suppress dysphoria and irritability during exacerbations of pathological craving for drugs in dependent patients at a dose of 100–600 mg per day [2-3].

Comments: Affective disorders, predominantly of the depressive spectrum, are manifestations of pathological craving for drugs and, as a rule, are at the "forefront" [2]. Antidepressants are used to relieve these disorders; in this case, the so-called anti-craving mechanism of action of antidepressants is utilized [2-3]. The latter is associated with the complex effect of antidepressants on serotonergic and dopaminergic neurotransmission. Differentiating manifestations of affective (usually depressive) pathology from a comorbid mental disorder is possible only on the basis of a syndromal approach. There is evidence that the effect of reducing pathological craving for drugs occurs already in the first days of taking antidepressants, sometimes 1.5–2 weeks before their antidepressant effect develops [2]. In other words, the suppression of pathological craving for drugs can be quite an independent property of theirs, along with the main one—the antidepressant effect [2].

Indications for prescribing antidepressants are: depressed mood background, anxiety, dysphoria, emotional lability, sleep disorders manifested by difficulty falling asleep and difficult awakenings, or early morning and/or frequent night awakenings with the inability to fall back asleep [34; 47; 51; 55; 57-59].

Clinical studies have demonstrated the efficacy of:

#Trazodone at a dose of 100–500 mg per day regarding the reduction in the amount of stimulants used and the maintenance of sobriety in dependent patients who took the drug for 3 months [55];

#Paroxetine** at a dose of 10–20 mg per day regarding the reduction in the amount of stimulants used and the maintenance of sobriety in dependent patients who took the drug for 2 months [58];

#Fluoxetine** at a dose of 40 mg per day regarding the reduction of pathological craving for drugs in the short term in patients with substance use disorder from methamphetamine [59];

#Imipramine** at a dose of 10–150 mg per day regarding the retention of patients with substance use disorder from amphetamine in the therapeutic program and increasing compliance [59].

In the presence of depressive disorders within the structure of pathological craving for drugs in patients with substance use disorder from psychoactive substances, other antidepressants are also used: #amitriptyline** at an average daily dose of 75–100 mg; #clomipramine** at an average daily dose of 75–150 mg; #mianserin at an average daily dose of 60 mg; #mirtazapine at a dose of 15–30 mg per day; #sertraline** at an average daily dose of 25–150 mg per day; #fluvoxamine at an average daily dose of 50–150 mg per day, #fluoxetine** at a dose of 20–80 mg per day; #escitalopram at a dose of 20–40 mg per day. The duration of drug intake is at least 1 month [2-3].

Comments: In patients with substance use disorders (SUD) and comorbid affective disorders, the inclusion of antidepressants in therapy promotes both the reduction of depressive, anxiety, or mixed disorders and the decrease in the severity of substance withdrawal symptoms (SWS) [2; 34]. When comorbid pathology is present, antidepressants are used for direct indications: in the treatment of depressions of various etiologies; conditions accompanied by anxiety; obsessive-compulsive disorders; panic disorders; generalized anxiety disorder; post-traumatic stress disorders [2; 34; 55; 57-59].

Preference should be given to antidepressants with mixed serotonergic and noradrenergic pharmacology, as they have demonstrated consistent mood improvement compared to selective serotonin reuptake inhibitors and possess lower toxicity compared to tricyclic antidepressants [47]. A sound methodology for prescribing antidepressants is initiating therapy with low doses and gradually increasing them to optimal therapeutic ones. An exception is made for antidepressants from the selective serotonin reuptake inhibitor group, which are prescribed immediately at therapeutically adequate doses. Dosage selection is individualized. If there is no positive clinical effect within the first 3–4 weeks of therapy, the prescribed antidepressant should be switched to a drug with a different mechanism of action. Treatment is prolonged, lasting at least 3–6 months. Withdrawal of medications, as well as their initiation, is carried out gradually. Antidepressants are used independently and in combinations with other drugs [2; 34; 47].

Comments: Indications for prescribing antipsychotics in SUD include: acute and transient psychotic states, comorbid mental disorders, mental and behavioral disorders accompanied by anxiety, psychomotor agitation, tense affect, state of agitation, increased restlessness, aggressiveness, and severe sleep disturbances [2; 34; 60-66].

Clinical studies have demonstrated the efficacy of:

#Quetiapine** at a dose of 400 mg per day regarding the reduction of cocaine use and maintenance of sobriety in dependent patients who took the drug for 12 weeks [63], including the presence of comorbid mental pathology [64];

#Aripiprazole at a dose of 10 mg per day regarding the reduction of cocaine use and maintenance of sobriety in dependent patients who took the drug for 3 months [65-66].

Other antipsychotics are used as symptomatic therapy according to relevant indications. During SWS exacerbations, when anxiety, agitation, sleep disturbances, agitated anxiety, and behavioral disorders such as aggression and hyperactivity are present in the clinical picture, the following are used: haloperidol** – 1.5–20 mg per day, divided into 2–3 doses orally or intramuscularly [2-3]; #zuclopenthixol** – 25–100 mg per day, divided into 1–2 doses orally, or 50–150 mg per day once intramuscularly [2-3]; chlorprothixene – 15–150 mg per day, divided into 2–3 doses orally [2-3]; chlorpromazine** – 25–100 mg per day, divided into 2–4 doses orally, or once intramuscularly [2-3]; #risperidone** – 2–4 mg per day, divided into 1–2 doses orally [2-3].

During SWS exacerbations, when psychomotor agitation, excitement, anxiety, and persistent insomnia predominate in the clinical picture, levomepromazine** – 25–200 mg per day, divided into 1–3 doses orally or once intramuscularly [3] is used.

If the clinical picture of an SWS exacerbation includes pathological motivations, cathymic formations, attitudinal behavior patterns, and overvalued ideas regarding substance use, the following are effectively used: #perphenazine** – 8–30 mg per day, divided into 2–4 doses orally [3]; #trifluoperazine** – 5–15 mg per day, divided into 2–3 doses orally [2].

In the presence of neurosis-like disorders or behavioral disorders associated with explosiveness, histrionic traits, and emotional disinhibition, thioridazine** is used, starting at 50–150 mg per day [2-3].

For anxiety states, psychomotor agitation, aggressive or dangerous impulsive behavior, periciazine** – 5–15 mg per day orally [2-3] is used as an additional drug for short-term treatment.

Antipsychotics should be prescribed for a limited time, as their long-term use leads to distressing states of lethargy and subdepression [2-3].

Comments: The analysis of the research evidence base indicates that there are currently no pharmacological agents with fully confirmed efficacy in the treatment of psychoactive substance use disorders (SUD). Treatment is administered symptomatically in accordance with medical indications [2-3; 34; 47; 67-69].

Comments: For a certain proportion of adolescents, pharmacotherapy is an important component, despite the fact that most drugs used to treat SUD are recommended for individuals over 18 years of age. Any medications are prescribed only after a risk/benefit assessment [2-3].

3.2. Psychotherapy

Psychotherapy (hereinafter referred to as PT) for SUD represents targeted professional assistance in altering and restoring the healthy state of the body through psychological means and is aimed at eliminating personal, affective, behavioral, and other disorders, optimizing the patient's interpersonal relationships, strengthening motives for participating in the treatment program, abstaining from psychoactive substances, and achieving social and professional reintegration [2-3; 70-73].

PT is an integral part of any therapeutic program for SUD. Psychotherapeutic interventions directly alter the psychological and social factors associated with psychoactive substance abuse and significantly increase the effectiveness of pharmacotherapy [2-3; 70-73].

The goal of PT: motivating the patient for treatment and rehabilitation, fostering abstinence from psychoactive substances, and achieving sustained remission.

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

From the first contact with a patient dependent on psychoactive substances, it is important to consider the formation of the main non-specific therapeutic factors of PT [71]:

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

- feedback (to and from the patient);

- expectancy effect (placebo effect);

- group dynamics (group cohesion).

Criteria for PT efficacy:

1) cessation of psychoactive substance use;

2) establishment of therapeutic remission;

3) established compliance with pharmacotherapy;

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

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

6) patient satisfaction with the resolution of addressed problems.

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

All PT methods with established (proven) efficacy possess therapeutic potential, but including the maximum possible number of methods, or even all possible ones, in each patient's treatment program is not advisable [2-3].

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

Methods with proven efficacy include:

– person-centered psychotherapy [80-85];

– motivational interviewing [86-92];

– cognitive-behavioral therapy [75; 80; 83; 93-95].

The following methods also demonstrate high efficacy:

– relapse-prevention training [75; 96-101];

– situational control therapy (contingency contracts; reinforcement with rewards) [102-107];

– development of emotional self-regulation, relaxation, and stress-coping skills [98; 108];

– family psychotherapy (various types) [99; 109].

These interventions can be conducted in individual, couples (family work), and group formats. In patients under 18 years of age, emphasis is placed on psychosocial and family therapy [2].

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

3.3. Assessment of treatment efficacy and safety

Comments: The assessment of complex treatment efficacy is carried out based on the dynamics of psychopathological, somatovegetative, and neurological disorders in patients with SUD [2-3].

Criterion for the efficacy of pharmacotherapy: stabilization of the patient's psychophysical state [2-3].

Criterion for the efficacy of PT treatment: patient retention in the treatment program and their consent to continue treatment [2-3].

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

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 causality of adverse events in relation to medications is assessed using the Naranjo algorithm (Appendix G) [110]. If an adverse event occurs, the physician must document their actions in the primary medical records, for example, prescribing additional drugs (which ones, at what dose, for what period), etc., and fill out the corresponding form [110].

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Rehabilitation of a patient diagnosed with SUD is a combination of medical, psychological, and social (public and interdepartmental) measures aimed at the maximum possible compensation or restoration of impaired/lost body functions and the social adaptation of the patient. According to the conclusion of the WHO Expert Committee on Medical Rehabilitation, this concept is defined as "the combined and coordinated use of medical and social measures, education, and vocational training or retraining aimed at ensuring that the patient achieves the highest possible level of functional activity" [2-3].

Rehabilitation is aimed at preserving the positive results obtained during prior treatment by restoring (forming) the normative personal and social status of the SUD patient through maintaining sobriety, further correction, and the development of their personal, intellectual, moral, emotional, and creative potential [111-114].

The strategic goals of rehabilitation in patients with SUD are [2-3]:

1) safe cessation of psychoactive substance use and maintenance of a sober lifestyle;

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

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

The pragmatic goals of rehabilitation are:

1) formation of conscious and stable motivation (attitude) in the patient to abstain from psychoactive substances and participate in the treatment and rehabilitation program (hereinafter referred to as TRP);

2) implementation of therapeutic measures aimed at arresting mental and behavioral disorders resulting from psychoactive substance use and preventing disease relapse;

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

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

5) correction of family relationships;

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

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

One of the problems complicating the rehabilitation process in patients with substance use disorders (SUD) is that a number of psychological functions necessary for the full restoration of normative personal and social status are severely impaired in them [85]. Nevertheless, these functions can be restored to a normative level as a result of completing a medical rehabilitation program (MRP) or compensated for through the development of other functions and the formation of entirely new skills and abilities. Therefore, when designing a rehabilitation program, it is necessary to consider not only the rehabilitation aspect but also the habilitation aspect of recovery [2; 112; 115-116].

Rehabilitation is carried out regardless of the duration of the disease and the severity of the SUD, provided the patient's clinical state is stable and depending on their rehabilitation potential level (hereinafter referred to as RPL).

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

Comments: Rehabilitation of patients with SUD requires a sufficient duration of therapeutic interventions and continuity between inpatient and outpatient care [61-64; 76-79; 117-118]. Diverse efforts are needed targeting different spheres of patient functioning: psychological, professional, familial, social, and leisure. Therefore, the following areas of rehabilitation are distinguished: medical (provision of necessary medical care for the treatment of SUD and existing somatic problems; therapy of comorbid mental disorders); organizational (creation of a structured therapeutic environment); psychological and psychotherapeutic (cognitive rehabilitation, psychotherapeutic and psychological correction of personal, family, and social functioning; motivation and compliance maintenance); work within the 12-step program; social and pedagogical (stimulation of physical activity, formation, development, and enhancement of self-care skills and social communication; occupational therapy); social support [2-3; 117-118].

5. Prevention and Dispensary Observation

In established SUD, tertiary (modification) prevention is of paramount importance. It is primarily medical, individualized, targets individuals with established SUD, and aims to prevent the further progression of the disease, reduce harmful consequences, and prevent relapse.

Dispensary observation is carried out in accordance with the Procedure for Dispensary Observation of Persons with Mental Disorders and/or Behavioral Disorders Associated with Psychoactive Substance Use [2-3] (Appendix A3).

6. Organization of Medical Care

Therapy for SUD can be provided in inpatient settings (including day hospitals) and outpatient settings. Continuity of care exists between the inpatient and outpatient units of addiction care [2-3].

Comments: A provisional diagnosis of SUD 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 [2-3], (Appendix A3).

The inpatient course of treatment continues until the patient's psychophysical state is stabilized, which involves the reduction of psychopathological and somatoneurological disorders. The duration of inpatient treatment averages 14-21 days. The duration of outpatient treatment and observation is determined by the procedure for providing medical care in the specialty of "psychiatry-narcology" and the procedure for dispensary observation of persons with mental and/or behavioral disorders associated with psychoactive substance use [2-3], (Appendix A3).

6.1. Indications for hospitalization:

· exacerbation of craving for psychoactive substances and/or other psychopathological disorders following the management of psychoactive substance withdrawal symptoms;

· necessity of special diagnostic methods to perform differential diagnosis;

· absence of a clinical effect from ongoing SUD therapy in outpatient and day hospital settings.

6.2. Indications for outpatient treatment:

· exacerbation of craving for psychoactive substances and/or other psychopathological disorders without a preceding relapse of remission.

6.3. Indications for discharge:

· elimination of psychopathological and somatoneurological disorders.

6.4. Referral for rehabilitation:

· all patients with a diagnosis of SUD who have received inpatient and/or outpatient addiction care are referred for further rehabilitation to stabilize remission [2-3; 113-114].

Optimal patient routing algorithm during sequential rehabilitation stages:

1) Treatment of mental and behavioral disorders due to psychoactive substance use: emergency addiction care unit or addiction department of an addiction hospital (dispensary).

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

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

4) Dispensary observation by the district psychiatrist-narcologist [119].

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 with SUD (ICD-10 code: F11.2-F16.2, F18.2-F19.2)

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

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

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

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

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

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

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

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

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

Procedure for updating clinical guidelines.

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

Appendix A3. Reference Materials

1. Order of the Russian Ministry of Health No. 1034n dated December 30, 2015, "On approval of the Procedure for providing medical care in the field of 'psychiatry-narcology' and the Procedure for dispensary monitoring of individuals with mental disorders and/or behavioural disorders associated with the use of psychoactive substances" (with amendments and addenda).

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

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

4. Order of the Ministry of Health and Social Development of the Russian Federation No. 40 dated January 27, 2006, "On the organization of chemical and toxicological studies in the analytical diagnosis of the presence of alcohol, narcotic drugs, psychotropic, and other toxic substances in the human body" (with amendments and addenda). https://base.garant.ru/12145258/

5. Order of the Russian Ministry of Health No. 103n dated February 28, 2019, "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 the clinical guidelines" (with amendments and addenda).

6. Federal Law No. 3-FZ of January 8, 1998, "On Narcotic Drugs and Psychotropic Substances" (with amendments and addenda)

7. Resolution of the Government of the Russian Federation No. 681 of June 30, 1998, "On approval of the list of narcotic drugs, psychotropic substances, and their precursors subject to control in the Russian Federation" (Collection of Legislation of the Russian Federation, 1998, No. 27, art. 3198; 2006, No. 29, art. 3253)

8. Resolution of the Government of the Russian Federation No. 427 of July 4, 2007, "On introducing amendments to certain resolutions of the Government of the Russian Federation on issues related to the circulation of narcotic drugs and psychotropic substances"

Appendix B. Physician Action Algorithms

Appendix C. Patient Information

OPIOID DEPENDENCE.

Opioid dependence is a disorder characterized by an irresistible urge to use increasing amounts of opium preparations or their synthetic derivatives, with the development of withdrawal syndrome upon cessation of their use.

Opioids belong to the class of narcotic analgesics and include a vast group of pharmacological drugs derived from various varieties of the opium poppy (Papaver somniferum) and other poppy varieties, as well as produced synthetically. The narcotic effect of all opium preparations is very similar, differing in potency, severity, clinical manifestations of withdrawal syndrome, and the rate of development of drug dependence. Overall, however, all the above-mentioned drugs exert a morphine-like effect, which has been studied in considerable detail to date.

Development of dependence.

Opioid abuse often begins with occasional drug use, during which the dose is not increased—so-called episodic use. The duration of the episodic use stage depends on the type of drug, access to it, and the route of administration. On average, this period lasts 1.5–2 months, and extremely rarely it may be longer (6 months or more). At the same time, in some patients, drug intake immediately acquires a regular, often daily character, with the rapid development of all major syndromes and symptoms of opioid dependence. Already at this stage, overdoses may occur, typically due to inexperience and the inability to measure the dose, along with various complications resulting from intravenous drug use.

The main signs of the initial stage of opioid dependence include: a compulsive desire to continuously or periodically take opioids in order to experience the desired effects or relieve symptoms of psychological discomfort that appear after stopping drug use; this often develops in a short period of time (after 2-3 opioid injections). There is also a restructuring of all functional activities of the body in response to the systematic use of opioids. Sometimes 1-2 weeks of daily use of an opium-group drug is sufficient for this. Pronounced physical and psychological disorders manifest when the action of opioids ceases or when their effect is neutralized by opioid receptor blockers. Tolerance develops, which is a state of adaptation to drugs in which the response to the administration of the previous amount of drug is weakened. A higher dose of the drug is required to achieve the desired effect. Cross-tolerance to psychoactive substances is also common, where increased tolerance extends to other psychoactive substances that were not previously used.

With the development of dependence, opioid use becomes systematic. The need to increase the dose is usually observed as early as 2 weeks to 1 month after the start of regular opioid use.

In the absence of the drug or during intervals between administrations, individuals using opioids experience dissatisfaction, depressed mood, and a state of psychological discomfort that disappears immediately after drug use. During this period, withdrawal syndrome may not yet be fully formed, and the physiological effects of the drug persist—decreased urine output, constipation, suppression of the cough reflex, and often unpleasant sensations associated with opioid use still persist. Already at this stage, all thoughts of drug users and all their interests are focused on the drug, while all other life problems recede into the background. All the life activities of the drug user are subordinated to only one thing: the search for the drug and the opportunity to administer it. At this stage, the initial stage of opioid dependence can be diagnosed.

The onset of withdrawal syndrome ("cold turkey") in opioid addiction indicates the formation of a qualitatively new stage of the disease: the second (middle) stage of opioid dependence. Withdrawal syndrome develops approximately 2 weeks to 1.5 months after the start of systematic opioid use. By this time, a craving for the drug has formed, and a specific rhythm of its administration has been established. The daily dose of the drug at this stage tends to increase, but may already reach maximum figures. In general, the tolerance to opioids in a dependent person significantly exceeds lethal doses for a non-dependent person. As the dose increases, the nature of the drug intoxication also changes. During this period, the physiological effects of opioids weaken and disappear, and the "high" changes significantly. In general, euphoria weakens, becomes shorter, and the stimulating effect of opioids begins to dominate its structure. At this stage of the disease, drug-dependent individuals become active and functional only under the influence of opioids. At the same time, irritability, aggressiveness, and explosiveness in a state of intoxication can occur, which are not typical for the initial stages of dependence. The duration of the middle stage of opioid dependence varies, depends on the type of opioid used, its doses, and the method of administration, and averages 5-10 years.

Then the terminal (third) stage of the disease sets in. At this stage, the effect of the drug changes significantly. Drugs are administered by patients solely to maintain working capacity and normal mood, and to prevent the development of withdrawal syndrome. Euphoria after drug administration is almost never observed, and the stimulating effect of opioids completely begins to dominate. The daily consumed dose tends to decrease. When the previous high dose is administered, dependent individuals experience severe lethargy and weakness. The nature of the withdrawal syndrome changes significantly. Pain symptoms are less pronounced and may be limited to general muscle discomfort. On the other hand, the withdrawal syndrome has a protracted character and is accompanied by a large number of cardiovascular complications, as a result of which this condition can become life-threatening. Dependent individuals constantly maintain a depressed mood, and suicidal thoughts are very frequently noted. The duration of the withdrawal syndrome reaches 5-6 weeks. However, even after several months, dependent individuals retain lethargy, weakness, and general malaise. Working capacity is reduced. Distinct mood swings are observed. Cravings for opioids are pronounced all the time.

Medical and social consequences.

Multiple organ and system damage in opioid abuse is caused by the toxic effect of the drug and impurities in "street" drugs, decreased immunity and autoimmune reactions resulting from drug use, unsterile injection of opioids, etc.

The main medical consequences of opioid dependence include parenterally transmitted infections (HIV, viral hepatitis, less commonly syphilis), bacterial endocarditis, as well as superficial vein diseases and rheumatic lesions. In the late stages of dependence, changes in the cardiovascular system, respiratory system, liver, kidneys, and central and peripheral nervous systems are observed. A characteristic feature of internal organ damage in drug use is the discrepancy between minor complaints and the severity of the disease, which significantly complicates the timely detection of such disorders. As a rule, these diseases worsen after quitting opioids. This occurs as a result of systematic intoxication masking internal organ diseases, as well as altered reactivity and metabolism in opioid-dependent individuals.

The appearance of opioid-dependent individuals changes, especially after prolonged drug use. Dependent individuals often look older than their age, their skin is dry and pale, their hair becomes dull and brittle, and their nails also become brittle. Dental destruction is very characteristic: caries and tooth loss. Weight loss and emaciation are common with prolonged opioid use.

Various venous lesions are typical for injection opioid users: thickening of veins into thick cords along which sensitivity is reduced, and vein obliteration. Numerous scars following suppurations and abscesses are often observed along the veins. Severe venous changes are especially common when using homemade preparations prepared by chemical processing of narcotic raw materials.

Treatment.

Once opioid dependence is established, the best option for the patient is to consult a physician. Only a doctor can competently select therapy that will help the patient quit drug use, prevent the negative consequences of dependence, or reduce existing disorders. Treatment for dependent individuals must be prolonged and comprehensive. Therapy involves several stages.

Stage 1: Treatment of withdrawal symptoms. At this stage, the drug is eliminated from the body, and pain is relieved. Currently, there are many good methods and medications that make it possible to alleviate this condition. The main task of this stage is to relieve pain, eliminate suffering, and restore vital body functions.

Stage 2: Treatment of cravings, maintenance therapy.

At this stage, specific medications are used that relieve tension, improve mood, and normalize sleep. Important attention is also paid to the treatment of internal organs, especially the liver, kidneys, and brain. Psychotherapy is carried out 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 result.

Prevention.

There are various specific therapeutic methods for opioid-dependent individuals to prevent relapse, such as the use of opioid receptor blockers—their action in the body protects a person from the effects of opioids; methods and drugs aimed at treating hepatitis C and other consequences of dependence are actively being developed. The use of each of these methods must be strictly individual and carried out under medical supervision.

CANNABINOID DEPENDENCE.

Cannabinoid dependence is a disease manifested by a craving for the continuous use of cannabis preparations, with the development of withdrawal syndrome upon cessation of their use.

Development of dependence.

The stage of occasional cannabis use can be quite prolonged. For several years, it may not even be accompanied by the development of dependence. In adolescence, cannabinoid use almost always occurs in the company of peers and can be irregular in nature. The main danger of cannabinoid use in adolescence is the transition to abuse of other psychoactive substances (opioids, alcohol).

With daily or near-daily smoking of cannabis preparations, signs of dependence appear on average after 3 months. Craving for the drug is accompanied by lethargy, drowsiness, and depressed mood. The dose of cannabinoids increases slowly. As dependence develops, cannabis use becomes solitary, while group use of the drug is less commonly retained. The terminal stage of cannabinoid dependence is extremely rare and may occur after 10 or more years of systematic cannabinoid use.

The timeline for the development of withdrawal syndrome is highly individual, averaging 2–3 years of regular use. The cannabinoid withdrawal syndrome is characterized by a feeling of fatigue and malaise. Sleep disturbances, hand tremors, sweating, nausea, and vomiting may be observed. Mood is depressed, and irritability, malice, sullenness, and apathy are frequently noted. In some cases, intense anxiety predominates in this state—a condition similar to panic reactions. Suicide attempts are possible. Sometimes unusual sensations in various parts of the body are noted: chest tightness, difficulty breathing, unpleasant sensations in the heart area, and a feeling of compression and squeezing of the head in the temporal region. The severity of the drug craving varies greatly, but irresistible craving is rare. The aforementioned disorders reach their peak on days 3–5, and their duration averages 7 days. Subsequently, the patients' state is characterized by marked weakness, apathy, and indifference to surroundings.

Medical and social consequences.

Chronic use of cannabis preparations leads to a number of somatic disorders. Even infrequent smoking of cannabis preparations can lead to burns and ulcerations in the oral cavity and pharynx. Inhalation of smoke containing numerous irritants and carcinogens, including tobacco, leads to chronic obstructive pulmonary diseases as well as lung cancer.

Cannabinoid use is frequently the cause of cardiac arrhythmias, blood pressure fluctuations, and syncope.

The impact of cannabinoids on the reproductive system includes various hormonal disorders, in particular testosterone deficiency and impaired sperm production in men, as well as secondary infertility in both men and women.

Chronic use of high doses of cannabinoids leads to personality changes in dependent individuals. The so-called amotivational syndrome develops, characterized predominantly by apathy, lack of energy, passivity, and a lack of ambitions. Cannabis-dependent individuals neglect any responsibilities (usually study, work) requiring attention and perseverance. Chronic intoxication with cannabis preparations leads to impairments in memory and attention, and may also serve as a trigger for the onset of other psychiatric disorders, particularly schizophrenia, especially in individuals with a corresponding predisposition. Rarely, with heavy cannabinoid use, a psychotic disorder with a late (delayed) onset may occur, resembling similar states seen with hallucinogen abuse.

Treatment.

Once cannabis dependence is established, the best option for the patient is to consult a physician. Only a physician can competently select therapy that will help the patient stop using the drug, prevent the negative consequences of dependence, or reduce existing impairments. The principles and approaches to therapy do not differ: treatment must be prolonged and comprehensive. It includes 3 stages (see above). Unlike therapy for opioid dependence, there are no specific drugs for the treatment of cannabinoid dependence.

Prevention.

It has been established that drug education is the most critical factor in preventing cannabinoid abuse. Therefore, the primary means of prevention is maintaining a healthy, sober lifestyle.

SEDATIVE OR HYPNOTIC DEPENDENCE.

Sedative and hypnotic dependence is a disorder manifested by a craving for the continuous intake of sedatives and hypnotics, with the development of withdrawal syndrome upon cessation of their use. Synonyms: barbiturate addiction; barbiturate type of dependence (WHO); substance use disorder.

Development of dependence.

Based on the mechanism of dependence development, two main groups of patients can be distinguished.

The first category includes patients who were prescribed these medications to treat an existing psychiatric disorder. The risk of developing dependence is high, especially in individuals with a pre-existing substance use disorder and when taking these medications for more than 1 month. The second category includes patients with established alcohol or drug dependence who independently began using sedatives or hypnotics for various purposes: self-treatment of withdrawal syndrome, reduction of anxiety or insomnia, or to enhance the effects of drugs. Acquired tolerance to alcohol or drugs proves to be cross-tolerance to anxiolytics (tranquilizers) and sedative-hypnotics, which is why dependent individuals rapidly increase their doses, discovering the intoxicating effect of these drugs. Systematic intake of high doses of hypnotics and sedatives is quickly established, adding a new dependence to existing ones. A distinctive sign of developing dependence on tranquilizers, hypnotics, or sedatives is the daytime intake of these psychoactive substances.

The initial stage of dependence lasts 2–6 months from the start of systematic intake of hypnotics and sedatives. It is characterized by the need to increase doses, the disappearance of the hypnotic effect when taking therapeutic doses, and sleep disturbances outside of taking these substances. When abstaining from hypnotics and sedatives, psychological discomfort, a sense of dissatisfaction, and depressed mood appear, along with an obsessive desire to take a new dose of medications. Medications begin to be taken during morning and daytime hours.

The second stage of dependence lasts from 6 months to 3 years or more. At this stage, tolerance stabilizes. The nature of intoxication changes noticeably: euphoria caused by taking the medications decreases, while motor and mood disorders increase. Control over the amount of the drug consumed is lost, and withdrawal syndrome appears. Clinically, the withdrawal syndrome is manifested by the following symptoms: tremors of the fingers, tongue, and eyelids; nausea or vomiting; tachycardia, hypotension; headache; insomnia; marked anxiety; with the mandatory addition of convulsive paroxysms. Transient visual, tactile, or auditory hallucinations (illusions) and delusions are also very frequently observed. Withdrawal syndrome occurs 12–24 hours after the last dose of medications, peaks on days 2–3, and lasts for at least a week.

Medical and social consequences.

Chronic intoxication with hypnotics and sedatives leads to pronounced and persistent changes in the somatic, neurological, and psychiatric spheres. Fatigue increases, attention and memory are impaired, and sharpness of mind decreases. As dependence progresses, slowness, withdrawal, and depression increase, at times replaced by bursts of anger and rage. Speech becomes slurred and monotonous, and the manner of speaking changes. Outwardly, patients look tired and exhausted. The skin acquires a pale, earthy hue, and tissue swelling increases. Examination reveals multiple neurological disorders, including weakened pupillary reaction to light, impaired reflexes and coordination (changes in fine motor skills and gait), hand tremors, sluggish facial expressions, and muscle weakness. Instrumental examination reveals a persistent decrease in blood pressure and signs of dystrophic changes in the myocardium. Progressive cognitive decline and gross neurological disorders lead to loss of working capacity and disability. The progression of dementia leads to moral and ethical personal decay.

Treatment.

Once dependence on hypnotics and sedatives is established, the best option for the patient is to consult a physician. Only a physician can competently select therapy that will help the patient stop using these substances, prevent the negative consequences of dependence, or reduce existing impairments. Dependence on hypnotics and sedatives is treated in accordance with general principles (see information above).

Prevention.

To prevent the development of dependence, it is recommended to consult a doctor in any cases of mood problems or sleep disorders. Self-medication is extremely dangerous. Characteristic complications of dependence on sleeping pills and sedatives are difficult to treat. It is necessary to consult a specialist in a timely manner who will help to quit using these substances.

COCAINE DEPENDENCE.

Cocaine dependence is a disorder manifested by a craving for the continuous use of increasing amounts of cocaine, with the development of a withdrawal syndrome upon cessation of use. Synonyms: cocainism, cocaine addiction.

Development of dependence.

Cocaine dependence is manifested by an impaired ability to control its use, resulting from repeated or continuous use of this drug. Cocaine use begins to occupy a central place in the individual's value system and continues despite harm or negative consequences. The characteristics of cocaine dependence are the rapid formation of a craving for the drug, which acquires an irresistible character. Cocaine withdrawal syndrome is generally stated when a state of depressed mood, irritability, and anger replacing euphoria persists for more than 24 hours. The formation of cyclicity in drug use also indicates established dependence.

Medical and social consequences.

When using cocaine, dependent individuals develop hallucinations and persistent persecutory delusions. Outside of intoxication, a person with cocaine dependence is in a state of chronic depression, irritability, and inability to derive pleasure from things that previously brought joy. Dependent individuals begin to clearly feel the inadequacy of their own existence, hopelessness, and experience a feeling of inner emptiness, joylessness, etc. In addition to pronounced mental disorders, chronic cocaine use leads to a variety of somatic disorders. Dependent individuals have a sharp decrease in appetite, leading to weight loss and other nutritional disorders. Regular inhalation of cocaine leads to a decrease in the sense of smell, hoarseness of the voice, irritation of the nasal septum, which manifests as a chronically inflamed or "runny" nose. Among somatic complications in chronic cocaine users, arterial hypertension, heart rhythm disorders and heart attacks, chest pain, and respiratory failure are most common. Myocardial infarctions, inflammation and weakness of the heart muscle, and aortic dissection are less frequently observed. Cocaine abuse leads to blood thickening, which in turn increases the risk of heart attacks and strokes. Gastrointestinal symptoms include abdominal pain and nausea, intestinal necrosis and perforation, and impaired liver function. When cocaine is taken orally, intestinal gangrene often occurs. Neurological complications include cerebral hemorrhages, seizures, persistent headaches, and blindness. Intravenous cocaine use carries a high probability of infectious complications (HIV, hepatitis), as well as the appearance of thrombosis and thrombophlebitis of superficial and deep veins.

Treatment.

Once cocaine dependence has formed, the best option for the patient is to consult a doctor. Only a doctor can competently select therapy that will help the patient stop using the drug, prevent the negative consequences of dependence, or reduce existing disorders. Treatment for dependence is comprehensive. The main task of therapy is to prevent the development of psychiatric complications. Unlike therapy for opioid dependence, there are no specific drugs for treating cocaine dependence.

Prevention.

Cocaine is extremely addictive—it is capable of rapidly causing dependence. Cocaine addiction is characterized by the rapid formation of psychological dependence, the development of psychoses in the form of hallucinations and delusions, and the appearance of chronic depression. The main means of preventing the development of dependence is maintaining a healthy, sober lifestyle.

DEPENDENCE ON OTHER STIMULANTS, INCLUDING CAFFEINE.

Stimulant dependence is an impaired ability to control their use, resulting from repeated or continuous use of these drugs. Stimulant use begins to occupy a central place in the individual's value system and continues despite harm or various negative consequences: mood disorders or escalating mental disorders.

Development of psychostimulant dependence.

The main sign of developing dependence is the appearance of a strong, conscious desire to take the stimulant, which acquires an irresistible character. The characteristics of stimulant dependence are: rapid formation of psychological dependence, mild manifestations of physical dependence, and predominantly periodic patterns of psychoactive substance use. Dependent individuals use the drug round-the-clock for several days, followed by a "rest" period, after which the drug cycle repeats. The number of days of drug use and rest days is individual. Against the background of developing mental and physical exhaustion, periods of use rarely last more than 5–7 days. At the end of such cycles, an aversion to the drug appears. The "rest" phase lasts an average of 3–4 days; during this period, pronounced drowsiness, increased appetite, and irritability are noted.

Continuous stimulant use is less common. At the initial stage of drug use, this group of dependent individuals often experiences sleep disturbances, which prompts them to resort to the use of sleeping pills or sedatives. Once adaptation to the drug's effect occurs, nighttime sleep is restored.

Signs of stimulant dependence usually form after 2–4 weeks of regular drug use. With an established disease, the stimulating effect of the drug weakens, and to obtain previous sensations, dependent individuals are forced to increase the dose and frequency of its use. During use, users often develop ideas of reference or persecution.

Withdrawal syndrome occurs 12–24 hours after the last use of stimulants, with symptoms reaching maximum severity on days 2–4. Withdrawal syndrome is characterized by fatigue, a feeling of being broken, lethargy, and sleep disturbances: insomnia or drowsiness with nightmares. Irritability, malice, and hysterical reactions with a tendency to self-harm are often noted. Depressive manifestations escalate, and ideas of self-blame and suicidal thoughts intensify. Acute manifestations of withdrawal syndrome disappear within 7–14 days; in severe cases, symptoms persist for up to 1 month. Upon cessation of stimulant use, delirium-type psychoses with motor agitation, delusions, and hallucinations may be observed, lasting from 2–3 weeks to several months. This is followed by a period of chronic irritability, depression, and a decrease or loss of the ability to experience pleasure. Patients clearly feel the inadequacy of their own existence, hopelessness, and experience a feeling of inner emptiness, joylessness, etc. At the same time, the craving for the drug becomes irresistible, leading to a relapse of the disease.

Medical and social consequences.

Stimulant use is dangerous due to its severe medical consequences. Stimulant abusers are usually emaciated, with sunken eyes and pale skin with a grayish tint. The presence of tactile hallucinations results in multiple scratch marks and infected skin ulcers. Intravenous drug use results in sharply pigmented "tracks" along the veins with a characteristic pinkish-purple hue.

Stimulant dependence contributes to the onset of cardiovascular disorders: flabbiness of the heart muscle, arrhythmia, persistent arterial hypertension, and irreversible damage to small cerebral vessels, which increases the risk of heart attacks, strokes, and death.

Chronic stimulant use leads to pronounced and often irreversible changes in the brain, beginning with coordination disorders and causing memory decline and loss of intellectual abilities.

The most severe neurological complications are observed with the intravenous use of illicitly manufactured stimulants: general stiffness appears, marked gait and speech disorders develop, toxic polyneuropathy with paresis or paralysis predominantly of the lower extremities, parkinsonian syndrome, and severe encephalopathy resulting in dementia develop. The appearance of a person dependent on illicit stimulants changes: the face becomes mask-like and expressionless, the mouth opens with difficulty, and salivation is increased. Therapy for these disorders is only symptomatic and does not achieve complete reversal of the impairments.

Stimulant abusers exhibit marked social and occupational decline, rapid personality changes manifesting as behavioral disorders, profound moral and ethical deterioration, and emotional blunting. Social maladaptation progresses rapidly: dependent individuals drop out of work and studies, their range of interests narrows down exclusively to drug use, and their social circle is limited to other dependent individuals. Memory and intellect progressively decline, reaching a state of dementia in some cases, combined with pronounced emotional and volitional disorders.

Treatment.

Once stimulant dependence is established, the best option for the patient is to consult a physician. Only a doctor can properly select therapy to help the patient stop using the drug, prevent the negative consequences of dependence, or mitigate existing impairments. The main objective of therapy is to prevent the development of psychiatric complications. Unlike opioid dependence, there are no specific medications for treating stimulant dependence.

Prevention.

All stimulants, except for caffeine, have an extremely high addiction potential. This type of substance use disorder is characterized by the rapid development of psychological dependence, psychotic disorders such as hallucinations and delusions, and the condition frequently culminates in dementia. The primary means of preventing substance use disorder is maintaining a healthy, sober lifestyle.

HALLUCINOGEN DEPENDENCE

Hallucinogens are a group comprising over 100 natural and synthetic substances that induce illusions, hallucinations, and altered states of consciousness when ingested. These substances are also capable of altering the user's perception, thinking, and mood. Psychedelics are "mind-altering drugs" that often do not cause hallucinations per se, but instead distort a person's self-awareness.

Development of dependence syndrome.

Regular use of hallucinogens leads to an intense desire to induce a state of intoxication: obsessive thoughts and memories regarding the pleasure derived from hallucinogen use appear, along with poorly controlled urges to use them. This drives the individual to seek out and repeatedly consume the drug despite potential negative consequences. Furthermore, such individuals exhibit a diminished interest in conventional life goals, replacing them with an obsession for everything related to hallucinogens—thus forming a "classic" psychological dependence.

Conversely, according to most researchers, a withdrawal syndrome does not occur with hallucinogen use. In rare cases involving prolonged systematic use, sleep disturbances, autonomic dysfunction, and general malaise lasting 7–10 days may be observed. Among hallucinogen-dependent individuals, there is a high prevalence of comorbid psychiatric pathology, particularly anxiety and mood disorders.

Medical and social consequences.

Long-term consequences of hallucinogen use manifest as mental dullness ("psychic numbness") observed many days after their intake, as well as psychoses (bad trips), including those persisting after the drug is eliminated from the body (HPPD). Recurrences of hallucinations in the absence of drug use occur in many hallucinogen users when triggered by stress, the use of another psychoactive substance, or a somatic illness. In some cases, hallucinogens trigger the development of schizophrenia, anxiety-depressive disorders, and suicidal tendencies.

Treatment.

Once hallucinogen dependence is established, the best option for the patient is to consult a physician. Only a doctor can properly select therapy to help the patient stop using the drug, prevent the negative consequences of dependence, or mitigate existing impairments. The main objective of therapy is to prevent the development of psychiatric disorders. Unlike opioid dependence, there are no specific medications for treating hallucinogen dependence.

Prevention.

Even a single use of hallucinogens can be dangerous due to the potential triggering of a schizophrenic process. Given the unpredictability of the consequences of hallucinogen use, the best means of prevention is maintaining a healthy, sober lifestyle.

INHALANT DEPENDENCE.

Inhalants are a diverse group of chemical compounds that release volatile vapors, the inhalation of which causes intoxication. Organic volatile solvents, household and industrial chemicals, and volatile hydrocarbons are commonly used as inhalants. As a rule, inhalant abuse begins in adolescence.

Development of dependence.

Inhalants are most commonly initiated by adolescent males; consumption rates decline in older adolescence and drop to zero by adulthood. Initially, inhalant use is typically group-based. The phase of episodic use lasts 1–6 months, less commonly longer. Some adolescents stop using inhalants on their own, but many transition to trying other psychoactive substances. With continued inhalation, dependence gradually forms. Inhalants are inhaled at least 3–4 times a week, later progressing to daily use, sometimes several times a day. One of the main signs of established dependence is the transition from group use of inhalants to solitary use. A powerful, uncontrollable craving for organic solvents emerges, accompanied by an increase in the amount of substance consumed through more frequent use or altered routes of administration.

Inhalant withdrawal syndrome develops 3–6 months after the onset of abuse and 1–3 days after the last use. It manifests as lethargy, malaise, bodily discomfort, headache, sweating, dizziness, nausea, poor sleep, depressed mood, and irritability. These symptoms resemble those of vegetative-vascular dystonia. Depressive symptoms join by days 5–7. On days 4–5, withdrawal may be complicated by acute psychosis lasting from several hours to 3 days, presenting as delirium with illusions, true visual and auditory hallucinations. Overall, the duration of withdrawal under treatment conditions is about 2 weeks.

Medical and social consequences.

Inhalant dependence rapidly leads to toxic encephalopathy with signs of brain atrophy and chronic movement disorders. Pronounced nervous system impairments appear. Polyneuropathy is frequently encountered, manifesting as reduced sensitivity, diminished reflexes, paresthesias in the hands and feet, "sock and glove" numbness, combined with muscle weakness and hyperhidrosis of the palms and soles. Toxic damage to nerve endings in the brain leads to impaired vision, up to blindness, as well as hearing loss. Chronic inhalant intoxication causes cardiac arrhythmias. Toxic kidney damage occurs, frequently accompanied by lower back pain. Toxic liver damage manifests as hypochondriac pain, nausea, vomiting, fever, and frequently jaundice of the skin.

Chronic inhalant intoxication leads to progressive personality changes, including increased aggressiveness, indifference to loved ones and former interests, and heightened irritability. Intellectual decline gradually develops with marked behavioral disorders, and social maladaptation escalates. There is an extremely high risk of developing alcohol and/or other substance use disorders, with rapid development of psychological and physical dependence among inhalant users.

Treatment.

Once inhalant dependence is established, the best option for the patient is to consult a physician. Only a doctor can properly select therapy to help the patient stop using inhalants, prevent the negative consequences of dependence, or mitigate existing impairments. In terms of therapeutic approaches, the condition is similar to the treatment of alcohol dependence. The main objectives of treatment are: combating the powerful craving for inhalants, mitigating behavioral disturbances; treating toxic brain damage; correcting mood disorders and other somatic pathologies; educational and pedagogical measures.

Prevention.

Considering the age factor, primary prevention measures originating from the family are crucial in preventing the development of dependence. The best means of preventing dependence is maintaining a healthy, sober lifestyle.

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

G1. 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 an ADR-drug relationship on the Naranjo scale, based on answers to 10 questions, are determined as:

Notes: none.