Acute poisoning with opioid narcotic substances: clinical guidelines

List of Abbreviations

Terms and Definitions

Detoxification is the process of neutralizing and removing an exogenous toxic substance from the body. As a natural defense process against a toxicant, detoxification includes various mechanisms aimed at converting the poison into non-toxic compounds (metabolites), carried out predominantly in the liver, and eliminating the poison or its metabolites through various pathways—via the kidneys, intestines, liver, lungs, and skin. During the biotransformation of a poison in the body, metabolites more toxic than the ingested toxicant may be formed (lethal synthesis); furthermore, the metabolism of the toxicant in the liver and its excretion along with its metabolites through the kidneys can lead to damage to these organs, resulting in acute kidney injury or liver failure.

Narcotic substances are natural or synthetic substances and preparations included in the List of Narcotic Drugs, Psychotropic Substances, and Their Precursors subject to control in the Russian Federation [1].

Opiates are opium poppy alkaloids (morphine, codeine, thebaine).

Opioids (opioid narcotics) are natural or synthetic chemical compounds that act on opioid receptors and have addictive potential, causing dependence.

Poisoning is a disease developing as a result of the external (exogenous) action of chemical compounds on the human or animal body in amounts that cause disturbances in physiological functions and create a life-threatening hazard [2].

Semisynthetic opioids (heroin (diacetylmorphine), etc.) are chemically modified opiates [2].

Psychoactive substance (PAS) is any substance (or mixture of substances) of natural or artificial origin that affects the functioning of the central nervous system, leading to a change in the mental state of the body [3].

Synthetic opioids (methadone, etc.) are products of chemical synthesis derived from morphine, thebaine, and nitroimidazole derivatives capable of acting on opioid receptors.

Somatogenic stage of poisoning is the period in the course of acute chemical illness characterized by structural damage and altered functions of various organs and systems after the toxic substance has been eliminated or destroyed [3]. It is characterized by various manifestations of somatic (pneumonia, acute renal and hepatic failure, anemia) and psychoneurological (toxic polyneuropathy, psycho-organic syndrome) complications. In this stage of poisoning, specific (antidote) therapy is ineffective, and detoxification is indicated for the relief of endotoxicosis.

Toxicogenic stage of poisoning is the period in the course of acute chemical illness, beginning from the moment the toxic substance enters the body at a concentration capable of causing specific effects [3] and lasting until its elimination. The specificity of clinical manifestations is determined by the chemical and toxicological properties of the toxic substance, the route and form of its administration, and its effect on target organs. The severity of this disease period is directly dependent on the dose of the ingested toxicant and the concentration of the toxicant and its metabolites in the blood. Treatment in this period is aimed at binding and eliminating the poison, as well as relieving the manifestations of intoxication using various methods of accelerated detoxification, antidote, pathogenetic, and symptomatic therapy.

Elimination is the combination of metabolic processes (biotransformation) and excretion of poisons. The first group includes enzymatic oxidation-reduction, hydrolysis, and conjugation reactions, which take place predominantly in the liver. Biotransformation can produce metabolites that are more toxic than the poison that entered the body. The excretion of toxicants and their metabolites is carried out through the lungs, kidneys, liver, gastrointestinal tract, skin, and skin appendages, which may be subject to toxic damage by the poison and its metabolites (acute renal or hepatic failure).

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Opioid poisoning (poisoning by opioid narcotic substances) is a condition caused by the entry of exogenous opioid narcotic substances into the body, whose activating effect on affine receptors directly or indirectly causes physiological function abnormalities of varying severity, including those posing a hazard to health and life. The use of opioids leads to dependence due to their addictive potential.

Due to its widespread prevalence, the synthetic opioid methadone currently holds the greatest significance in toxicological practice [4, 5, 6, 7, 8].

Poisoning by opioid narcotic substances is characterized by a specific syndrome complex (opioid syndrome) that includes varying degrees of impaired consciousness, early development of acute respiratory failure (ARF) due to a decrease in depth and respiratory rate, and miosis with absent pupillary light reflex [2].

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

Currently, opioid narcotic substances are among the most relevant in terms of frequency of use and seeking medical care due to life-threatening conditions resulting from poisoning. Over the past 20 years in Russia, there has been an increase in the number of poisonings by opioid narcotic substances, including indicators of the number of complicated forms of acute poisoning and fatal outcomes. Over the past 10 years, methadone has become the most frequent cause of opioid poisonings [4, 5, 6, 7, 8].

Routes of administration. To achieve narcotic effects, the most common routes of administration are injection (intravenous, subcutaneous, intramuscular), inhalation (smoking), and intranasal (inhaling and sniffing through the nose), while oral (ingestion), rectal, and vaginal routes are significantly less common.

Intravenous administration of opioids accounts for clinical signs of intoxication in nearly 80% of all cases of opioid narcotic use, while the share of intranasal use is about 15%. It should be noted that these routes of administration practically affect the clinical picture in terms of the duration of the narcotic effect (due to delayed elimination of the toxicant) and the onset speed of the narcotic (toxic) effect [7, 8].

Mechanism of toxic action. The action of opioid narcotic substances is realized through the activation of corresponding receptors that regulate the activity of specific groups of neurons in the mammalian brain. Opioid receptors are involved in regulating the body's pain response to stimuli. The classification of the receptors forming this system includes 3 receptor types: µ (mu)-receptors of the morphine type (MOR receptors, OP3 receptors), δ (delta)-receptors (DOP receptors, OP1 receptors), and κ (kappa)-receptors of the ketocyclazocine type (KOP receptors, OP2 receptors). All receptors share ≈ 70% sequence identity in their transmembrane domains, with greater variation in the extracellular loops containing ligand-binding sites and low identity in the N- and C-termini. Endogenous ligands of opioid receptors (endorphins, enkephalins, and dynorphins) are capable of interacting with any of their types, though with varying degrees of affinity. All the mentioned members of the opioid receptor family share common inhibitory influences at the molecular-biological level, but differences between receptors are noted in both anatomical location and receptor environment [2, 3, 8, 26]. Consequently, the effects arising from receptor activation partially differ within subtypes and can be multidirectional (Table 1).

Table 1 – General localization and functions of human opioid receptors [137, 138, 139]

It should be noted that receptors of all types are widely represented in the lung tissue. Furthermore, their maximum number is located within the alveolar walls, with significantly fewer in the smooth muscle of the trachea and major bronchi [2].

Risks of opioid toxicity. Illicit chemical laboratories are exploring alternatives to morphine and heroin. Consequently, the greatest risks of poisoning are associated precisely with semi-synthetic and synthetic opioids, among which groups currently under consideration include: thebaine and oripavine derivatives, meperidine derivatives, fentanyl derivatives, nitazenes (benzimidazoles), orphines, and other compounds.

Despite a high therapeutic index, all of them are capable of causing respiratory depression even at "therapeutic" doses and therefore cannot be used safely.

Oripavine and thebaine derivatives. Of particular interest are semi-synthetic analgesics derived from thebaine. The best known and most studied is etorphine, which exceeds morphine in potency by 500–1000 times. It has found application in veterinary medicine for immobilizing wild animals. This substance is so potent that just 4 mg is sufficient to put a 5-ton elephant to sleep, and 1 mg is enough to immobilize a 2-ton rhinoceros. When dissolved in dimethyl sulfoxide (up to 10 mg/mL), it is capable of penetrating the skin. At a dose of 0.1 mg, it is fatal to humans. Despite its complex structure, etorphine is synthesized from thebaine in a two-step reaction with methyl vinyl ketone followed by the corresponding organometallic reagent. Annually, law enforcement agencies in various countries seize tens of tons of opium—practically free raw material for the production of etorphine and its analogs. Depending on the route of administration and animal species, dihydroetorphine is 2.7–5.5 times more active than etorphine and 6,277–1,500 times more active than morphine. In large doses, it exerts an immobilizing effect. It has a high therapeutic index.

This group also includes potent hallucinogens, such as CL 110 393. At a dose of 1–4.8 µg/kg, it caused mental changes in subjects similar to those after taking LSD, but more pronounced and prolonged (about 12 hours). Somatic disorders were present: ptosis, sweating, as well as irritability, dysphoria, and slurred speech. Hallucinogens 35 times more active than nalorphine also include M285 (cyprenorphine hydrochloride)—a morphine antagonist. It exerts a psychotomimetic effect in humans at a dose of less than 1 mg.

Meperidines. In 1962, P. M. Carabateas and L. Grumbach, in search of an analgesic that could replace meperidine (which was widely used in those years), investigated 1-substituted 4-phenyl-4-propoxypiperidines [140]. Many of the synthesized substances surpassed their precursor by several thousand times! The thienyl and furyl derivatives were recognized as the most active and least toxic of the obtained narcotics.

Fentanils. Carfentanil can rightfully be called the most potent fentanyl analgesic, and sufentanil the safest, as it suppresses the respiratory center the least. At the same time, alfentanil surpasses them in the speed of onset of the effect (sleep and anesthesia occur 20 seconds after intravenous administration; it is 3–5 times more active than fentanyl, but its action is 3 times shorter—about 15 minutes; at a dose of 5–11 µg/kg used for single-agent anesthesia, it does not cause respiratory depression).

The most well-known representative of the fentanyl group is unquestionably 3-methylfentanyl. It was synthesized in 1965 in the laboratories of Janssen Pharmaceutica. Soon, the method was significantly simplified by Chinese chemists, and the use of amphetamine or phenethylamine as starting materials reduced production costs and increased the final product yield to up to 90%. A new drug, named "CHINA WHITE", appeared on the streets of America. It could not displace heroin, of course, but due to its low cost, it quickly found its market. In the 1990s, it began to spread in the USSR under the name "Krokodil" (Crocodile).

Carfentanil is used in veterinary practice for the temporary immobilization of animals (even such large ones as bears and elephants). It is recognized as one of the most potent known analgesics (0.04–0.05 mg per person – 40 times more potent than fentanyl and 8,000–10,000 times more potent than morphine) and has a high therapeutic index.

Sufentanil is considered the safest analgesic among fentanyl derivatives and one of the few synthetic narcotic analgesics that have found clinical application in medicine. In surgery, it is used, for example, in open-heart procedures. It is 7–10 times more potent than fentanyl and approximately 1,000 times more potent than morphine. In humans, at a dose of 0.013 mg/kg, it induces deep analgesia, and at a dose of 0.019 mg/kg, complete loss of consciousness occurs within 3 minutes of administration.

Lofentanil was a more toxic and less studied analgesic, although it surpassed morphine by 4,000–8,000 times, second only to carfentanil. Like alfentanil, it is carried by the bloodstream to rapidly reach brain cells, immobilizing the subject within just 1–2 minutes with minimal side effects.

Nitazenes (benzimidazoles). The most frequently encountered agent, isotonitazene, has been identified in numerous fatal poisoning cases since its emergence in 2019. These compounds are structurally unrelated to fentanyl [141]. Ten nitazene compounds and four metabolites have been described, which were analyzed using four different methods and pharmacologically evaluated using two β-arrestin2/mini-Gi recruitment cellular assays tracking μ-opioid receptor (MOR) activation. Based on absorption spectra and retention times, high-performance liquid chromatography with diode-array detection (HPLC-DAD) allowed the differentiation of most analogs. Liquid chromatography-quadrupole time-of-flight mass spectrometry (LC-QTOF-MS) identified the fragment with m/z 100.11 from 12/14 compounds, which can serve as a basis for MS-based nitazene screening. MOR activity determination confirmed that nitazenes generally exhibit high activity, with the potency and efficacy of certain analogs exceeding those of fentanyl. A very high activity of the N-desethylisotonitazene metabolite was noted, which is comparable to the activity of etonitazene and exceeds that of isotonitazene itself. Judging by their detection in autopsy samples, this is likely significant in vivo. These findings provide the foundation for their analytical detection as well as important new insights into their MOR-activating potential.

Orphines. A recently introduced designation for a class of synthetic opioid analgesics first developed in the 1960s by Paul Janssen, classified as a distinct group in 2025 by international drug control agencies such as the EUDA and UNODC. Initially, the term "orphines" referred to brorphine and bezitramide with an aniline nitrogen cyclized into a benzimidazole ring system. Subsequently, a group of spiropiperidine derivative compounds was assigned to this group, a typical representative of which is spirochlorphine (R6890), where an N-phenylimidazole ring is attached at the 4-position of the piperidine ring via a shared carbon atom [142, 143, 144, 145].

Other synthetic opioids include analgesics from the piperidylidene-2-sulfon(cyan)amide group. Compound W-18 (1-(4-nitrophenylethyl)piperidylidene-2-(4-chlorophenyl)sulfonamide) in mouse experiments at a dose of only 3.7 ng/kg produced an analgesic effect equivalent to 0.038 mg/kg of morphine! In 1981, Lednicer D. and Von Voigtlander P. published the synthesis of a novel potent analgesic, 4-(n-bromo-phenyl)-4-(dimethylamino)-1-phenylethyl-cyclohexanol (bromadol), the trans-isomer of which exhibited analgesic activity at a dose of 0.1 µg/kg [146].

Respiratory effects of opioid exposure are mediated by the stimulation of µ2-receptors and consist of the suppression of the brainstem respiratory center's response to elevated blood carbon dioxide concentrations and the inhibition of respiratory centers in the pontine and medullary regions that regulate respiratory rhythm. This leads to a prolongation of pauses between breaths, slowed inspiration, and the appearance of periodic breathing. Activation of δ-receptors can lead to a prolongation of the expiratory phase of respiration. Clinically, this manifests as a decrease in respiratory rate (down to apnea), initially coupled with an increased tidal volume, which decreases as the condition progresses. In addition, the cough center in the medulla oblongata is suppressed [2, 7, 8].

Sedative effects are associated with action on µ- and κ-receptors. Miosis is also associated with the irritation of these receptors.

Stimulation of the chemoreceptor trigger zone of the medulla oblongata by opioid narcotic substances induces nausea and vomiting. The effect of opioids on the gastrointestinal tract is mediated by both central and peripheral mechanisms involving the stimulation of µ1- and δ-receptors, leading to the inhibition of longitudinal peristalsis in the small and large intestines and a slowdown in the transit of their contents. Under the influence of opioid narcotic substances, the tone of the pylorus, anal sphincter, ileocecal valve, and sphincter of Oddi increases, which, combined with impaired consciousness, creates the prerequisites for aspiration syndrome [2].

Urinary system. Central and peripheral mechanisms of opioid narcotic action lead to impaired urinary function due to pronounced spasm of the urinary bladder sphincter, antinatriuretic, and antikaliuretic manifestations. Furthermore, a direct nephrotoxic effect of the toxicants and their metabolites on the tubules, interstitial tissue, glomeruli, and renal vessels has been noted [2, 8].

Cardiovascular system. Through central cytotoxic mechanisms, opioids exert a stimulating effect on the vagus nerve, exhibiting a negative chronotropic effect leading to bradycardia—up to the formation of heart blocks and arrhythmias—as well as an inotropic effect. In addition, their action is associated with peripheral vasodilation and a protective effect during ischemia and reperfusion [9].

Toxicokinetics. Despite the great diversity of opioids, their toxicokinetics share common properties, such as high lipophilicity and, consequently, the ability to cross tissue barriers [133]. Upon entering the body, opioids interact with specific opioid receptors and plasma proteins, rapidly leaving the bloodstream. Their accumulation has been traced in the lungs, liver, spleen, kidneys, and muscles. They are metabolized in the liver and conjugated with glucuronic acid, which largely ensures their excretion (by 90%) by the kidneys within the first 24 hours. The half-life of morphine in the blood averages 3.5 hours (ranging from 1 to 7 hours), the volume of distribution is 3.3 L/kg, and plasma protein binding is 20–30%. The main metabolites are inactive morphine-3-O-glucuronide (65–75%), active morphine-6-O-glucuronide (0.3–33%), free morphine, normorphine, and normorphine glucuronide. Unlike morphine, the pharmacokinetics of heroin (diacetylmorphine) is characterized by rapid penetration into the brain and tissues due to its lower polarity and higher lipid solubility. In addition, it undergoes rapid biotransformation in the blood into 6-monoacetylmorphine (an active metabolite with a t_1/2 = 1.3 h), and subsequently into morphine via a deacetylation reaction. Codeine possesses pharmacological activity at opioid receptors both independently and through its metabolic products. Thus, up to 20% of codeine undergoes biotransformation with the formation of morphine as an intermediate product. These features of opioid metabolism must be taken into account for effective chemical-toxicological, clinical, and forensic diagnosis. Synthetic opioid compounds, including methadone, rapidly enter the bloodstream. With oral administration, it can be analytically identified within 15–45 minutes, with peak concentration recorded between 2.5 and 4 hours [7, 8, 10]. The absorption of methadone depends on the purity of the substance and its concentration, the intensity of gastrointestinal (GI) motility, the magnitude of intestinal perfusion, and the pH of the intestinal contents [7, 11]. The average oral bioavailability of methadone is 70–80%, although variations from 36% to 100% have been observed. This depends on individual variability and the activity of cytochrome P450 3A4, which is involved in methadone metabolism [7, 12]. The opioid diffuses well through body tissues, with an average volume of distribution of 4.0 L/kg (1.9–8.0 L/kg) [13]. Methadone is characterized by rapid tissue accumulation and slow release back into the plasma, contributing to its prolonged elimination. The opioid readily crosses the placenta, and its concentration in amniotic fluid is comparable to that in blood plasma [14], where the free (unbound) methadone fraction averages 13% with up to a fourfold variation in values [2, 7, 15, 16].

1.3 Epidemiology of the Disease or Condition

Acute poisonings by opioid narcotic and psychoactive substances represent one of the leading causes of emergency hospitalization among poisonings of various etiologies. For instance, according to reports from the Center for Acute Poisonings in St. Petersburg (Form No. 64), patients with this pathology accounted for 12.6%, 13.8%, and 12.2% of all admissions to toxicology departments in 2022–2024, respectively. The proportion of in-hospital mortality from poisoning by this class of drugs relative to total mortality from acute poisonings averaged 38.5%, 42.4%, and 40% during the period 2022–2024, respectively. In most cases, patients with acute opioid poisoning are admitted in critical condition. For example, the Center for Acute Poisonings at the St. Petersburg I.I. Janelidze Research Institute of Emergency Medicine admitted 1105 patients with opioid poisoning in 2022, of whom 35 died (mortality in the methadone poisoning group was 3.2%). In 2023, a sharp increase in patients admitted with opioid poisonings was recorded, reaching 1245. The overall mortality in this group in 2023 was 2%, which included 25 patients out of 1221 admitted with acute methadone poisoning. In 2024, out of 1090 patients with drug poisonings, 1066 patients (97.8%) were admitted with acute methadone poisoning, of whom 30 died (2.8% of all patients admitted with acute methadone poisoning) [17, 18, 19].

Data analysis of annual statistical reports from the pediatric toxicology department of the N.F. Filatov City Children's Clinical Hospital in Moscow showed that from 2015 to 2022, the number of hospitalized pediatric patients with acute poisoning by narcotic and psychoactive substances increased significantly. The figures rose from virtually isolated cases to 13-14% of all annual hospitalizations due to chemical poisonings. At the same time, opioid poisonings rank second in frequency among all poisonings by narcotic and psychoactive substances in pediatric toxicological practice and accounted for hospital mortality in 2022–2024.

1.4 Features of Coding the Disease or Condition

In ICD-10, acute poisonings by opioid narcotic substances are presented in the following categories:

T40.0 Opium poisoning.

T40.1 Heroin poisoning.

T40.2 Poisoning by other opioids.

T40.3 Methadone poisoning.

1.5 Classification of the disease or condition

Depending on the severity, poisonings by opioid narcotic substances can be classified into 3 degrees.

In mild poisoning, impaired consciousness is noted at the level of lethargy, corresponding to 15–13 points on the Glasgow Coma Scale (GCS) (Appendix G1); however, the patient remains accessible for contact despite pronounced lethargy and drowsiness. Neurological symptoms are predominated by a decrease in pupil diameter (miosis) and sluggish reaction to light, ptosis, nystagmus, and impaired convergence. Muscle hypotonia, decreased deep tendon reflexes, and cerebellar ataxia are detected. Sometimes muscle hypotonia is replaced by periodic increases in muscle tone of a spastic type and hyperactive deep tendon reflexes. Pain sensitivity is reduced. Respiratory impairment is manifested by a tendency toward a slowed respiratory rate down to 10–12 breaths per minute during sleep or lethargy. There are no impairments of vital functions.

Moderate poisonings are characterized by depression of consciousness down to superficial coma, although tactile and painful stimuli can cause the comatose state to transition into stupor; the patient's position is passive, and the skin is pale. Leading symptoms include miosis, up to the appearance of "pinpoint pupils" with decreased or absent reaction to light, hyperactive or preserved tendon and periosteal reflexes, and decreased or absent response to painful stimuli. In some cases, catatonia is observed in the form of waxy rigidity of the muscles with the ability to assume a forced posture. Bradypnea is more pronounced, reaching 6–8 breaths per minute.

Severe poisoning is characterized by the development of deep coma. The pupillary light reflex, corneal, cough, and pharyngeal reflexes are absent. Areflexia, atonia, and no response to painful stimuli are noted. Hemodynamics is impaired in the form of hypotension. Respiratory disorders are recorded as bradypnea of less than 6 breaths per minute or single breaths up to complete respiratory arrest [20]. When opioids are administered via inhalation in high doses, early apnea occurs abruptly, often against the background of hypertonus and convulsive paroxysms, which in favorable cases is replaced by paradoxical breathing as muscle relaxation occurs.

1.6 Clinical presentation of the disease or condition

The rapid development of symptoms and complications makes acute poisoning by opioid narcotic substances one of the most severe diseases of chemical etiology. Signs of acute poisoning appear immediately after substance intake; the severity of clinical manifestations and poisoning depends on the dose (concentration) of the substance taken, its exposure time, the patient's age, and underlying comorbidities.

Clinical manifestations of acute poisonings by opioid narcotic substances are uniform and consist of a combination of symptoms involving central nervous system and consciousness depression (lethargy, stupor, coma), respiratory depression (bradypnea, suppression of the cough reflex, asphyxia), gastrointestinal disorders (decreased peristalsis), renal impairment (urinary retention), and persistent miosis. The most informative signs of poisoning by this class of substances are miosis and pronounced respiratory depression (bradypnea down to 4–8 per minute), which are detected upon examination in patients in both stuporous and comatose states. During opioid intoxication, the pupils appear constricted. In poisoning by κ-agonists, aggressiveness and behavioral abnormalities are observed in some cases; poisoning by opioids of this type in higher doses leads to hallucinatory-delusional manifestations with loss of consciousness, possibly without respiratory impairment. Most κ-agonists have an activating effect on parasympathetic innervation and lead to persistent miosis. In addition, opioids also suppress cortical inhibition in the Edinger-Westphal nucleus, which also results in pupillary constriction [2]. Suppression of respiratory center activity represents one of the most significant and serious effects of this group of substances, mediated through the activation of µ-receptors, which is why poisoned patients exhibit hypopnea, bradypnea, or respiratory arrest.

The criteria for assessing the severity of poisoning should be the degree of consciousness and respiratory depression, as well as cardiovascular system disorders.

Complications should be considered taking into account the toxicogenic and somatogenic stages of poisoning. The most dangerous are rapidly developing complications in the toxicogenic stage, such as respiratory arrest, especially after intravenous administration of a toxic dose of an opioid narcotic substance or asphyxia following the aspiration of gastric contents, leading to cerebral edema and swelling, which develops against the background of altered blood-brain barrier permeability and prolonged hypoxia. Another complication is non-cardiogenic pulmonary edema caused by hypoxia and vasoconstriction, leading to increased capillary pressure and the influx of proteinaceous transudate into the parenchyma and alveoli. Characteristic complications of the somatogenic stage include pneumonia, toxic-hypoxic encephalopathy, and myorenal syndrome associated with positional trauma during prolonged forced positioning of the patient [6, 7].

2. Diagnostics, medical indications and contraindications for diagnostic methods

The diagnosis must take into account the following diagnostic criteria:

• evidence of recent use of an opioid narcotic substance (or substances) in toxic doses;

• presence of symptoms and signs of poisoning consistent with the known action of the opioid narcotic substance, sufficiently pronounced to lead to clinically significant impairments of consciousness and life support systems (respiratory, cardiovascular) that are hazardous to the patient's life and health;

• inability to explain the diagnosed symptoms or signs by a disease unrelated to the use of an opioid narcotic substance, or by another mental or behavioral disorder.

2.1 Complaints and Anamnesis

Complaints in acute poisoning depend on the type and dose of the opioid narcotic substance and are determined by its primary or side effects. Additionally, patient complaints may be due to complications. In most cases of acute poisonings by opioid narcotic substances, complaints are generally absent due to difficulty or inability to communicate with the patient.

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Comments: in acute poisonings by narcotic substances, many drug-abusing patients are admitted to toxicological centers or intensive care units in an unconscious state or are unwilling to communicate with medical staff [21].

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Comments: in cases of opioid poisoning, the general principles of toxicological anamnesis collection are far from always applicable. Ascertaining such information as the type or name of the toxic substance taken by the victim; the time of its ingestion (toxin exposure duration in the body), which allows estimating the poisoning phase (toxicogenic or somatogenic) with a certain degree of accuracy; the dose of the toxic substance taken, which determines the severity of its clinical course; the route of administration of the toxic substance into the body; and circumstances accompanying the poisoning (accidental or intentional) is very difficult in patients due to impaired consciousness. The absence of relatives or acquaintances of the victim who can clarify the anamnestic features of the poisoning necessitates making a diagnosis based on the leading clinical syndrome. Diagnosis of opioid poisoning should be based on the toxicological situation (discovery of syringes, means for illegal drug manufacturing, packaging from psychotropic drugs, etc.), toxicological anamnesis aimed at identifying information about the use of drugs, other psychoactive substances, dependence on certain substances, as well as the clinical picture of the poisoning.

A specific feature of narcotic poisoning is the absence in most cases of subjective complaints from the patient – medical assistance is usually sought by relatives or acquaintances who noticed impairments in their consciousness, behavior, or appearance [22, 23].

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Comments: the diagnosis of opioid poisoning is based on anamnestic data and characteristic symptoms such as depressed consciousness, respiratory depression, and the presence of miosis. In addition, with intravenous administration of opioids, injection marks along the subcutaneous veins of the extremities may be identified, although this does not happen in every case, which complicates the correct assessment of the situation. The symptom complex of opioid poisoning in terms of diagnostics is the most specific among all psychoactive substances used for the purpose of narcotic intoxication. Also, in opioid poisoning, a parasympathetic orientation of autonomic reactions predominates: skin moisture, salivation, miosis, bradycardia, and a tendency toward hypotension. Considering that patients with impaired consciousness are among the most difficult diagnostically, a particularly thorough differential diagnosis of the pathological condition is necessary in such cases [23].

2.2 Physical Examination

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Comments: there is no specific skin coloration; with respiratory depression, cyanosis of the lips, face, and acrocyanosis are noted; the skin is cold, and in deep coma, it is hyperhidrotic. It is necessary to identify the presence/absence of rashes, local changes, the so-called "pressure sores" as a result of positional trauma due to pressure from the body's own weight with the appearance of areas of skin hyperemia, which are often regarded as bruises, hematomas, burns, phlebitis, allergic edema, etc., and are usually detected at early stages (1–3 days).

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Comments: it is necessary to evaluate the psychoneurological status [22, 23, 25, 26, 27]: state of consciousness – alert, lethargy, stupor, coma, psychomotor agitation, hallucinations. If coma is present, evaluate its depth using the GCS (Appendix G1). Assess the presence or absence of reflexes, pupil diameter, their reaction to light, the presence or absence of anisocoria, and muscle tone. When anisocoria or pathological reflexes are detected, pay attention to their constancy ("wandering pupils"). In the somatogenic stage, negative psychopathological symptoms may be noted, which include: asthenic clouded consciousness, psycho-organic and asthenic symptom complexes, opioid withdrawal syndrome, as well as abstinence, epileptic, and delirium syndromes [22, 23].

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Comments: it is necessary to assess the condition and severity of acute poisoning with an opioid narcotic substance using the Poisoning Severity Score (Appendix G3) [106, 107].

Level of Reliability of Evidence (LRE) – 4, Level of Recommendation Validity (LRV) – C.

Comments: in acute poisonings with opioid narcotic substances, external respiration disorders with the progression of acute respiratory failure are frequently detected. Acute respiratory failure may occur due to alveolar hypoventilation, possible aspiration pneumonitis, or non-cardiogenic pulmonary edema [22, 23, 28, 29, 30]. Among life-threatening conditions, the greatest clinical significance is attributed to the syndrome based on the mechanisms of action of opioid drugs, which clinically presents in acute poisoning as impaired respiratory function manifested by decreased depth and slowed respiratory rate, leading to acute respiratory failure requiring mechanical ventilation [20, 21]. Furthermore, acute poisonings with opioid narcotic substances are frequently complicated by aspiration-obstructive disorders associated with mechanical asphyxia and other pathological processes in the lungs (atelectasis and pneumonia). In the pathogenesis of pneumonia, which is one of the frequent causes of patient death in the somatogenic stage, a prolonged coma complicated by aspiration-obstructive disorders plays a significant role. These disorders allow assessing the severity of poisoning and predicting treatment outcomes [2, 22, 23].

LoE – 3, GoR – C.

Comments: toxic damage to the cardiovascular system may manifest as circulatory disorders caused by arrhythmias, arterial hypotension with tissue hypoperfusion, including due to systemic hypoxia [2, 28]. Hemocirculatory decompensation with the progression of hypoxic damage and metabolic disorders is the most frequent cardiovascular complication.

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Comments: The clinical presentation of acute opioid poisoning depends on numerous factors. Significant factors include the dynamics of substance intake (the time interval over which the total amount was consumed), individual characteristics of the subject (age, ethnicity, gender, mental and physical condition), toxicological characteristics of the opioid substance (degree of purity, presence of toxic impurities), and ambient temperature. Finally, the degree of tolerance to opioids in dependent individuals is of major importance. When diagnosing acute opioid poisoning, it must also be taken into account that its symptoms do not always reflect the primary action of the substance; for example, opioids with sedative properties may cause symptoms of psychomotor agitation [22, 23, 33]. Furthermore, clinical diagnosis must be performed taking into consideration the stage of poisoning—toxicogenic and somatogenic. The leading symptom, first and foremost, should be considered the presence of signs of toxic CNS damage and depression of consciousness in the form of obtundation, sopor, or coma.

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

2.3 Laboratory Diagnostics

Level of Reliable Evidence (LRE) – 2, Level of Legitimate Recommendations (LLR) – C.

Comments: the choice of laboratory diagnostic method depends primarily on the circumstances in which the study is conducted (primary health care in an outpatient clinic or emergency department of a non-specialized hospital, specialized inpatient medical care), as well as on the objective of the study: 1) determination of the fact of use of narcotic drugs or psychoactive substances; 2) identification of a specific substance or substances in the patient's biological media. In the first case, a qualitative IA test is sufficient. When using IA, it should be kept in mind that a negative result always indicates the absence of the target narcotic substance in the sample, whereas a positive result, due to a potential false-positive outcome, may lead to a diagnostic error, thus necessitating verification by a more precise GC-MS and/or LC-MS/MS method.

Level of Reliable Evidence (LRE) – 2, Level of Legitimate Recommendations (LLR) – C.

Level of Reliability of Evidence (LRE) – 4, Level of Recommendation Validity (LRV) – C.

Comment: when determining methadone and its metabolites, samples are analyzed without hydrolysis. For liquid-liquid extraction, a mixture of solvents is used: isopropyl alcohol, dichloromethane, dichloroethane, heptane. At low concentrations of opiates, derivatization with silylating reagents may be performed. Solid-phase extraction is generally carried out using a universal 3 mL column. For solid-phase cleanup using the QuEChERS method, kits containing a C18 phase and magnesium sulfate (MgSO₄) are used.

Level of Reliability of Evidence (LRE) – 4, Level of Recommendation Validity (LRV) – C.

Comment: for the detection and identification of narcotic, psychoactive, and other toxic substances, gas chromatography with a single-quadrupole mass spectrometer is used. Separation is performed using an HP-5ms capillary column (30 m × 0.25 mm × 0.25 µm). The mass spectrometer is operated under electron ionization conditions (EI, 70 eV) with total ion current (TIC, 40–550 m/z) acquisition. The injected sample volume is 1 µl.

To process the results, the Automated Mass Spectral Deconvolution and Identification System (AMDIS) and component identification confirmation using the National Institute of Standards and Technology (NIST) general-purpose library are used.

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Comments: in chemical and toxicological studies, a modular liquid chromatograph with a tandem mass spectrometer is used. The injected mixture is separated using a liquid chromatography column thermostatted at 40 °C. Component elution is performed using a binary eluent consisting of phase A (0.3 vol.% formic acid in water) and phase B (acetonitrile) according to the following program: 1% phase B (2 min); linear gradient to 100% B (18 min); hold (2 min). The mobile phase flow rate is 0.5 ml/min, and the injected sample volume is 5 µl. The mass spectrometer is configured for electrospray ionization (ESI) operation. The measured parameter is the peak area on product ion spectra at a collision energy of 22 eV.

The use of LC-MS/MS, owing to its superior sensitivity, makes it possible to detect opioid-type narcotic drugs such as fentanyl derivatives [42, 44].

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Comment: currently, qualitative IA detection of the following narcotic substances is available: morphine/heroin, methadone, plant cannabinoids, amphetamine, methamphetamine, α-pyrrolidinovalerophenone, cocaine, phenobarbital, benzodiazepines. Rapid diagnostics is performed using test strips. Both monotests (one test – one psychoactive substance) and multitests (detection of up to 10 different psychoactive substances in a single test) can be used. IA with photometric detection allows not only determining the presence of a psychoactive substance but also estimating its approximate concentration. As noted previously, a disadvantage of IA is the possibility of obtaining false-positive results. Therefore, when positive or borderline IA results are obtained, chemical and toxicological confirmation using analytical methods, specifically GC-MS and/or LC-MS/MS, is required.

LRE – 3, LLR – B.

Comments: GC-MS is a precise method for the qualitative and quantitative determination of psychoactive substances in biological fluids. It allows for non-targeted (screening) analysis, i.e., the simultaneous determination of a large number of various psychoactive substances. LC-MS/MS is less accessible due to the high cost of testing, but it has a significant advantage: it enables the detection of psychoactive substances that degrade upon heating, as well as the minimization of sample preparation, which substantially reduces analysis time.

Level of Reliability of Evidence (LRE) – 4, Level of Recommendation Validity (LRV) – C.

Level of Reliability of Evidence (LRE) – 4, Level of Recommendation Validity (LRV) – C.

Level of Reliability of Evidence (LRE) – 4, Level of Recommendation Validity (LRV) – C.

Level of Reliability of Evidence (LRE) – 4, Level of Recommendation Validity (LRV) – C.

Level of Reliability of Evidence (LRE) – 4, Level of Recommendation Validity (LRV) – C.

Comments: severe acute opioid poisoning is frequently complicated by water-electrolyte balance (WEB) and acid-base balance (ABB) disorders. These are diagnosed as severe abnormalities, most commonly manifesting as decompensated mixed respiratory and metabolic acidosis, as well as hyperkalemia.

Table 2 – Criteria for the severity of acid-base balance disorders [132]

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Level of Reliability of Evidence (LRE) – 4, Level of Recommendation Validity (LRV) – C.

Comment: the frequency of these tests will depend on the severity of poisoning and the duration of the patient's stay in the hospital [2, 21].

Level of Reliability of Evidence (LRE) – 4, Level of Recommendation Validity (LRV) – C.

Comments: individuals abusing opioid substances are classified as a high-risk group for contracting socially significant diseases. To detect these diseases, the following serological tests are performed:

• Determination of hepatitis B virus (Hepatitis B virus) HBeAg in the blood;

• Determination of hepatitis B virus (Hepatitis B virus) HBsAg in the blood;

• Determination of hepatitis C virus (Hepatitis C virus) Core antigen in the blood;

• Determination of antibodies to hepatitis B virus (Hepatitis B virus) surface antigen (anti-HBs) in the blood, qualitative assay;

• Determination of hepatitis B virus (Hepatitis B virus) DNA in the blood by PCR, qualitative and quantitative;

• Determination of total class M and G antibodies (anti-HCV IgG and anti-HCV IgM) to hepatitis C virus (Hepatitis C virus) in the blood;

• Determination of hepatitis C virus (Hepatitis C virus) Core antigen in the blood;

• Determination of hepatitis C virus (Hepatitis C virus) RNA in the blood by PCR, qualitative assay;

• Investigation of the level of class M, G antibodies (IgM, IgG) to human immunodeficiency virus HIV-1/2 and p24 antigen (Human immunodeficiency virus HIV 1/2 + Agp24) in the blood;

• Qualitative determination of human immunodeficiency virus RNA by PCR.

2.4 Instrumental Diagnostics

Performing these diagnostic procedures does not allow for clarifying the diagnosis of acute opioid poisonings. However, they are necessary for the early diagnosis of complications in moderate and severe opioid poisonings, which may affect the outcome of acute poisoning.

LCE – 5 GLE – C.

Leads of Evidence Level – 4, Recommendation Grade – C.

Comments: electrocardiography (ECG) makes it possible to assess the probability of the presence/development of cardiomyopathy and chronic cardiac pathology, especially since the life history of such patients upon admission to the hospital is virtually unknown.

LCE – 5 GLE – C.

Leads of Evidence Level – 4, Recommendation Grade – C.

Comments: monitoring of vital functions should, whenever possible, be performed instrumentally using an intensive care cardiac monitor. In the absence of a monitor, periodic control of vital signs must be performed manually.

The frequency of repeated measurements is determined by the attending physician depending on the severity of the patient's condition [3, 53, 68].

Instrumental diagnostic methods are an integral part of the diagnostic process performed to monitor the patient's condition.

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Level of Reliability of Evidence (LRE) – 4, Level of Recommendation Validity (LRV) – C.

2.5 Other Procedures

Additional diagnostic methods may be prescribed by specialists based on the specific clinical situation and indications. Since acute opioid poisonings are associated with impaired consciousness, they are characterized by high variability of clinical manifestations, the likelihood of life-threatening conditions and complications, and a frequent need for differential diagnosis.

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Comments: the presence of severe injuries, persistent focal neurological symptoms, prolonged coma, and lack of positive dynamics under ongoing treatment indicate the presence of neurological or infectious pathology and serve as an indication for an in-depth examination using echocardiography (EchoCG), electroencephalography (EEG), spiral computed tomography (SCT), and lumbar puncture [3], which often necessitates involving the following specialists to resolve diagnostic and treatment issues:

• psychiatrist;

• neurosurgeon;

• neurologist;

• infectious disease specialist;

• otorhinolaryngologist;

• surgeon;

• general practitioner / internist;

• pediatrician;

• child psychiatrist;

• pediatric surgeon.

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

3.1. General approaches to the treatment of acute poisoning with opioid narcotic substances

Clinical manifestations of mild acute opioid poisoning may include behavioral disorders, which warrant psychopharmacotherapy and dynamic monitoring. Moderate and severe acute opioid poisoning conditions require emergency medical care. The severity of acute opioid poisoning does not always correlate with the concentration of opioids in the patient's blood. The ability to immediately quantitatively determine opioid concentrations in body fluids is not always technically feasible; therefore, when choosing a treatment strategy, the physician is often forced to use a syndromic approach. Assessing the patient's degree of agitation or sedation is extremely important for clinical diagnosis. The GCS is recognized as a convenient diagnostic tool for this purpose (Appendix G1) [73].

In children older than 4 years, an adult-like GCS is used to assess the functional state of the central nervous system. For children under 4 years of age, a scale similar to the adult GCS is used, except for the verbal response assessment (Appendix G2).

3.2. Provision of pre-hospital emergency medical care for acute opioid poisoning

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

In mixed-type disorders, aspiration-obstructive respiratory disorders are eliminated first, followed by the initiation of mechanical ventilation.

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Comments: the diameter of the orogastric tube for gastric lavage in children should be 24-28 French scale (8-9 mm). When consciousness is depressed to sopor and coma, gastric lavage is performed only after tracheal intubation [108, 109, 110].

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Comments: in patients with acute opioid poisoning, the causes of pre-hospital cardiac arrest are typically the development of a comatose state with impaired external respiration, the progression of which leads to mixed decompensated respiratory and metabolic lactate acidosis. Electrolyte disturbances in the form of hyperkalemia are very frequently observed. Timely correction of acid-base balance disorders in some cases influences the efficacy of resuscitation measures in acute opioid poisoning [7, 8, 22, 23, 120, 147, 148].

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Comments: in patients with acute opioid poisoning complicated by cardiac arrest, there are severe metabolic disorders in the form of decompensated mixed respiratory and metabolic acidosis, and hyperkalemia, which are not corrected by the administration of naloxone** and, accordingly, do not eliminate the causes of cardiac arrest. Moreover, the use of naloxone** can exacerbate the severity of the condition due to its mechanisms of action, i.e., eliminating the anti-hypoxic protection of opioids in the context of progressing hypoxic brain damage. The use of naloxone** under conditions of severe hypoxia leads to an increased tissue demand for oxygen against the background of a failing oxygen transport system, which may also cause ineffective resuscitation measures or lead to irreversible brain damage. In the intensive care of acute severe methadone poisoning with complications such as acute respiratory failure (ARF), hemodynamic disorders, and urinary system disorders, it is necessary to adhere to general resuscitative management tactics for patients [7, 8, 22, 23, 121, 148].

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

3.3. Treatment at the stage of specialized medical care

3.3.1. Treatment of respiratory disorders

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Comments: the main goal of respiratory support in ventilatory ARF is considered to be the replacement of lost or sharply weakened spontaneous breathing due to impaired function of the respiratory center and/or disorders of respiratory muscle activity (paralysis, paresis). Impairment of the respiratory center function in acute opioid poisoning leads to the suppression or weakening of the sensitivity of central chemoreceptors, causing hypoventilation, which leads to life-threatening hypercapnia and hypoxemia.

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Comments: the goal of sedation is to achieve comfort and safety for the patient and their surroundings, to ensure that diagnostic and therapeutic procedures are performed under optimal comfortable and safe conditions for the patient, and ultimately to improve the patient's condition and eliminate the consequences associated with a particular pathology [81].

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Level of Evidence (LE) – 5, Grade of Recommendation (GR) – C.

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

3.3.2. Treatment of hemodynamic disorders

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Level of Evidence (LE) – 5, Grade of Recommendation (GR) – C.

Comments: the presence of shock is an absolute indication for initial volume loading at a volume of 20 ml/kg to eliminate hypovolemia and maintain adequate cardiac output. The goal of therapy is to achieve an optimal mean arterial pressure, which in children over 12 years of age should not be lower than 60–65 mm Hg. If there is no effect from fluid bolus administration, myocardial dysfunction and a cardiac cause of shock must be excluded [113, 114].

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Comments: infusion therapy with solutions affecting water-electrolyte balance is recognized as one of the simplest and most accessible methods for maintaining adequate cardiac output and the fastest possible elimination of the toxicant from the patient's body. The optimal volume of volume loading should take into account the individual characteristics of the patient and the presence of comorbid conditions. To calculate the daily age-related fluid requirement in children, it is advisable to use the Holliday-Segar formula (see Table 3).

Table 3 – Calculation of fluid volume for maintenance infusion therapy (Holliday M.A., Segar W.E., 1957)

If clinical and instrumental signs of intracranial hypertension are present, the volume of administered fluid should be restricted to 75% of the calculated value.

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Comments: hypoglycemia is the most common and dangerous complication of acute poisonings in children, which can cause secondary brain injury and neurological deficit against the background of experienced hypoxia and metabolic disorders. The presence of clinically significant hypoglycemia is recognized as an absolute indication for emergency correction.

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Comment: infusion therapy should be tailored to the individual patient. The volume and composition of the infusion program depend on age, patient condition, comorbid pathology, and complications [21, 69, 83, 84]. Affected patients are indicated to receive infusion therapy with solutions affecting water and electrolyte balance to achieve a stable urine output rate of at least 1 mL/kg per hour. Hydroxyethyl starch preparations** are not indicated. The infusion volume must not be lower than the physiological requirement, which is 30 mL per 1 kg of body weight. The reduction of infusion therapy volume is carried out under the control of fluid balance, central venous pressure (CVP) measurement, and pulse oximetry [21, 69, 83, 84].

Level of Reliability of Evidence (LRE) – 4, Level of Recommendation Validity (LRV) – C.

Level of Reliability of Evidence (LRE) – 4, Level of Recommendation Validity (LRV) – C.

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Comments: in patients with acute opioid poisoning complicated by severe hypoxia, metabolic disorders occur in the form of decompensated mixed respiratory and metabolic acidosis and hyperkalemia, which are not resolved by the administration of naloxone**. Furthermore, the use of naloxone** may aggravate the severity of the condition due to its mechanisms of action, i.e., the elimination of the antihypoxic protection of opioids in the context of progressing hypoxic brain damage. The use of naloxone** under conditions of severe hypoxia leads to an increased tissue oxygen demand against the background of failing oxygen transport systems, which can lead to irreversible brain damage clinically manifested by the development of epileptiform seizures [7, 8, 22, 23, 121].

3.3.3. Correction of homeostasis disorders

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Comments. In patients with diabetes mellitus, dextrose** is administered under the control of blood and urine glucose levels [47, 53, 56, 73, 80].

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Comments: in patients with acute opioid poisoning, the development of a comatose state with external respiratory disorders leads to mixed decompensated respiratory and metabolic lactate acidosis; electrolyte disorders in the form of hyperkalemia are very frequently observed. Therefore, the early elimination of acid-base balance disorders plays a crucial role in the course of acute opioid poisoning, since persistently prolonged metabolic acidosis, which naturally develops in opioid poisoning, is capable of exerting a pronounced adverse effect on various organ systems by itself, aggravating the severity of respiratory disorders [7, 8, 22, 23, 120].

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Comments: depending on the indications for use, age, body weight, patient condition, and concomitant therapy, the doses as well as the treatment efficacy in terms of general symptoms and laboratory parameters, the rate and duration of use are selected individually. Before administration, solutions are warmed to 36-38 ^oC [47, 53, 56, 73, 80].

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Comments: the total dose, duration, and rate of administration depend on individual requirements, taking into account the monitoring results of routine circulatory parameters (e.g., blood pressure), which should be adjusted if necessary. To detect allergic (anaphylactoid/anaphylactic) reactions as early as possible, the first 20-30 mL of gelatin** should be infused slowly and under close supervision [21, 69, 83, 84].

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Comments: Furosemide** is administered intravenously and, in exceptional cases, intramuscularly. The rate of intravenous administration should not exceed 4 mg per minute. In patients with severe renal impairment (serum creatinine concentration > 5 mg/dL), the intravenous infusion rate should not exceed 25 mg per minute. For dilution, 0.9% sodium chloride solution** can be used. The diluted drug solution should be used as soon as possible after preparation [2, 3, 21, 23, 47, 56].

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

3.3.4. Detoxification

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

3.3.5. Antidote therapy

LNC – 2, GDE – A.

Comments: the pharmacological antagonist naloxone** eliminates the effects of opioids by specifically blocking µ-opioid receptors, which is why it is considered an opioid antidote. The duration of action of naloxone** is 45-90 min. [2, 21, 33]. Administration of naloxone** in high doses is indicated for the treatment of acute poisonings with propoxyphene, diphenoxylate, methadone, levo-alpha-acetylmethadol (LAAM), pentazocine, and oxycodone [2]. When performing antidote therapy with naloxone**, certain conditions for its use must be strictly observed. The administration of naloxone** in cases of severe respiratory disorders, prolonged exposure to the toxin, or signs of severe hypoxia is strictly contraindicated! Potential serious side effects of naloxone** must be taken into account, including pulmonary edema, seizures, and the onset of opioid withdrawal syndrome. The use of naloxone** without considering these conditions can lead to life-threatening complications such as progressive cerebral edema/swelling and progressive pulmonary edema [2, 21, 33].

When using naloxone**, it should be taken into account that the half-life of certain opioids, in particular methadone, is up to 48 hours, which can lead to a secondary manifestation of respiratory disorders after the drug's effect wears off (re-intoxication). Therefore, the patient requires prolonged monitoring despite the positive effect obtained from a single dose of the antidote. After intravenous administration, the effect is observed in 1-2 minutes, after intramuscular administration in 2-5 minutes, reaching a maximum in 5-15 minutes; the duration of the effect depends on the dose and route of administration – after intravenous administration of 0.4 mg, the duration of the effect is 45 minutes, while after intramuscular administration, the effect can persist for up to 4 hours [2, 21].

Patients who have received intravenous naloxone** require continuous monitoring of their respiratory status for the early diagnosis of non-cardiogenic pulmonary edema, the occurrence of which may necessitate mechanical ventilation with positive end-expiratory pressure to achieve adequate oxygenation. It is worth noting that since this group of patients may present with hypovolemia, treating pulmonary edema with forced diuresis can exacerbate hypotension.

3.3.6. Other treatment

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

In uncomplicated poisoning, rehabilitation is not required.

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Level of Evidence (LE) – 5, Grade of Recommendation (GR) – C.

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

5. Prevention and Dispensary Observation

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

6. Organization of Medical Care

All patients with acute opioid poisoning are indicated for hospitalization in a 24-hour inpatient facility that includes a toxicology department or an intensive care unit.

Hospitalization of patients with acute opioid poisoning is carried out in a toxicology department (toxicology treatment center), or, if unavailable, in an intensive care unit or an intensive care ward of a therapeutic hospital.

Upon admission to a medical organization, patients with acute opioid poisoning must be evaluated by a toxicologist and/or an anesthesiologist-resuscitologist.

Hospitalization in the intensive care unit is indicated:

• in acute opioid poisoning accompanied by depression of consciousness with a GCS score of less than 11;

• in acute opioid poisoning complicated by disorders of the respiratory, circulatory, renal, or hepatic systems;

• in acute opioid poisoning complicated by seizure(s) within 24 hours;

• in acute opioid poisoning combined with concurrent life-threatening somatic or neurological pathology.

If a hospitalized patient develops acute cerebral insufficiency with a Glasgow Coma Scale (GCS) score below 11, with or another acute respiratory, cardiac, renal, or hepatic failure in the setting of acute opioid poisoning, they are urgently transferred to the intensive care unit of a toxicology center or to a general intensive care unit (if the toxicology department lacks an ICU).

Treatment in the intensive care unit is continued until vital functions are stabilized and detoxification measures are completed; subsequently, patient rehabilitation is carried out in an acute poison treatment center, therapeutic, or pediatric departments.

After the recovery of consciousness and vital functions in patients with acute poisoning by opioid drugs without complications and dependence syndrome, the patient is discharged from the hospital (recovery applies only to the poisoning). Patients with acute opioid poisoning and dependence syndrome are referred to a psychiatrist-narcologist.

Hospitalization periods are determined by the severity of the poisoning.

Average duration of inpatient treatment:

1. mild severity – 1 to 2 bed-days;

2. moderate severity – 3–5 bed-days;

3. severe grade without complications – 6–14 days;

4. severe grade with complications (pneumonia, acute renal failure, acute hepatorenal failure) – treatment duration from 14 to 24 bed-days.

7. Additional Information

Not applicable.

Criteria for Evaluating the Quality of Medical Care

Table 4 – Criteria for assessing the quality of medical care [24].

References

Appendix A1. Working Group Composition

1. Lodyagin Alexey Nikolaevich – D.Sc. in Medicine, Associate Professor, Chief Freelance Toxicologist of the Russian Ministry of Health, Head of the Department of Clinical Toxicology, I.I. Dzhanelidze Saint Petersburg Research Institute of Emergency Medicine.

2. Potskhveriya Mikhail Mikhailovich – D.Sc. in Medicine, Head of the Department of Acute Poisoning and Somatopsychiatric Disorders, N.V. Sklifosovsky Research Institute for Emergency Medicine of the Moscow City Health Department.

3. Batotsyrenov Bair Vasilievich – D.Sc. in Medicine, Associate Professor, Chief Researcher at the Department of Clinical Toxicology, I.I. Dzhanelidze Saint Petersburg Research Institute of Emergency Medicine, Anesthesiologist-Resuscitator at the Intensive Care Unit No. 11 (Toxicology) of the Department of Clinical Toxicology, I.I. Dzhanelidze Saint Petersburg Research Institute of Emergency Medicine.

4. Sukhodolova Galina Nikolaevna – D.Sc. in Medicine, Professor, Leading Researcher at the Department of Acute Poisoning and Somatopsychiatric Disorders, N.V. Sklifosovsky Research Institute for Emergency Medicine of the Moscow City Health Department.

5. Golfarb Yury Semyonovich – D.Sc. in Medicine, Professor, Leading Researcher at the Department of Acute Poisoning and Somatopsychiatric Disorders, N.V. Sklifosovsky Research Institute for Emergency Medicine of the Moscow City Health Department.

6. Tsarenko Sergey Vasilyevich – D.Sc. in Medicine, Professor, Chief Freelance Specialist in Anesthesiology and Resuscitation of the Ministry of Health of the Russian Federation, Director of the Medical and Rehabilitation Center of the Ministry of Health of the Russian Federation.

7. Afonchikov Vyacheslav Sergeevich – Ph.D. in Medicine, Associate Professor, Deputy Chief Medical Officer for Anesthesiology and Resuscitation, I.I. Dzhanelidze Saint Petersburg Research Institute of Emergency Medicine.

8. Sinenchenko Andrey Georgievich – D.Sc. in Medicine, Associate Professor, Head of the Department of Emergency Psychiatry, Narcology, and Psychorehabilitation, I.I. Dzhanelidze Saint Petersburg Research Institute of Emergency Medicine.

9. Irina A. Shikalova – Ph.D. in Medicine, Senior Researcher at the Department of Clinical Toxicology, Saint Petersburg Research Institute of Emergency Medicine named after I.I. Dzhanelidze.

10. Narziculov Rustam Abdukhalimovich – D.Sc. in Medicine, Leading Researcher at the Department of Clinical Toxicology, I.I. Dzhanelidze Saint Petersburg Research Institute of Emergency Medicine.

11. Kuznetsov Oleg Anatolyevich – Candidate of Medical Sciences, Researcher at the Department of Clinical Toxicology, Dzhanelidze St. Petersburg Research Institute of Emergency Medicine.

12. Kuznetsov Semyon Valerievich – Ph.D. in Medicine, Associate Professor, Senior Researcher at the Department of Clinical Toxicology, I.I. Dzhanelidze Saint Petersburg Research Institute of Emergency Medicine, Associate Professor at the Department of Disaster Medicine, Traumatology, Orthopedics, and Military Field Surgery, Saint Petersburg State Pediatric Medical University of the Ministry of Health of the Russian Federation.

13. Simonova Anastasia Yuryevna – Ph.D. in Medicine, Leading Researcher at the Department of Acute Poisoning and Somatopsychiatric Disorders, N.V. Sklifosovsky Research Institute for Emergency Medicine of the Moscow City Health Department, Chief Freelance Toxicologist of the Moscow City Health Department, Associate Professor, Head of the Department of Clinical Toxicology, Russian Medical Academy of Continuous Professional Education of the Ministry of Health of the Russian Federation, Senior Researcher at the L.M. Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of the Federal Medical-Biological Agency.

14. Balabanova Olga Leonidovna – Ph.D. in Medicine, Head of the Chemical-Toxicological Laboratory, Senior Researcher at the Department of Clinical Toxicology, I.I. Dzhanelidze Saint Petersburg Research Institute of Emergency Medicine.

15. Matkevich Victor Anatolyevich – D.Sc. in Medicine, Scientific Consultant at the Department of Acute Poisoning and Somatopsychiatric Disorders, N.V. Sklifosovsky Research Institute for Emergency Medicine of the Moscow City Health Department.

16. Alexandrovich Yury Stanislavovich – D.Sc. in Medicine, Professor, Chief Freelance Pediatric Anesthesiologist-Resuscitator of the Northwestern Federal District of the Russian Ministry of Health, Head of the Department of Anesthesiology, Resuscitation, and Emergency Pediatrics of the Faculty of Postgraduate and Additional Professional Education, Saint Petersburg State Pediatric Medical University of the Ministry of Health of the Russian Federation.

17. Preshisnov, Konstantin V. – D.Sc. in Medicine, Associate Professor, Professor at the Department of Anesthesiology, Critical Care and Emergency Pediatrics, Faculty of Postgraduate and Continuing Professional Education, St. Petersburg State Pediatric Medical University of the Russian Ministry of Health.

18. Zabolotsky, Dmitry V. – D.Sc. in Medicine, Professor, Head of the Professor V.I. Gordeev Department of Anesthesiology, Critical Care and Emergency Pediatrics, St. Petersburg State Pediatric Medical University of the Russian Ministry of Health.

19. Kaziahmedov, Vitaly A. – Ph.D. in Medicine, Associate Professor, Associate Professor at the Department of Anesthesiology, Critical Care and Emergency Pediatrics, Faculty of Postgraduate and Continuing Professional Education, St. Petersburg State Pediatric Medical University of the Russian Ministry of Health.

20. Tkeshelashvili, Tengiz T. – Head of the Resuscitation Department for Emergency Detoxification, Sklifosovsky Research Institute for Emergency Medicine of the Moscow Healthcare Department.

21. Konovalov, Alexey V. – Ph.D. in Medicine, Deputy Head of the Department of Neurotoxicology, State Research and Testing Institute of Military Medicine of the Russian Ministry of Defense.

22. Subbotina, Svetlana N. – Ph.D. in Biology, Senior Researcher at the Department of Neurotoxicology, State Research and Testing Institute of Military Medicine of the Russian Ministry of Defense.

23. Mosin, Alexey V. – Head of the Resuscitation Unit, Scientific and Clinical Center of the State Research and Testing Institute of Military Medicine of the Russian Ministry of Defense.

24. Kovalenko, Lilia A. – Ph.D. in Medicine, Associate Professor at the Department of Pediatric Anesthesiology, Critical Care and Toxicology, Russian Medical Academy of Continuing Professional Education of the Russian Ministry of Health, Toxicologist at the N.F. Filatov Children's City Clinical Hospital of the Moscow Healthcare Department and the Academician Yu.M. Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of the Federal Medical-Biological Agency.

25. Baturova, Vera Yu. – Chief Specialist of the Department for Organizational and Methodological Work and Regional Cooperation, National Medical Research Center for Rehabilitation and Balneology of the Russian Ministry of Health.

26. Yazenok, Arkady V. – D.Sc. in Medicine, Associate Professor, Head of the Department of Military Field Therapy, S.M. Kirov Military Medical Academy of the Russian Ministry of Defense.

27. Fomichev, Alexey V. – Ph.D. in Medicine, Associate Professor at the Department of Military Field Therapy, S.M. Kirov Military Medical Academy of the Russian Ministry of Defense.

28. Kuzmich, Vladimir G. – Ph.D. in Medicine, Associate Professor at the Department of Military Field Therapy, S.M. Kirov Military Medical Academy of the Russian Ministry of Defense.

29. Vetryakov, Oleg V. – D.Sc. in Medicine, Associate Professor, Senior Lecturer at the Department of Military Field Therapy, S.M. Kirov Military Medical Academy of the Russian Ministry of Defense.

30. Sarmanaev, Salavat Kh. – D.Sc. in Medicine, Professor, Head of the Department of Toxicology and Clinical Pharmacology, Academy of Postgraduate Education of the Federal Research and Clinical Center of Specialized Medical Care and Medical Technologies of the Federal Medical-Biological Agency.

31. Akhmetov, Ildar R. – Ph.D. in Medicine, Associate Professor, Head of the Toxicology Center of the FMBA of Russia, Federal Research and Clinical Center of Physical-Chemical Medicine of the FMBA of Russia.

There is no conflict of interest.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience of these clinical guidelines:

1. anesthesiologist-intensivist;

2. gastroenterologist;

3. infectious disease physician;

4. immunologist;

5. cardiologist;

6. laboratory diagnostic physician;

7. neurologist;

8. neurosurgeon;

9. general practitioner (family physician);

10. otorhinolaryngologist;

11. emergency and critical care physician;

12. forensic medical expert;

13. internist;

14. district general practitioner;

15. toxicologist;

16. transfusiologist;

17. functional diagnostics physician;

18. surgeon;

19. endoscopist;

20. psychiatrist-narcologist.

Methodology for Developing Clinical Guidelines

Working group members independently performed a systematic search and selection of publications. The search was conducted in the PubMed search engine (http://www.ncbi.nlm.nih.gov/pubmed/), the Cochrane Library (http://www.cochranelibrary.com/), the eLIBRARY.ru scientific electronic library (http://elibrary.ru/defaultx.asp), as well as clinical trial registries: https://clinicaltrials.gov/ and https://www.clinicaltrialsregister.eu/ctr search/search. A total of 220 publications were found, of which 116 were selected. Based on the selected publications, thesis-recommendations were formulated and evaluated using scales for assessing levels of evidence (LE) for diagnostic methods (diagnostic interventions), levels of evidence (LE) for prevention, treatment, and rehabilitation methods (preventive, therapeutic, rehabilitation interventions), and levels of recommendation consensus (LC) for prevention, diagnostics, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, rehabilitation interventions) (Table 5, Table 6, Table 7). Subsequently, each thesis-recommendation was thoroughly discussed at a general meeting of the working group, and consensus was reached in all cases of disagreement.

Table 5 – Scale for assessing levels of evidence (LE) for diagnostic methods (diagnostic interventions)

Table 6 – Scale for assessing levels of evidence (LE) for prevention, treatment, and medical rehabilitation methods, including those based on natural therapeutic factors (preventive, therapeutic, rehabilitation interventions)

Table 7 – Scale for assessing levels of recommendation consensus (LC) for prevention, diagnostics, treatment, and medical rehabilitation methods, including those based on natural therapeutic factors (preventive, diagnostic, therapeutic, rehabilitation interventions)

Procedure for updating clinical guidelines.

The clinical guidelines update mechanism provides for their systematic revision—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 specific diseases, or the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

1. Order of the Russian Ministry of Health No. 289 dated October 5, 1998, "On Analytical Diagnostics of Narcotic Drugs, Psychotropic and Other Toxic Substances in the Human Body."

2. Order of the Russian Ministry of Health No. 262n dated April 29, 2025, "On Approval of the Procedure for Conducting Medical Examination for Intoxication (Alcoholic, Narcotic or Other Toxic), Including Determination of Clinical Signs of Intoxication and Rules for Chemical-Toxicological Studies, as well as Criteria Giving Sufficient Grounds to Believe That a Person Is Intoxicated and Subject to Referral for Medical Examination, the Accounting Form of the Act of Medical Examination for Intoxication (Alcoholic, Narcotic or Other Toxic), and the Form and Procedure for Maintaining the Register of Medical Examinations for Intoxication (Alcoholic, Narcotic or Other Toxic)."

3. Order of the Russian Ministry of Health No. 925n dated November 15, 2012, "On Approval of the Procedure for Providing Medical Care to Patients with Acute Chemical Poisoning."

4. Order of the Russian Ministry of Health dated April 14, 2025, No. 203n "On approval of criteria for assessing the quality of medical care."

5. Order of the Ministry of Health of the Russian Federation No. 804n dated October 13, 2017, "On Approval of the Nomenclature of Medical Services."

6. Federal Law No. 489-FZ dated December 25, 2018, "On Amendments to Article 40 of the Federal Law 'On Compulsory Medical Insurance in the Russian Federation' and the Federal Law 'On the Basics of Protecting the Health of Citizens in the Russian Federation' Regarding Clinical Practice Guidelines".

7. Order of the Russian Ministry of Health No. 103n dated February 28, 2019, "On Approval of the Procedure and Timeframes for Developing Clinical Guidelines, Their Revision, the Standard Template for Clinical Guidelines, and Requirements for Their Structure, Composition, and Scientific Validity of the Information Included in Clinical Guidelines".

8. Order of the Russian Ministry of Health No. 919n dated November 15, 2012, "On Approval of the Procedure for Providing Medical Care to the Adult Population in the Profile 'Anesthesiology and Critical Care Medicine.'"

9. Decree of the Government of the Russian Federation No. 2406-r dated October 12, 2019, "On Approval of the List of Vital and Essential Drugs, as well as Lists of Medicinal Products for Medical Use and the Minimum Assortment of Medicinal Products Required for the Provision of Medical Care."

Table 8 – Volume of water used for gastric lavage in children of various age groups

Table 9 – Mild poisoning

Table 10 – Moderate and severe uncomplicated poisoning

Table 11 – Severe poisoning with complications (pneumonia, toxic encephalopathy, positional trauma, toxic nephro-hepatopathy, acute renal failure, multiorgan failure, sepsis, vegetative state)

Appendix B. Physician Action Algorithms

Appendix C. Patient Information

Information for a patient admitted in a state of narcotic coma is provided after the restoration of consciousness. It must contain information about complications that occurred in the toxicogenic stage of poisoning, and the planned treatment during the rehabilitation process (if necessary for this patient).

In cases of acute mild and moderate opioid poisoning, the patient is informed about the health hazards of these toxic substances, potential complications, long-term consequences of poisoning, planned examinations (chemical-toxicological, clinical-biochemical, instrumental), and treatment (detoxification methods, pathogenetic, specific therapy). The patient (or their legal representatives) signs an informed voluntary consent for the proposed scope of examination and treatment.

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

Appendix G1. Glasgow Coma Scale

Russian name: Glasgow Coma Scale, GCS.

Original name (if any): The Glasgow Coma Scale, GCS.

Source (official developers' website, publication with validation): Teasdale G., Jennett B. Assessment of coma and impaired consciousness. A practical scale. // The Lancet. – 1974. – Vol. 2, № 7872. – P. 81-84.

Type (underline):

• rating scale;

• index;

• questionnaire.

Purpose: for quantitative assessment of the severity of coma and neuropsychiatric disorders.

Content:

Table 12 – Glasgow Coma Scale

Interpretation of the results:

• 15 points – alert / clear consciousness;

• 10–14 points – moderate and deep obtundation;

• 8–10 points – stupor;

• 6–7 points – moderate coma;

• 4–5 points – terminal coma;

• 3 points – brain death.

Appendix G2. Pediatric Glasgow Coma Scale (for children under 4 years of age)

Russian name: Paediatric Glasgow Coma Scale (for children under 4 years of age).

Original name (if any): Paediatric Glasgow Coma Scale.

Source (official developers' website, publication with validation): Morrav J.P. et al: Coma scale for use in brain-injured children. // Critical Care Medicine. – 1984. – Vol. 12, № 12. – P 1018-1020. doi: 10.1097/00003246-198412000-00002.

Type (underline):

• rating scale;

• index;

• questionnaire.

Purpose: for quantitative assessment of the severity of coma and neuropsychiatric disorders.

Content:

Table 13 – Paediatric Glasgow Coma Scale (for children under 4 years of age)

Interpretation of the results:

• 15 points – alert consciousness;

• 13–14 points – moderate obtundation;

• 11–12 points – deep obtundation;

• 9–10 points – stupor;

• 7–8 points – moderate coma;

• 4–6 points – deep coma;

• 3 points – terminal coma.

Appendix G3. Poisoning Severity Score

Russian name: Poisoning Severity Score.

Original name: Poisoning severity score (The European Association of Clinical Poison Centres and Clinical Toxicologists).

Source: H.E. Persson, G.K. Sjöberg, J.A. Haines, J. Pronczuk de Garbino. Poisoning severity score. Grading of acute poisoning. Assessment of coma and impaired consciousness. A practical scale. // J. Clin. Toxicol. – 1998. – Vol. 36, № 3. – P. 205-13.

Highlight type:

• rating scale;

• index;

• questionnaire.

Purpose: for quantitative assessment of the severity of acute poisoning.

Content:

Table 14 – Poisoning Severity Score