Naloxone

Pharmacological properties of the drug Naloxone-m

Naloxone is a competitive antagonist of opiate receptors and belongs to the group of so-called pure opiate receptor antagonists. It blocks predominantly m-receptors and, due to its significant affinity for these receptors, naloxone displaces narcotic analgesics from binding sites, thus eliminating the symptoms of opioid overdose and eliminating the effect of both endogenous opiate peptides and exogenous opioid analgesics; has a lesser effect on other opiate receptors. Administration of naloxone prevents, weakens or eliminates (depending on the dose and time of administration) the effects of opioid analgesics, restores breathing, reduces sedation and euphoria, and weakens the hypotensive effect. Naloxone eliminates the action of a wide group of drugs, both agonists and agonists-antagonists of opiate receptors: morphine, apomorphine, diamorphine (heroin), codeine, dihydrocodeine, trimeperidine, methadone, pentazocine, fentanyl, buprenorphine. The drug eliminates central and peripheral toxic symptoms: respiratory depression, constriction of the pupils, slow gastric emptying, dysphoria, coma and convulsions, as well as the analgesic effect of narcotic analgesics, in addition, it eliminates the toxic effect of high doses of alcohol. Naloxone is also effective in combating respiratory dysfunction in mixed poisoning caused by opioids in combination with barbiturates, benzodiazepines and alcohol. Naloxone provokes withdrawal symptoms in patients with opioid dependence. The drug does not have analgesic activity, does not cause dysphoria and psychomimetic symptoms, the development of addiction and the formation of drug dependence. When administered intravenously, the effect of the drug begins within 0.5–2 minutes, the duration of action is 20–40 minutes. When administered intramuscularly or subcutaneously, it acts within 2–3 minutes, duration of action is 2.5–3 hours. The average half-life is 1–1.5 hours; in newborns it is longer (3 hours). Naloxone is metabolized in the liver to form glucuronides. Metabolites are excreted in the urine. Use in liver and kidney failure has not been studied. Penetrates through the blood-brain and placental barriers.

Prescription antidote. Nikita Sologub - about the scarcity of naloxone

Overdose is the leading cause of death among opioid drug users. It happens for a variety of reasons: you can get an overdose if the drug is too pure or too dirty, if the user takes opiates along with alcohol, sedatives and stimulants, or if, due to the body's addiction, it seems to him that the previous dose is no longer enough. According to the chief narcologist of the Ministry of Health, Evgeniy Bryun, about 8 thousand people die from overdoses in Russia every year; in Moscow there are about one and a half thousand of them. At the same time, Brun notes, in the vast majority of such cases (85%) death occurs before the ambulance arrives.

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The only drug that, according to the vast majority of experts, actually reduces overdose mortality is the opioid receptor antagonist naloxone. This drug uses the same brain receptors as heroin and other opioids, displacing and blocking their effects for 30 to 90 minutes, helping restore breathing and help avoid death. Blocking opioid receptors is the exclusive purpose of this drug; a drug user will not get a “high” from it, and if you inject naloxone into a person who does not use opiates, then nothing will happen to him at all, as if he received an injection of water.

In 2014, the World Health Organization published recommendations to reduce overdose deaths, including calling on the global community to develop programs to increase access to naloxone. In different countries, the situation looks different: in some places there is simply nowhere to buy naloxone, in others harm reduction programs operate at the state level and the antidote is sold without a prescription and given to employees of all services that may encounter cases of overdose, from the police to the ambulance. help. The high number of overdose deaths and increasing political awareness of the problem are pushing more and more countries towards the second option.

In Russia, naloxone is one of nine antidotes included in the list of vital, essential drugs. However, it is sold strictly according to prescription. This is probably due to the form of release: in Russia, all drugs that need to be administered intravenously or intramuscularly, even water for injections, are dispensed by prescription. Since Russian doctors are often dismissive of the lives of drug users, most of them, even knowing about the existence of naloxone, will not go to the doctor for a prescription for it, and if they did, they would hardly receive a prescription.

“Some time ago we thought: since naloxone is available by prescription, any drug addict can come to a regular district drug clinic and say: “I inject heroin to reduce the risk of an overdose, write me a prescription for naloxone, I’ll buy it, let it go.” I’m lying, and if my mother injects it into me, let her know that it’s there,” says Maxim Malyshev, an employee of the Andrei Rylkov Foundation for the Promotion of Health Protection and Social Justice (an organization that, according to the Russian Ministry of Justice, performs the functions of a foreign agent). – A couple of months ago we conducted such an experiment; two of our friends went to their drug dispensaries. Narcologists don’t give prescriptions, they say: “We shouldn’t give it, we are narcologists, but we don’t prescribe naloxone.” That is, they don’t motivate or explain in any way.” And from Branch No. 6 of the State Budgetary Healthcare Institution “Moscow Scientific and Practical Center for Narcology of the Department of Healthcare”, the following answer came to the request of the Rylkov Foundation: naloxone is used only “either in emergency conditions or in a hospital setting.”

The Rylkov Foundation has been fighting for universal access to naloxone for drug users for many years. On August 31, 2015, on International Overdose Awareness Day, activists from the Foundation and the Eurasian Network of People Who Use Drugs picketed the Ministry of Health and the Moscow Scientific and Practical Center for Narcology. Participants in the action demanded that the drug be given over-the-counter status and that drug users (in particular, those undergoing treatment in state drug treatment hospitals) be informed about the existence of naloxone. Soon, Dr. Brun promised to distribute 30 thousand packages of naloxone to Moscow drug users who were being treated at a drug dispensary. However, few go for treatment; the majority prefer not to seek the help of doctors in solving their problems. Therefore, many are still at risk of dying from an overdose.

People whose lives naloxone could save continue to die

To save these people, in 2014, volunteers of the Rylkov Foundation began distributing naloxone in their office and during street work. At that time, three versions of this drug were presented on the Russian market: from Spanish, Polish and Russian manufacturers, now only one (from the Moscow Endocrine Plant). Activists purchased it through online pharmacies that did not ask for a prescription. On average, one purchase cost about 10 thousand rubles (this is approximately 50 packs, each containing 10 ampoules, or 500 lives potentially saved from an overdose). In order not to create problems for the Foundation with the tax inspectorate, employees and volunteers purchase the drug at their own expense. The Foundation keeps statistics: in 2014, 223 drug users with whom the Foundation worked reported using naloxone for an overdose, in 2015 - 194, in 2016 - 318, in 2017 - 423. Although these estimates are approximate, thus one can guess how many lives were saved thanks to this drug.

The Rylkov Foundation has been corresponding with the Ministry of Health for more than three years in the hope of changing the state’s position on the issue of prescription of the drug. “This is a conversation between a mute and a deaf person. We ask specific questions: Why, based on what research, was the decision made to make naloxone available for prescription? They take a long time to prepare a response - after each request we wait at least a month, but we receive an absolutely meaningless response,” says Malyshev. In 2015, for example, in response to a request from the ministry, they reported that the prescription of a drug is determined “in the process of examining the ratio of the expected benefit to the possible risk of using the drug,” which is carried out during its state registration. Later they added: “The range of indications for use and the method of administration of the drug do not correspond to the accepted concept of dispensing over-the-counter drugs in Russia.”

A solution could be to produce the drug in a form that does not require dispensing from pharmacies with a prescription (for example, intranasal naloxone is freely sold in the USA). Since the only enterprise on the Russian market selling naloxone was the Moscow Endocrine Plant, Foundation activists approached its management with a proposal to add a new release form, but the appeal was simply ignored. Not long ago, injectable naloxone also disappeared from Russian pharmacies. As Malyshev says, the problems began in April 2021: in online pharmacies, the Fund’s employees began to respond that only one or two packs of the drug were left in stock, and it became impossible to purchase 10–15 thousand rubles, as before, as before. In July, naloxone completely disappeared from sale - pharmacies promised that the drug would be available any day now, but then it turned out that suppliers had stopped purchasing it.

At the end of October, in response to a request from the Moscow Endocrine. Malyshev explains this answer as follows: “Apparently, the MEZ does not produce naloxone on its own, but buys the substance, and at the plant it is bottled into ampoules, brought to a marketable state, and for some reason the old supplier had to be changed. Now, for sure, this substance will also need to be certified, and it will take two to three months for naloxone to reach pharmacies.” At the office of the Rylkov Foundation today, when World AIDS Day is celebrated, there are only two packs of naloxone left out of 13, which Malyshev brought from his last trip abroad.

The Andrey Rylkov Foundation is the only organization that tries to inform drug users about the existence of naloxone and provide access to it. But the Foundation is now mainly busy trying to raise money to pay an exorbitant fine of 800 thousand rubles for a newspaper article that talked about the consequences of consuming “salts”. “Naloxone is a vital drug that can save lives, and it is very important that it is available to people who use opiates, and their relatives and friends, so that at a critical moment the life of a loved one can be saved,” says the President of the Foundation Rylkova Anna Sarang.

At the state level, the problem of the lack of naloxone on the market has not yet received attention. And people whose lives naloxone could save continue to die.

Nikita Sologub – journalist

Opinions expressed in the “Blogs” section may not reflect the views of the editors

Indications for use of the drug Naloxone-m

Overdose of narcotic analgesics, benzodiazepines, barbiturates, coma in acute alcohol poisoning. In anesthesiology, it is used to accelerate recovery from anesthesia, neuroleptanalgesia, in case of depression of the respiratory center caused by halothane or ketamine, during operations for focal epilepsy, before completing controlled breathing; to restore breathing in newborns after administering opioid analgesics to a woman in labor; for shock in combination therapy; as a diagnostic tool in patients with suspected opioid addiction.

Solution for injection Naloxone is used intravenously as a stream (injection), intravenously as a drip (infusion), as well as intramuscularly and subcutaneously. The dose is determined by the doctor individually for each patient. Intramuscular and subcutaneous injections are prescribed when intravenous administration is not possible.

In acute cases, preference should be given to intravenous use of the drug, as it provides the fastest therapeutic effect.

When administered intramuscularly, the effect of the drug appears later, but lasts longer (compared to intravenous use).

The duration of action of Naloxone injection solution depends on the administered dose, route of administration and ranges from 45 minutes to 4 hours.

Because the effects of some opioids last longer than naloxone, patients should be under continuous medical supervision and repeat doses should only be given if necessary.

In case of opioid overdose.

Adults

The initial dose is 0.4 - 2 mg intravenously. If breathing is not restored, administration should be repeated after 2 - 3 minutes. Naloxone can also be administered intramuscularly, the initial dose is 0.4 - 2 mg if intravenous administration is not possible. If the patient's condition does not improve with the administration of naloxone 10 mg, we can conclude that respiratory depression is caused by other factors or drugs other than opioids.

Children

The recommended initial dose is 0.01 mg per 1 kg of body weight intravenously. If the desired effect is not achieved, naloxone is re-administered at a dosage of 0.1 mg per 1 kg of body weight. Depending on the patient's condition, intravenous infusion may be indicated. If intravenous administration is not possible, the drug is administered slowly, intramuscularly or subcutaneously at an initial dose of 0.01 mg per 1 kg of body weight. If necessary, repeated administration is possible.

For respiratory depression caused by opioids.

Adults

Doses are determined by the doctor individually in order to normalize respiratory function while maintaining adequate analgesia. Intravenous injection of naloxone at a dose of 0.1 - 0.2 mg (approximately 0.0015 - 0.003 mg per 1 kg of body weight) is usually sufficient. If necessary, an additional 0.1 mg can be administered at intervals of 2 minutes until breathing and consciousness are completely restored. Additional administration may be needed over a period of 1 to 2 hours, depending on the type of action of the active substance (short-term effect or delayed action),

regarding which naloxone is an antagonist, its amount used, duration and route of administration.

Alternatively, the drug can be used as an intravenous infusion.

The duration of action of some opioids is longer than that of naloxone given as an intravenous bolus. Therefore, if depression of the respiratory center is caused by such substances or there is a suspicion of this, the drug should be used as an intravenous infusion. The rate of administration depends on the patient's condition, as well as his response to intravenous injection and infusion. Continuous intravenous fluids should be considered and measures to support breathing should be used if necessary.

Children

The initial dose of Naloxone injection solution is 0.01 - 0.02 mg per 1 kg of body weight intravenously over 2-3 minutes until breathing and consciousness are completely restored. Additionally, doses may be given at intervals of 1 to 2 hours depending on the patient's response and the dose and duration of action of the opiates used.

To restore breathing in newborns after administration of opioid analgesics to the mother in labor.

The usual dose is 0.01 mg per 1 kg of body weight intravenously. If respiratory function is not restored when using this dose, administration can be repeated after 2-3 minutes. If intravenous administration is not possible, naloxone is administered intramuscularly or subcutaneously at an initial dose of 0.01 mg per 1 kg of body weight.

Elderly patients

In elderly patients with cardiovascular disease or who have received cardiac medications, the drug should be used with caution. Undesirable effects such as tachycardia and ventricular fibrillation in postoperative patients should be taken into account when prescribing Naloxone.

As a diagnostic tool in patients with suspected opioid addiction.

The initial dosage for adults is 0.4 - 2 mg intravenously. Must be administered twice at three-minute intervals. If the patient's condition does not improve with naloxone 10 mg, it can be concluded that respiratory depression is caused by other factors or drugs other than opioids.

Postoperative use: accelerating the patient's recovery from general anesthesia, before the end of controlled breathing (postoperatively, the drug is used only in the case of the administration of opioid analgesics during anesthesia).

The usual dose is 0.1 - 0.2 mg intravenously, which corresponds to 0.0015 - 0.003 mg per kilogram of body weight. The dose should be titrated according to the patient's individual response to the drug. To maintain adequate pain relief and optimal respiratory recovery, naloxone should be administered slowly in 0.1 mg doses. The next 0.1 mg is administered again 2 minutes after the first injection. Additional administration of naloxone may be necessary one to two times per hour depending on the patient's response and the duration of action of previously administered opioids.

— Dilution of the solution

For intravenous infusion, Naloxone injection solution is diluted with 0.9% sodium chloride solution or 5% glucose solution. The contents of 5 ampoules of the drug (2 mg) are diluted in 500 ml in one of the listed solvents to obtain a concentration of the finished solution of 0.004 mg/ml.

Before use, it is necessary to check the solution (also after dilution) for transparency.

Only a transparent, colorless solution without visible particles is used.

Use of the drug Naloxone-m

The dose of the drug and the route of administration depend on the patient’s condition and the amount of opioid in the body. In case of an overdose of narcotic analgesics, Naloxone-M is administered intravenously (slowly by drip, over 2–3 minutes), intramuscularly or subcutaneously: for adults - at a dose of 0.4 mg. For life-threatening conditions, the preferred route of administration is intravenous. If the effect is insufficient, the drug is re-administered in the same dose every 3-5 minutes until consciousness and spontaneous breathing are restored. If, after administration of a total dose of 10 mg of the drug, there is no restoration of consciousness and breathing, then the diagnosis of poisoning with opioid analgesics is questioned. The initial dose for children is 0.005–0.01 mg/kg body weight. If necessary, repeated administration of the drug is possible. To speed up recovery from surgical anesthesia, Naloxone-M is prescribed intravenously to adults at a dose of 0.1–0.2 mg (0.0015–0.003 mg/kg body weight); children - 0.001–0.002 mg/kg body weight every 2–3 minutes until spontaneous breathing appears and the patient’s consciousness is restored, but without distinct pain and discomfort. If the desired effect is not present, the drug is re-administered in doses of up to 0.1 mg/kg body weight every 2–3 minutes. If intravenous injection is not possible, the drug is administered intramuscularly or subcutaneously in fractional doses. For newborns, the initial dose is 0.01 mg/kg body weight. Administration may be repeated according to guidelines for use in adults with postoperative respiratory depression secondary to opioid analgesics. For respiratory depression in newborns caused by the administration of opioid analgesics during labor, Naloxone-M is administered at a dose of 0.1 mg/kg body weight IM, SC or IV. Before administering the drug, it is necessary to ensure that the newborn's airway is open. Prophylactic intramuscular administration of 0.2 mg (0.06 mg/kg body weight) is possible. To diagnose opioid addiction, Naloxone-M is administered at a dose of 0.8 mg IV and the patient’s condition is monitored to identify signs of withdrawal syndrome.

The history of opium antagonists, and in particular naloxone, as one of the members of this group of pharmaceuticals, dates back to the middle of the 20th century, when the first allylic derivatives of opium derivatives were synthesized [1–3]. As a result of experimental tests of the obtained compounds, it turned out that the replacement of the methyl group at the nitrogen atom of the morphinan nucleus of opioids with more massive hydrocarbon radicals (Fig. 1) is accompanied by a significant increase in the affinity (affinity) of such a modified molecule for opiate receptors of the brain [4–6].

Rice. 1. Substitution of the methyl group (–CH3) at the nitrogen atom of the morphinan ring of opioids with hydrocarbon radicals (–R3)

It is known from neurophysiology that for the normal passage of a nerve impulse through a synapse, it is necessary that molecules of ligands (substances capable of interacting with the corresponding receptors, in this case opioids), after interacting with the receptors of the postsynaptic membrane, are quickly removed from the synaptic cleft or enzymatically destroyed in it, in order to make room for their next portion. The increased affinity of these modified opioids led to the fact that they remained longer than usual at opiate receptors, were removed from the synaptic cleft more slowly and, consequently, disrupted the transmission of nerve impulses at the synapses of the endogenous opioid system, which are related to the control of the perception of pain stimuli and the formation of emotions. Thus, the synthesized compounds acquired the properties of opium antagonists.

In the process of chemical transformation of “pure” opium agonists (narcotics), substances with intermediate properties, the so-called. agonists-antagonists, as well as “pure” opium antagonists (Fig. 2), which should be considered an example of the classic transition of quantity (affinity to receptors) into quality (agonism-antagonism). Moreover, only “pure” opiate antagonists, namely naloxone and naltrexone, can rightfully be called opiate receptor blockers.

Rice. 2. Change in the properties of opioids (from agonistic to antagonistic) as their affinity for opiate receptors increases

Over half a century of clinical use of opiate receptor blockers, the world medical community has gone through all the stages of the well-known evolution of views on any new drug: “enthusiasm - disappointment - a well-deserved place in everyday practice.” The most clear idea of this evolution is given by the dynamics of the number of publications devoted to opiate receptor blockers in medical journals around the world (Fig. 3), according to the information system of the National Library of Medicine of the United States of America “MedLine” [7].

Rice. 3. Dynamics of the number of publications containing the words “naloxone” or “naltrexone” in the title according to search results in the MedLine information system [7]

It is important to note that the majority of publications were devoted specifically to naloxone (a total of 4623 articles, as of 01/01/2007), which allows us to classify this drug as one of the most studied drugs in the history of pharmacology. Another well-known opiate receptor blocker, naltrexone, is more than three times inferior to naloxone in this indicator (a total of 1502 articles, as of 01/01/2007).

It is clearly noticeable that the peak of interest in naloxone was observed in the 80s of the 20th century. Then came a decline that continued until the turn of the millennium and, finally, in recent years there has been a stabilization in the dynamics of publications with signs of revival of interest in the world community in this drug. The reasons for this recovery lie in the continued growth in the number of opioid-dependent individuals in the modern world (the main population requiring the prescription of opiate receptor blockers), as well as in new indications for the use of naloxone, which will be detailed below.

Naloxone in the treatment of acute poisoning

As already mentioned, naloxone is a “pure” opiate antagonist, i.e. a compound that is practically devoid of the properties of classical opioid drugs (analgesia, euphoricity, respiratory depression, etc.). Its ability to block opiate receptors is widely used in clinical practice and, above all, in the treatment of acute poisoning (overdose) with opiate drugs (morphine, heroin, methadone, etc.).

Usually, intravenous administration of naloxone is enough to bring the patient to consciousness in a matter of seconds. However, when reversing opioid poisoning with naloxone, three factors must be taken into account.

First, rapid withdrawal of opioid-dependent patients from intoxication can lead to the development of severe withdrawal symptoms. To avoid this, naloxone should be administered in small doses, starting with a dose of 0.2–0.4 mg, and then repeated intravenously at this dose at intervals of half an hour to an hour or more often (if necessary) until stable clearing of consciousness. If withdrawal syndrome does develop, then clonidine (clonidine) is administered to reduce its severity.

Second, the half-life of naloxone is significantly shorter than that of most opioids. Therefore, a patient poisoned by opioids needs long-term observation and, possibly, the administration of an additional dose of an opiate receptor blocker after consciousness has been restored, in order to avoid re-aggravation of the condition due to the residual dose of the opioid that caused intoxication remaining in the body. The last note is especially relevant in cases of poisoning with long-acting drugs such as methadone, pentazocine or levomethadyl.

Third, respiratory depression due to buprenorphine poisoning cannot be treated with naloxone!

In addition, it should be borne in mind that in case of opioid poisoning, there are often cases when it is impossible to limit oneself to the administration of naloxone. In addition to prescribing an antidote, in such cases, restoration and maintenance (sometimes long-term) of vital functions is required. In case of sudden disruption of breathing and blood circulation, cardiopulmonary resuscitation is started. Tracheal intubation is often indicated, but if it is not performed, then measures are taken to prevent aspiration of gastric contents. During other diagnostic and therapeutic measures, maintenance of vital functions is not interrupted.

In any case, a venous catheter should be installed to provide a reliable route for the prompt administration of the necessary medications, since all saphenous veins large enough for injection in patients with opioid dependence, especially those with a long history of narcotics, are almost completely obliterated. Blood is drawn through a catheter for all necessary studies.

If it is known that the drug was taken orally and this happened recently, then the stomach is washed. However, in case of respiratory depression in non-intubated patients, gastric lavage is contraindicated.

Possible pulmonary edema of varying severity (from asymptomatic to life-threatening) during opioid poisoning is interstitial and alveolar, therefore cardiac glycosides and diuretics are ineffective in this case and are not indicated. Required: oxygen inhalation and artificial ventilation.

Given the duration of action of some opioids during overdose, as well as the possibility of combined use of various psychoactive substances, patients should be observed for at least 24 hours. It must also be remembered that an opioid overdose could be a suicide attempt [8, 9].

As can be seen from the above, treating opioid drug poisoning with the specific antidote naloxone is a complex medical procedure that requires the participation of qualified personnel. However, in recent years, the world's specialized literature has increasingly discussed the possibility of dispensing naloxone to people suffering from opioid addiction for self- and mutual assistance during drug overdose in community settings [11–24]. There is evidence that this practice can significantly reduce mortality among this category of patients.

For the same purpose, studies are being conducted on the possibilities of intranasal administration of naloxone solution in the treatment of opium drug overdoses. It has been established that through the mucous membrane of the nasal cavity, naloxone penetrates into the systemic circulation almost as quickly as when administered intravenously [25–30].

Naloxone is also recommended for use in all cases of poisoning by unknown poisons in the presence of respiratory depression and confusion, since such an unknown poison may be an opioid or a combination of substances containing opioids [9].

In addition, there have recently been reports that naloxone can be successfully used to treat poisoning with valproic acid drugs (anticonvulsants) [31, 32], as well as ibuprofen [33].

Naloxone in the diagnosis and treatment of opioid dependence conditions

Treatment of acute poisoning is not the only area of application for naloxone. For example, naloxone is used to determine the presence and severity of opioid dependence [34]. Due to the painful symptoms of withdrawal syndrome for the patient, naloxone is used, mainly in the case of an unconscious patient. In this case, diagnostic purposes (determining the type of psychoactive substance that caused the coma) and therapeutic purposes (emergency care) of prescribing this drug can be achieved simultaneously. In addition, a naloxone test is performed before starting long-term anti-relapse treatment with naltrexone.

Naloxone at a dose of 0.2–0.4 mg is administered intravenously over 5 minutes, subcutaneously or intramuscularly, after which the patient is carefully monitored, trying to detect early signs of withdrawal syndrome: dilated pupils, tachypnea, lacrimation, rhinorrhea and sweating. If there is no response to naloxone within 15–30 minutes, the drug is re-administered intravenously at a dose of 0.4 mg or subcutaneously at a dose of 0.4–0.8 mg and the patient is monitored again. If there is no response to naloxone upon repeated administration, this indicates the absence of physical dependence on opioids at the time of this study. It should be remembered that the naloxone test can be negative, including in patients with opiate addiction who are in remission.

There are known schemes for the use of this drug intended to relieve withdrawal syndrome, in particular: forced detoxification according to A. P. Chuprikov - A. A. Pedak [35–37], as well as ultra-rapid opioid detoxification (UROD) under general anesthesia according to A. V Butrov - A. G. Goffman - S. G. Tsimbalov [38].

The implementation of the A.P. Chuprikov - A.A. Pedak scheme begins with the selection of the minimum dose of naloxone, leading to the development of a withdrawal state. Then treatment measures are carried out in accordance with the “Method for relieving withdrawal symptoms due to opiate use”[37].

In order to maintain the precipitated withdrawal reaction, a previously selected individual dose of naloxone is administered every 30–40 minutes. At the same time, the development of signs and symptoms of withdrawal is assessed. In cases of severe withdrawal reaction, 10 mg of diazepam is administered. Opium detoxification is stopped in the absence of signs of withdrawal syndrome after two-time administration of an individually selected dose of naloxone. A control systemic naloxone test (dose 0.4 mg intravenously) is repeated the next day after detoxification.

During forced detoxification, the intensity of withdrawal symptoms in response to the next administration of naloxone naturally decreases over 7–9 hours until they are completely absent. The course dose of naloxone with the described forced detoxification scheme is on average 4.4±0.8 mg. The results of a follow-up naloxone test the next day are usually negative.

Ultrafast opioid detoxification under anesthesia according to A.V. Butrov - A.G. Goffman - S.G. Tsimbalov [38] is used mainly for long durations of drug use and large daily dosages of opiates. The main criterion for selecting patients for UBOD is the presence of a commitment to treatment, the willingness to completely give up drug use, participate in rehabilitation programs, and start a healthy lifestyle.

Contraindications to UBI are: a combination of dependence on opioids with dependence on other drugs or psychoactive drugs; pregnancy or breastfeeding; combination of opioid addiction with severe somatic diseases in the stage of decompensation; fourth degree of anesthetic risk (according to a standard five-point anesthetic risk scale) in patients with opioid dependence.

To implement this technique, the following conditions are required:

the presence of a room that meets the standards of the anti-shock ward of the intensive care unit;
availability of the results of a comprehensive clinical blood test (with blood clotting indicators); biochemical blood test (total protein, bilirubin, creatinine, urea, ALT, AST); blood electrolytes (K, Na, Cl); general urinalysis; blood test for HIV infection, hepatitis B and C; ECG; chest radiographs; results of determining blood group and Rh factor, as well as coagulogram (according to indications);
availability of monitoring of vital functions: heart rate; blood pressure (non-invasive); ECG; respiratory rate; tidal volume; minute ventilation; peak airway pressure; inhaled oxygen concentration; temperature gradient; hourly diuresis; heroin degradation products in urine.

To implement the technique, the following drugs are needed: naloxone; naltrexone; clonidine (clonidine). The group of anesthetic and resuscitation drugs is standard and does not relate to the specific material and technical base of the proposed method.

The start of the UBOD procedure is determined by a narcologist individually based on the clinical picture. A receipt is taken from the patient indicating his consent to the treatment. On average, the time between taking the last dose of a narcotic drug and the start of UBOD is 6–12 hours.

The detoxification itself is preceded by the patient being put into a state of general anesthesia: the patient is given induction anesthesia, intubated, a nasogastric tube is installed, and the UBI procedure is continued under anesthesia with controlled ventilation.

This guarantees adequate protection of the respiratory tract and the possibility of deep anesthesia. Careful monitoring of vital functions allows you to correct and maintain them within the normal range. Since the patient is under anesthesia, he does not feel any manifestations of withdrawal symptoms. Anesthesia usually lasts from 6 to 8 hours.

The detoxification itself is carried out in accordance with the scheme. Naloxone is administered intravenously in doses of 0.4 mg, 0.8 mg, 1.6 mg, 3.2 mg, 6.4 mg every 15 minutes during the first hour after intubation (total dose of naloxone 12.4 mg), then drip 0.4–0.8 mg/hour for 24 hours on the first day (thus, the naloxone infusion begins during anesthesia and continues into the immediate post-detoxification period).

Ultrafast opioid detoxification time under general anesthesia is 6–8 hours. The criterion for completing UBOD is the regression of symptoms of withdrawal syndrome: normalization of blood pressure and pulse, decrease in discharge through the nasogastric tube, decrease in temperature, decrease in lacrimation, decrease in diarrhea. After awakening and extubation, residual withdrawal symptoms may be observed, which quickly regress or are relieved by additional drug therapy.

There is evidence that the use of naloxone in opioid-dependent patients may also be beneficial during the post-withdrawal period. Thus, it has been shown that small doses of naloxone (0.2–0.4 mg) as part of complex therapy for heroin addicts significantly prolong the half-life of leu-enkephalin in the blood serum, significantly reduce the intensity of craving for the drug and the intensity of affective disorders in the post-abstinence period, which, according to the authors, helps to improve the quality and duration of therapeutic remissions [39, 40].

Potentially promising indications for naloxone use

Naloxone, being an opiate receptor blocker, does not have its own analgesic activity. However, as evidenced by the results of some clinical studies, in low and ultra-low doses, naloxone can potentiate the analgesic effect of opioids such as buprenorphine and nalbuphine. Some researchers are already using naloxone as an adjuvant in the complex treatment of pain syndromes of various origins [41–44].

Another important feature of naloxone is its ability to suppress the adverse effects and consequences of general and epidural anesthesia, as well as the adverse effects of pain relief in oncological practice. The drug effectively eliminates postoperative insufficiency of intestinal motility [45, 46], reduces the incidence of opioid-induced esophageal reflux and associated pneumonia in patients in intensive care and/or intensive care [47], suppresses nausea and vomiting in patients with epidural morphine anesthesia [48, 49] and alleviates opioid-induced intolerance to intragastric tube feeding [50].

In addition, it has been shown [51] that early administration of moderate doses of naloxone in the acute period of traumatic brain injury can significantly reduce the mortality of victims and improve their post-traumatic neurological status. It has also been established that the administration of naloxone for shock improves hemodynamic parameters and, in particular, blood pressure [52].

Unexpected and encouraging results were obtained when studying the effect of naloxone in patients with depersonalization - in more than half of the patients receiving this drug, a complete reversal of this disorder was observed [53]. This observation sheds light on the role of the endogenous opioid system in the genesis of depersonalization disorders. Equally surprising is the ability of naloxone to reduce excess insulin secretion in postmenopausal women, which makes naloxone a potentially useful agent in appropriate hormone replacement therapy [54].

Naloxone has also attracted the attention of researchers developing treatments for Tourette syndrome [55].

The successful use of naloxone in traumatic shock, depersonalization disorders and dishormonal conditions allows us to confidently predict a rapid and significant expansion of the scope of use of this drug.

Today, naloxone is used mainly in addiction medicine, toxicology and anesthesiology.

It is interesting to discuss the possibility of issuing naloxone to people suffering from opioid addiction for self- and mutual assistance during drug overdose in out-of-hospital conditions, as well as the introduction of naloxone into the list of medications included in the equipment of mobile ambulance teams.

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Side effects of the drug Naloxone-m

With rapid administration of Naloxone-M, various reactions may occur. From the gastrointestinal tract : nausea, vomiting. From the cardiovascular system : tachycardia, hypertension (arterial hypertension), cardiac arrest. From the side of the central nervous system : trembling, convulsions. Allergic reactions : skin rash, itching. Other : increased sweating. When using Naloxone-M in the postoperative period in doses exceeding the required ones, disappearance of analgesia and agitation, arterial hypotension or hypertension (arterial hypertension), ventricular tachycardia, ventricular fibrillation, pulmonary edema are possible. When used in therapeutic doses in patients whose bodies do not contain opioids, Naloxone-M usually does not cause side effects.

Special instructions for the use of the drug Naloxone-m

The duration of action of some opioid analgesics may exceed the duration of action of Naloxone-M, so patients should be under constant medical supervision and in conditions that make it possible to carry out mechanical ventilation and other resuscitation measures. Patients with opioid dependence should administer the drug very carefully, as withdrawal syndrome may occur. Use with caution during pregnancy and breastfeeding. It is not known whether naloxone is excreted in breast milk. The use of the drug during pregnancy and breastfeeding is possible after assessing the risk/benefit ratio. While using Naloxone-M, it is prohibited to drive vehicles or service moving machinery.