RU2726048C1 - Method of treating chronic pain - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention refers to experimental medicine, namely to neurology, and concerns treating chronic pain. That is ensured by 99.9 % subcutaneous injection of medical xenon, sufficient amount of xenon for analgesia.

EFFECT: it provides effective and prolonged analgesia in chronic pain without side effects and neurotoxic action, which, in turn, enables using the given method in patients with accompanying diseases.

4 cl, 3 tbl, 2 ex, 6 dwg

Description

The most important reason for patients seeking medical attention is pain. In the last 30 years, there has been a steady increase in chronic pain in the structure of morbidity. To date, the issues of pain treatment in the world are one of the most socially significant and discussed in the medical community. There is evidence that at least 6-8% of the population suffers from pain with a neuropathic component. These figures are close to the prevalence of such common diseases as coronary heart disease, diabetes mellitus, for the treatment of which the public health allocates the necessary resources. In this regard, the problem of managing patients with chronic pain arises.

The chronic type of pain is difficult to treat. Many of the patients with chronic pain eventually develop drug-resistant forms of pain. It is also known that even 10 to 30% of patients with chronic pain are insensitive or insufficiently sensitive.

Despite the fact that at the moment there is a wide range of analgesia methods of varying degrees of effectiveness and cost level, all of them have a low level of evidence. Available pharmacological agents for the treatment of chronic pain syndromes have a low coefficient of effectiveness of application, not exceeding 0.3 (i.e. any drug helps no more than every third patient). The severity and scale of the problem requires the introduction of new techniques - more effective, easier to use and with less cost.

Based on international experience with the use of inert gases in medicine, it is known that Xenon, a drug for inhalation anesthesia, has a pronounced analgesic effect. The prospect of using xenon is due to the presence of a number of physicochemical and biological properties of this gas. Xenon is an inert gas; it has neither color nor odor. The xenon density is 3 times higher than the density of nitrous oxide, i.e. xenon is the heaviest inhalation anesthetic. It surpasses nitrous oxide in narcotic (1.5 times), analgesic and muscle relaxant activity. Xenon is characterized by a minimal effect on systemic and pulmonary geodynamics, which allows it to be used in patients compromised in this regard. The functions of the heart during its use practically do not change, myocardial contractility does not decrease. There is evidence of cardioprotective and neuroprotective effects of xenon. In patients with severe cardiac pathology, xenon practically does not change the parameters of systemic hemodynamics.

Xenon is not metabolized in the liver and kidneys, has no teratogenic effect and does not cause malignant hyperthermia, is free from allergenicity, and has a moderate immunostimulating effect. Xenon and xenon anesthesia are completely independent of the multiplicity and duration of xenon use. And it differs, therefore, from all known anesthetics.

Xenon is the drug of choice when conducting anesthesia in patients with drug allergy, since it has good analgesic, vegetative stabilizing properties and a sedative effect.

The positive environmental impact of xenon is that it does not destroy the ozone layer of the stratosphere and thus does not contribute to the progression of the greenhouse effect on the planet.

Thus, xenon meets all the requirements for an ideal anesthetic.

When inhaled with an oxygen-xenon mixture (xenon concentration of 70%), analgesia and general anesthesia occur. That allows the use of xenon for anesthesia during surgical operations. Methods have also been developed for the treatment of pain syndromes using xenon and with preserved consciousness.

A known method of autoanalgesia xenon-oxygen mixture [RF Patent 2271815, publ. 03/20/2016], which consists in self-inhalation of a xenon-oxygen mixture by a patient in a ratio of xenon and oxygen in vol.% From 30:70 to 50:50 before relief of the pain syndrome using an autoanalgesia device.

There is also a method of stopping pain syndromes, including their neuropathic component, due to cancer [RF Patent 2695350, publ. 07/23/2019]. Xenotherapy is carried out in normobaric conditions on a closed respiratory circuit using a gas analyzer with a gas mixture of xenon and oxygen 50/50 vol.%, The amount of the mixture from 4 to 6 liters. courses from 5 to 10 days for 1-2 procedures, each from 5 to 15 minutes per day with intervals between procedures 4-6 hours.

The disadvantages of the above methods are the need to use equipment for inhalation, in addition, during the application of these methods there is an increased consumption of xenon.

And since the problem of the high cost of manufacturing xenon is not solved, this is also a disadvantage of these methods.

Known methods of enrichment of food products with xenon for use with therapeutic purposes. For example, xenon-enriched dairy products when consumed in food, in addition to a positive effect on most of the functional processes of the body, relieved migraine-like headaches [RF Patent 2341095, publ. 12/20/2018]. However, the use of xenon in this form has mainly a preventive and restorative effect.

There is a method of treating destructive diseases of the joints of the limbs and spine, which consists in subcutaneous injection of nitrous oxide in the joints or segments, which helps to reduce pain [RF Patent 2239381, publ. November 10, 2004]. This method is proposed to be used only for the treatment of diseases of the musculoskeletal system, moreover, the analgesic effect in nitrous oxide is weaker than in xenon. In addition, in recent years, the attitude to nitrous oxide as a safe anesthetic has been revised, as the drug has a neurotoxic and cardiodepressive effect (Atlee J.L. 2007). The use of nitrous oxide negatively affects the environment and contributes to the destruction of the ozone layer.

Studies were conducted subcutaneous administration of cyclopropane, traditionally used as an inhalation anesthetic during surgical operations.

It was found that with subcutaneous administration of cyclopropane, analgesic and sedative effects are expressed (without narcotic), there is no toxic effect on blood formation, liver, kidney and other organs (experiments on white mice and dogs).

Studies were interrupted due to the cessation of cyclopropane production in Russia. In addition, cyclopropane is extremely explosive. When using cyclopropane, it is necessary to take all measures that exclude the possibility of an explosion, including precautionary measures associated with the use of electrical and X-ray equipment and excluding the formation of static electricity. In connection with these shortcomings, as well as with the advent of new methods and means of general anesthesia, cyclopropane is currently extremely rarely used as an anesthetic.

It is known to use a liquid preparation containing xenon for the induction and maintenance of anesthesia, sedation, analgesia, muscle relaxation. The drug is a fat emulsion containing xenon.

After saturation of the emulsion with xenon, it is placed in storage containers. Further, a gradual intravenous administration of such an emulsion is proposed [Patent EP 0864329-B1 - 2000-12-13]. A similar solution is proposed in another method [Patent EP 1100514 - A2 - 2001-05-23].

The disadvantage of this analogue is the need to use additional components: a fat emulsion, a device for saturating an emulsion with xenon, gas-tight containers for storing a saturated emulsion.

In addition, the method involves its use in a hospital and takes time to implement.

The proposed method for the treatment of chronic pain is the introduction of medical xenon 99.9% by subcutaneous injection.

The objective of the proposed method: - development of a method for the effective treatment of chronic pain, providing a long-lasting analgesic effect, the absence of side effects of local and general nature. At the same time, affordable and easy to use.

The advantages of the proposed method are a pronounced analgesic effect, its preservation for a long time, the complete absence of side effects, ease of implementation. No need for additional equipment and components. Xenon consumption is economical. The method can be used on an outpatient basis. Performing a subcutaneous injection does not take much time, in contrast to the gradual intravenous administration.

The problem is solved due to the fact that against the background of modeling chronic pain in an experiment in a rat by cutting the sciatic nerve under general ether anesthesia, starting from 2 days after the operation, xenon is injected subcutaneously into the chest area at a dose of 10 ml daily. Subcutaneous administration of xenon is continued for 5 days.

This leads to a pronounced analgesic effect that persists for a long time and after the end of the injection course.

The method is as follows.

For the experiment, 18 adult (2 months) male outbred laboratory white rats were used. The initial mass of rats ranged from 240 to 360 g. During the experiment, the rats were in individual cages with free access to food and water. The light cycle is 12 hours of light and 12 hours of darkness.

Under general anesthesia (inhalation of ether vapor), an incision was made on the middle part of the outer surface of the thigh, and the sciatic nerve was proximal to the trifurcation. Next, the nerve is taken on rubber holders - ligatures and crossed in an acute way with a surgical scalpel. The wound was sutured by individual silk ligatures.

After surgery, 1 day in rats was reserved for acclimatization before any procedures. The following is a standard test of the effectiveness of the pain model using Won Frey filaments (range 2-15 g). The mechanical paw withdrawal threshold (PWT) indicator was used as a criterion. For the further experiment, only rats were used, whose mechanical allodynia was less than 12 g by the 4th day. 12 rats with a successfully executed model of chronic pain were divided into 2 groups - control and experimental, 6 animals in each group.

Starting from the second day after surgery, rats of the experimental group received subcutaneous injections of xenon into the chest area. Injections were carried out daily for 5 days at a dose of 10 ml.

Rats in the control group received daily subcutaneous injections of 10 ml of air for 5 days.

For injection, animals from the experimental group used medical xenon XeMed (99.99%). Injections were performed with a sterile medical syringe with a 21G needle. Gas is in a metal cylinder under pressure. The syringe was filled with gas using a gearbox and a silicone tube with a valve.

The device for filling the syringe with xenon consists of a cylinder with compressed gas (1), a pressure reducing gear (2), a sterile U-shaped tube with clamps and valves for the needle syringe cones at the ends (3), a large (buffer) syringe (4) , small syringe (5) - FIG. 1.

The filling technique that avoids "mixing" of air with an inert gas is as follows: open the gearbox on the bottle, fill a 100 ml (large) syringe with gas, close the gearbox, then sip the piston of a small 10 milliliter syringe and add xenon from the large one. The first portion of the gas is released into the atmosphere, the next portion of the accumulated gas is pure xenon. Valves at the ends of the U-shaped tube prevent air from being drawn into the system from the atmosphere.

Within a week after the operation, behavior and pain sensitivity were assessed in both groups (won Frey test), weight dynamics (increase / loss) - Table 1, FIG. 2; the appearance of the rat (neatness / disheveled hair), the uniform distribution of the litter along the bottom of the cage, the number of fingers of a sick limb damaged and bitten by animals - Tables 2, 3.

The pronounced analgesic effect of subcutaneous administration clearly demonstrates the “painful” behavior of rats in the control group (gnawed fingers, untidy, disheveled appearance of the animal, sedentary lifestyle in the cage, which shows the appearance of litter - Fig. 3, 5. Rats of the experimental group: all fingers whole legs, rats take care of themselves, actively behave in a cage - Fig. 4, 6.

The observation showed that the insignificant decrease in body weight in the first days after nerve transection compensates the animals of the experimental group faster and then gain weight, while the animals of the control group stably lose weight due to the developed pain by the 5th day of observation - Table 1.

The pronounced analgesic effect in the rats of the experimental group remained until the conclusion from the experiment.

10 days after surgery, all animals were removed from the experiment by deep ether anesthesia.

Histological studies have proven the absence of local irritating and systemic toxic effects of xenon injections on the liver, kidneys, heart, lungs.

Examples of the method.

All manipulations were performed in compliance with the requirements for the humane treatment of animals (Strasbourg, France, 1986).

Example 1

A healthy laboratory male rat, 2 months old and with an initial weight of 310 g, under general anesthesia (inhalation of ether vapor), an incision was made on the middle part of the outer surface of the thigh, the sciatic nerve proximal to the trifurcation was isolated. Next, the nerve is taken on rubber holders - ligatures and crossed in an acute way with a surgical scalpel. The wound was sutured by individual silk ligatures.

One day was allotted to the animal for acclimatization after surgery.

Starting from the second day after the operation, the rat was taken out of the cage and subcutaneous xenon was injected alternately into the left-right lateral surfaces of the chest with an xenon amount of 10 ml, which amounted to 33 ml of xenon / kg of animal weight on the first day of observation (second day after surgery) .. Injections were performed daily for 5 days.

During the experiment, behavior and pain sensitivity were evaluated, the rat was weighed daily, and its appearance, behavior, activity, appetite, and state of the cell were monitored. During the experiment, the rat retained a neat appearance - 2 points on a scale for assessing the degree of pain. The litter is evenly distributed along the bottom of the cage, the rat is active - 2 points on a scale for assessing the degree of pain. Weight that decreased immediately after surgery by 10 g, and by day 3 of observation to 260 g, by day 5 of observation was restored to 300 g. All fingers and toes are whole - 3 points on a scale for assessing the degree of pain. The pronounced analgesic effect persisted until the rat was removed from the experiment 10 days after the operation by deep ether anesthesia.

Example 2

A healthy laboratory male rat, 2 months old and with an initial weight of 250 g, under general anesthesia (inhalation of ether vapors), an incision was made on the middle part of the outer surface of the thigh, the sciatic nerve proximal to the trifurcation was isolated. Next, the nerve is taken on rubber holders - ligatures and crossed in an acute way with a surgical scalpel. The wound was sutured by individual silk ligatures.

One day was allotted to the animal for acclimatization after surgery.

Starting from the second day after the operation, the rat was taken out of the cage, and she was injected subcutaneously with xenon alternately in the left-right lateral surfaces of the chest with xenon amount of 10 ml, which amounted to 42 ml of xenon / kg of animal weight on the first day of observation (second day after surgery ) Injections were performed daily for 5 days.

During the experiment, behavior and pain sensitivity were evaluated, the rat was weighed daily, and its appearance, behavior, activity, appetite, and state of the cell were monitored. During the experiment, the appearance of the rat remained satisfactory - 1 point on a scale for assessing the degree of pain. By the 5th day of observation, the litter is evenly distributed along the bottom of the cell, the rat is active - 2 points on a scale for assessing the degree of pain. The weight that decreased immediately after surgery to 240 g, by the 5th day of observation, not only recovered to the original, but increased to 300 g. All fingers and toes are whole - 3 points on a scale for assessing the degree of pain. The pronounced analgesic effect persisted until the rat was removed from the experiment 10 days after the operation by deep ether anesthesia.

The technical result of the invention is the development of an effective, easy-to-use method of treating chronic pain, which provides a significant reduction in pain up to its complete absence. The analgesic effect lasts a long time. There is no neurotoxic effect. There are no side effects, which allows the use of this method in patients with concomitant diseases. The application of the method does not require additional equipment, can be performed on an outpatient basis.

Claims (4)

1. A method of treating chronic pain, including xenon therapy by performing injections containing xenon, characterized in that a course of hypodermic injections of medical xenon is carried out 99.9%, the amount of xenon sufficient for analgesia. 2. The method according to p. 1, characterized in that the injection is performed with a course of at least 5. 3. The method according to p. 1, characterized in that the injection is performed daily 1 time per day. 4. The method according to p. 1, characterized in that the amount of xenon in 1 injection is from 33 to 42 ml / kg of body weight.

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