EA049509B1 - METHOD OF TREATMENT OF PAIN SYNDROME AND MEDICINE FOR USE IN PAIN SYNDROME - Google Patents

Abstract

The invention relates to medicine, namely to methods for treating, relieving and preventing pain syndrome using the tetrapeptide Tyrosyl-O-arginyl-phenylalanyl-glycine amide (HTyr-D-Arg-Phe-Gly-NH2), as well as to a medicinal product based on the said tetrapeptide and can be used for acute or chronic pain syndrome, in particular in patients with oncological diseases, as well as in the early postoperative period during various surgical interventions. A method for treating, relieving, and preventing pain syndrome is proposed, which includes the administration of the tetrapeptide Tyrosyl-O-arginyl-phenylalanyl-glycine amide (H-Tyr-D-Arg-Phe-Gly-NH2) in a single dose of 2 to 7 mg, with a daily dose of no more than 42 mg, with intervals between administrations of 4 hours, with a duration of the course of treatment for pain syndrome of up to 96 days, with the subsequent possibility of multiple repetition of the course. Also proposed is a medicinal product for use in the claimed methods of treating and/or preventing and/or relieving pain, comprising the tetrapeptide Tyrosyl-O-arginyl-phenylalanyl-glycine amide (H-Tyr-D-Arg-Phe-Gly-NH2) and excipients: sodium chloride, mannitol, glycine, sodium acetate trihydrate, acetic acid, water, in the following ratio of components, wt.%: tetrapeptide - 0.380-0.420; sodium chloride 0.475-0.525; mannitol - 0.475-0.525; glycine - 0.475-0.525; sodium acetate trihydrate - 0.0380-0.0420; acetic acid - up to pH 4.0-6.0; water - up to 100.

Description

The invention relates to medicine, namely to methods of treating, relieving and preventing pain syndrome using the tetrapeptide Tyrosyl-E-arginyl-phenylalanyl-glycine amide (H-Tyr-DArg-Phe-Gly-NH2), as well as to a medicinal product based on the said tetrapeptide, and can be used for acute or chronic pain syndrome, in particular in patients with oncological diseases, as well as in the early postoperative period during various surgical interventions.

Acute and chronic pain is one of the most difficult to bear and psychologically difficult manifestations of disease, in particular oncological diseases, as well as the early postoperative period in various surgical interventions. The high frequency of occurrence of pain syndrome indicates the need for a constant search and selection of new therapeutic schemes to prevent it or reduce the severity of pain.

The modern spectrum of pharmacological methods of pain relief includes the use of drugs of various groups: opioid analgesics, non-steroidal anti-inflammatory drugs (NSAIDs), combination drugs, corticosteroids, anticonvulsants, etc. However, the search for new painkillers and therapeutic methods based on their use remains an urgent task, since known analgesics have a number of serious drawbacks. As is known, opioid drugs are associated with a high risk of drug dependence, observed in patients with chronic pain, as well as a number of adverse events (AE), including nausea, drowsiness, decreased cognitive function, fatigue, increased risk of loss of balance (risk of falls), immunosuppression, etc. Unlike opioid drugs, drugs such as NSAIDs, corticosteroids, anticonvulsants do not have a high risk of drug dependence and AE, but the effectiveness of the analgesic effect of these drugs is far from always sufficient, especially in oncological diseases.

A special direction in the search for new methods of treatment, prevention and relief of pain syndrome is the development of methods of pain relief based on the use of peptides. In particular, a number of publications have described the high analgesic activity of the tetrapeptides H-Tyr-D-Arg-PheGly-NH2 and H-Tyr-D-Arg-Phe-Sar-OH (JPS58213743 (A), published 12.12.1983, and JPS6054400 (A), published 28.03.1985).

The prototype of the proposed invention is a method for preventing and/or treating acute or chronic pain syndrome, which includes the administration of a product based on the tetrapeptide H-Tyr-D-ArgPhe-Gly-NH ₂ or H-Tyr-D-Arg-Phe-Sar-OH in an amount of 0.5-10 mg/dose (patent RU 2622980).

The prototype method specifies a wide range of single doses - from 0.5 to 10 mg / dose, and, according to the full description of the patent, this range is established by extrapolating to humans the results obtained in a study of the effect of the tetrapeptide H-Tyr-D-Arg-Phe-Gly-NH ₂ or H-Tyr-DArg-Phe-Sar-OH on the behavioral reactions of animals, a study of the toxicity of large doses in the Open Field test and the test for maintaining balance on a horizontal rod (example 8 of patent RU 2622980). Extensive clinical studies have not been conducted. Example 9 of patent RU 2622980 contains information on the use of the said tetrapeptides only in 6 patients, and the drug was used in cases where the patient was prescribed treatment with painkillers of the morphine group (stage 3 according to the WHO system), but for one reason or another the drug was not available; When the standard morphine preparation appeared, the therapy with the experimental preparation was stopped. Of the 6 patients, 5 had stage IV cancer of various localizations (pancreatic cancer; colon cancer; breast cancer), and one patient had a vertebral fracture. The preparation based on the tetrapeptide H-Tyr-D-Arg-Phe-Gly-NH2 or the tetrapeptide H-Tyr-D-Arg-Phe-Sar-OH was administered to them in the form of subcutaneous injections in doses from 0.7 to 3 mg 2 times a day (usually for 4-5 days, when for one reason or another the morphine prescribed for pain relief was not available in the clinic). The pain-relieving effect, according to the description of patent RU 2622980, was manifested in a decrease in pain within 10-15 minutes after the administration of the preparation, with the pain-relieving effect maintained for 4-10 hours.

Since the range of therapeutic doses of the tetrapeptide in the prototype method was selected by extrapolating to humans the results obtained in studying the effect of the tetrapeptide on the behavioral reactions of experimental animals and extensive clinical studies were not conducted, the safety and efficacy of the proposed range of single therapeutic doses (0.5 - 10 mg/dose) raises questions. There is no necessary justification for the efficacy of the minimum dose in the range (0.5 mg), or for the safety of the maximum (10 mg), or for several specific doses (0.7 mg, 1 mg, 1.5 mg, 3 mg) selected for clinical use in 6 patients. The prototype method also does not contain information on the maximum daily dose of the tetrapeptide. There is also no information on how long the prototype method can be used for pain relief (clinical studies in the prototype method, as indicated, include information on the use of the drug only in 6 patients and only during short periods of unavailability of the pain reliever in the form of morphine prescribed to these patients for one reason or another). In addition, in specific examples of the use of the drug in patients, it is not indicated which of the two tetrapeptides proposed in the prototype method (tetrapeptide H-TyrD-Arg-Phe-Gly-NH ₂ or tetrapeptide H-Tyr-D-Arg-Phe-Sar-OH) was used in each specific patient.

- 1 049509 ent, and therefore there is no certainty that clinical efficacy has been confirmed specifically for the tetrapeptide H-Tyr-D-Arg-Phe-Gly-NH2.

In this regard, increasing the effectiveness and safety of pain relief with the tetrapeptide H-Tyr-DArg-Phe-Gly-NH2 through more substantiated development of optimal doses, regimens and courses of administration of this tetrapeptide, obtained from the results of extensive clinical studies, is an urgent need.

Also relevant is the development of a medicinal product based on the tetrapeptide H-Tyr-DArg-Phe-Gly-NH2 for use in the method of treating and/or preventing and/or relieving pain syndrome.

Patent RU 2622980, selected as a prototype, describes a means for treating and/or preventing pain syndrome based on the tetrapeptide H-Tyr-D-Arg-Phe-Gly-NH ₂ , in particular, a means for injection, made in the form of a solution. Paragraphs 12 and 15 of the formula of the invention characterize compositions in the form of a liquid dosage form, including certain auxiliary substances in a certain ratio.

Item 12 of the invention formula describes a pharmaceutical composition comprising the tetrapeptide H-Tyr-D-ArgPhe-Gly-NH ₂ , as well as such auxiliary substances as a buffer, filler, stabilizer, solvent, with an indication of a certain range of possible quantitative contents for each substance. However, the specified ranges of quantitative contents of the components partially remained hypothetical, since they are not confirmed in the full description of the patent by specific examples. Thus, in the invention formula, a range of 0.01 - 0.5 wt.% is indicated for the tetrapeptide, while in the examples of a specific embodiment, compositions are given only with a tetrapeptide content of 0.15 wt.%. Also, the patent description does not contain information on compositions with a quantitative content of the tetrapeptide in mg other than 1.5 mg (all liquid injection compositions given in the examples are characterized only by a tetrapeptide content of 1.5 mg). However, as shown by the extensive clinical studies conducted by the authors of the claimed group of inventions, the optimal compositions for the production of a drug based on the tetrapeptide H-Tyr-D-Arg-Phe-Gly-NH ₂ are those with a much higher than 0.15 wt.% (or 1.5 mg) content of the tetrapeptide, because, as will be shown further in the description of the results of extensive clinical studies, the recommended initial dose is 4 mg of the tetrapeptide, and the optimal course for the treatment of pain syndrome is a course including 4 mg of the tetrapeptide 2-3 times a day. Therefore, the development of a drug for use in the claimed method for treating pain syndrome is also an urgent need.

The objective of the proposed invention is to increase the effectiveness and safety of the method of treating and/or preventing and/or relieving pain syndrome, in particular in cancer patients and also in the early postoperative period during various surgical interventions by developing optimal doses, regimens and courses of administration of the tetrapeptide H-Tyr-D-Arg-Phe-Gly-NH ₂ .

The objective of the proposed invention also includes the development of a medicinal product for use in a method for treating and/or preventing and/or relieving pain syndrome.

The stated objective is achieved by proposing a method for treating pain syndrome, which includes the administration of the tetrapeptide Tyrosyl-D-arginyl-phenylalanyl-glycine amide (H-Tyr-D-Arg-Phe-GlyNH2) in a single dose of 2 to 7 mg, with a daily dose of no more than 42 mg, with intervals between administrations of 4 hours, with a duration of the course of treatment of pain syndrome of up to 96 days, with the subsequent possibility of repeated course.

Moreover, this method is characterized by the following individual aspects:

a method in which the introduction of a tetrapeptide is carried out for pain syndrome in patients with oncological diseases, as well as in the early postoperative period during various surgical interventions;

a method comprising administering the tetrapeptide Tyrosyl-O-arginyl-phenylalanyl-glycine amide (HTyr-D-Arg-Phe-Gly-NH2) in the form of a solution for subcutaneous injections;

a method in which the tetrapeptide is administered under the control of the severity of the pain syndrome and/or the severity of the patient's reaction to the administration of the tetrapeptide, with an increase or decrease in the single dose and/or the number of administrations per day and/or the duration of the breaks between administrations and/or the duration of the course of treatment;

a method in which, depending on the severity of the pain syndrome, tetrapeptide injections are administered daily or with intervals of one to several days;

a method in which the total duration of pain syndrome treatment is determined by the patient's condition, while in patients with oncological diseases the duration of one course of pain syndrome treatment can be up to 96 days or more, with the possibility of subsequently repeating the course several times, while repeating the course is recommended after at least a 2-5 day break between courses, and the number of repetitions of courses is determined by the patient's condition;

a method in which the total duration of treatment is determined by the patient's condition, while in patients with pain syndrome in the early postoperative period with various surgical

- 2 049509 interventions, the duration of pain syndrome treatment ranges from 1 to 10 days;

a method in which a single dose of tetrapeptide from 4 to 7 mg is used;

a method in which the recommended initial single dose of the tetrapeptide Tyrosyl-O-arginylphenylalanyl-glycine amide (H-Tyr-D-Arg-Phe-Gly-NH2) is 4 mg;

a method in which an increase or decrease in a single dose, if necessary, is carried out by increasing or decreasing the dose by 25-50% of the previous one;

a method in which the tetrapeptide is administered at a dose of 4 mg 2-3 times a day.

The stated task is also solved by the fact that a method for relieving pain syndrome is proposed, including the introduction of the tetrapeptide Tyrosyl-O-arginyl-phenylalanyl-glycine amide (H-Tyr-D-Arg-PheGly-NH2) in a single dose of 2 to 7 mg, with a daily dose of no more than 42 mg, with breaks between administrations of 4 hours.

The stated task is also solved by the fact that a method for preventing an attack of pain in a pain syndrome is proposed, including the introduction of the tetrapeptide Tyrosyl-O-arginyl-phenylalanyl-glycine amide (H-Tyr-D-Arg-Phe-Gly-NH2) in a single dose of 2 to 7 mg, with a daily dose of no more than 42 mg, with breaks between administrations of 4 hours.

Another aspect is that a medicinal product is proposed for use in the claimed methods of treatment and/or prevention and/or relief of pain syndrome, including the tetrapeptide Tyrosyl-O-arginyl-phenylalanyl-glycine amide (H-Tyr-D-Arg-Phe-Gly-NH2) and excipients: sodium chloride mannitol, glycine, sodium acetate trihydrate, acetic acid, water, in the following ratio of components, wt.%:

Tetrapeptide Sodium chloride Mannitol 0.380-0.420 0.475 - 0.525 0.475 - 0.525 Glycine Sodium acetate trihydrate Acetic acid Water 0.475 - 0.525 0.0380 - 0.0420 to pH 4.0 - 6.0 to 100.

The proposed medicinal product is characterized by the following individual aspects:

a medicinal product characterized by the following ratio of components, wt.%:

Tetrapeptide Sodium chloride Mannitol 0.40 0.50 0.50 Glycine Sodium acetate trihydrate Acetic acid Water 0.50 0.04 up to pH 4.0 - 6.0 up to 100

a medicinal product characterized by the following ratio of components, mg:

Tetrapeptide 3.8-4.2 Sodium chloride 4.75 - 5.25 Mannitol 4.75 - 5.25 Glycine 4.75 - 5.25

Sodium acetate trihydrate Acetic acid Water 0.38-0.42 up to pH 4.0 - 6.0 up to 1 ml

a medicinal product characterized by the following ratio of components, mg:

Tetrapeptide 4.00 Sodium chloride 5,00 Mannitol 5,00 Glycine 5,00 Sodium acetate trihydrate 0,40 Acetic acid up to pH 4.0 - 6.0 Water up to 1ml

a medicinal product made in the form of a solution for subcutaneous administration.

Unless otherwise defined, all technical and scientific terms used herein have the meanings commonly understood by those skilled in the art to which the invention belongs.

- 3 049509 n. In the event that there are multiple definitions for terms, the one described in this application is considered valid. It should be noted that if a link is given in the form of a URL or a similar address or identifier, it is obvious that the identifier may change, and specific information on the Internet may appear and disappear, but equivalent information can be found by searching the Internet. A link to this information indicates that it is available and can be distributed. It is obvious that the above brief description and the following detailed description of the invention are given for illustrative purposes only and in no way limit any of the claimed objects. The use of the terms to which they relate, including, and their synonyms is not limiting. It should be noted that the methods and compositions described in the present invention are not limited to the specific methodologies, protocols, constructs and reagents that are described in this document and can vary. It should also be noted that the terminology used herein is used solely for the purpose of describing particular embodiments and is not intended to limit the scope of the described methods and compositions, which are limited only by the appended claims.

Clinical studies were conducted that included the administration of the tetrapeptide Tyrosyl-O-arginyl-phenylalanyl-glycine amide (H-Tyr-D-Arg-Phe-Gly-NH2) to patients in the form of subcutaneous injections of the finished drug Tafalgin.

Tetrapeptide Tyrosyl-O-arginyl-phenylalanyl-glycine amide (H-Tyr-D-Arg-Phe-Gly-NH2) is a highly specific agonist of μΐ-opioid receptors and has virtually no interaction with other opioid receptors (interaction with δ-receptors is 3 orders of magnitude lower than with μ-opioid receptors, interaction with other receptors is not detected). There are two subtypes of μ-receptors: activation of μ1-receptors causes pronounced analgesia; activation of μ2-receptors leads to respiratory depression, cardiovascular disorders such as bradycardia, and suppression of intestinal motility. Thus, the high specificity of this tetrapeptide to μΐ-receptors ensures the absence of side effects characteristic of most narcotic opioid analgesics. The specified tetrapeptide interacts with both peripheral and central receptors, but acts primarily at the spinal level. After the tetrapeptide binds to μΐ receptors, a G-protein complex is released, which inhibits the release of neurotransmitters by the cell by reducing the amount of cAMP produced, closing calcium channels and opening potassium channels, which, in particular, reduces the passage of a pain signal in nociceptors. The tetrapeptide activates the antinociceptive system and, thus, disrupts interneuronal transmission of pain impulses at various levels of the central nervous system, and also changes the intensity of pain perception, affecting the higher parts of the brain.

The drug Tafalgin is a solution for subcutaneous administration, which includes as an active substance the tetrapeptide Tyrosyl-O-arginyl-phenylalanyl-glycine amide (H-Tyr-D-Arg-Phe-GlyNH ₂ ), as well as auxiliary substances in the form of sodium acetate trihydrate, sodium chloride, mannitol, glycine, water, in the following ratio of components:

tetrapeptide Tyrosyl-O-arginyl-phenylalanyl-glycine amide - 0.4 wt.%, sodium acetate trihydrate - 0.04 wt.%, sodium chloride - 0.5 wt.%, mannitol - 0.5 wt.%, glycine - 0.5 wt.%, water - up to 100 wt.%.

The quantitative content of ingredients may fluctuate within 15-20% of the above indicator for each component.

The drug Tafalgin 4 mg/ml was used.

To prepare the drug Tafalgin, the excipients are dissolved in water, then the tetrapeptide solution is dissolved in the resulting solution, the resulting solution is sterilized, passed through filters and poured into ampoules or syringes.

To evaluate the safety, tolerability and pharmacokinetics of tafalgin after subcutaneous administration, an initial phase I clinical study was conducted in 39 healthy male volunteers. The study was conducted in cohorts with dose escalation for each subsequent cohort (0.05 mg; 0.5 mg; 1 mg; 2 mg; 3 mg; 4 mg; 5 mg; 6 mg; 7 mg). Tafalgin was administered as a single subcutaneous dose, starting with the cohort in which the lowest dose of the drug was used. Each participant received only 1 dose. Dose escalation for each subsequent cohort was performed only after a comprehensive assessment of AEs/serious AEs (SAEs), vital signs, electrocardiography, physical examination and laboratory tests, as well as data on the incidence of dose-limiting toxicities (DLTs). If in any cohort, DLT was detected in 1 person who received the study drug, then the number of volunteers would have to be increased by 3 people. If, however, none of the volunteers in the expanded cohort who received tafalgin had dose-limiting toxicity - DLT (i.e. DLT was observed in 1 of 6 people), then in the next cohort, the number of volunteers would have to be increased by 3 people.

- 4 049509 the dose of the drug could be continued. To study the pharmacokinetics of tafalgin, 22 blood samples were collected from each volunteer (before drug administration (0 h), 10, 20, 30, 45 min, 1; 1.5; 2; 2.5; 3; 4; 5; 6; 7; 8; 10; 12; 24; 48; 72; 96 and 120 h after its administration). The following parameters were calculated: area under the pharmacokinetic curve within the observation duration (AUC _0-t ), area under the pharmacokinetic curve from the moment of drug administration to infinity (AUC _0-M ), maximum concentration (C _max ), time to reach maximum concentration (T _max ), half-life (T1/2), mean plasma residence time (MRT), elimination constant (Kel), volume of distribution (Vd). Plasma tafalgin concentrations were determined by high-performance liquid chromatography with tandem mass spectrometry (HPLC-MS/MS) using a Triple Quad 4500 system (AB Sciex) [49]. Clinical and biochemical blood tests were also performed at the study completion stage, and coagulogram parameters were studied. The total duration of the study for each volunteer was no more than 14 days. The study demonstrated good safety and tolerability of various doses of tafalgin (0.05 mg; 0.5 mg; 1 mg; 2 mg; 3 mg; 4 mg; 5 mg; 6 mg; 7 mg) with a single subcutaneous administration to healthy volunteers. During the escalation, the maximum dose of the drug of 7 mg was reached, while no cases of dose-limiting toxicity (AE of grade III and higher according to the Common Terminology Criteria for Adverse Events (CTCAE)) were registered. According to the assessment of the medical investigators, the tolerability of tafalgin in all volunteers was characterized as good or excellent. The most common AEs registered during the study (more than 5% of the total number of AEs) were: asthenia (n = 11; 28.20%), dry mouth (n = 11; 28.20%), hypoesthesia (n = 9; 23.08%), discomfort in the head (n = 9; 23.08). The observed AEs were mild in severity, did not require treatment and almost all resolved with recovery.

The period of reaching the maximum concentration of the drug after subcutaneous administration averaged 30 minutes, which indicates its rapid absorption from the subcutaneous fat tissue. After a single administration, tafalgin was intensively distributed not only in the bloodstream, but also in the peripheral tissues, as indicated by the volume of distribution (on average from 24 to 39 l), significantly exceeding the volume of circulating blood. Following the distribution, a fairly rapid elimination phase occurred: the half-life of the drug was from 1.3 to 2.5 hours, thus, in approximately 15 hours it was completely eliminated from the systemic bloodstream.

In general, such elimination rates are typical for therapeutic polypeptides, which include tafalgin. The average retention time of 1 molecule of the drug in the human body was 3.03 ± 0.42 h.

In a phase II clinical trial, the efficacy and safety of different doses of tafalgin were studied in patients with malignant neoplasms accompanied by pain syndrome. The optimal dosing regimen for the drug was also selected and its pharmacokinetic parameters were assessed with repeated administration. Pain intensity was assessed using the Numeric rating scale for pain (NRS) from 0 to 10 points. The study included patients of both sexes with a verified diagnosis of malignant neoplasms, aged 18 to 70 years inclusive, with severe pain syndrome caused by cancer and relieved with morphine at the time of inclusion in the trial (pain level at the time of screening according to the NRS scale <3 points, maximum daily dose of morphine - 60 mg intramuscularly, duration of administration of a stable dose of morphine - at least 7 days before screening), and an expected life expectancy of more than 1 month. Patients did not receive other analgesics, except for those provided for by the protocol. The patients' physical activity according to the Eastern Cooperative Oncology Group (ECOG) scale ranged from 0 to 3 points, i.e. they were active and spent more than 50% of their waking time in an upright position (2 points according to the ECOG scale) or were capable of only limited self-care, spent more than 50% of their waking time in a chair or bed (3 points according to the ECOG scale). The study included 2 stages. The total duration of the trial for each patient was no more than 20 days. At the 1st stage (duration 10 days), the dose of tafalgin was selected: each participant received a starting single dose of the drug according to randomization (2, 3, 4, 5, 6 or 7 mg) with subsequent titration according to the established scheme. The frequency of drug administration depended on the intensity of the pain syndrome, which was assessed according to the NRS scale, in each patient. The acceptable safety profile of different doses of tafalgin selected for this clinical trial demonstrated in the phase I clinical trial allowed for a parallel design using different starting doses for each group. In stage 2, patients received either tafalgin (solution for subcutaneous administration in an individually selected dose established in stage 1; maximum single dose - 7 mg, maximum daily dose - 42 mg) or the comparator drug morphine (solution for intramuscular injection in an individually selected dose established before the start of stage 1) for 7 days.

In case of breakthrough pain in patients, it was suggested to use morphine in the form of an injection solution of 10 mg/1 ml.

- 5 049509

The choice of the comparison drug was justified by its widespread use in this category of patients, as well as the results of preclinical studies of tafalgin, which allowed us to put forward a hypothesis about its comparability with morphine in terms of the strength of the analgesic effect. The primary endpoint for assessing the effectiveness of the therapy was the frequency of achieving a sufficient analgesic effect throughout the day. This effect was understood as mandatory compliance with 2 criteria, including the patient achieving an average daily pain intensity score according to NRS <3 and the need for no more than 2 injections of morphine (at a dose of 10 mg intramuscularly) to relieve breakthrough pain over 10 days. To confirm the analgesic efficacy of tafalgin, the following secondary endpoints were additionally selected:

dynamics of the average daily pain intensity score on the NRS scale (in points);

average pain intensity for 1 hour according to the NRS scale in the interval between the 1st and 2nd administration at the 10th visit;

dynamics of the daily dose of additional analgesic for relief of breakthrough pain (in mg);

quality of night sleep on a 3-point Likert scale based on the patient's diary data (the duration of night sleep not interrupted by pain was determined: 1 point - good sleep (6-8 hours), 2 points - satisfactory sleep (4-6 hours), 3 points - poor sleep (less than 4 hours));

frequency of increasing the dose of the drug;

frequency of need for change of therapy.

Patients were divided into 6 groups receiving different starting doses of tafalgin: Group 1 (n = 6) - 2 mg; Group 2 (n = 6) - 3 mg; Group 3 (n = 12) - 4 mg; Group 4 (n = 6) - 5 mg; Group 5 (n = 6) - 6 mg; Group 6 (n = 6) - 7 mg. All groups were comparable in demographic characteristics (p>0.05).

At the first stage, the results of the analysis revealed a statistically significant difference in the average daily pain intensity score on the NRS scale between the days of the study in the groups of patients who received tafalgin at a dose of 2 mg (p<0.00001), 3 mg (p<0.03681), 4 mg (p<0.00131), 6 mg (p<0.00497) and 7 mg (p<0.01788), which indicates the presence of positive dynamics in the severity of pain in the listed groups and a decrease in the intensity of the pain syndrome under the influence of this drug. Moreover, as a result of a comparative analysis of the average daily pain intensity score on the NRS scale on days 1-10, no significant differences were found between the study groups, which indicates that even the minimum studied single dose of tafalgin (2 mg) with an average daily dose in the subgroup on day 10 of 8.33 mg was sufficiently effective within the dose subgroup with an average starting dose of morphine in this subgroup of 18.33 mg.

At the 2nd stage of the study, in the group of patients receiving morphine, the analysis showed no significant difference in the average daily pain intensity score on the NRS scale between the study days; thus, there was no intragroup dynamics of pain sensations (p = 0.88079). Dynamics of the average daily pain intensity score on the NRS scale in the tafalgin group were also not noted, the patients' pain sensations were stable (p = 0.46607). Thus, the drug controlled the severity of pain sensations as well as morphine, which is proven by the intergroup comparison: throughout the 2nd stage, the severity of pain sensations between the groups did not differ (p> 0.05).

Table 1

Dynamics of the average daily pain intensity score according to the Numeric rating scale for pain (NRS) at the 2nd stage of the study

Time of administration, days Tafalgin Morphine R 11th 0.07 ±0.16 0.12 ± 0.22 0,4392 12th 0.18 ±0.34 0.30 ± 0.38 0,5581 13th 0.19 ±0.26 0.24 ± 0.35 0,6814 14th 0.16 ±0.25 0.24 ± 0.35 0,5061 15th 0.09 ± 0.22 0.28 ± 0.30 0,1252 16th 0.14 ±0.19 0.17 ±0.21 0.3721 17th 0.11 ±0.15 0.17 ±0.23 0,4656

A study of sleep quality in patients taking tafalgin showed an improvement: by the 9th-10th day of the study, 76-79% of patients had satisfactory sleep, and 20-23% had good sleep.

Before the start of the study, all patients participating in the 1st stage of the study took morphine in an individually selected dose providing sufficient pain relief. The average stable daily dose of this drug for all dose subgroups of tafalgin before the start of the study was 20.31 mg; 14 (33.33%) patients received morphine at a dose of 10 mg, 18 (42.86%) - at a dose of 20 mg, 6 (14.29%) - at a daily dose of 30 mg, 3 (7.14%) - at a daily dose of 40 mg, 1 (2.38%) - at a dose of 60 mg. In the process

- 6 049509 of tafalgin use at the 1st stage, the dosage was adjusted until the patient reached the daily dose providing sufficient pain relief. The average daily dose of the drug at the 10th visit during pulping of all dose subgroups was 8.25 mg, in the 2 mg dose subgroup - 8.33 mg, in the 3 mg dose subgroup - 6.80 mg, in the 4 mg dose subgroup - 10.10 mg, in the 5 mg dose subgroup - 7.25 mg, in the 6 mg dose subgroup - 8.80 mg, in the 7 mg dose subgroup - 6.00 mg. As a result, it was possible to compare the individual daily doses of morphine and tafalgin for each patient taken into account in the study. On average, by the 6-7th days of the 1st stage of the study, patients received a stable dose of the drug. The average daily dose of tafalgin for 7-10 days of the study was taken into account and compared with the pre-established dose of morphine for each patient. The average daily dose of tafalgin is generally 3 times less than the dose of morphine for the same patient.

Regarding adverse events (AE), the obtained results are presented below in Table 2.

Table 2

Number of adverse events (AE) reported in patients during the 2nd stage of the study, abs. (% of the total number of AE for this group)

НЯ Morphine Tafalgin Anemia 1 (3.7) 0(0) Asthenia 4 (14.8) 0(0) Insomnia 1 (3.7) 0(0) Dizziness 1 (3.7) 0(0) Postural dizziness 0(0) 1 (33.3) Urinary retention 1 (3.7) 0(0) Constipation 4 (14.8) 2 (66.7) Cough 1 (3.7) 0(0) Shortness of breath 1 (3.7) 0(0) Peripheral edema 1 (3.7) 0(0) Vomit 1 (3.7) 0(0) Sedative state 2(7.4) 0(0) Decreased appetite 2(7.4) 0(0) Dry mouth 1 (3.7) 0(0) Nausea 1 (3.7) 0(0) Flatulence 1 (3.7) 0(0) Acute heart failure (SHF) 1 (3.7) 0(0) Pulmonary edema (PED) 1 (3.7) 0(0) Multiple organ dysfunction syndrome (MOD) 1 (3.7) 0(0) Total 27 (100) 3 (100)

Notes: 1. There were 32 patients in 2 groups, 16 in each group. 2. SAE – serious adverse events.

During the 2nd stage of the study, 30 AEs were observed in 10 (31.25%) of 32 patients. The analysis of the incidence of AEs in the tafalgin and morphine groups at the 2nd stage of the study is presented in Table 2. It was shown that the safety profile was statistically significantly more favorable in the tafalgin group compared to the morphine group: the incidence of AEs in the morphine group was 50.0%, with 27 AEs registered in 8 patients of this group and SAEs in 1. The incidence of AEs in the tafalgin group was only 12.5%, with 3 AEs registered in 2 patients of this group. As a result of the comparative analysis of the presence of AEs, a significant difference was revealed between the groups (p = 0.022). At the same time, no significant differences were found in the severity of AEs, the presence of a causal relationship between the development of AEs and therapy, and the outcome of AEs between the groups.

The dynamics of opioid-associated conditions in patients transferred from morphine to tafalgin was also studied, and it was shown that during all 10 days of dose titration, a dynamic reduction in the incidence of opioid-associated conditions was noted: if before the start of therapy their frequency was 59.52% (25/42), then after 10 days of treatment with tafalgin it decreased to 14.29% (6/42). Thus, tafalgin not only does not cause opioid-associated AEs, but also helps to reduce them in patients who previously received morphine.

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The obtained data indicate the pronounced clinical efficacy of tafalgin. Thus, the use of this drug allowed maintaining sufficient analgesia throughout the study, achieved by preliminary intramuscular administration of morphine. The obtained data on the frequency of use of this drug demonstrate that even in a low dose range (2-4 mg), characterized by a favorable safety profile, it allows for control of pain syndrome caused by the tumor process for 8-12 hours. However, the pathogenesis of pain, the intensity of its perception and severity vary individually, and therefore the dose of tafalgin for proper control of pain syndrome should be selected individually. With a clinically effective dose of 2 mg, other doses up to 7 mg are well tolerated and are not associated with dose-limiting toxicity. The maximum daily dose of tafalgin should not exceed 42 mg. The drug should be administered with intervals between administrations of at least 4 hours.

Against the background of the use of tafalgin, no patient experienced a sedative state associated with a decrease in attention and ability to concentrate. Drowsiness, memory and concentration impairment are classic AEs that develop in response to the use of opioid drugs and significantly reduce the quality of life and performance of patients.

It is also important that tafalgin, unlike opioid drugs, does not have an inhibitory effect on the respiratory center: not a single patient receiving this drug experienced shortness of breath, while in the morphine group, difficulty breathing was detected.

Thus, the described studies have shown that the tetrapeptide Tyrosyl-E-arginylphenylalanyl-glycine amide (H-Tyr-D-Arg-Phe-Gly-NH2) for pain syndrome should be administered in a single dose of 2-7 mg, with a daily dose of no more than 42 mg, with breaks between administrations of 4 hours.

The recommended initial dose is 4 mg. The dose and frequency of administration are then selected individually, taking into account the severity of the pain syndrome and the reaction to the drug. If it is necessary to increase the single dose, it is increased by 25-50% of the previous dose. If it is necessary to reduce the dose (with a good therapeutic effect of a higher dose or in the event of adverse effects), the reduction is also carried out by 25-50% of the previous dose.

The developed recommendations were further used in the next series of clinical trials (phase III clinical trials).

Further clinical studies were conducted on 180 male and female patients aged 18 to 80 years with pain syndrome caused by malignant diseases. The patients were divided into 2 groups:

The 1st group (n = 120) of patients received Tafalgin, a solution for subcutaneous administration in an individually selected dose throughout the study.

Group 2 (n = 59) of patients received the comparator drug, oral morphine, for 28 days from the end of the drug dose adjustment (Period 1). Then (Period 2), patients in this group were transferred to Tafalgin, a solution for subcutaneous administration, which they received until the end of participation in the clinical trial at an individually adjusted dose.

For patients randomized to the study drug group, the starting dose of Tafalgin, solution for subcutaneous administration was 4 mg. The single dose of the drug was increased or decreased (if necessary) in 2 mg increments. The maximum single dose of Tafalgin is 7 mg. The maximum daily dose of Tafalgin is 42 mg. The duration of use of the study drug for the patient was no more than 94±2 days.

Visits during which the main assessment of treatment efficacy was performed: visit 1 (day 1 of tetrapeptide treatment), visit 2 (day 28±2 of tetrapeptide treatment), visit 3 (day 56±2 of tetrapeptide treatment), visit 4 (day 86±2 of tetrapeptide treatment).

Performance evaluation criteria:

The effectiveness of therapy was assessed at the following points:

Primary endpoint:

Frequency of maintenance of response to analgesic therapy at 28 days.

Maintenance of response to therapy was considered to be the simultaneous observance of the following conditions.

1. No more than 2 increases in the dose of the study drug/comparator drug from the start of therapy with the selected dose until the 28th day of therapy.

2. Maintenance of the average daily pain intensity during the last week of the 28-day therapy period at <50% of the intensity at the start of titration.

Secondary endpoints:

The proportion of patients who required an increase in the drug dose by Visits 2, 3, 4 from the start of therapy with the selected dose.

Proportion of patients who failed Tafalgin/morphine therapy at Visits 2, 3, 4.

The proportion of patients who experienced at least one episode of breakthrough pain by Visits 2, 3, 4 from the start of therapy with the selected dose.

- 8 049509

Dynamics of the average daily pain intensity score on the NRS scale at Visits 2, 3, 4 from the start of therapy with the selected dose.

Proportion of patients requiring concomitant analgesic therapy at Visits 2, 3, 4.

Assessment of patients' quality of life using the SF-36 questionnaire.

Investigator assessment of treatment efficacy at the end of the dose titration period at Visit 1 and at Visit 2.

Evaluation of the patient's treatment efficacy at the end of the dose titration period at Visit 1 and at Visit 2.

Safety assessment criteria:

Total number of adverse events (AEs), stratified by severity and frequency;

Proportion of adverse reactions;

Proportion of serious adverse events (SAEs) associated with the use of Tafalgin/morphine;

Proportion of patients experiencing at least one AE;

Proportion of patients who discontinued treatment due to AEs.

In Group 1 (Tafalgin), the proportion of patients with a preserved response to analgesic therapy by day 28 was 98.97% (96/97), in Group 2 (morphine drug) - 100.00% (46/46). The difference in the proportions of patients with a preserved response to analgesic therapy by day 28 between the Tafalgin drug group and the morphine drug group was 0.0103 (1.03%). The lower limit of the 95% CI for the difference in proportions was -0.0862 (8.62%), the upper limit of the 95% CI for the difference in proportions was 0.0643 (6.43%).

As a result of a comparative analysis of the frequency of patients with a maintained response to analgesic therapy by day 28, no statistically significant differences were identified between Group 1 (Tafalgin) and Group 2 (morphine drug) (one-sided Fisher's exact test, p=0.6783).

In Group 1 (Tafalgin), the proportion of patients who required an increase in the drug dose by Visit 2 was 4.12% (4/97), in Group 2 (morphine preparation) - 6.52% (3/46). As a result of a comparative analysis of the frequency of patients who required an increase in the drug dose by Visit 2, statistically significant differences between Group 1 (Tafalgin) and Group 2 (morphine preparation) were not revealed (Fisher's exact test, p = 0.6809).

By Visit 2, there were no patients in either Group 1 (Tafalgin) or Group 2 (morphine preparation) who had failed Tafalgin/morphine preparation therapy. As a result of a comparative analysis of the frequency of patients who had failed Tafalgin/morphine preparation therapy by Visit 2, no statistically significant differences were found between Group 1 (Tafalgin) and Group 2 (morphine preparation) (Pearson Chi-square test, p=1.0000).

By Visit 3, there were no patients in whom Tafalgin therapy was ineffective.

By Visit 4, there were no patients in whom Tafalgin therapy was ineffective.

In Group 1 (Tafalgin), the proportion of patients who experienced at least one episode of breakthrough pain by Visit 2 was 0.00% (0/97), in Group 2 (morphine preparation) - 2.17% (1/46). As a result of a comparative analysis of the frequency of patients who experienced at least one episode of breakthrough pain by Visit 2, no statistically significant differences were found between Group 1 (Tafalgin) and Group 2 (morphine preparation) (Fisher's exact test, p = 0.3217).

Against the background of the use of the drug Tafalgin, the proportion of patients who experienced at least one episode of breakthrough pain by Visit 3 and 4 was 1.40% (2/143).

The mean value of the average daily pain intensity score on the NRS scale for the entire population (Mean±SD) was 0.38±0.47 points at the beginning of therapy with the selected dose, 0.34±0.40 points at Visit 2. The mean value of the average daily pain intensity score on the NRS scale in Group 1 (Tafalgin) (Mean±SD) was 0.42±0.48 points at the beginning of therapy with the selected dose, 0.38±0.44 points at Visit 2. The mean value of the average daily pain intensity score on the NRS scale in Group 2 (morphine drug) (Mean±SD) was 0.30±0.47 points at the beginning of therapy with the selected dose, 0.28±0.30 points at Visit 2.

The mean value of the average daily pain intensity score on the NRS scale for the entire population (Mean±SD) was 0.38±0.46 points at the start of therapy with the selected dose, 0.35±0.54 points at Visit 3 and 0.35±0.65 points at Visit 4. Based on the analysis, no significant differences were found between visits (p=0.0770), indicating the absence of dynamics in the average daily pain intensity score on the NRS scale to Visits 3 and 4 against the background of the use of Tafalgin.

The average score of the physical component of health according to the SF-36 quality of life questionnaire in the entire population at Visit 0 was 33.91±11.39 points, at Visit 2 - 51.18±11.50 points. The average score of the physical component of health according to the SF-36 quality of life questionnaire in Group 1 (Tafalgin) at Visit 0 was 34.71±11.64 points, at Visit 2 - 51.96±11.36 points. The average score of the physical component of health

- 9 049509 The SF-36 quality of life questionnaire score in Group 2 (morphine drug) at Visit 0 was 32.22±10.76 points, at Visit 2 - 49.52±11.73 points.

The average score of the psychological component of health according to the SF-36 quality of life questionnaire in the entire population at Visit 0 was 34.84±13.12 points, at Visit 2 - 48.13±10.22 points. The average score of the psychological component of health according to the SF-36 quality of life questionnaire in Group 1 (Tafalgin) at Visit 0 was 36.46±13.30 points, at Visit 2 - 49.06±9.71 points. The average score of the psychological component of health according to the SF-36 quality of life questionnaire in Group 2 (morphine drug) at Visit 0 was 31.42±12.16 points, at Visit 2 - 46.17±11.08 points.

At Visit 2 in Group 1 (Tafalgin), the proportion of patients with excellent treatment effect was 55.67% (54/97), with good effect - 41.24% (40/97), with satisfactory effect - 3.09% (3/97). At Visit 2 in Group 2 (morphine drug), the proportion of patients with excellent treatment effect was 32.61% (15/46), with good effect - 67.39% (31/46), with satisfactory effect - 0.00% (0/46). As a result of comparative analysis of the frequency of patients with different scores of treatment effectiveness assessment by the investigator at Visit 2, statistically significant differences were revealed between the study groups (Pearson Chi-square test, p = 0.0103).

The safety assessment included the following phases: Dose titration, Period 1, the comparative phase of the study (continued for 28±2 days from the start of therapy at the titrated dose) and Period 2, the non-comparative phase of the study (continued for 56±2 days after Period 1).

The incidence of patients in Group 1 (Tafalgin) with reported cases of AE during Period 1 was 34.17% (41/120), with a total of 95 cases of AE observed in 41 patients. The incidence of patients in Group 2 (morphine preparation) with reported cases of AE during Period 1 was 71.19% (42/59), with a total of 119 cases of AE observed in 42 patients. A comparative analysis of patients in Groups 1 and 2 by the presence of AE in Period 1 revealed significant differences between the study groups (Pearson Chi-square test, p<0.00001).

The severity of AEs observed during Period 1 in patients of Group 1 was mild in 66.32% (63/95) of cases and moderate in 33.68% (32/95) of cases; in patients of Group 2 - mild in 65.55% (78/119) of cases, moderate in 33.61% (40/119) of cases and severe in 0.84% (1/119) of cases. As a result of comparative analysis of the severity of AEs, no significant differences were found between Groups 1 and 2 (p=0.6693).

According to the assessment of the physician-investigators, the causal relationship of AEs with therapy in Period 1 in Group 1 was assessed as certain in 1.05% (1/95) of cases, probable in 3.16% (3/95) of cases, possible in 44.21% (42/95) of cases, doubtful in 13.68% (13/95) of cases, conditional in 12.63% (12/95) of cases, unclassifiable in 1.05% (1/95) of cases, and not related in 24.21% (23/95) of cases; in Group 2 it was assessed as definite in 13.44% (16/119) of cases, probable in 29.41% (35/119) of cases, possible in 38.66% (46/119) of cases, doubtful in 11.76% (14/119) of cases, conditional in 0.84% (1/119) of cases, unclassifiable in 0.84% (1/119) of cases, and not associated with 5.04% (6/119) of cases. As a result of comparative analysis of patients in Groups 1 and 2 for the causal relationship of the development of AE with the drug in Period 1, significant differences were found between the study groups (Pearson Chi-square test, p<0.00001).

In order to further evaluate the differences identified between Groups 1 and 2, a comprehensive analysis of AEs was performed in the study groups. According to the results of this assessment, a lower frequency of patients with identified cases of AEs was noted in Group 1 (Tafalgin): 36.69% (44/120) versus 72.88% (43/59) in Group 2 (morphine drug). In addition, the frequency of registration by the investigator of the causal relationship between the development of AEs with the use of the drug of the categories definite, probable and possible was higher in Group 2 (morphine drug): 46 AEs in Group 1 (Tafalgin) versus 97 AEs in Group 2 (morphine drug), also in Period 1 in the group using the drug Tafalgin, there were no cases of therapy discontinuation due to the development of AEs.

The incidence of patients with reported AEs and/or SAEs during Period 2 was 12.74% (20/157). A total of 35 AEs and/or SAEs were reported in 20 patients during Period 2. The incidence of patients with reported AEs during Period 2 was 7.64% (12/157). A total of 24 AEs were reported in 12 patients during Period 2. The severity of AEs reported in patients during Period 2 was mild in 54.17% (13/24) of cases and moderate in 45.83% (11/24) of cases. According to the assessment of the medical investigators, the causal relationship between the development of AE and therapy with the study drug Tafalgin, registered in patients in Period 2, was assessed as definite in 16.67% (4/24) of cases, possible - in 33.33% (8/24), doubtful - in 12.50% (3/24) of cases, conditional - 4.17% (1/24) of cases, not associated - in 33.33% (8/244) of cases. Analysis of the frequency of AE outcomes in patients showed that by the end of Period 2, recovery without consequences was noted in 83.33% (20/24) of cases and improvement in condition in 16.67% (4/24) of cases.

Overall, based on the results of the safety parameter assessment, a lower frequency of patients with identified cases of adverse events was noted in the group of patients using Tafalgin.

- 10,049,509 cases: 36.69% (44/120) of patients versus 72.88% (43/59) of patients in the morphine group. In addition, the frequency of cases of registration by the physician-investigator of the causal relationship of the development of adverse events with the use of the drug of the categories definite, probable and possible was higher in the morphine group: 46 cases of adverse events in the group of patients using the drug Tafalgin versus 97 cases of adverse events in the morphine group.

Clinical studies were also conducted on the treatment of pain syndrome in the early postoperative period during surgical interventions for various diseases, including urological, gynecological, etc. The studies were conducted on 100 patients, who were divided into 5 groups of 20 people, while in three groups the patients were administered the drug Tafalgin in different dosages (2 mg 2 times a day; 4 mg 2 times a day; 4 mg 3 times a day), and in two groups - the comparison drug Promedol (20 mg 3 times a day).

Tafalgin (or the comparison drug Promedol) was started to be administered on the first day after the surgical intervention if the pain intensity on the NRS scale was > 4 points. If on the second day the pain intensity on the NRS scale was > 4 points, Tafalgin was administered in the same dose and at the same interval, but if necessary, the administration regimen during the day could be adjusted (as a rule, the number of administrations was reduced due to the relief of pain syndrome). If on the second day the pain intensity on the NRS scale was < 4 points, only paracetamol was administered, if necessary, in the form of intravenous injections with a maximum daily dose of 4 mg. The total duration of treatment did not exceed 8 days. As a rule, the pain syndrome was relieved within 1-2 days of the early postoperative period.

In the group treated with Tafalgin at a dose of 4 mg twice a day, the proportion of patients who achieved pain reduction by more than 50% one hour after the first dose of the drug was 65.0%, in the group treated with Tafalgin at a dose of 2 mg 3 times a day - 55.0%, in the group treated with Tafalgin at a dose of 4 mg 3 times a day - 80.0%, in the groups treated with Promedol at 20 mg 3 times a day - 50%.

The average daily value of the average daily pain assessment according to the NRS scale was 2.35 ± 0.70 points on the first day in the group treated with Tafalgin at a dose of 2 mg 3 times a day, in the group treated with Tafalgin at a dose of 4 mg 2 times a day - 2.51 ± 0.84, in the group treated with Tafalgin at a dose of 4 mg 3 times a day - 2.14 ± 0.94, in the groups treated with Promedol at 20 mg 3 times a day - 2.16 ± 0.66. On the second day, this indicator was 1.45 ± 2.06 in the group treated with Tafalgin at a dose of 2 mg 3 times a day, in the group treated with Tafalgin at a dose of 4 mg 2 times a day - 1.48 ± 1.83, in the group treated with Tafalgin at 4 mg 3 times a day 0.92 ± 1.77, in the groups treated with Promedol at 20 mg 3 times a day - 1.41 ± 1.92. The average change in pain intensity was 60.0 ± 25.45% in the group treated with Tafalgin at a dose of 2 mg 3 times a day, in the group treated with Tafalgin at a dose of 4 mg 2 times a day - 57.56 ± 21.12%, in the group treated with Tafalgin at 4 mg 3 times a day - 67.21 ± 20.11%, in the groups treated with Promedol at 20 mg 3 times a day - 55.44 ± 33.17%.

Among patients who required repeated administration of the drug on the second day in the group with the administration of Tafalgin on the first day at 2 mg 3 times a day, on the second day the drug was administered 3 times to 16.67% of patients, 1 time per day to 66.67% of patients, and 2 times per day to 16.67% of patients.

Among patients who required repeated administration of the drug on the second day in the group with the administration of Tafalgin on the first day at 4 mg 2 times a day, on the second day the drug was administered 2 times to 50.00% of patients, and 1 time per day to 50.00% of patients.

Among patients who required repeated administration of the drug on the second day in the group with the administration of Tafalgin on the first day at 4 mg 3 times a day, on the second day the drug was administered 3 times to 11.11% of patients, 2 times a day to 89.89% of patients.

Among patients who required repeated administration of the drug on the second day in the group with the administration of Promedol on the first day at 20 mg 3 times a day, on the second day the drug was administered 3 times to 16.67% of patients, 2 times a day to 83.33% of patients.

AE were observed in 23 patients out of 100. The severity of AE was mild in 76.74% of patients, moderate - in 23.53%. At the same time, in the groups with treatment of pain syndrome with Promedol, AE were in 35% of patients, in the group with treatment with Tafalgin 2 mg 3 times a day - in 15% of patients, in the group with treatment with Tafalgin 4 mg 2 times a day - in 10% of patients, in the group with treatment with Tafalgin 4 mg 3 times a day - in 20% of patients. According to the assessment of the physician-researchers, the causal relationship of AEs with therapy with the study drug/comparator drug was assessed as determined in 73.53%, probable in 5.88% of cases, possible in 11.76%, doubtful in 5.88% of cases, and not associated in 2.94% of cases.

The proposed method is carried out as follows.

The relief and/or treatment and/or prevention of pain syndrome is carried out with a drug based on the tetrapeptide Tyrosyl-E-arginyl-phenylalanyl-glycine amide (H-Tyr-D-Arg-Phe-Gly-NH ₂ ). In particular, this can be the drug Tafalgin, which is a solution for subcutaneous administration, including the tetrapeptide Tyrosyl-E-arginyl-phenylalanyl-glycine amide as an active substance.

- 11 049509 yes (H-Tyr-D-Arg-Phe-Gly-NH2) (4 mg/ml), as well as auxiliary substances in the form of sodium acetate trihydrate, sodium chloride, mannitol, glycine, water, in the following ratio of components:

tetrapeptide Tyrosyl-^-arginyl-phenylalanyl-glycine amide - 0.4 wt.%, sodium acetate trihydrate - 0.04 wt.%, sodium chloride - 0.5 wt.%, mannitol - 0.5 wt.%, glycine - 0.5 wt.%, water - up to 100 wt.%.

The quantitative content of ingredients may fluctuate within 15-20% of the above indicator for each component.

The drug is administered to the patient in a single dose of 2-7 mg 1-6 times a day with a maximum daily dose of 42 mg and intervals between administrations of 4 hours. The recommended initial dose is 4 mg. A specific dose is selected for the patient individually, depending on the severity of the pain syndrome, the severity of the analgesic effect after administration of the drug, the presence / absence of AE (adverse events) when administering the drug. Usually, the dose is selected in the first days of treatment with the drug, then the drug is administered under the control of the severity of the pain syndrome and, if necessary, the dose and number of administrations of the drug per day are adjusted. The recommended initial single dose of the drug, as already indicated, is 4 mg. The recommended optimal administration regimen: 4 mg 2-3 times a day. If it is necessary to increase the dose of the drug, this increase is carried out each time by 25-50% higher than the previous value. If it is necessary to reduce the dose, this decrease is also carried out by 25-50% of the previous dose.

The drug Tafalgin can be used for a long time, the duration of therapy is usually determined by the attending physician.

In the conducted clinical trials of phase III in patients with oncological diseases, the course of treatment was up to 96 days. In patients with pain syndrome in the early postoperative period in various surgical interventions, the duration of treatment in clinical trials III was, as a rule, from 1 to 10 days.

In the treatment of chronic pain, it is preferable to administer the drug on a regular basis according to a fixed schedule.

In case of long-term use, it is recommended to regularly check the need for prolongation of the drug use (for example, by short-term breaks), and also to review the dose. Therefore, courses of treatment lasting up to 96 days can be repeated several times, but at the same time, breaks between courses of at least 2-5 days are recommended.

It is possible to use the tetrapeptide Tnrosyl-^-arginyl-phenylalanyl-glycine amide (H-Tyr-D-ArgPhe-Gly-NH ₂ ) to prevent attacks of pain in pain syndrome. This is especially important in patients with oncological diseases. In this case, the drug is administered on a regular basis according to a fixed schedule, and the administration is carried out not only in case of severe pain, but also to prevent attacks of pain.

The proposed method is illustrated by the following examples.

Example 1.

Patient N., 65 years old, male.

Diagnosis: sarcoma of the left retroperitoneal space T2NIMI St.IV; metastases in the peritoneum, in the bones. Chronic pain syndrome of severe severity.

The patient is treated on an outpatient basis, is capable of self-care, but cannot perform work. He spends more than 50% of his waking time actively - in an upright position (50-60 points on the Karnofsky scale).

To relieve pain, morphine was used at a dose of 20 mg per day before the course was prescribed according to the proposed method. In this case, such opioid-associated adverse events (AE) as dizziness, sleep disturbance, sedation, weakness, and constipation were observed.

The pain syndrome was treated using the proposed method, using a drug based on the tetrapeptide Tyrosyl-^-arginyl-phenylalanyl-glycine amide (H-Tyr-D-Arg-Phe-Gly-NH ₂ ) drug Tafalgin, a solution for subcutaneous administration. Tafalgin was administered as subcutaneous injections in a single individually selected dose of 3 mg 2 times a day with a break of 12 hours (at 9 am and at 9 pm) for 14 days. The pain intensity was assessed 0.5-1.5 hours before the drug administration, immediately before the administration, 1 hour after the administration and at 1 pm daily. Before the drug was administered, the pain intensity was usually 1-2 points on the NRS scale (in some cases, 3 or 0 points) and always decreased to 0 points after the drug was administered (when assessed one hour after the drug was administered, the pain intensity was usually 0; when assessed at 13:00, it was usually 0-1). The patient noted an improvement in his physical and emotional state, as well as his sleep.

AEs were observed in the form of two short-term episodes of mild dizziness and two episodes of constipation. However, the relationship of AEs with the administration of Tafalgin was not assessed as definite. AEs resolved on their own.

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Example 2.

Patient N., 64 years old, male.

Diagnosis: cancer of the middle third of the esophagus T4NOMI St IV. Chronic pain syndrome of severe severity.

The patient is treated on an outpatient basis, is capable of self-care, but cannot perform work. He spends more than 50% of his waking time actively - in an upright position (50-60 points on the Karnofsky scale).

To relieve pain, morphine was used at a dose of 20 mg per day before the course was prescribed according to the proposed method. In this case, such opioid-associated adverse events (AE) as sedation and constipation were observed.

The pain syndrome was relieved using the proposed method, using a drug based on the tetrapeptide Tyrosyl-O-arginyl-phenylalanyl-glycine amide (H-Tyr-D-Arg-Phe-GlyNH ₂ ) - the drug Tafalgin, a solution for subcutaneous administration. Tafalgin was administered as subcutaneous injections in a single individually selected dose of 4-6 mg 2 times a day with a break of 12 hours (at 9 am and at 9 pm) for 14 days. The pain intensity was assessed 0.5-1.5 hours before the drug administration, immediately before the administration, 1 hour after the administration and at 1 pm daily. In the first 1.5 days, the drug was administered in a single dose of 6 mg, then 4 mg. Before the drug administration, the pain intensity was 3 points on the NRS scale on the first day, 3 points at 9 a.m. on the second day, and 2 points at 9 p.m. After the drug administration, the pain intensity decreased to 0-1 points. On days 3-14, the drug was administered at a dose of 4 mg 2 times a day. The pain intensity before the drug administration was usually 1 point (rarely 2) and decreased to 0 points after the drug administration. When assessing the pain intensity at 1 p.m., the intensity was also 0 (rarely 1). The patient noted an improvement in his physical and emotional state, as well as sleep.

AEs were observed in the form of single episodes of mild insomnia and dry mouth. However, the relationship of AEs with the administration of Tafalgin was not assessed as definite. AEs resolved on their own.

Example 3.

Patient N., 68 years old, male.

Diagnosis: Malignant neoplasm of the left retromolar region T3NIMI 3 st. Squamous cell carcinoma, keratinizing. Chronic pain syndrome (pain intensity 2-3 points).

The patient is unable to perform heavy work, but can perform light or sedentary work (for example, housework or office work) (70-80 points on the Karnofsky scale).

To relieve pain, morphine was used at a dose of 30 mg per day before the course was prescribed according to the proposed method. In this case, such opioid-associated adverse events (AE) as a sedative effect were observed.

The pain syndrome was relieved using the proposed method, using a drug based on the tetrapeptide Tyrosyl-O-arginyl-phenylalanyl-glycine amide (H-Tyr-D-Arg-Phe-GlyNH ₂ ) - Tafalgin, a solution for subcutaneous administration. Tafalgin was administered as subcutaneous injections in a single individually selected dose of 2-4 mg 2-3 times a day with a break of 6-12 hours for 14 days. The pain intensity was assessed 0.5-1.5 hours before the drug administration, immediately before the administration, 1 hour after the administration and at 13 o'clock daily. During the first 4 days, the drug was administered at a dose of 4 mg 2 times a day. Before the drug administration, the pain intensity was usually 2-4 points on the NRS scale (in some cases - 5 or 1) and always decreased to 1-0 points after the administration. On days 5-6, the drug was administered at 2 mg 2 times a day. In this case, the pain intensity before the drug administration was, as a rule, 1 point, after the administration - 0 points. On the seventh day, the drug was administered 2 times at 2 mg, and then a third time at a dose of 4 mg; the dose was increased due to the pain intensity of 5 points. In this case, after the drug administration, the pain intensity was 2 points. On days 8-14, the drug was administered at a dose of 4 mg 3 times a day with breaks of 6-8 hours. The pain intensity decreased from 2-4 points to 0-2.

The patient noted an improvement in his physical and emotional state, as well as his sleep.

AEs were observed in the form of several episodes of mild drowsiness, decreased appetite, and a slight increase in body temperature. However, the connection of AEs with the administration of Tafalgin was assessed as questionable.

Example 4.

Patient N., 64 years old, male.

Diagnosis: cancer of unclear primary localization, mts in the subclavian lymph node, liver, retroperitoneal lymph nodes, inguinal lymph nodes, skeletal bones. Chronic pain syndrome. The patient is treated on an outpatient basis, is capable of self-care, but cannot perform work. Spends more than 50% of his waking time actively - in a vertical position (50-60 points on the Karnofsky scale).

To relieve pain, morphine was used at a dose of 30 mg per day before the course of treatment according to the proposed method was prescribed.

The treatment of pain syndrome was carried out using the proposed method, using a drug based on the tetrapeptide Tyrosyl-O-arginyl-phenylalanyl-glycine amide (H-Tyr-D-Arg-Phe-Gly-NH ₂ )

- 13 049509 drug Tafalgin, solution for subcutaneous administration. Tafalgin was administered as subcutaneous injections in a single individually selected dose of 4-5 mg 3 times a day with a break of 6-8 hours for 14 days. Pain intensity was assessed 0.5-1.5 hours before drug administration, immediately before administration, 1 hour after administration and at 13:00 daily. During the first 2 days, the drug was administered in a single dose of 4 mg, then 5 mg. Before drug administration, pain intensity was 2-4 points on the NRS scale on the first day, 3-4 points on the second day. After drug administration, pain intensity decreased to 2 points. On days 3-14, the drug was administered at a dose of 5 mg 3 times a day. Pain intensity before drug administration was, as a rule, 1 point and decreased to 0 points after drug administration. The patient noted an improvement in physical and emotional state, as well as sleep.

AE were observed in the form of single episodes of mild drowsiness, mild dizziness, and a slight increase in body temperature. However, the connection of AE with the administration of Tafalgin was assessed as questionable. AE resolved on their own.

Example 5.

Patient N., 57 years old, female.

Diagnosis: cervical cancer pT2abNxMO, stage IIab. Chronic pain syndrome.

The patient is unable to perform heavy work, but can perform light or sedentary work (for example, housework or office work) (70-80 points on the Karnofsky scale).

A patient with uncontrolled pain syndrome (not including episodes of breakthrough pain or other causes not associated with constant pain) against the background of the use of weak opioid analgesics ± NSAIDs ± adjuvant drugs before treatment according to the proposed method.

The pain syndrome was treated using the proposed method, using a drug based on the tetrapeptide Tyrosyl-E-arginyl-phenylalanyl-glycine amide (H-Tyr-D-Arg-Phe-Gly-NH ₂ ) drug Tafalgin, a solution for subcutaneous administration. Tafalgin was administered as subcutaneous injections in a single individually selected dose of 4-6 mg 1-3 times a day for 84 days. Pain intensity was assessed 1-1.5 hours before administration of the drug, 1-1.5 hours after 4 hours, and 12 hours after administration.

During the first 5 days, the drug was administered at 4 mg 3 times a day with breaks of 7-8 hours. In this case, the pain intensity according to the NRS scale was 3-4 points in the first two days before the drug administration, and 1-3 points after the administration (after 1 hour and after 4 hours). On days 3-5 of drug administration, the pain intensity was 1-2 points before the drug administration and 0 points after the administration (after 1 hour and after 4 hours). From day 6 to 42, the drug was administered at 4 mg once a day. The pain intensity was 1-2 points before the drug administration and decreased to 0 points after the administration (after 1 hour and after 12 hours) until day 37 of treatment. From day 37 to 42, the pain intensity was 2 points before the drug administration, 1 point an hour after the administration, and 1-2 points 4 hours after the administration. From day 43 to day 84, the drug was administered at a dose of 6 mg once a day. In this case, the pain intensity before the drug administration was, as a rule, 1 point, and after the administration 0 points (1 hour and 12 hours after the administration).

No adverse events associated with the analgesic drug Tafalgin were recorded.

Example 6.

Patient N., 49 years old, male.

Diagnosis: cancer of the right kidney T4NOMI, St.IV. Chronic pain syndrome of moderate severity.

The patient is treated on an outpatient basis, is capable of self-care, but cannot perform work. He spends more than 50% of his waking time actively - in an upright position (50-60 points on the Karnofsky scale).

A patient with uncontrolled pain syndrome (not including episodes of breakthrough pain or other causes not associated with constant pain) against the background of the use of weak opioid analgesics ± NSAIDs ± adjuvant drugs before treatment according to the proposed method.

The pain syndrome was relieved using the proposed method, using a drug based on the tetrapeptide Tyrosyl-E-arginyl-phenylalanyl-glycine amide (H-Tyr-D-Arg-Phe-GlyNH2) - the drug Tafalgin, a solution for subcutaneous administration. Tafalgin was administered as subcutaneous injections in a single individually selected dose of 4 mg once a day for 83 days. The pain intensity was assessed 1-1.5 hours before the drug was administered, as well as 1-1.5 hours and 12 hours after the administration.

The pain intensity according to the NRS scale in the first 2 days of treatment with Tafalgin was 3-4 points before the drug administration and 0-2 points after the administration (after 1 hour and after 12 hours). From the third day, the pain intensity before the drug administration was usually 1 point, and after 1 hour and after 12 hours after the administration - 0 points.

The patient's general physical and emotional state improved, as did his sleep.

No adverse events associated with the administration of Tafalgin were registered.

Example 7.

Patient N., 43 years old, female.

- 14 049509

Diagnosis: cancer of the right breast T3NIMO, stage II B. Chronic pain syndrome of moderate severity.

The patient is unable to perform heavy work, but can perform light or sedentary work (for example, housework or office work) (70-80 points on the Karnofsky scale).

A patient with uncontrolled pain syndrome (not including episodes of breakthrough pain or other causes not associated with constant pain) against the background of the use of weak opioid analgesics ± NSAIDs ± adjuvant drugs before treatment according to the proposed method.

The pain syndrome was treated using the proposed method, using a drug based on the tetrapeptide Tyrosyl-O-arginyl-phenylalanyl-glycine amide (H-Tyr-D-Arg-Phe-Gly-NH ₂ ) drug Tafalgin, a solution for subcutaneous administration. Tafalgin was administered as subcutaneous injections in a single individually selected dose of 4 mg 1-3 times a day for 83 days. Pain intensity was assessed 1-1.5 hours before drug administration, 1-1.5 hours after 4 hours, and 12 hours after administration.

The pain intensity in the first 3 days was 4 points on the NRS scale before the drug was administered and 2 points 1-4 hours after the drug was administered. During these 3 days, the drug was administered 2 times a day.

In the following days, the drug was administered at 4 mg once a day. The pain intensity was usually 1 point before the drug was administered and 0 points after the administration (1 hour and 12 hours after the administration). On some days, the pain intensity was 0 points throughout the day.

An episode of mild numbness of the lower limb was noted among the AEs, which was easily tolerated by the patient, did not interfere with daily activities and caused minimal inconvenience. The causal relationship with the drug Tafalgin was assessed as possible. The AE resolved on its own, no special treatment or change in the dose of Tafalgin was required.

Example 8.

Patient N., 67 years old, female.

Diagnosis: left breast cancer, stage T1NOMO, st. I. Chronic pain syndrome of moderate severity.

The patient is treated on an outpatient basis, is capable of self-care, but cannot perform work. She spends more than 50% of her waking time actively - in an upright position (50-60 points on the Karnofsky scale).

A patient with uncontrolled pain syndrome (not including episodes of breakthrough pain or other causes not associated with constant pain) against the background of the use of weak opioid analgesics ± NSAIDs ± adjuvant drugs before treatment according to the proposed method.

The pain syndrome was treated using the proposed method, using a drug based on the tetrapeptide Tyrosyl-O-arginyl-phenylalanyl-glycine amide (H-Tyr-D-Arg-Phe-Gly-NH ₂ ) drug Tafalgin, a solution for subcutaneous administration. Tafalgin was administered as subcutaneous injections in a single individually selected dose of 4 mg 1-3 times a day for 85 days. Pain intensity was assessed 1-1.5 hours before administration of the drug, 1-1.5 hours, 4 hours, and 12 hours after administration.

During the first 5 days, the drug was administered at 4 mg 3 times a day with 6-8 hour intervals. The pain intensity during the first 3 days was 3-4 points (6 points at certain hours) on the NRS scale before drug administration and 0-1 points 1 hour and 4 hours after administration. On days 4-5, the pain intensity was 2-3 points before drug administration and 0-1 points 1 hour and 4 hours after administration.

In the following days, the drug was administered at 4 mg once a day. The pain intensity was usually 1 point before the drug was administered, decreased to 0 points after the administration and remained so throughout the day.

The patient noted an improvement in her physical and emotional state.

No adverse events associated with the administration of Tafalgin were registered.

Example 9.

Patient N., 43 years old, female.

Diagnosis: uterine fibroids.

Surgical intervention: hystoscopy, minilaparotomy, myomectomy, pelvic cavity sanitation, active drainage of the abdominal cavity.

To relieve pain in the early postoperative period, treatment was carried out with Tafalgin, 2 mg 3 times a day.

The pain intensity according to the NRS scale on the first day before the drug administration was initially 6 points, 30 minutes after the administration - 6 points, 1 hour after the administration - 5 points, 2 hours after the administration - 8 points, 4 hours after the administration - 5 points, 6 hours after the administration - 3 points. With a pain intensity of 8 points, the patient was additionally administered 500 mg of paracetamol. Then, on the first, second and third days, only Tafalgin was administered for pain relief, while the pain intensity before the drug administration was 4-5 points on the NRS scale and decreased to 3-2 points 0.5-1 hour after the administration and to 0-2 points 4-6 hours after the administration.

- 15 049509

No adverse events were observed.

Example 10.

Patient N., 30 years old, female.

Diagnosis: infertility; hydrosalpix on both sides.

Surgical intervention: laparoscopy, bilateral tubectomy, hysteroscopy, separate diagnostic curettage of the walls of the uterine cavity and cervical canal.

To relieve pain in the early postoperative period, treatment was carried out with Tafalgin, 4 mg 2 times a day.

The pain intensity according to the NRS scale on the first day before the drug administration was initially 4 points, 30 minutes after the administration - 4 points, 1 hour after the administration - 3 points, 2 hours after the administration - 3 points, 4 hours after the administration - 6 points, 6 hours after the administration - 3 points. With a pain intensity of 6 points (4 hours after the administration of the first dose of Tafalgin), the patient was additionally administered 500 mg of paracetamol. Then, on the first and second days, only Tafalgin was administered for pain relief, while on the first day the pain intensity before the drug administration was 4-3 points on the NRS scale, decreased to 3-2 points an hour after the administration and remained so for 4-6 hours. On the second day, the pain intensity was 2 points before the drug administration, decreased to 0 after the drug administration and remained so for 4-6 hours. No adverse effects were observed.

Example 11.

Patient N., 36 years old, female.

Diagnosis: uterine fibroids.

Surgical intervention: minilaparoscopy, hysteroscopy. Myectomy without opening the uterine cavity. Sanitation of the pelvic cavity.

To relieve pain in the early postoperative period, treatment was carried out with Tafalgin, 4 mg 3 times a day.

The pain intensity according to the NRS scale on the first day before the drug administration was initially 4 points, 30 minutes after the administration - 4 points, 1 hour after the administration - 4 points, 2 hours after the administration - 5 points, 4 hours after the administration - 3 points, 6 hours after the administration - 2 points. Against the background of pain intensity of 5 points (2 hours after the administration of the first dose of Tafalgin), the patient was additionally administered 500 mg of paracetamol. Then, on the first, second and third days, only Tafalgin was administered for pain relief, while the pain intensity before the administration of the drug was 2-1 points on the NRS scale, and after the administration of the drug - 1 point for 6 hours.

An AE in the form of an increase in the ESR level was observed. The AE was mild and did not require special treatment or a change in the dose of the drug; recovery was without consequences. A causal relationship with the drug Tafalgin was assessed as possible.

Example 12.

Patient N., 31 years old, male.

Diagnosis: inguinal hernia on the right.

Surgical intervention: laparoscopic inguinal hernioplasty with an implant on the right.

To treat pain syndrome in the early postoperative period, treatment was carried out with the drug Tafalgin at 4 mg 3 times a day.

The pain intensity according to the NRS scale on the first day before the drug administration was initially 6 points, 30 minutes after the administration - 4 points, 1 hour after the administration - 2 points, 2 hours after the administration - 1 point, 4 hours after the administration - 0 points, 6 hours after the administration - 1 point. Then, on the first day, as well as on the second day, the pain intensity before the drug administration was 2-1 points on the NRS scale, and after the drug administration - 1-0 points for 6 hours. On the third day, the pain intensity before the drug administration was 1 point, after the administration it decreased to 0 and remained so for 6 hours.

No adverse events were observed.

Example 13.

Patient N., 51 years old, female.

Diagnosis: urinary incontinence.

Surgical intervention: cystoscopy. Uretropexy of the middle third of the urethra with a free synthetic loop Urosling.

To treat pain syndrome in the early postoperative period, treatment was carried out with the drug Tafalgin, 2 mg 3 times a day.

The pain intensity according to the NRS scale on the first day before the drug administration was initially 3 points, 30 minutes after the administration - 2 points, 1 hour after the administration - 2 points, 2 hours after the administration - 2 points, 4 hours after the administration - 2 points, 6 hours after the administration - 3 points. Then, on the first, second and third days, the pain intensity before the drug administration was 2-1 points on the NRS scale, and after the drug administration - 1-0 points for 6 hours.

No adverse events were noted.

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Claims (32)

Example 14. Patient N., 37 years old, female. Diagnosis: asymptomatic cyst (dermoid) of the right ovary. Based on the results of laboratory tests and magnetic resonance imaging, the oncological nature of the disease was excluded. Surgical intervention: laparoscopy, adhesiolysis, right oophorectomy. To relieve pain in the early postoperative period, treatment was carried out with Tafalgin, 2 mg 3 times a day. The pain intensity according to the NRS scale on the first day before the drug administration was initially 4 points, 30 minutes after the administration - 3 points, 1 hour after the administration - 1 point, 2 hours after the administration - 1 point, 4 hours after the administration - 0 points, 6 hours after the administration - 0 points. Then, on the first day, as well as on the second day, the pain intensity before the drug administration was 1 point on the NRS scale, and after the drug administration - 0 points for 6 hours. No adverse events were noted. To summarize, it should be noted that the studies conducted indicate the effectiveness and safety of the declared method of treating pain syndrome and the broad prospects for its use both in the early postoperative period during various surgical interventions and in long-term treatment of pain syndrome in cancer patients. One of the most important features of the biological action of the peptide H-Tyr-D-Arg-Phe-GlyNH ₂ and the drug Tafalgin based on it is the absence of such serious side effects as the effect on the central nervous system in the form of impaired consciousness and the development of euphoria, as well as the absence of an effect on the respiratory center. Another positive feature is the wide therapeutic range of application without the development of pronounced side effects. These features allow us to talk about the possibility of using the claimed methods of relief, treatment, prevention of pain syndrome in much wider areas of therapy, including outside hospitals, in the field or at home by low-skilled personnel or by the patient himself, which is extremely important both for the treatment of pain syndrome in oncological diseases and for the treatment of this syndrome in the early postoperative period in various surgical interventions. CLAUSE OF INVENTION 1. A method for treating pain syndrome, including the administration of the tetrapeptide Tyrosyl-^-arginylphenylalanyl-glycine amide (H-Tyr-D-Arg-Phe-Gly-NH ₂ ) in a single dose of 2 to 7 mg, with a daily dose of no more than 42 mg, with intervals between administrations of 4 hours, with a duration of the course of treatment of pain syndrome up to 96 days, with the subsequent possibility of multiple repetition of the course. 2. The method according to item 1, in which the administration of the tetrapeptide is carried out for pain syndrome in patients with oncological diseases or in the early postoperative period during various surgical interventions. 3. The method according to paragraphs 1-2, including the administration of the tetrapeptide Tyrosyl-D-arginyl-phenylalanyl-glycine amide (H-Tyr-D-Arg-Phe-Gly-NH ₂ ) in the form of a solution for subcutaneous administration. 4. The method according to claims 1-3, in which the tetrapeptide is administered under control of the severity of the pain syndrome and/or the severity of the patient's reaction to the administration of the tetrapeptide, with an increase or decrease in the single dose and/or the number of administrations per day and/or the duration of the breaks between administrations and/or the duration of the course of treatment. 5. The method according to paragraphs 1-4, in which, depending on the severity of the pain syndrome, injections of the tetrapeptide are carried out daily or with breaks from one to several days. 6. The method according to paragraphs 1-5, in which the total duration of treatment of pain syndrome is determined by the patient's condition, while in patients with oncological diseases the duration of one course of treatment of pain syndrome can be up to 96 days, with the possibility of subsequently repeating the course several times, while repeating the course is recommended after at least a 2-5 day break between courses, and the number of repetitions of courses is determined by the patient's condition. 7. The method according to paragraphs 1-5, in which the total duration of treatment is determined by the patient’s condition, wherein in patients with pain syndrome in the early postoperative period during various surgical interventions, the duration of treatment for pain syndrome is from 1 to 10 days. 8. The method according to paragraphs 1-7, in which a single dose of tetrapeptide from 4 to 7 mg is used. 9. The method according to claims 1-8, wherein the recommended initial single dose of the tetrapeptide Tyrosyl-D-arginyl-phenylalanyl-glycine amide (H-Tyr-D-Arg-Phe-Gly-NH ₂ ) is 4 mg. 10. The method according to paragraphs 1-9, in which an increase or decrease in a single dose, if necessary, is carried out with an increase or decrease in the dose by 25-50% of the previous one. 11. The method according to paragraphs 1-10, wherein the tetrapeptide is administered at a dose of 4 mg 2-3 times a day. - 17 049509 12. A method for relieving pain syndrome, including the administration of the tetrapeptide Tyrosyl-D-arginyl-phenylalanyl-glycine amide (H-Tyr-D-Arg-Phe-Gly-NH ₂ ) in a single dose of 2 to 7 mg, with a daily dose of no more than 42 mg, with intervals between administrations of 4 hours. 13. The method according to item 12, in which the administration of the tetrapeptide is carried out for pain syndrome in patients with oncological diseases or in the early postoperative period during various surgical interventions. 14. The method according to paragraphs 12-13, in which the tetrapeptide is administered under control of the severity of the pain syndrome and/or the severity of the patient's reaction to the administration of the tetrapeptide, with an increase or decrease in the single dose and/or the number of administrations per day and/or the duration of the breaks between administrations and/or the duration of the course of treatment. 15. The method according to paragraphs 12-14, including the administration of the tetrapeptide Tyrosyl-O-arginyl-phenylalanylglycine amide (H-Tyr-D-Arg-Phe-Gly-NH2) in the form of a solution for subcutaneous administration. 16. The method according to paragraphs 12-15, in which a single dose of tetrapeptide from 4 to 7 mg is used. 17. The method according to paragraphs 12-16, in which the recommended initial single dose of the tetrapeptide Tyrosyl-D-arginyl-phenylalanyl-glycine amide (H-Tyr-D-Arg-Phe-Gly-NH ₂ ) is 4 mg. 18. The method according to paragraphs 12-17, in which an increase or decrease in a single dose, if necessary, is carried out with an increase or decrease in the dose by 25-50% of the previous one. 19. The method according to paragraphs 12-18, wherein the tetrapeptide is administered at a dose of 4 mg 2-3 times a day. 20. A method for preventing an attack of pain in a pain syndrome, including the administration of the tetrapeptide Tyrosyl-O-arginyl-phenylalanyl-glycine amide (H-Tyr-D-Arg-Phe-Gly-NH ₂ ) in a single dose of 2 to 7 mg, with a daily dose of no more than 42 mg, with intervals between administrations of 4 hours. 21. The method according to claim 20, in which the administration of the tetrapeptide is carried out at the risk of an attack of pain during pain syndrome in patients with oncological diseases or in the early postoperative period during various surgical interventions 22. The method according to claims 20-21, in which the tetrapeptide is administered under control of the severity of the pain syndrome and/or the severity of the patient's reaction to the administration of the tetrapeptide, with an increase or decrease in the single dose and/or the number of administrations per day and/or the duration of the breaks between administrations. 23. The method according to paragraphs 20-22, including the administration of the tetrapeptide Tyrosyl-O-arginyl-phenylalanylglycine amide (H-Tyr-D-Arg-Phe-Gly-NH ₂ ) in the form of a solution for subcutaneous administration. 24. The method according to paragraphs 20-23, in which a single dose of tetrapeptide from 4 to 7 mg is used. 25. The method according to claims 20-24, wherein the recommended initial single dose of the tetrapeptide Tyrosyl-D-arginyl-phenylalanyl-glycine amide (H-Tyr-D-Arg-Phe-Gly-NH ₂ ) is 4 mg. 26. The method according to paragraphs 20-25, in which an increase or decrease in a single dose, if necessary, is carried out with an increase or decrease in the dose by 25-50% of the previous one. 27. The method according to paragraphs 20-26, in which the tetrapeptide is administered at a dose of 4 mg 2-3 times a day. 28. Use of a medicinal product in the method according to any one of claims 1-27, comprising the tetrapeptide Tyrosyl-E-arginyl-phenylalanyl-glycine amide (H-Tyr-D-Arg-Phe-Gly-NH ₂ ) and excipients: sodium chloride mannitol, glycine, sodium acetate trihydrate, acetic acid, water, in the following ratio of components, wt.%: tetrapeptide - 0.380-0.420; sodium chloride - 0.475-0.525; mannitol - 0.475-0.525; glycine - 0.475-0.525; sodium acetate trihydrate - 0.0380-0.0420; acetic acid - up to pH 4.0-6.0; water - up to 100. 29. Use according to item 28, characterized by the following ratio of components of the medicinal product, wt.%: tetrapeptide - 0.40; sodium chloride - 0.50; mannitol - 0.50; glycine - 0.50; sodium acetate trihydrate - 0.04; acetic acid - up to pH 4.0-6.0; water - up to 100. 30. Use according to item 28, characterized by the following ratio of components of the medicinal product, mg: tetrapeptide - 3.8-4.2; sodium chloride - 4.75-5.25; mannitol - 4.75-5.25; glycine - 4.75-5.25; - 18 049509 sodium acetate trihydrate - 0.38-0.42; acetic acid - up to pH 4.0-6.0; water - up to 1 ml. 31. Use according to item 30, characterized by the following ratio of components of the medicinal product, mg: tetrapeptide - 4.00; sodium chloride - 5.00; mannitol - 5.00; glycine - 5.00; sodium acetate trihydrate - 0.40; acetic acid - up to pH 4.0-6.0; water - up to 1 ml. 32. Use according to paragraphs 28-31, characterized in that the medicinal product is made in the dosage form of a solution for subcutaneous administration. About Eurasian Patent Organization, EAPO Russia, 109012, Moscow, Maly Cherkassky per., 2 -