Method for treating pain syndrome in patients with osteoarthritis of large joints

Abstract

FIELD: medicine.SUBSTANCE: invention relates to medicine, namely to neurology, traumatology, and orthopedics. It can be used in the treatment of pain syndrome in patients with osteoarthritis of large joints. The method involves conducting 5-10 xenon therapy procedures using the Carboxica device. The drug is injected subcutaneously, para-articularly around the joint at a distance of 2-3 cm from each other, with an interval of 48 hours. The xenon dosage per procedure is 5 ml / kg of the patient's weight.EFFECT: method is available, increases the effectiveness of treating pain syndrome in patients, and has a long-term analgesic effect.1 cl, 3 tbl, 3 ex

Description

[0001] The invention relates to medicine, namely to neurology and traumatology-orthopedics, and is intended for the treatment of pain syndrome in patients with osteoarthritis.

[0002] Osteoarthritis (OA) is a widespread disease. According to the World Health Organization, OA affects approximately 4% of the world's population and causes disability in 10% of cases. The incidence of OA increases with age. OA affects approximately 50% of individuals over 65 years of age (Nasonov E.L., Rheumatology. Clinical Guidelines, 2nd ed., corrected and expanded, Moscow: GEOTAR-Media, 2010, pp. 703-705).

[0003] The main symptom of osteoarthritis is chronic pain. It reduces patients' quality of life and prompts them to seek medical attention.

[0004] Pain syndrome in OA is a classic model of chronic musculoskeletal pain (Golubev V.L., Pain syndromes in neurological practice, 3rd ed., 2010, pp. 7-12, 44-68).

[0005] According to modern concepts, chronic pain is an independent disease that manifests itself not only as pain, but also as vegetative, emotional and other mental disorders, and the formation of maladaptive pain behavior.

[0006] The pathogenesis of chronic pain is a complex, multi-level system involving peripheral sensitization mechanisms caused by the activation of peripheral pain receptors. With ongoing peripheral sensitization, central mechanisms are activated: central pain neurons become hyperexcitable, their activation threshold decreases, and they begin to perceive non-painful stimuli as pain, generating pain impulses themselves (secondary hyperalgesia)—a phenomenon known as central sensitization (CS). The activity of antinociceptive systems also decreases, which is facilitated by both CS and numerous psychosocial factors (anxiety, fear, inappropriate coping strategies, etc.).

[0007] Pain in OA is caused by structural and biochemical changes in bone, synovium, periarticular tissues, and muscles. Cartilage itself is avascular and non-innervated tissue, not a source of pain. In OA, pain sources are non-cartilaginous structures of the joint, including the synovial membrane, bone, and periarticular tissues (Turovskaya E.F. et al., Current Concepts of the Pathogenetic Mechanisms of Pain in Osteoarthritis, Scientific and Practical Rheumatology, 2014, Vol. 52, No. 4, pp. 438-444).

[0008] Inflammatory stimuli initiate a cascade of biochemical events: the release of substance P, bradykinin, tumor necrosis factor-alpha, interleukins, chemokines, nerve growth factor, sympathetic amines, leukotrienes, prostaglandins, etc. This inflammatory process induces hyperalgesia of peripheral nociceptors. Angiogenesis accompanying inflammatory changes stimulates the growth of new sensory fibers in the tissue of the damaged joint and can contribute to the chronicity of pain even after the inflammation subsides (Im HJ et al, Alteration of sensory neurons and spinal response to an experimental osteoarthritis pain model, Arthritis Rheum, 2010, Vol. 62, No. 10, pp. 2995-3005). Thus, the mechanisms of peripheral sensitization in OA are well studied and known.

[0009] The processes occurring in the central nervous system during OA are currently poorly understood. However, a number of facts point to the pathogenetic significance of central mechanisms. The study of chronic pain syndrome in OA revealed a number of contradictions: there is no correlation between the degree of structural changes in the affected joint and the intensity of pain, 40% of patients with changes in the joints and surrounding tissues have no pain at all (Sofat N. et al, What makes osteoarthritis painful? The evidence for local and central pain processing, Rheumatology (Oxford), 2011, Vol. 50, No. 12, pp. 2157-2165), and up to 44% of patients continue to experience pain after adequately performed knee arthroplasty (Wylde V. et al, Persistent pain after joint replacement: prevalence, sensory qualities, and postoperative determinants, Pain, 2011, Vol. 152, No. 3, pp. 566-572).About a third of patients with OA have qualitative characteristics of neuropathic pain: numbness, burning, allodynia, shooting pain comparable to electric shock, etc. (Turovskaya E.F. et al., Mechanisms of chronic pain in osteoarthritis of the knee joint, Scientific and Practical Rheumatology, 2014, Vol. 52, No. 5, pp. 526-529.) The listed features of chronic pain syndrome in OA can be explained by the presence of pronounced CS in a number of patients.

[0010] As the disease progresses, changes occur in pain control and modulation processes, leading to a number of sensory manifestations associated with typical neuropathy: local and referred hyperalgesia, allodynia, dysesthesia, and hypoesthesia. A cascade of inflammatory mechanisms increases the activity of peripheral nociceptors, a phenomenon known as peripheral sensitization. If persistent, it leads to spontaneous activity of central nociceptive neurons and disinhibition, i.e., cerebral ischemia and chronicity of the process (Hochman JR et al., Neuropathic pain symptoms on the modified painDETECT correlate with signs of central sensitization in knee osteoarthritis, Osteoarthritis Cartilage, 2013, Vol. 21, No. 9, pp. 1236-1242).

[0011] Thus, the complex mechanism of pain syndrome in OA is the cause of many failures in various approaches to its treatment, and the search for an optimal effect on pain in this case is a pressing issue.

[0012] The drugs of choice for OA therapy are non-steroidal anti-inflammatory drugs (NSAIDs) taken systemically, but 27 to 61% of patients continue to experience chronic pain and are dissatisfied with treatment (Breivik H. et al, Survey of chronic pain in Europe: prevalence, impact on daily life, and treatment, Eur. J. Pain, 2006, Vol. 10, No. 4, p. 287-333).

[0013] The primary indication for NSAID use is secondary synovitis. According to current concepts, synovitis is an obligatory component of OA, which is why the term "osteoarthritis" has been adopted abroad, emphasizing the persistent inflammatory component in the synovium. NSAIDs certainly effectively reduce inflammation and relieve pain in OA; however, the inevitability of side effects affecting the gastrointestinal tract, liver, kidneys, and cardiovascular system necessitates careful selection of a drug for a specific patient, focusing on the presence of any concomitant diseases, age, bad habits, etc. It is also known that non-selective NSAIDs, especially with long-term use, negatively affect cartilage. This fact also complicates the effective treatment of pain and inflammation in OA (Chichasova N.V. Non-steroidal anti-inflammatory drugs in the treatment of osteoarthritis: the problem of choice, taking into account safety and the effect on cartilage).Consilium Medicum, Appendix, Neurology and Rheumatology, 2017, No. 9, pp. 122-128).

[0014] Synovitis resistant to treatment with systemic and local NSAIDs can be relieved by performing a joint puncture with evacuation of synovial fluid and subsequent intra-articular administration of glucocorticosteroids (GCS). The introduction of GCS into the cavity of the affected joint inhibits the synthesis of interleukin (IL)-1 and tumor necrosis factor-α (TNFα) (Olyunin Yu.A., Osteoarthritis. Current issues in diagnostics and treatment, RMJ, 2012, No. 7, pp. 385-388). The analgesic effect of local application of GCS develops rapidly, lasts for 4-6 weeks, allows for rapid suppression of secondary synovitis and provides a significant reduction in arthralgia; however, in many patients the treatment effect is not sufficiently stable. In some cases, potentiation of the analgesic effect of GCS is achieved by the simultaneous administration of local anesthetics, but this is fraught with the development of unwanted allergic reactions.In addition, the frequency of use of local injections of GCS should not exceed 3 per year (to avoid the development of symptoms of exogenous hypercorticism).

[0015] An alternative that also allows for the relief of synovitis using local injection therapy is the introduction of intra-articular NSAIDs. The only drug in this group with a number of reports on its use for intra-articular administration is lornoxicam (Xefocam), an oxicam derivative. This drug inhibits COX-1 / COX-2 balance, as well as the formation of IL-6, nitric oxide, and, to a lesser extent, TNF-α, IL-1, and IL-8. However, the disadvantages of this approach include infectious complications. Bacteria can enter the joint cavity or nearby bursae, leading to the development of septic arthritis or septic bursitis. Complications related to the procedure technique include bleeding, tendon ruptures, and damage to neurovascular structures. Complications due to the pharmacological action of the drug.For example, hot flashes, local changes in the skin and adipose tissue, osteonecrosis, damage to cartilage tissue, allergic reactions.

[0016] Thus, modern methods and treatment regimens for osteoarthritis are associated with the use of a large number of different pharmacological drugs, which, in turn, leads to an increase in the number of side effects and allergic reactions.

[0017] Physiotherapy also plays a significant role in OA treatment, aimed at correcting and relieving various pathological manifestations. Physiotherapeutic methods are most often prescribed in combination: as a combination (using several techniques simultaneously on the same area of ​​the body) or as a combination (using physiotherapeutic techniques sequentially or on different days) (Ponomarenko, G.N., Tactics of a Physician of Physical and Rehabilitation Medicine: A Practical Guide, Moscow, GEOTAR-Media, 2023, 160 p.)

[0018] Pulsed currents are actively used in the treatment of patients with OA. Of particular interest is the use of fluctuating currents. Fluctuating currents are low-intensity, low-voltage alternating currents that chaotically vary in amplitude and frequency in the range of 100 to 2000 Hz. A distinctive feature of the effect of fluctuating currents on the body is that, due to the random change in their parameters, no tissue adaptation occurs throughout the entire exposure period. In addition to analgesic, trophic stimulating, and vasoregulatory effects, these currents also have an anti-inflammatory effect (Bogolyubov V.M., Physiotherapy and Balneology: A Guide, Moscow, 2020, Vol. 1, 312 p.).

[0019] In recent decades, pulsed magnetic field sources, as well as LED sources, have become widespread and are successfully used for various groups of diseases, including osteoarthrosis. Low-frequency magnetic therapy is known to have an anti-inflammatory effect associated with the influence on prostaglandin synthesis, stabilization of mast cell and basophil membranes, and inhibition of the release of histamine and other mediators. Magnetic therapy has vasoactive, anti-edematous, trophic, and analgesic effects (Konchugova T.V., Efficiency of magnetic therapy methods in the treatment and rehabilitation of patients with joint diseases from the standpoint of evidence-based medicine, Voprosy balneologii, physiotherapy i therapeutic physi. Kultury, 2019, Vol. 96, No. 4, pp. 63-68).

[0020] The effect of polarized optical radiation depends on its wavelength, which determines the individual approach to its use. For example, red and infrared LED radiation have physiological and therapeutic effects similar to those caused by low-frequency magnetic fields. Therefore, the combination of these two physical factors enhances the therapeutic effect.

[0021] The effectiveness of the combined use of low-frequency pulsed magnetic fields and optical radiation is determined by the physiological and therapeutic effects of light, magnetic field and their mutual influence on a number of shifts in the body.

[0022] However, the physiotherapeutic approach to the treatment of pain in OA has a number of disadvantages, the use of physiotherapy has a fairly long list of contraindications: exacerbation of synovitis, old age, atherosclerosis of the cerebral vessels, stage II-III hypertension, ischemic heart disease, climacteric disorders, vegetative-vascular dystonia, mastopathy, uterine fibroids and the main contraindication is oncological diseases, regardless of the duration of remission.

[0023] In this regard, the introduction of alternative methods of treatment for this category of patients into practical healthcare, aimed at reducing pain, reducing inflammation and metabolic processes, as well as tissue regeneration, is of great socio-economic significance.

[0024] A promising direction in this area is the use of the inert gas Xenon, due to the presence of a number of physical, chemical and biological properties in this gas, which can be successfully used in the complex treatment of pain syndromes of various etiologies:

[0025] - has a pronounced analgesic, sedative and muscle relaxant effect;

[0026] - reduces the concentration of adrenaline and hydrocortisone in the blood, slightly increasing the insulin content;

[0027] - slightly soluble in the body's liquid environments, which ensures rapid induction of the desired effect and an equally rapid restoration of normal consciousness after cessation of its inhalation;

[0028] - does not cause physical and psychological dependence;

[0029] - biologically inert, does not undergo biotransformation in the body and is quickly eliminated from it unchanged.

[0030] - xenon's ability to activate Hif-1 alpha protein production in cells. Hif-1 alpha triggers the synthesis of many other biologically active proteins, including EPO (erythropoietin). Erythropoietin is the main protein stimulating tissue regeneration.

[0031] A method for treating chronic pain (patent RU 2726048 C1, published July 8, 2020) is known. It involves xenon therapy using xenon-containing injections. A course of subcutaneous injections of 99.9% medical xenon is administered, with an amount sufficient for analgesia, in an experimental setting. A disadvantage of this method is that xenon is administered subcutaneously, which prevents the gas from penetrating deep into the muscles, especially the tissue around the joint. This method does not have a device for precisely dosing the xenon administered. Dilution of the xenon with air is possible during the procedure.

[0032] Therefore, there is a need for a method for treating pain in patients with OA.

[0033] The technical result of the proposed method is to increase the effectiveness of pain treatment in patients with OA due to the optimal selection of dosage and mode of administration of xenon in the maximum concentration, without admixture of foreign gases, while maintaining a long-term analgesic effect in the absence of toxic and side effects.

[0034] In order to achieve the specified technical result in the method for treating pain syndrome in patients with osteoarthritis, which includes xenon therapy by performing subcutaneous injections containing xenon at intervals of 48 hours, it is proposed to perform xenon injections paraarticularly around the circumference of the joint at a distance of 2-3 cm from each other using the Carboxica device, with a working gas pressure at the outlet of the dispenser of 0.1±0.03 MPa using injection needles of caliber 30-32 G, with a total dosage per procedure of 5 ml / kg of patient weight (about 300-400 ml per procedure) in a course of 5-10 procedures.

[0035] The method is carried out as follows.

[0036] A comprehensive examination of a patient with OA and severe pain is performed: collection of complaints, anamnesis, physical examination, CT scan of the affected joint, determination of interleukin 2, 6, and 8, as well as tumor necrosis factor. Pain relief (algological tests) include the VAS, McGill questionnaire, WOMAC, analgesic assessment, and psychoemotional testing.

[0037] Treatment is performed using injections of the medical gas xenon KseMed®. These injections are administered using the "Carboxica" device, adapted for subcutaneous xenon administration. The operating gas pressure at the dispenser outlet should be 0.1 ± 0.03 MPa. Needles for administration are 30-32 G. Xenon is administered at a volume of 5 ml / kg paraarticularly at a distance of 2-3 cm from each other at least once every 48 hours. A total of 5-10 xenon therapy sessions may be required during treatment.

[0038] Xenon does not undergo biotransformation in the body, does not undergo any reactions, and is quickly eliminated through the lungs. Preclinical studies of XeMed® have shown it to be free of both acute and chronic toxicity. XeMed® does not exhibit mutagenic, teratogenic, carcinogenic, or embryotoxic properties, and does not adversely affect reproductive function.

[0039] Using Xenon medical gas, KseMed®, will improve the prognosis of the disease and significantly reduce pain, which will ultimately reduce the incidence of disability in patients with osteoarthritis and delay the need for endoprosthetics. For paraarticular administration of Xenon, to prevent leakage and mixing with air, the "Carboxica" medical device for xenon injection is optimal, significantly simplifying the gas administration technique.

[0040] The high efficiency of the proposed method is confirmed by the clinical examples below.

[0041] Example 1. Patient A., 58 years old.

[0042] Diagnosis M17.5 (other secondary gonarthrosis), complaints of pain in the knee joint for 4 years. CT scan of the affected joint - reveals pronounced degenerative changes in the form of arthrosis of grade II-III, partial, uneven narrowing of the joint space, more pronounced in the medial part, widespread subchondral osteosclerosis, isolated bone growths along the articular surface. Pain syndrome according to VAS 6-7 points. Eight xenon therapy procedures were performed according to the proposed method, paraarticularly at a distance of 2 cm from each other, the frequency is every 48 hours, using the Carboxica device, with an operating gas pressure at the outlet of the dispenser of 0.1 ± 0.03 MPa using 30 G injection needles, a total dosage per procedure of 5 ml / kg of patient weight. During treatment, the patient reported a significant reduction in pain, down to a VAS score of 1-2, along with improved mood and sleep. No discomfort was observed in the injection site.

[0043]

[0044] Example 2. Patient K, 48 years old.

[0045] Diagnosis M17.3 (other posttraumatic gonarthrosis), complaints of pain in the left knee joint for 5 years following a sports injury. At the first session, the pain syndrome was 7 points on the VAS scale.

[0046] CT scan of the affected joint reveals pronounced degenerative changes in the form of stage II arthrosis. Pain syndrome according to the VAS is 6-7 points. Eight sessions of paraarticular xenon therapy were performed using the proposed method, paraarticularly at a distance of 2 cm from each other, every 48 hours, using the Carboxica device, with an operating gas pressure at the dispenser outlet of 0.1 ± 0.03 MPa using 32 G injection needles, a total dosage per procedure of 5 ml / kg of patient weight. During treatment, the patient noted a significant reduction in pain syndrome to a VAS score of 2-3, as well as improved mood and sleep. No discomfort was observed in the injection area.

[0047] The dynamic change data are shown in Table 2.

[0048]

[0049] Example 3. Patient M: Diagnosis M16.6 (other secondary coxarthrosis, bilateral), complaints of pain in the right hip joint for 3 years. At the first session, the pain syndrome was 5 points on the VAS scale.

[0050] CT - right-sided coxarthrosis grade 2, initial signs of left-sided coxarthrosis against the background of dysplastic changes.

[0051] Six xenon therapy sessions were administered using the proposed method, administered paraarticularly at a distance of 3 cm from each other, every 48 hours, using the "Carboxica" device. The gas outlet pressure was 0.1 ± 0.03 MPa, using 32G injection needles. The total dosage per session was 5 ml / kg of patient weight. During treatment, the patient reported a reduction in pain, up to VAS, and improved mood and sleep. No discomfort was observed in the injection area.

[0052]

[0053]

[0054] During treatment and 3 months after the treatment, patients did not report any increase in pain or adverse events.

[0055] Thus, the proposed method allows to increase the effectiveness of pain treatment in patients with OA due to the optimal selection of the dosage and administration regimen of Xenon in the maximum concentration, without the admixture of foreign gases, while maintaining a long-term analgesic effect in the absence of toxic and side effects.

Claims

A method for treating pain syndrome in patients with osteoarthritis of large joints, including xenon therapy by performing subcutaneous injections containing xenon at intervals of 48 hours, characterized in that xenon injections are performed paraarticularly around the circumference of the joint at a distance of 2-3 cm from each other using the Carboxica device, with a working gas pressure at the outlet of the dispenser of 0.1±0.03 MPa using injection needles of caliber 30-32 G, a total dosage per procedure of 5 ml / kg of patient weight, a course of 5-10 procedures.

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