A. E. Karateev’s research while affiliated with V.A. Negovsky Scientific Research Institute of General Reanimatology and other places

Pain control is the most important task in the complex treatment of osteoarthritis (OA). One of the promising methods to increase the efficacy of analgesics in OA may be the combined use of nonsteroidal antiinflammatory drugs (NSAIDs) with a complex of vitamins B1, B6 and B12 (СVB). Objective: to evaluate the efficacy of combination of NSAIDs + CVB compared to monotherapy with NSAIDs in the treatment of knee OA using a meta-analysis of randomized controlled trials (RCTs). Material and methods. We selected articles during the period 1981–2024 years using electronic databases PubMed (English-language sources), eLIBRARY.ru (Russian-language sources) and Yandex search engine. The search yielded a total of 55 publications on this topic. RCTs investigating the efficacy of CVB in patients with OA were presented in 5 articles, of which only 3 had a unified design that included a comparison of the therapeutic effect of the combination of NSAIDs + CVB and NSAIDs monotherapy. These papers were included in the meta-analysis, in which the dynamics of pain intensity on the visual analogue scale (VAS) and the WOMAC index were evaluated. A weighted mean difference (WMD) and the heterogeneity of the data (index I ² ) were calculated. Results and discussion. The meta-analysis included 3 RCTs (n = 298) with a duration of 3 to 8 weeks. The groups analyzed were homogeneous regarding the initial values of pain and the WOMAC index: the I ² index was 0%. The analysis of these parameters after treatment showed a slight heterogeneity: the I ² index for pain – 20%, for the WOMAC index – 39%. Initially there were no statistically significant difference between the main group (NSAID + CVB) and the control group (NSAIDs) in terms of pain level (by VAS): WMD=0.20 (95% CI, -0.05; 0.45). After treatment, the difference between the main and control groups in the dynamics of pain (by VAS) was statistically significant: WMD=-0.81 (95% CI -1.11; -0.50). Significant differences between the main and control groups in the baseline indicators and the dynamics of the WOMAC index were not found. No serious adverse reactions were detected in 3 RCTs. Conclusion. According to the meta-analysis of 3 RCTs, the combination of NSAIDs + CVB in OA reduces the severity of pain more effectively than NSAIDs monotherapy.

Non-steroidal anti-inflammatory drugs (NSAIDs) are the main class of analgesics used in Russian medical practice to control acute and chronic pain in various conditions. NSAIDs have proven to be effective, easy to use and affordable. On the other hand, NSAIDs are potentially unsafe: the use of these drugs is clearly associated with an increased risk of class-specific complications in the gastrointestinal tract, cardiovascular system and kidneys. None of the NSAIDs available on the modern pharmaceutical market can be considered ideal in terms of efficacy/safety ratio. This determines the feasibility of developing new drugs from this group. A new NSAID has now found its way into the therapeutic arsenal of Russian doctors – a member of the 2-arylpropionic acid derivative family, pelubiprofen. This drug, which is structurally similar to ibuprofen, is a moderately selective inhibitor of cyclooxygenase 2 with a very favorable profile of pharmacological properties. Pelubiprofen has been extensively tested in a series of double-blind, randomized and controlled trials comparing it with aceclofenac and celecoxib. These studies have shown the efficacy and low incidence of adverse events in the treatment of non-specific back pain, osteoarthritis and rheumatoid arthritis with the new drug.

Avascular osteonecrosis (AON) is a common condition that can occur at any age, but more often in young and able-bodied people. The disease leads to rapid destruction and collapse of the subchondral bone with subsequent formation of secondary osteoarthritis of the affected joint. The review presents modern methods of instrumental diagnostics of AON. Particular attention is paid to the detection of stage I AON. An approach to early diagnosis of AON is discussed that may change the misconception of viewing bone tissue edema as a sign characteristic only of AON and may improve differential diagnosis of the disease from other conditions and treatment outcomes.

Long-term therapy with non-steroidal anti-inflammatory drugs (NSAIDs) may be appropriate in patients with osteoarthritis (OA) who have chronic pain. The aim – to evaluate the efficacy and safety of nimesulide in the 3-month treatment of osteoarthritis. Material and methods . The study group consisted of 282 patients, 79.4% women (age 54.5±8.9 years), with knee OA (50.0%), hip OA (12.4%) and multi-joint OA (37.6%). All patients had comorbidity, including 94.3% arterial hypertension (AH) and 22.7% type 2 diabetes mellitus. All patients had moderate to severe pain (≥4 on a numerical rating scale (NRS 0–10)) for at least 3 months. All patients were prescribed nimesulide 100 mg twice daily. If pain decreased, a reduction in the dose of nimesulide to 100 mg daily or a switch to an on-demand regimen was suggested. Results . After 1 and 3 months of therapy, 82.3% and 49.3% of patients continued to take nimesulide regularly, and 17.4% and 39.7% continued to take it ‘on demand’. 11,0% of patients stopped taking the drug by 3 months, mainly because of pain control or significant pain reduction. In 1 and 3 months all patients showed significant improvement in the severity of the main symptoms of OA. Thus, pain on movement (NRS) decreased from 6.7 to 4.3 and 2.0; WOMAC pain from 11.3 to 7.3 and 3.9; impaired function (NRS) from 5.4 to 3.4 and 1.6; WOMAC function from 38.9 to 25.4 and 14.7 (for all parameters p<0.001). For all parameters, more than 75% of patients showed improvement ≥50% from baseline. 83% of patients reported an acceptable symptom state (PASS). After 3 months, no serious adverse events (AEs) were noted. Dyspepsia was noted in 3.9%, stool disturbance and gastroesophageal reflux disease in 3.2% each, AH in 4.6%, and hyperglycaemia in 1.1%. No withdrawal of nimesulide due to HP was noted. Conclusion . Nimesulide is effective and relatively safe in the long-term treatment of patients with OA and chronic pain.

Central sensitization (CS) is a pathophysiological phenomenon that plays a fundamental role in the development of chronic pain and fibromyalgia. The presence of CS can significantly worsen the condition of patients with rheumatoid arthritis (RA) and reduce the response to antirheumatic therapy. The aim of the study – to evaluate the effect of central sensitization on satisfaction in patients with rheumatoid arthritis. Material and methods . The study group consisted of 521 patients with a reliable diagnosis of RA (ACR/EULAR (American College of Rheumatology / European Alliance of Associations for Rheumatology) 2010 criteria), 82.3% of women, 52.0±14.3 years old, with moderate and high disease activity (DAS28-CRP (Disease Activity Score with C-reactive protein) – 4.7±1.0), observed at the clinic of the V.A. Nasonova Research Institute of Rheumatology in 2021– 2022. During hospitalization, all patients underwent correction of the individual therapeutic regimen. At the time of discharge, therapy with genetically engineered biologic DMARDs or Janus kinase inhibitors (JAKi) was continued, induced or modified in 364 patients (69.8%). The presence of a CS was determined by the CSI (Central Sensitisation Inventory) and painDETECT questionnaires. Satisfaction with their condition was assessed during a telephone survey using the PASS index (patient acceptable symptom state) 6 months after discharge from the hospital. Results . Signs of CS according to the CSI questionnaire (≥40 points) were noted in 56.0%, according to the pain- DETECT questionnaire (>18 points) – in 22.5% of patients. A telephone survey was conducted after 6 months in 473 patients (90.8%). 52.0% of respondents considered their condition acceptable (PASS “+”). PASS “+” was significantly more common in patients receiving biologic DMARDs or JAKi, compared with those receiving only synthetic (s) DMARDs: 65.0% and 33.6% (p<0.001). In patients with signs of CS according to CSI, the PASS index “+” was noted in 41.7%, without signs of CS in 65.0% (p<0.001), with signs of CS according to painDETECT, the PASS index “+” was noted in 40.6%, without signs of CS in 55.6% (p<0.001). A significantly lower frequency of PASS “+” was observed in patients with CS both on the background of taking biologic DMARDs or JAKi, and on the background of taking only sDMARDs.

Chronic pain is the main manifestation of musculoskeletal diseases (MSDs), leading to deterioration of quality of life and loss of ability to work. The importance of this problem is determined by the widespread prevalence of MSDs, osteoarthritis (OA), acute and chronic non-specific back pain (NBP), periarticular soft tissues lesions. Introduction of effective methods of treatment of musculoskeletal pain (MSP) into medical practice is one of the fundamental tasks of modern medicine. The pathogenesis of MSP includes mechanisms such as injury, inflammation, peripheral sensitization, biomechanical disorders, dysfunction of the nociceptive system and psychoemotional disorders. Painful muscle tension plays an important role in the development of MSP, especially in NBP. Given the complex pathogenesis of MSP, its treatment is based on the combined use of drugs with different mechanisms of action and nonpharmacological methods. Non-steroidal anti-inflammatory drugs (NSAIDs) have a central place in this context. However, they can cause serious adverse reactions (ARs), so when choosing NSAIDs, it is necessary to consider comorbid pathology and risk factors. One of the most acceptable NSAIDs with a pronounced analgesic effect and low incidence of ARs is aceclofenac, which is available in various dosage forms (tablets, sachets, topical cream for external use). This medication is characterized by proven efficacy and good tolerability. Centrally acting muscle relaxants (CM) play an important role in the treatment of MSP. They eliminate muscle spasm, enhance the effect of analgesics and reduce the need for NSAIDs. The effect of CM has been demonstrated in spasticity and NBP. However, the use of many drugs of this group can be associated with serious ARs, which limits their use. Tolperisone has the best combination of efficacy and favorable safety profile among CM. Its positive effect in the complex treatment of NBP has been confirmed in several well-organized, placebo-controlled trials. There are also studies demonstrating the efficacy of tolperisone in OA. An important advantage of this drug is virtually no sedative effect, and no negative impact on hemodynamics and on the ability to perform concentration-intensive work. Emergence of a new form of tolperisone – extended-release tablets (Mydocalm® Long 450 mg) – increases patient compliance with CM therapy and facilitates the physician's work.

Chronic pain is the main manifestation of rheumatic diseases (RD), it determines the main complaints and worsens the quality of life of patients. The problem of effective control of chronic pain in rheumatology remains a current issue despite the successes in the development of new drugs for pathogenetic therapy, especially in immunoinflammatory RD. For example, 40-50% of patients with rheumatoid arthritis (RA), even those receiving biologic disease-modifying antirheumatic drugs and Janus kinase inhibitors, require analgesics. According to several population studies, about 50% of patients with the most common RD, osteoarthritis (OA) are forced to take various analgesics on a regular basis. The most popular class of analgesics with proven efficacy in RA, spondyloarthritis (SpA) and OA are non-steroidal anti-inflammatory drugs (NSAIDs). As has been shown in several meta-analyses, NSAIDs are superior to placebo and paracetamol in their therapeutic effect, are not inferior to opioids and are better tolerated overall. However, the use of NSAIDs can be associated with the development of dangerous adverse events (AEs), which requires careful monitoring of the patient's condition, considering comorbid diseases and risk factors. It is very important to choose a drug with a balanced ratio of efficacy and low risk of gastrointestinal and cardiovascular AEs. One such drug is celecoxib, whose therapeutic potential and relative safety have been confirmed in RA, SpA and OA. A differentiated approach to celecoxib prescription makes it possible to achieve a maximum therapeutic result with a minimum risk of AEs. For severe pain, treatment starts with a dose of 400 mg/day, followed by a switch to a maintenance dose of 200 mg/day.

Chronic post-traumatic pain (CPTP) is diagnosed when pain persists for ≥3 months after injury. This is a serious condition that significantly limits patients' quality of life and ability to work and is one of the predictors of the development of post-traumatic osteoarthritis. Objective . To investigate the clinical features of CPTP after knee injury. Material and methods . The study group comprised 103 patients (mean age 39.4±12.5 years, 51.5% women). All patients had a knee injury with diagnosed involvement of the anterior cruciate ligament and/or meniscus and suffered from pain ≥1 month after the injury ≥4 points on the numerical rating scale (NRS, 0–10). Patients were assessed after 3 and 6 months. Pain intensity during movement, at rest and at night and functional impairment were assessed using NRS. KOOS, EQ-5D, PainDETECT, CSI, Pain Catastrophizing, HADS, FIRST and FACIT questionnaires. Results and discussion . After 3 months, the number of patients with CPTP was 33 (32.0%). After 6 months, these patients had significantly more severe symptoms than patients with knee injuries without CPTP (control group, n=70). In the CPTP and control groups, the median pain during movement was 5.0 [4.0; 6.0] and 1.0 [0.0; 1.0] respectively, p12 was found in 24.2 and 2.9% of cases, p <0.001 ; pain at rest – 2.0 [2.0; 3.0] and 0.0 [0.0; 1.0], p <0.001 <0.001;; pain at night – 2.0 [1.0; 3.0] and 0.0 [0.0; 0.0], p <0.001; KOOS score – 4.0 [1.0; 5.5] and 2.0 [1.0; 3.5], p <0.001; quality of life according to EQ-5D – 0.65 [0.52; 0.73] and 0.89 [0.69; 1.0], p <0.001; according to EQ-5D scale – 64.0 [50.0; 70.0] and 80.0 [70.0; 90.0], p <0.001 ; a PainDETECT score of >12 was found in 24.2 and 2.9% of cases, p< 0.0037; according to HADS, depression ≥11 – in 21.2 and 2.9%, p< 0.001, according to HADS, anxiety ≥11 – in 24.2 and 4.3%, p=0.0038; CSI ≥40 – in 9.0 and 0%, p=0.03; pain catastrophizing ≥30 – in 12.1 and 0%, p=0.005; FIRST ≥5 – in 6.1 and 0%, p=0.358; FACIT <30 – in 15.2 and 2.9%, p=0.004. After 6 months, statistically significant differences were found between the CPTP group and the control group in all sections of KOOS questionnaire (p <0.001 for all parameters). Conclusion . Three months after knee injury, 32.0% of patients developed CPTP. All had moderate/severe pain with impaired function and reduced quality of life, one in five patients had symptoms of neuropathic pain, signs of depression and anxiety. Patients with CPTP showed significant changes in all sections of KOOS questionnaire.

Increased production of proinflammatory cytokines in serum and synovial fluid plays an important role in the pathogenesis of RA. JAK inhibitors and bDMARD are aimed at suppressing various pathological reactions caused by them. The aim of the study . To determine the effect of therapy with JAK and IL-6 inhibitors on the concentration of proinflammatory cytokines in RA patients in real clinical practice. Materials and methods. The study included 30 patients with a reliable diagnosis of RA, advanced stage of disease, with moderate or high RA activity and ineffectiveness of previous therapy with csDMARD or bDMARD for at least 6 months. 10 patients received TOFA at a dose of 5 mg twice daily 10 received UPA at a dose of 15 mg once daily and 10 were on OKZ therapy at a dose of 64 mg subcutaneously every 4 weeks. Studies were performed before treatment, after 3 and 6 months of therapy. The levels of IL-1β, IL-6, IL-17A, IL-17F, IL-23, IL-31, IL-33, INF-γ, TNF-α in serum were investigated using multiplex xMAR technology on Bio-PlexTM 200 System analyser (BIO-RAD, USA). Results. In all groups of patients after 3 and 6 months from the start of therapy, there was a significant decrease in the RA activity index compared to baseline values. The concentration of IL-1β, IL-17A, IL-17F and IL-23 did not change significantly during treatment with any of the drugs. IL-6 values on TOFA background significantly decreased after 3 and 6 months of follow-up compared to the baseline level. UPA therapy had no effect on IL-6 level during the whole observation period, and against the background of OKZ application its values significantly increased after 3 months, and after 6 months – decreased, remaining higher than the initial values. The concentration of IL-31 after 3 months of TOFA treatment significantly decreased (respectively: 6.95 (3.85; 17.72) pg/ml and 3.00 (1.50; 3.85) pg/ml, p<0.05), and after 6 months – increased, but remained lower than baseline (5.09 (3.85; 6.33) pg/ml, p<0.05). IL-33 level on the background of UPA decreased and after 6 months was significantly lower than baseline (1.11 (0.86; 3.95) pg/ ml; 1.05 (0.37; 3.95) and 0.37 (0.12; 1.23) pg/ml, p<0.05). The concentration of INF-γ after 3 and 6 months of TOFA administration decreased significantly compared to the start of therapy (2.05 (1.48; 3.19) pg/ml; 0.99 (0.49; 2.05) pg/ml and 0.99 (0.49; 2.62) pg/ml, p<0.05). Treatment with OKZ resulted in increased TNF-α levels after 6 months compared to baseline values of 0.79 (0.41; 0.98) pg/ml and 1.23 (0.67; 2.06) pg/ml, p<0.05. Conclusions. The use of TOFA, UPA and OKZ in RA patients has a positive effect on disease activity, but has different effects on the level of proinflammatory cytokines in serum.

The aim of the study – Is to evaluate the effectiveness and safety of the use of a functional unloading orthosis with the possibility of varus–valgus correction (FUOVVC) in patients with stage III osteoarthritis of the knee joint. Materials and methods. The study involved 10 patients with stage III osteoarthritis of the knee joint who underwent outpatient treatment at the V.A. Nasonova Federal State Medical University of the Russian Academy of Medical Sciences. All patients used the FUOVVC for 3 months. To evaluate the results, pain intensity was determined using a visual analog scale (VAS) and knee joint function according to the knee injury and osteoarthritis KOOS (Knee injury and Osteoarthritis Outcome Score) questionnaire before using the orthosis, after 1 and 3 months. Additionally, the assessment of VAS was carried out immediately after fixation of the orthosis on the knee joint. Results. The median age of the patients was 63.5 [55.0; 74.0] years, body mass index – 29.9 [27.9; 34.0] kg/m ² , pain according to VAS baseline – 40.0 [40.0; 60.0] mm, pain according to VAS 1 hour after the start of the use of The median age of the patients was 63.5 [55.0; 74.0] years, body mass index – 29.9 [27.9; 34.0] kg/m ² , pain according to VAS baseline – 40.0 [40.0; 60.0] mm, pain according to VAS 1 hour after the start of the use of FUOVVC – 25.0 [10.0; 30.0] mm, pain according to VAS after 1 month – 10.0 [0.0; 20.0] mm, VAS after 3 months – 10.0 [0.0; 20.0] mm. The median score according to the KOOS questionnaire was initially 41.5 [38.0; 50.0], after 1 month – 61.0 [53.0; 63.0], after 3 months – 63.5 [58.0; 64.0]. None of the patients had any adverse events when wearing the FUOVVC. – 25.0 [10.0; 30.0] mm, pain according to VAS after 1 month – 10.0 [0.0; 20.0] mm, VAS after 3 months – 10.0 [0.0; 20.0] mm. The median score according to the KOOS questionnaire was initially 41.5 [38.0; 50.0], after 1 month – 61.0 [53.0; 63.0], after 3 months – 63.5 [58.0; 64.0]. None of the patients had any adverse events when wearing the FUOVVC.