Nonsteroidal anti-inflammatory drugs (NSAIDs)

Co-author, editor and medical expert – Petrashevich Anna Aleksandrovna.

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Last updated date: 11/16/2021

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How NSAIDs work When NSAIDs are needed When NSAIDs are contraindicated Non-steroidal anti-inflammatory drug Motrin®

NSAIDs (non-steroidal anti-inflammatory drugs) or NSAIDs (non-steroidal anti-inflammatory drugs) are one of the most popular drug groups in medicine. Their advantage is their complex action (antipyretic, anti-inflammatory and analgesic), as well as a wide range of indications for which they can be used. But what are these drugs, when can they be used and what is their analgesic effect based on?

How do NSAIDs work?

Non-steroidal anti-inflammatory drugs contain substances that cause anti-inflammatory, analgesic and antipyretic effects.

Pain, inflammation, increased body temperature are the result of a number of chemical reactions in the body that occur under the influence of some factor (infection, injury, dysfunction of internal organs, etc.). But if you exclude any link from this chain of reactions, it is interrupted - the mechanism for the formation of pain and inflammation is disrupted. This is precisely the principle of action of NSAIDs: they block the synthesis of prostaglandins - substances that play an important role in the development of inflammatory processes and pain.

It is this combination – anti-inflammatory, analgesic and antipyretic effects – that has made NSAIDs one of the most popular medications today. After all, many diseases are accompanied by fever, pain and inflammation. These agents are usually distributed depending on the severity of anti-inflammatory activity and the chemical structure of the active substance, duration of action and selectivity.

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When are NSAIDs needed?

The range of indications for taking NSAIDs is quite wide. But, since these drugs have a pronounced analgesic effect, in modern medical practice it is the analgesic property of these drugs that has become most in demand. In each individual case, the choice of one or another NSAID remains with the doctor. It takes into account the nature of the pain and its cause, the severity of the pain syndrome, the state of the gastrointestinal tract, the characteristics of the person’s general health, his age and other circumstances that are important when prescribing a particular remedy.

Thus, for episodic and short-term pain, it is better to give preference to drugs with a short-term effect, which eliminate pain relatively quickly. At the same time, if attacks of pain continue for several hours in a row, preference is given to NSAIDs, which have a long duration of action (pain relief for up to 12 hours in a row after a single dose).

NSAIDs are used as an independent remedy for pain of traumatic origin, in the postoperative period, for menstrual, headache, muscle and joint pain.

As a symptomatic medicine as part of a complex treatment, NSAIDs are prescribed for a large number of diseases that are accompanied by pain and inflammation (rheumatism, arthritis, tonsillitis, ARVI, etc.).

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When NSAIDs are contraindicated

It should be understood that even the strongest NSAIDs are not a cure for the underlying disease (for example, if they are taken for headaches caused by hypertension). They help reduce the intensity of the inflammatory process, alleviate or completely eliminate pain for a certain time, but do not affect the pathological processes that caused the pain syndrome.

Each NSAID is accompanied by instructions that introduce the indications and contraindications for taking the drug, and also indicate the compatibility of various drug groups and possible side effects. It is very important to read this information carefully before you start taking any medicine, including NSAIDs. Pay special attention to the state of the gastrointestinal tract; in case of diseases of the digestive system, drugs in this group should be taken with caution and only after consultation with a doctor.

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Features of the use of NSAIDs in clinical practice

As mentioned above, the main pharmacodynamic effects of NSAIDs are: analgesic, anti-inflammatory, antipyretic. Thus, drugs in this group are used for diseases of the musculoskeletal system, joints, postoperative pain, tension headaches, migraines, dysmenorrhea, renal and hepatic colic, chronic pain syndrome, colds, and fever.

The effectiveness of a drug is determined by a number of factors: the mechanism of action, bioavailability (the percentage of the dose taken that enters the systemic circulation), metabolic characteristics, concentration in the blood and tissues of the body, the rate of development of the therapeutic effect and the duration of its retention. The safety of using a drug depends on the mechanism of action and characteristics of metabolism, excretion of the drug, and its ability to enter into drug interactions.

The mechanism of action of NSAIDs is due to their ability to inhibit the enzyme cyclooxygenase-2 (COX-2) at the site of inflammation (Fig. 1). It is COX-2 that takes part in the formation of pro-inflammatory prostaglandins, which potentiate the activity of inflammatory mediators (histamine, serotonin, bradykinin) that activate pain receptors; participate in controlling the activity of the thermal regulation center, promote cell proliferation, mutagenesis and destruction [1, 2]. At the same time, NSAIDs also block cyclooxygenase-1 (COX-1), which is present in all organs and ensures normal physiological processes (synthesis of protective stomach mucus, some stages of hematopoiesis, filtration and reabsorption in the kidneys). There is also “constitutive” COX-2, which is found in high concentrations in the brain, bones, organs of the female reproductive system, and kidneys, ensuring their normal functioning.

Additional mechanisms of anti-inflammatory action of NSAIDs are:

• inhibition of interleukin-1 synthesis activity;
• suppression of neutrophil function and interaction of leukocytes with the vascular endothelium;
• inhibition of activation of NF-kB (transcription factor), which regulates the synthesis of “pro-inflammatory” mediators;
• activation of PPARs (peroxisoma proliferator activated receptors).
• A decrease in the synthesis of “beneficial” prostanoids underlies the mechanisms of development of ADRs when using NSAIDs.

NSAIDs can be divided into two groups: non-selective COX inhibitors (ibuprofen, diclofenac, naproxen, etc.) and selective, predominantly inhibiting COX-2 (meloxicam, nimesulide, coxibs). When using drugs of the second group, NSAID gastropathy and NSAID enteropathy, gastrointestinal bleeding develop much less frequently, but the risk of complications from the cardiovascular system increases [1]. The effect of NSAIDs increases with increasing dose of the drug, while at maximum doses the selectivity of the action of selective NSAIDs decreases (Fig. 2) [3].

It should also be noted that when using medium and high doses of various NSAIDs, their effectiveness is comparable, which follows from the results of multicenter clinical studies that compared the analgesic and anti-inflammatory effects of NSAIDs in injuries, operations and diseases of the musculoskeletal system. Thus, a meta-analysis of data from 29 randomized clinical trials (n=18,000) assessed the effectiveness of various NSAIDs in osteoarthritis. The differences in pain reduction (in visual analogue scale millimeters) between NSAIDs and placebo were:

• for naproxen 1000 mg/day - 12.9 (95% confidence interval (CI) - 8.2–17.7),
• ibuprofen 2400 mg/day - 9.0 (95% CI 5.0–13.1),
• diclofenac - 16.2 (95% CI 11.7–20.6),
• celecoxib 200 mg – 14.7 (95% CI 12.1–17.3),
• etoricoxib 30 mg – 14.2 (95% CI 12.6–16.8),
• etoricoxib 60 mg – 16.2 (95% CI 12.7–19.8) [4].

There is an opinion that intravenous or intramuscular administration of the drug provides a faster and more pronounced therapeutic effect than taking the drug orally. However, this position is not confirmed by data from clinical studies [5]. A systematic review of 26 RCTs (n=2225) analyzed the effectiveness of NSAIDs administered parenterally, rectally, or orally. Indications for the prescription of NSAIDs were musculoskeletal diseases, postoperative pain, dysmenorrhea, and renal colic. There were no significant differences in the analgesic effect of various dosage forms of NSAIDs, with the exception of renal colic, in which a significant advantage of intravenous NSAIDs compared with oral administration was shown [6].

Thus, the following conclusions can be drawn [1].

• All NSAIDs in adequate anti-inflammatory (average and maximum) doses with long-term use have equal analgesic potential (evidence level 1a).
• The effectiveness of NSAIDs depends on the dose. The use of higher doses provides more pronounced analgesic and anti-inflammatory effects (evidence level 1b).
• There is no evidence that injectable or rapidly dissolving oral NSAIDs are superior to oral NSAIDs for longer than 1 day of treatment (LE: 1b).

Non-steroidal anti-inflammatory drug Motrin®

Motrin® is a modern drug from the group of non-steroidal anti-inflammatory drugs, which includes naproxen. This substance allows you to have a pronounced anti-inflammatory and analgesic effect, which lasts up to 12 hours in a row. Its effectiveness and high safety profile have been clinically proven, making Motrin® a recommended treatment for pain across a wide range of indications. The drug is intended for adults and children over 15 years of age. Before taking Motrin®, carefully read the instructions for the drug and consult your doctor.

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The information in this article is for reference only and does not replace professional advice from a doctor. To make a diagnosis and prescribe treatment, consult a qualified specialist.

Nonsteroidal anti-inflammatory drugs in the treatment of joint diseases

For citation.
Imametdinova G.R., Chichasova N.V. Non-steroidal anti-inflammatory drugs in the treatment of joint diseases // Breast Cancer. 2015. No. 25. pp. 1491–1495. Diseases of the musculoskeletal system are one of the most common reasons for patients to visit a doctor. Widespread prevalence in the population, long-term persistence of pain and inflammation, steady progression, rapid development of disability, deterioration in the quality of life, reduction in its duration, as well as significant economic damage to patients and society determine not only the clinical, but also the social significance of chronic diseases of the musculoskeletal system [1–3]. The main symptoms of musculoskeletal diseases are pain and inflammation. In most cases, pain in various structures of the musculoskeletal system is chronic, and the most common cause of its development is chronic inflammation in the synovium. Long-term persistence of pain and inflammation invariably leads to joint destruction and loss of musculoskeletal function. Treatment of chronic pain and inflammation is a complex task and requires long-term complex anti-inflammatory therapy, one of the components of which is non-steroidal anti-inflammatory drugs (NSAIDs). NSAIDs are among the most widely used drugs in clinical practice [4]. They are used by approximately every 4th person on the planet, every 3rd person over the age of 60 [5]. It is well known that the main mechanism of action of NSAIDs is inhibition of cyclooxygenase (COX) activity [6]. Moreover, most of the positive effects of NSAIDs (suppression of inflammation, pain, fever) are associated with suppression of COX-2 activity, and adverse reactions are associated with suppression of COX-1 activity [7–9]. According to the mechanism of action, NSAIDs are divided into non-selectively suppressing the activity of COX-1 and COX-2 (n-NSAIDs) and selectively suppressing the activity of COX-2 (s-NSAIDs). S-NSAIDs are effective in treating pain and inflammation with a lower incidence of adverse reactions compared to n-NSAIDs. Suppression of COX-1 causes a wide range of adverse reactions of n-NSAIDs. The most common is damage to the gastrointestinal tract (GIT) (NSAID gastropathy) [10, 11], which often becomes the basis for interrupting treatment. It should be emphasized that there is no connection between subjective side effects and endoscopically detected ulcers and severe gastrointestinal complications. Thus, in 58–80% of cases, ulcers are asymptomatic against the background of the analgesic effect of NSAIDs [12]. However, clinicians must clearly identify risk factors for the development of severe complications from the gastrointestinal tract - ulcerative bleeding and the cardiovascular system (CVS): myocardial infarction, stroke. In 2015, new clinical recommendations “Rational use of non-steroidal anti-inflammatory drugs in clinical practice” were published, prepared by the Association of Rheumatologists of Russia, the Russian Society for the Study of Pain, the Russian Gastroenterological Association, the Russian Society of Cardiology, and the Association of Orthopedic Traumatologists of Russia [13]. A joint discussion at the expert council developed a unified approach to identifying risk factors for adverse events from the gastrointestinal tract and cardiovascular system. The main provisions presented in the recommendations include: a structured approach to prescribing NSAIDs, stratification of cardiovascular risk factors, and an algorithm for prescribing NSAIDs. The algorithm for prescribing NSAIDs in accordance with the recommendations is presented in Table 1. According to these recommendations, s-NSAIDs are indicated for moderate risk of cardiovascular complications and moderate to high risk of gastrointestinal complications.

It is known that n-NSAIDs have a negative effect on cartilage and aggravate the course of arthrosis, have a negative effect on the function of the liver and kidneys, and in patients with concomitant bronchial diseases, they can cause bronchospasm and aggravate the course of bronchial asthma. In recent years, new data have emerged on the frequency of concomitant pathologies in patients with diseases of the musculoskeletal system. The need for anti-inflammatory therapy, sometimes long-term, more often occurs in elderly people, usually with comorbid conditions and accompanying therapy. According to many authors [14–17], the most common comorbid conditions are arterial hypertension (AH), coronary heart disease (CHD), diabetes mellitus, and gastrointestinal pathology. On the one hand, these are risk factors for intolerance to NSAIDs, and on the other hand, taking NSAIDs aggravates the course of hypertension, congestive heart failure, and reduces the effectiveness of antihypertensive therapy [18–22]. Thus, a drug for the treatment of chronic pain and inflammation should not only have high efficacy, but also a good safety profile. In this regard, the selective COX-2 inhibitor nimesulide, which has been successfully used by doctors of various specialties for about 30 years, is of interest. In terms of its analgesic, anti-inflammatory and antipyretic effects, nimesulide is not inferior to n-NSAIDs, and according to some data, even slightly superior to them [23]. The results of a number of in vitro and ex vivo studies indicate that nimesulide inhibits COX-2 more selectively than COX-1 [24–28] (Fig. 1).

At therapeutic concentrations, nimesulide inhibits 88% of COX-2 activity and 45% of COX-1 activity [29]. Moreover, if the effect on COX-1 stops after 24 hours, the effect on COX-2 lasts much longer [30], and this difference persists with long-term use [31]. This unique mechanism of action explains the low number of gastrointestinal complications. It is very interesting that the low incidence of gastrointestinal lesions during treatment with nimesulide is associated not only with the COX-2 selectivity of the drug, but also with the antihistamine effect, leading to a decrease in the secretion of hydrochloric acid in the stomach [32]. It was also found that nimesulide has the ability to inhibit interleukin-1β (IL-1β) in cultured synovial fibroblasts [33]. There is evidence that, along with COX inhibition, nimesulide has a number of COX-independent mechanisms, among which its ability to inhibit chondrocyte apoptosis is especially important [34]. In addition, the drug and its metabolites exhibit direct antioxidant activity against various free radicals [35]. Nimesulide reduces the degranulation of proteoglycans, inhibits the activity of elastase, collagenase, stromelysin, and suppresses hyperalgesia induced by bradykinin and tumor necrosis factor-α (TNF-α) [25, 27, 36]. The drug is able to suppress the activity of pro-inflammatory cytokines: interleukin-6, TNF-α, metalloproteinases, phosphodiesterase IV enzyme, which activates macrophage and neutrophil activity [25, 37, 38]. The short half-life (1.8–4.7 hours), the rapid achievement of maximum concentrations in blood plasma and synovial fluid determines the high rate of onset of the analgesic effect and a decrease in the frequency of side effects of nimesulide. When taken orally, the drug is quickly and almost completely absorbed, regardless of food intake. Due to its biochemical properties, nimesulide easily enters the site of inflammation. The concentration of free nimesulide directly at the site of inflammation (especially in the joint tissue), where the pH of the environment is lower, can be much higher than its plasma concentration [39, 40]. The results of studies conducted by domestic and foreign authors confirm the high effectiveness of nimesulide in the treatment of acute [41, 42] and chronic pain. Thus, it was shown that the effectiveness of nimesulide was comparable to the effectiveness of diclofenac [43] and naproxen [44] in patients with osteoarthritis (OA) and rheumatoid arthritis (RA) [44, 45]. A number of short-term and long-term studies have been devoted to assessing the safety of nimesulide. According to world literature, the frequency of side effects during treatment with nimesulide ranges from 6.8–36% with a clear dependence on the dose and duration of drug use. In particular, when analyzing the results of several clinical studies that included 22,938 patients with OA treated with nimesulide at a dose of 100–400 mg for 5–21 days (average 12 days), the overall incidence of adverse reactions was 8.2% [47]. According to another multicenter study, which involved 12,607 patients with various rheumatic and orthopedic diseases, during treatment with nimesulide 400–200 mg/day for 21 days, the incidence of side effects was 6.8% [48]. As evidenced by the results of numerous studies conducted by domestic and foreign authors, nimesulide is characterized by good tolerability in the gastrointestinal tract. Thus, Kriegel W. et al. conducted a comparative study of 370 patients with OA who received nimesulide 200 mg/day and naproxen 750 mg/day for 12 months. The effectiveness of both drugs was comparable, and the total number of drug complications when using nimesulide compared to naproxen was lower: 47.5 and 54.5%, respectively [44]. Studies conducted in real clinical practice deserve special attention. Bradbury F. presented data on the frequency of gastrointestinal complications when using diclofenac, nimesulide and ibuprofen. The total incidence of gastrointestinal lesions when using nimesulide was significantly lower compared to that of diclofenac (12.1%) and did not differ from that of ibuprofen - 8.1% and 8.6%, respectively [49]. Domestic authors assessed the safety of the use of nimesulide in real clinical practice in 322 patients with rheumatic diseases who received nimesulide at a daily dose of 200 mg for a long period (12 months). None of these patients had serious gastrointestinal complications such as bleeding or ulcer perforation. Gastric and duodenal ulcers were found in 13.3% of patients [50]. Data obtained from a previous endoscopic study of 4931 patients receiving n-NSAIDs demonstrated a higher incidence of upper gastrointestinal ulcers in 18.1% of patients [51] (Fig. 2). Attention should be paid to the data from a population-based study that assessed the risk of developing gastrointestinal bleeding while taking various NSAIDs. It was shown that the relative risk of bleeding for nimesulide was 3.2, for diclofenac – 3.7, meloxicam – 5.7 [52]. The results of the endoscopic examination conducted by A.E. Karateev demonstrated that when using nimesulide, damage to the upper gastrointestinal tract occurred much less frequently than when using diclofenac, ketoprofen, and indomethacin - the total number of gastric and duodenal ulcers was 4.4% and 14.6%, respectively [53]. In an analysis of 10,608 spontaneous reports of serious side effects of NSAIDs for the period 1988–2000, conducted by Italian scientists [54], it turned out that the frequency of adverse reactions from the gastrointestinal tract while taking nimesulide was 2 times lower than against the background of comparator drugs (Fig. 3).

Of great interest are studies of the safety of using nimesulide in a high daily dose. Thus, the use of nimesulide in a daily dose of 400 mg in patients with RA demonstrated not only high efficiency, but also good tolerability of the drug [55]. Later, domestic authors conducted a multicenter study of the effectiveness and safety of nimesulide in daily doses of 200 and 400 mg in comparison with diclofenac 100 and 200 mg/day for 4 weeks. with EGD control in early RA. The results of the study demonstrated that the effectiveness of nimesulide was slightly higher than that of diclofenac, and the development of ulcers and multiple erosions of the stomach or duodenum while taking nimesulide was significantly lower than in patients taking diclofenac - 1.3% and 5.9%, respectively [ 45]. More recently, the results of a population-based study conducted by Italian scientists were published. The risk of developing NSAID-associated gastrointestinal complications was assessed in 588,827 patients with 3,623,341 prescriptions of various NSAIDs for the period from 2001 to 2008. It should be especially emphasized that the low risk of developing serious gastrointestinal complications while taking nimesulide was comparable to that of celecoxib [56]. Aspects of the cardiovascular safety of s-NSAIDs are widely discussed in the world literature. According to the results of the analysis conducted by A. Helin-Salmivaara et al., the relative risk of myocardial infarction for nimesulide was 1.69, which did not exceed the total risk for the entire class [57]. According to domestic authors, out of 322 patients with RA, myocardial infarction was recorded in 1 man, 68 years old, with a long history of coronary artery disease and hypertension. A persistent increase in blood pressure was observed in 11.5% of patients; in 2 patients with a history of high risk of hypertension, negative dynamics were detected on the ECG [50]. It should be noted that in studies conducted by foreign authors (the results of which were mentioned above), there was no significant increase in the incidence of cardiovascular complications while taking nimesulide [43, 44]. The issues of hepatotoxicity of nimesulide have been repeatedly discussed by the medical community over the past few years. Analysis of literature data indicates that the hepatotoxicity of nimesulide is no higher than that of other NSAIDs [58]. With short-term use of nimesulide (no more than 30 days), an increase in ALT and AST by 2 or more times is observed in only 0.4% of patients, and with long-term use (more than 6 months) the frequency of such changes does not exceed 1.5% [59, 60]. In 322 patients who received nimesulide for 12 months, not a single case of the development of clinical symptoms of liver damage (jaundice, hepatomegaly, symptoms of liver failure) was detected. An increase in the level of hepatic transaminases (AST, ALT) by more than 2 times was recorded in 7 cases (2.2%) in RA patients who also received methotrexate and leflunomide [50]. The largest population-based study of nimesulide hepatotoxicity [61] analyzed the incidence of drug-induced liver injury in 397,537 patients treated with various NSAIDs during the period 1997–2001. It was shown that nimesulide caused hepatopathy in 35.5 cases per 100 thousand patients, which is significantly less common than diclofenac - 39.2 and ibuprofen - 44.6. According to Spanish researchers [62], over a 10-year period of nimesulide use, serious hepatotoxic complications developed extremely rarely (Fig. 4). Interesting are the results obtained by domestic authors while studying the effect of nimesulide on liver function in the treatment of gouty arthritis. As is known, patients with gout often have metabolic disorders and a high frequency of alcohol abuse, which increases the risk of developing adverse reactions from the liver. However, with the use of nimesulide in doses up to 400 mg/day, there was no negative dynamics of biochemical blood parameters indicating damage to liver cells or cholestasis [63].

The results of a meta-analysis over a 10-year period (from 1988 to 1997) demonstrated that per 100 thousand patients taking nimesulide, there were only 11 cases of possible association of renal complications with taking the drug, of which only 4 were treated with nimesulide monotherapy [ 64]. It has been established that nimesulide extremely rarely causes increased bronchospasm in patients suffering from bronchial asthma and hypersensitivity to acetylsalicylic acid or other NSAIDs, since it does not have cross-reactivity with acetylsalicylic acid and n-NSAIDs in relation to the induction of exacerbation of asthma and is one of the drugs of choice (among -NSAIDs) in these patients [25, 65]. As already mentioned, experimental data have demonstrated that nimesulide has no negative effect on cartilage [33, 34]. Somewhat later, W. Kullch et al. in a pilot clinical study, a positive effect of nimesulide on the course of OA of the hip and knee joints was noted [66]. The results of scientific research and extensive clinical experience with nimesulide indicate its high analgesic and anti-inflammatory activity and good tolerability. All of the above served as the basis for the emergence of a number of generics of this drug. Recently, a new generic nimesulide appeared in Russia - Nemulex® in the form of granules for the preparation of a suspension. This dosage form of the drug provides a faster onset of clinical effect compared to the tablet form. A distinctive feature of Nemulex is the absence of the high-calorie polysaccharide maltodextrin in its composition, which allows the drug to be prescribed to patients with diabetes, excess body weight, and metabolic disorders. To date, there are already data on the results of open prospective short-term (10–15 days) clinical studies of the drug at a daily dose of 200 mg in rheumatological and neurological practice [67–69]. Thus, the positive effect of the drug Nemulex® in relation to the main clinical manifestations of ankylosing spondylitis in 30 patients was demonstrated in the NAUTILUS study. According to the authors, 60% of patients achieved clinically significant improvement, while the severity of back pain decreased by 2 times. Adverse reactions included an increase in AST, ALT in 10% of patients (resolved within 1 week with diet and hepatoprotectors) and dyspeptic manifestations in 10% of patients (without the presence of erosive changes in the gastrointestinal tract during EGD control) [67]. Another study was devoted to assessing the effectiveness and safety of Nemulex® in comparison with diclofenac and indomethacin in 30 patients with OA. According to the authors, the effectiveness of all drugs was comparable and did not differ statistically. However, when using Nemulex, the analgesic effect developed approximately 2 days earlier than with comparison drugs. Side effects while taking Nemulex were observed in 4 patients (13% of cases). 3 patients had dyspeptic disorders, 1 had an increase in blood pressure. Adverse reactions were mild and did not require discontinuation of the drug [68]. According to D.I. Lakhin, in 30 patients with OA after 15 days of treatment, there was a disappearance of signs of synovitis, a significant reduction in pain (from 69.3±0.74 to 21±0.29), as well as an improvement in joint function in all patients. Among the adverse reactions, only signs of gastropathy appeared in 2 (6.7%) patients (with a history of gastric ulcer). According to the vast majority of patients (23 people - 76.6%), the treatment was well tolerated, and in 7 (23.3%) it was satisfactory [69]. A study was conducted in an outpatient setting that included 49 patients with dorsopathy. All patients received complex treatment, including Nemulex® and Chondroguard. After 15 days, the majority of patients (29 people - 59.5%) noted the disappearance of back pain. 2 patients (4%) noted the appearance of discomfort in the epigastrium, which led to independent discontinuation of the drug. At the same time, according to the author, control endoscopy did not reveal any pathological changes [72]. Thus, the research results showed that Nemulex® has distinct analgesic and anti-inflammatory properties combined with good tolerability. However, given the short time frame and small number of studies, it is advisable to study the effectiveness and safety of the drug over a longer period of time in different cohorts of patients.