The choice of non-steroidal anti-inflammatory drugs in rheumatological patients with concomitant cardiovascular diseases

To help the body cope with the inflammatory process, anti-inflammatory drugs are prescribed. They are also called non-steroidal or non-hormonal. The short name is NSAID. The first known anti-inflammatory drug is Aspirin or acetylsalicylic acid.

Such drugs have many side effects, so their uncontrolled use is not permissible. Classic NSAIDs have side effects on the digestive organs, cardiovascular and nervous systems.

New generation non-steroidal anti-inflammatory drugs simultaneously have anti-inflammatory, analgesic and antipyretic effects.

How and why does the inflammatory process occur in the human body?

Inflammation is the body's defense method, allowing it to eliminate germs, harmful substances and dead cells. The inflammatory process can begin due to many reasons, including infections caused by bacteria and viruses, the action of chemicals, and also as a result of foreign bodies entering the body.

Inflammation can be acute or chronic. In the chronic form it occurs more slowly and for a long time. The main symptoms of the inflammatory process are redness, swelling, pain, fever and loss of certain functions.

Introduction

Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most commonly used medications, both among prescription drugs and among over-the-counter drugs, i.e., used by patients themselves for self-medication without prescription. The frequency of use of NSAIDs in clinical practice is due to the spectrum of their pharmacological effects: analgesic, anti-inflammatory, antipyretic, antiaggregation (acetylsalicylic acid). However, a wide range of therapeutic effects and high clinical effectiveness also have a downside: NSAIDs are among the group of drugs that most often cause adverse drug reactions (ADRs) associated with toxic effects, hypersensitivity, drug and food interactions. Therefore, the clinician faces a difficult task: selecting NSAIDs for a specific patient.

The choice of drug is carried out according to a certain algorithm.

• Determination of indications for use of a medicinal product , which is determined by the clinical diagnosis of the patient: the underlying disease, the presence of comorbid pathology, complications, concomitant diseases. Of great importance is the assessment of risk factors for the development of complications of drug therapy: allergy history; previously identified symptoms of drug intolerance; concomitant therapy, including the use of herbal remedies, vitamin preparations, over-the-counter medications, dietary supplements; the patient's dietary preferences, alcohol abuse, smoking.
• Having determined the indication (“problem” of the patient), the doctor selects a group of drugs and a specific drug within this group, based on the criteria of effectiveness, safety, cost and ease of use.
• Having decided on the choice of a specific drug, the doctor chooses the mode of use of the drug: dose, frequency of use, duration of therapy.
• The doctor explains to the patient in an accessible form what is wrong with him and why the symptoms that bother him appeared, provides information about possible non-drug methods for correcting the pathological condition, explains to the patient why this drug was chosen and what the patient should pay attention to when using this drug, if any symptoms, he should immediately consult a doctor and even stop taking the drug. Almost 50% of cases of ineffective pharmacotherapy are due to low patient compliance, which is why it is so important to achieve cooperation with the patient and his compliance with the drug therapy regulations.
• During the treatment process, the doctor himself evaluates the effectiveness and safety of the pharmacotherapy being carried out, decides on the indications for prescribing protective therapy, stopping/prolonging treatment when the goal is achieved, or changing the drug if it is ineffective.

The implementation of this algorithm is possible only if the doctor is well aware of the indications for use and the clinical and pharmacological properties of the selected drug.

Indications for the use of anti-inflammatory drugs

• Rheumatic diseases (rheumatic fever, ankylosing spondylitis, rheumatoid, gouty and psoriatic arthritis, Reiter's syndrome).
• Non-rheumatic diseases of the musculoskeletal system (myositis, tendovaginitis, household and sports injuries, osteoarthritis).
• Neurological diseases (sciatica, neuralgia, lumbago, sciatica).
• Renal and hepatic colic.
• Pain syndrome of various origins, including abdominal pain, headache and toothache, pain after surgery.
• Fever.
• Dysmenorrhea.
• For the prevention of arterial thrombosis.

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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What are the contraindications?

• Ulcerative lesions of the gastrointestinal tract in the acute stage.
• Severe renal and liver dysfunction.
• Individual intolerance to the main active ingredient and auxiliary ingredients.
• Pregnancy and lactation.
• Individual intolerance to drug components.
• Children under 2 years old.

Anti-inflammatory drugs should be prescribed with caution to people suffering from bronchial asthma, as well as people who have already experienced adverse reactions when taking medications. For patients with arterial hypertension or heart failure, NSAIDs are chosen that have the least effect on renal blood flow. Elderly people are prescribed the minimum effective doses of NSAIDs in short courses.

Non-steroidal anti-inflammatory drugs (NSAIDs) are a large group of drugs with different chemical structures, united by a common mechanism of pharmacological action: blockade of the enzyme cyclooxygenase (COX-2), a decrease in the synthesis of prostaglandins (PG) at the site of inflammation or tissue damage and the ability to provide analgesic, anti-inflammatory and antipyretic action.

NSAIDs are one of the main tools for the treatment of acute and chronic pain in a wide range of diseases and pathological conditions. The use of NSAIDs is an integral part of the work of therapists, rheumatologists, neurologists, anesthesiologists, surgeons, traumatologists, gynecologists and representatives of other medical specialties. The scale of use of NSAIDs can be assessed by the level of sales - in 2013, 103,777,084 packages of these drugs were sold in our country.

NSAIDs are effective and convenient to use, but can cause serious complications, primarily from the gastrointestinal tract (GIT), cardiovascular system (CVS) and kidneys. Thus, according to Russian and foreign studies [1–4], at least 40–50% of cases of acute bleeding from the upper gastrointestinal tract requiring endoscopic or surgical hemostasis are associated with the use of NSAIDs. The development of methods for effectively controlling these complications, given the widespread use of NSAIDs, is considered by the world's leading experts and medical organizers as an important medical and social task. The main element of national and international recommendations is a structured approach to prescribing NSAIDs, taking into account the clinical characteristics of diseases and the pharmacological properties of specific drugs from this group.

It should be taken into account that in Russia there are specific features of prescribing analgesic therapy, which determine the importance of developing appropriate recommendations. Thus, in our country there is no practice of a consistent approach to pain therapy, when paracetamol is recommended as a “first-line” drug for moderate pain. To relieve moderate or severe pain, Russian doctors prefer to immediately prescribe more effective drugs, such as NSAIDs. The use of opioid analgesics (including tramadol), which in most countries of the world occupy the position of one of the most important classes of analgesics, in Russia for non-oncological diseases is minimized due to administrative restrictions. In addition, almost all NSAIDs, although technically prescription drugs, are readily available without a prescription. This creates the preconditions for their uncontrolled use by patients.

In Russia there is an exceptional variety of NSAIDs (19 generic names). At the same time, an active advertising campaign on the part of manufacturing companies and an abundance of insufficiently reliable information can create among doctors an erroneous idea about the clinical merits of certain NSAIDs. It should be noted that there is a lack of objective data on the real situation with drug complications, since the system of centralized collection of information on adverse reactions (ARs) of drugs, including NSAIDs, does not work effectively enough. At the same time, Russia has not conducted its own epidemiological studies aimed at studying the real risk of developing serious complications while taking various NSAIDs.

There are also problems in the postgraduate education system, in particular with regard to training practicing doctors in modern principles of managing patients with chronic non-cancer pain. This leads to significant errors in pharmacotherapy - abuse of injectable forms of NSAIDs, use of insufficient or unacceptably high doses of these drugs, as well as prescription of too short or excessively long courses. As data from epidemiological studies show, the lack of clear criteria for assessing the risk of complications leads to the unjustified prescription of these drugs for preventive purposes and, conversely, to their insufficient use in patients for whom they are clearly indicated.

All of the above determines the need to create a new edition of recommendations for the rational use of NSAIDs, which will be based on modern data obtained from well-organized clinical trials, their meta-analysis, as well as data from large-scale population studies - a high level of evidence (Table 1).

Table 1. Grading of recommendations and level of evidence used to create these recommendations

These recommendations contain 3 sections, which present the main provisions on the effectiveness of NSAIDs, complications that may arise during their use, as well as methods for preventing these complications (the last section will be published in the 2nd part of the recommendations).

The main sections of the recommendations are preceded by the classification of NSAIDs and general provisions.

Classification of NSAIDs

NSAIDs are divided into selective (s-NSAIDs) and non-selective (n-NSAIDs). The latter in therapeutic doses block not only COX-2, but also COX-1, which plays an important role in maintaining a number of leading functions of the human body, in particular the resistance of the gastrointestinal mucosa to the damaging effects of external aggressive factors. This feature determines the significant difference between s-NSAIDs and n-NSAIDs in terms of the degree of negative effect on the gastrointestinal tract. The main NSAIDs used in Russia are presented in Table. 2.

Table 2. NSAIDs used in Russian medical practice Note. * - p/o - oral (tablets, capsules, suspensions, powders for preparing a solution), local preparations - means for cutaneous application (ointment, gel, spray), IM - intramuscularly, IV - intravenously.

Selective COX-2 inhibitors (for which in the English literature there is a name “coxibs”, from the abbreviation “COX-2 inhibitor”) are two drugs - celecoxib and etoricoxib. A number of Russian experts also recommend the selection of drugs with moderate selectivity for COX-2 - meloxicam and nimesulide. The remaining representatives of this drug group belong to n-NSAIDs.

General position

The use of NSAIDs for various diseases and pathological conditions may have its own characteristics. This concerns the duration of use, the advisability of combinations with other drugs, assessment of the effectiveness of treatment, etc. However, approaches to prescribing NSAIDs, primarily with regard to the rational choice of a drug, taking into account the need to prevent possible complications, are of a general nature and must comply with the basic provisions presented in these recommendations .

Efficacy of NSAIDs

The use of NSAIDs is indicated as a symptomatic pain reliever for a wide range of diseases and pathological conditions:

1. For acute or chronic musculoskeletal pain arising from diseases of the musculoskeletal system: osteoarthritis (OA), rheumatoid arthritis (RA), spondyloarthritis (SpA), nonspecific back pain (NSBP), gout and other metabolic arthropathy, local inflammation of soft tissues of a rheumatic nature (tendinitis, tendovaginitis, bursitis), etc.

2. Acute injuries and other conditions accompanied by pain associated with damage or acute inflammation (in particular, dental diseases).

3. Pain in the perioperative period (as a component of anesthesia).

4. Renal and biliary colic.

5. Tension headaches and migraines.

6. Pain associated with cancer (as a component of palliative pain therapy).

7. Pain due to gynecological diseases, dysmenorrhea.

The effectiveness of various drugs from the NSAID group when used in adequate doses (medium and high therapeutic doses) does not differ. This is confirmed by data from numerous randomized clinical trials (RCTs), which compared the analgesic and anti-inflammatory effects of s-NSAIDs and n-NSAIDs in injuries, surgical interventions and diseases of the musculoskeletal system [5-9]. This fact is demonstrated, for example, by assessing the effectiveness of various NSAIDs for OA (Table 3).

Table 3. Dynamics of the general assessment of the condition of OA patients treated with various NSAIDs (total data from 29 RCTs, 18,000 patients) [6]

The severity of the analgesic and anti-inflammatory effects of NSAIDs is largely determined by the dose of the drug. Although this relationship is not always linear, the use of higher doses may provide a more significant analgesic effect.

An example is the evaluation of the effectiveness of a single dose of celecoxib 200 and 400 mg for the relief of acute pain (meta-analysis of 10 RCTs, n

=1785).
The NNT index (“number needed to treat” - the number of patients who need to be treated to obtain one episode of improvement >50% of the initial level) was 4.2 and 2.6 for these doses; repeat anesthesia was required after 6.6 and 8.4 hours, respectively [10]. The relationship between drug dose and the number of discontinuations due to ineffectiveness was shown in a meta-analysis of 10 RCTs in which etoricoxib ( n
= 2162) was compared with placebo (
n
= 974) in patients with OA. Thus, when using 30 mg etoricoxib, therapy was interrupted in 7.3%, 60 mg - 3.6%, 90 mg - 1.8%, 120 mg - 0.9% (when using placebo - in 16%) [11 ].

Many Russian doctors believe that intramuscular administration of NSAIDs provides a significant advantage over their oral administration, both in the speed of onset of the effect and in the severity of pain relief. However, this idea is refuted by data from clinical studies [12–14]. Thus, there is a systematic analysis of data from 26 RCTs ( n

=2225), which compared the results of various methods of administering NSAIDs: intravenous and intramuscular injections, the use of rectal suppositories, intrawound administration, as well as oral administration of these drugs. Indications for prescribing NSAIDs were different: diseases of the musculoskeletal system, postoperative pain, renal colic, dysmenorrhea. According to the data obtained, there is no significant difference in effectiveness between different dosage forms of NSAIDs. The only significant advantage was shown for intravenous administration of NSAIDs (compared to oral administration) in relieving renal colic [15].

In case of intense acute pain (due to injuries, surgical interventions, etc.), the speed of pain relief can be of fundamental importance. In this case, the use of intravenous or intramuscular injections of NSAIDs, as well as rapidly dissolving forms for oral administration, is quite justified. However, the advantage of such methods of administration persists only during the first day of treatment.

It should also be borne in mind that injections, especially multiple ones, can cause serious complications, such as inflammation and infection of soft tissues in the area of ​​drug administration [16-20].

NSAIDs are more effective than paracetamol. This is confirmed by a series of RCTs and a corresponding meta-analysis [21]. As an illustration, we can provide an assessment of the results of two similar cross-over 12-week RCTs, PACES-a and PACES-b [22]. They compared the effectiveness of celecoxib 200 mg, paracetamol 4 g per day and placebo in 1080 patients with OA of the knee or hip joints. The total effectiveness of NSAIDs, assessed by the dynamics of the WOMAC index, was ~40% higher than that of paracetamol ( p

<0.05);
at the same time, patients themselves significantly more often preferred celecoxib compared to paracetamol - 53% versus 24% ( p
< 0.001) in PACES-a and 50% versus 32% (
p
= 0.009) in PACES-b.

For diseases of the musculoskeletal system and pain associated with minor surgical operations, NSAIDs are not inferior, and, according to a number of RCTs, superior to “soft” opioid drugs, such as tramadol and codeine [23-26]. This is confirmed, in particular, by the results of two 6-week RCTs ( n

=1598), which compared the effectiveness of celecoxib 400 mg per day and tramadol 200 mg per day in patients with back pain [26].
Both studies found that celecoxib was more effective in reducing pain than tramadol: in the first RCT, the number of patients with an improvement >30% was 63.2 and 49.9%, in the second - 64.1 and 55.1% ( p
= 0.001). At the same time, the number of adverse reactions while taking tramadol was significantly higher: for example, due to drug complications, treatment had to be interrupted in 16% of patients receiving this drug, and only in 4% of those receiving celecoxib.

One of the most important areas of application of NSAIDs is the relief of acute or control of chronic NBS [27–30]. According to a meta-analysis of 65 RCTs ( n

=11.237), NSAIDs in this pathology are significantly more effective than placebo in terms of such indicators as reduction in pain intensity, time of complete cessation of pain, need for additional analgesia and restoration of functional activity [9]. All NSAIDs in an equivalent dose are equally effective in relieving acute NBS. A single oral dose of NSAID reduces pain by at least 50% for 4-6 hours in one in two or three patients (NNT index 2-3). Evidence has been obtained of equivalent effectiveness of s-NSAIDs and n-NSAIDs, while s-NSAIDs have a significant advantage in terms of safety, since they are significantly less likely to cause serious gastrointestinal complications [9, 27, 29].

Usually, to relieve an episode of acute NPS, taking NSAIDs for 7-14 days is sufficient, however, if the pain persists for a longer time, the course of treatment with these drugs can be extended to 4-8 weeks. In acute NBS, it is rational to use NSAIDs in combination with muscle relaxants, in chronic cases - with antidepressants and gabapentinoids [27-30].

The use of NSAIDs in the perioperative period as a component of multimodal analgesia can significantly increase the effectiveness of pain relief, the quality of life of patients, and also reduce the need for opioid analgesics. The latter effect is especially important because it makes it possible to reduce the incidence of complications associated with narcotic drugs - nausea and vomiting, excessive sedation and impaired intestinal motility.

The effectiveness of NSAIDs in reducing postoperative pain and reducing opioid dosage has been confirmed by a series of RCTs [31, 32]. Very indicative are the data from a meta-analysis of 60 RCTs that studied the opioid-sparing effect of paracetamol, n-NSAIDs and s-NSAIDs after major surgical interventions. An opioid analgesic (morphine) was used in a patient-controlled analgesia system. Its amount (in mg) required per day for effective pain control decreased significantly both when taking n-NSAIDs - by 10.18 - (95% CI 8.72-11.65), and with s-NSAIDs - by 10.92 - (95% CI 9.08-12.77). Moreover, the effect of NSAIDs was significantly higher than the effect of paracetamol, which reduced the need for morphine by 6.34 (95% CI 3.65-9.02) mg. Accordingly, the use of NSAIDs reduced the risk of developing opioid-related adverse events: OR 0.7 (95% CI 0.53–0.88) [33].

NSAIDs occupy an important place among drugs used for palliative analgesic therapy in patients with cancer [34]. In some cases, with moderate pain, they can be used as monotherapy, but most often they are used in combination with opioid analgesics. According to RCTs and the corresponding meta-analysis (including data from 42 RCTs, n

=3084), for cancer pain, NSAIDs are significantly superior to placebo [35-38]. Data on the increased effectiveness of pain relief when combining NSAIDs and opioids are conflicting. Thus, of the 14 RCTs that examined this issue, 5 found no difference between combination therapy and opioid monotherapy; 9 RCTs showed a statistically significant (albeit relatively small) benefit from the combination of NSAIDs and opioids [38].

Many experts recommend using NSAIDs only in short courses, sufficient to relieve acute pain or suppress episodes of worsening chronic pain. However, there is evidence that long-term continuous use of NSAIDs may provide greater effectiveness than on-demand use [39, 40]. This is shown, in particular, by data from an RCT [40], during which 853 patients with OA received celecoxib 200 mg “on demand” (only during exacerbation) or continuously (regardless of the presence of pain) for 6 months. If, while taking NSAIDs “on demand,” exacerbations occurred almost monthly (0.93 episodes/month), then those who took NSAIDs constantly were almost 2 times less likely (0.54), p

<0,001 [40].

Of particular importance is the use of NSAIDs for ankylosing spondylitis. There is now strong evidence supporting the ability of NSAIDs to slow the progression of this disease (the process of ankylosis of the axial skeleton). Therefore, NSAIDs occupy the position of the main pathogenetic agent for the treatment of AS; they are recommended for long-term, continuous use, in medium and high doses, even in the absence of severe musculoskeletal pain [41, 42]. In a study by A. Wanders et al. [43] 205 patients with AS received celecoxib at a dose of 200 mg per day for 2 years; half of them - daily, regardless of the presence of symptoms, and the second half - only when necessary to relieve pain (“on demand”). The main criterion for assessing the effectiveness of therapy was the dynamics of radiological changes in the spine. During the observation period, deterioration of the X-ray picture with regular use of celecoxib was observed 2 times less often than with its use “on demand”: the number of patients who had any negative changes and those who had serious negative dynamics was 23 versus 45 % and 11 versus 23%, respectively ( p

<0,001).

The use of local forms of NSAIDs (ointments, gels, solutions for application to the skin, spray) should be considered as an important and independent element of analgesic therapy. The effectiveness of local forms of NSAIDs is beyond doubt [44, 45]. It is confirmed by the results of a meta-analysis of 34 RCTs ( n

=7688), which assessed the therapeutic effect of NSAID-containing ointments, gels and solutions for cutaneous application in various musculoskeletal diseases. Local forms of NSAIDs showed a statistically significant advantage compared to placebo, with the NNT index after 8-12 weeks of treatment for diclofenac solution being 6.4 and diclofenac gel being 11.0 [46]. One more important point should be taken into account: local forms of NSAIDs, in contrast to the systemic use of these drugs, practically do not cause specific complications from the gastrointestinal tract (GIT) and kidneys and can be prescribed even to patients with severe comorbid pathology.

Basic principles of the relative effectiveness of NSAIDs

1. All NSAIDs in adequate anti-inflammatory doses (average and maximum therapeutic) have an equal analgesic effect (1a).

2. The effectiveness of NSAIDs generally depends on the dose. The use of higher doses of drugs provides a more pronounced analgesic effect (1b).

3. The use of injectable forms of NSAIDs (IV and IM administration), as well as water-soluble drugs for oral administration, may have an advantage in the speed of onset of the analgesic effect compared to taking standard tablets and capsules (1b). At the same time, there is no clear evidence that the use of NSAIDs in the form of injections or water-soluble forms for oral administration has an advantage over oral administration in terms of the severity of analgesic and anti-inflammatory effects when treatment is carried out for more than 1 day (1b).

4. NSAIDs at moderate and maximum therapeutic doses are more effective than the maximum therapeutic dose of paracetamol (4 g per day) (1a).

5. NSAIDs in moderate and maximum therapeutic doses in the treatment of chronic pain are not inferior in their effectiveness to “soft” opioid drugs (1a).

6. The use of NSAIDs in the perioperative period (as a component of multimodal analgesia) and as an additional means for pain control in cancer patients can increase the effectiveness of pain relief, reduce the need for narcotic analgesics and the frequency of opioid-related adverse events (1a).

7. In some situations (particularly in the treatment of OA), long-term, continuous use of NSAIDs provides better symptom control than on-demand NSAIDs (1b).

8. When treating AS, long-term use of NSAIDs can slow the progression of the disease (1a).

9. Local forms of NSAIDs have proven analgesic and anti-inflammatory effectiveness (1a).

Note.

In brackets (number and letter) is the level of evidence according to the table. 1.

Complications of NSAID treatment

The use of NSAIDs is associated with a wide range of adverse reactions, many of which pose a threat to the health and life of patients. The problem of complications seems especially serious given the fact that the majority of “consumers” of NSAIDs are elderly people with comorbid diseases.

NSAIDs and gastrointestinal tract

Gastrointestinal complications are the most common and well-studied pathology associated with NSAID use. The main element in the pathogenesis of these complications is considered to be blockade of the COX-1 enzyme (which is typical for n-NSAIDs) and a decrease in the synthesis of “cytoprotective” P.G. A decrease in the protective potential of the mucous membrane leads to its damage under the influence of external factors of aggression - hydrochloric acid in the upper gastrointestinal tract, intestinal contents - enzymes, bile acids, bacteria (as well as products of their destruction), etc. in the small and large intestine [47-49 ].

NSAID gastropathy.

The most well-known complication of NSAIDs, which is manifested by the development of erosions of the mucous membrane and ulcers of the stomach and/or duodenum, as well as bleeding, perforations and disorders of the gastrointestinal tract.
The risk of such complications in patients using NSAIDs is more than 4 times higher compared to the general population: it was estimated at 0.5-1 case per 100 patients per year. Patients treated with NSAIDs die due to complications from the gastrointestinal tract 2-3 times more often than persons who did not receive any drugs of this group. Currently, in developed countries of the world, against the background of a decrease in the frequency of H. . pylori
, it is the use of NSAIDs that determines the majority of episodes of bleeding in the gastrointestinal tract [49-51].

NSAID enteropathy.

The development of this complication is associated with an increase in the permeability of the intestinal wall, making it less resistant to external factors, and the movement of bacteria and their components with the development of chronic inflammation. The most common manifestation of this pathology is subtle blood loss, the source of which can be difficult-to-diagnose changes in the mucous membrane of the jejunum and ileum, leading to the development of clinically significant iron deficiency anemia (IDA). However, in some cases, NSAID enteropathy can manifest as profuse bleeding, intestinal perforation and the development of characteristic ring-shaped strictures (“membranes”). There are no clear statistics for this pathology: according to clinical studies, the incidence of bleeding from the lower gastrointestinal tract is at least 30-50% of the total number of bleeding episodes during treatment with NSAIDs [47, 52, 53]. According to RCTs, video capsule endoscopy (VCE) can detect erosions and ulcers of the small intestine in 30-50% of people who took n-NSAIDs (naproxen and ibuprofen) for 2 weeks [54, 55].

It should be noted that IDA, which develops as a consequence of NSAID enteropathy, poses a significant threat to health. IDA is associated with a decrease in the oxygen capacity of the blood, a decrease in resistance to exercise and, ultimately, an increase in the risk of cardiovascular accidents. This is confirmed by a meta-analysis of 51 RCTs [56], which compared the safety of celecoxib and n-NSAIDs ( n

=50.116) in order to determine the relationship between a decrease in hemoglobin levels and threatening systemic complications. The presence of anemia sharply increased the risk of cardiovascular complications. Thus, in 932 individuals who developed a clinically significant decrease in hemoglobin (more than 20 g/l), the incidence of myocardial infarction (MI) was 0.6%, while in patients who had no signs of anemia it was only 0.2%. Similarly, progression of coronary heart disease (CHD) was noted in 1.2% and 0.3% of patients [56].

NSAID-associated dyspepsia.

This is the most common complication associated with taking NSAIDs. Dyspepsia (usually this term refers to all unpleasant symptoms arising from the upper gastrointestinal tract, except heartburn and reflux) occurs or worsens in 20-30% of patients regularly taking these drugs. Dyspepsia does not threaten the life of patients, but significantly affects its quality and is the main subjective criterion for the tolerability of NSAIDs. Due to dyspepsia, more than 10% of patients stop taking their prescribed medications [57, 58].

NSAIDs and the cardiovascular system

Taking NSAIDs can have a negative effect on the cardiovascular system, and the medical and social significance of this pathology is no less than complications from the gastrointestinal tract [59]. The range of possible undesirable effects is quite wide; various manifestations of cardiovascular pathology are often combined, mutually aggravating each other - for example, arterial hypertension (AH) and ischemic heart disease.

Destabilization of hypertension while taking NSAIDs.

COX-1/COX-2 dependent PG synthesis plays an important role in the physiological regulation of vascular tone and renal function. PGs interact with the renin-angiotensin system, modulating the vasoconstrictor and antinatriuretic effects of angiotensin II. Several interrelated mechanisms are discussed that determine the prohypertensive effect of NSAIDs: a decrease in sodium excretion due to the effect on glomerular filtration and an increase in its proximal tubular reabsorption; vasoconstriction due to suppression of the synthesis of PGs with vasodilator activity (PGE2 and PGI2) and/or by increasing the release of norepinephrine from sympathetic nerve endings, as well as increasing the sensitivity of vascular wall receptors to the action of vasoconstrictor substances; decreased renal blood flow and glomerular filtration, increased secretion of endothelin-1; toxic effect of NSAIDs on the kidneys (drug-induced nephropathy). Renal regulation of blood pressure is largely determined by the activity of COX-2. Therefore, any NSAIDs (s-NSAIDs and n-NSAIDs) can have a prohypertensive effect [60, 61].

It is quite difficult to estimate the actual frequency of this pathology, since chronic diseases of the musculoskeletal system (as a reason for prescribing NSAIDs) and hypertension are very often combined, especially in the elderly. For example, according to population-based studies [62, 63], in the United States, approximately 20 million people take both NSAIDs and antihypertensive drugs at the same time, and in general, NSAIDs are prescribed to more than a third of patients suffering from hypertension [62, 63].

The results of a series of large retrospective and prospective epidemiological studies conducted in the United States clearly show the relationship between NSAID use and the development of A.G. Thus, according to the results of NHS (Nurses' HealthStudy) I, II, the risk of this pathology in women who regularly take NSAIDs increases by 30-60% [64, 65]. The incidence of development or destabilization of hypertension recorded in long-term RCTs varies widely, but does not exceed 5-7% [66-68]. According to a meta-analysis [69], 51 RCTs ( n

=130,541), taking s-NSAIDs is associated with a significant increase in the risk of developing hypertension compared with placebo (OR 1.49, 95% CI 1.18-1.88,
p
=0.04).
There was no significant difference between s-NSAIDs and s-NSAIDs: (OR 1.12, 95% CI 0.93-1.35, p
= 0.23). At the same time, the most significant negative effect on blood pressure was demonstrated by rofecoxib and etoricoxib.

The results of RCTs show that indomethacin, piroxicam and naproxen in moderate therapeutic doses, as well as ibuprofen in high doses, have the ability to reduce the effectiveness of beta-blockers, diuretics, ACE inhibitors, but have a significantly lesser effect on the antihypertensive effect of calcium antagonists [70-83] , s-NSAIDs can also reduce the effectiveness of antihypertensive drugs [84–87]. According to clinical studies [66, 88], celecoxib has a lesser effect on the destabilization of hypertension compared to diclofenac.

Thromboembolic complications of NSAIDs.

The “prothrombogenic” potential of s-NSAIDs is determined by the ability of these drugs to suppress COX-2-dependent synthesis of prostacyclin by vascular endothelial cells, without affecting the synthesis of thromboxane A2 by platelets, which is controlled by COX-1. The resulting imbalance of prostacyclin/TxA2 under unfavorable circumstances can lead to increased activation, aggregation and adhesion of platelets and an increased risk of thrombosis [89–91]. In addition, the risk of developing cardiovascular accidents may increase due to the prohypertensive effect of NSAIDs and due to their negative effect on the preventive effect of low doses of aspirin.

Currently, thromboembolic complications are considered a class-specific complication of NSAIDs, characteristic of both n-NSAIDs and s-NSAIDs. According to long-term RCTs, acute cardiovascular and cerebrovascular disorders occur in more than 1-2% of patients during 6-12 months of continuous use of high doses of NSAIDs. In total, more than 10% of patients with such complications die [92]. An example is the large-scale MEDAL study, during which 34,701 patients with OA and RA took etoricoxib 60 and 90 mg or diclofenac 150 mg for at least 1.5 years. The incidence of myocardial infarction in patients with etoricoxib and diclofenac was 1.9 and 1.9%, and ischemic stroke - 0.48 and 0.53%, respectively. In each of the study groups, 43 patients died due to these complications [68].

The risk of cardiovascular complications (including fatal) is especially high in patients with coronary artery disease who have undergone MI, as well as heart and vascular surgery (coronary artery bypass grafting, stenting). This is confirmed by the study of the relationship between taking NSAIDs and the risk of death in patients who underwent I.M. The study group consisted of 58,432 patients who underwent successful treatment after their first MI in 1995–2002. Subsequently, 9,773 suffered this complication again, and 16,573 died. As the analysis showed, taking any NSAIDs was associated with a significant increase in the risk of patient death: the OR for celecoxib was 2.57 (95% CI 2.15-3.08), for diclofenac 2.40 (95% CI 2.09-2 .80), for ibuprofen - 1.50 (95% CI 1.36-1.67) [93].

Interaction of NSAIDs with aspirin and the risk of cardiovascular complications.

According to experimental studies, some NSAIDs (ibuprofen, naproxen, indomethacin) can compete with aspirin for binding to the active site of COX-1 and cancel its antiplatelet effect [94, 95]. However, no interaction of ketoprofen [96], celecoxib [97] and meloxicam [98] with aspirin was observed. Data from epidemiological studies regarding the risk of cardiovascular events in patients taking ibuprofen and aspirin concomitantly are contradictory. For example, according to some authors, taking ibuprofen or any n-NSAIDs (more than 60 days) is associated with an increased risk of I.M. However, other studies have not found an association between the concomitant use of aspirin and n-NSAIDs (including ibuprofen) and the development of these complications [99–104]. According to G. Singh et al. [105], (California Medicade database, 1999–2004) use of aspirin reduces the risk of MI during treatment with rofecoxib (OR 1.31; 95% CI 1.20–1.43 vs. 1.03; 95% CI 0.86–1.24), celecoxib (OR 1.12; 95% CI 1.04–1.19 vs. 0.88; 95% CI 0.76–1.02), meloxicam (OR 1.52 ; 95% CI 1.03–2.11 vs. 0.53; 95% CI 0.26–1.10). Taking aspirin did not affect the risk of MI in people taking indomethacin (OR 1.65; 95% CI 1.14–2.03 vs. 1.21; 95% CI 0.65–2.27) and ibuprofen (OR 1 .08; 95% CI 0.98–1.19 vs. OR 1.20; 95% CI 0.94–1.51) [105].

Taking NSAIDs and chronic heart failure (CHF).

Regular use of NSAIDs is associated with an increased risk of CHF decompensation in patients with initial CV pathology. The pathogenesis of this complication is mainly associated with the ability of NSAIDs to negatively affect renal function, which leads to water and sodium retention, increased peripheral vascular tone and an increase in afterload [60, 61].

According to the meta-analysis, in 5 case-control studies (4657 cases, 45,862 controls) there was a significant increase in the risk of CHF with the use of NSAIDs - OR 1.36; (95% CI 0.99–1.85). Two cohort studies (27,418 patients and 55,367 controls) also confirmed this relationship: OR 1.97 (95% CI 1.73-2.25). Data from 6 RCTs comparing NSAIDs with placebo in non-rheumatic diseases ( n

=15,750), the risk of developing CHF was 2.31 (95% CI 1.34-4.00).
At the same time, the negative effect of NSAIDs on the development of CHF was not clearly confirmed by the results of RCTs in rheumatic pathology (6 RCTs, n
= 62,653): OR 1.14 (95% CI 0.85–1.53) [106].

A study of the impact of individual NSAIDs based on observational and case-control studies showed that the risk of hospitalization for CHF increased with n-NSAIDs and rofecoxib, but not with celecoxib [107–109].

According to RCT data, decompensation of CHF while taking NSAIDs is quite rare, but undoubtedly a serious condition. In the SUCCESS-1 RCT [63], the incidence of CHF decompensation was 0.22 episodes with celecoxib versus 1.0 per 100 patient-years with diclofenac or naproxen. According to the MEDAL program [67], CHF was the cause of treatment interruption in 0.1–0.7% of patients receiving etoricoxib (depending on dose) and 0.2% of those receiving diclofenac. CHF often develops while taking n-NSAIDs in patients who already have this pathology, as well as in those suffering from hypertension, kidney pathology and diabetes mellitus. The risk increases with the use of high doses of NSAIDs [110].

Nephrotoxicity of NSAIDs

Complications associated with impaired renal function are observed in 1-4% of patients regularly taking NSAIDs. The development of this complication is determined by the influence on COX-1- and COX-2-induced synthesis of PGE2 and prostacyclin, which regulate the tone of the renal arterioles (hence, the glomerular filtration rate), as well as the excretion of salt and water in the renal tubules [4, 111].

The nature and severity of renal complications can vary widely. While taking NSAIDs, the development of membranous nephropathy, interstitial nephritis with nephrotic syndrome and acute papillary necrosis has been described. There is a known relationship between the development of acute renal failure (ARF) and the use of NSAIDs. This is confirmed by data from a population-based case-control study of 386,916 UK residents who had 103 episodes of AKI. When compared with control ( n

=5000) a significant increase in the risk of acute renal failure was noted against the background of p

Types of anti-inflammatory drugs

Modern medications cope with inflammation of any nature and have a long-lasting effect. They are often prescribed when pain needs to be relieved.

• Hormonal drugs . They have a much stronger effect than non-hormonal ones. The basis of such drugs is cortisol. They act on the principle of local immune suppression. And at the same time, such drugs have many more contraindications and side effects.

They are prescribed for severe skin allergies, rheumatoid arthritis, vascular inflammation, hepatitis, and inflammation of skeletal muscles.

• Combined means . These medications include combinations of several components. Thanks to this, the therapeutic effect is greatly increased.
• Nonsteroidal drugs . These drugs act selectively on types of cyclooxygenase, inhibiting their activity. COX is responsible for the creation of biologically active components. Due to the suppression of COX activity, the amount of these substances in tissues decreases and inflammation disappears.

pharmachologic effect

Anti-inflammatory drugs inhibit inflammation by blocking enzymes that are involved in the formation of special inflammatory factors - prostaglandins: glucocorticosteroids inhibit the enzyme phospholipase A2, non-steroidal anti-inflammatory drugs - the enzyme cyclooxygenase-2.

Glucocorticoids additionally have an antiallergic, immunosuppressive (immunosuppressive) effect, increase blood pressure (anti-shock effect), and activate the liver’s ability to neutralize toxins (antitoxic effect).

In addition to their anti-inflammatory effect, non-steroidal anti-inflammatory drugs also have the ability to reduce pain (analgesic effect) and reduce elevated body temperature (antipyretic effect).

Antirheumatic drugs have an anti-inflammatory and immunosuppressive effect due to inhibition of the formation of specific signaling molecules responsible for the implementation of inflammation - cytokines: tumor necrosis factor-α, interleukin-1 receptors.

How to take anti-inflammatory medications correctly?

First you need to carefully read the instructions. The drugs must be prescribed by the attending physician and the optimal dose and course of treatment determined. To protect the stomach, tablets should be taken with a sufficient amount of clean water.

Under no circumstances should you mix medications with alcohol. This will further affect the functioning of the stomach.

You can buy all drugs for the treatment of inflammatory processes in the network of state pharmacies “Provincial Pharmacies”. We provide medicines with a state quality guarantee. There is a pick-up system and home delivery when ordering drugs online.

Side effects during long-term treatment with high doses of GC

In conclusion, I would like to add that in the fight against chronic pain syndrome, which accompanies many diseases, steroid analgesics help indirectly and are only part of the therapy. It is important that the drug, dosage and duration of the course are selected by the attending physician in accordance with the results of examinations, indications, medical history and the individual characteristics of the patient’s body. It is not recommended to independently adjust the course of treatment to avoid side effects.