NON-STEROID ANTI-INFLAMMATORY DRUGS IN OSTEOARTHROSIS THERAPY

Arthrosis is a chronic disease of the joints associated with their deformation and limited mobility. Doctors at the Yusupov Hospital prescribe non-selective and selective NSAIDs to patients suffering from arthrosis. Nonsteroidal anti-inflammatory drugs reduce pain and inflammation, improve the functional state of joints, and prevent further destruction of articular cartilage. Patients are taught to adequately assess disease activity, rational use of symptomatic therapy, and physical exercises that support joint function.

According to the recommendations of the Association of Rheumatologists of Russia, treatment of patients with arthrosis is carried out on an outpatient basis. Patients are admitted to the therapy clinic when the standard therapy is clearly ineffective. Rheumatologists conduct examinations using diagnostic equipment from leading global manufacturers and modern laboratory tests. Severe cases of arthrosis are discussed by candidates and doctors of medical sciences at a meeting of the expert council. Leading specialists in the field of rheumatology collectively develop tactics for further patient management, select optimal doses and combinations of drugs, and determine how long NSAIDs can be taken.

NSAIDs

The most effective drugs for the treatment of arthrosis are non-steroidal anti-inflammatory drugs. Paracetamol is the drug of choice for the treatment of arthrosis of the knee joint and other localizations in patients with moderate pain. According to European recommendations (ESCISIT), the daily dose of paracetamol for continuous use is 2-4 g. In Russian recommendations, which are closer to real clinical conditions, the recommended dose of the drug for continuous use should not exceed 2 grams per day. At the indicated dose, paracetamol can be safely taken for the treatment of arthrosis for two years. When using higher doses of the drug, especially in elderly patients, the frequency of adverse reactions significantly increases.

To treat patients with arthrosis, doctors at the Yusupov Hospital use the following NSAIDs:

• acetylsalicylic acid - duration of action from 4 to 6 hours, single dose varies from 500 to 1000 mg, the highest daily dose is 3000 mg;
• ibuprofen – duration of action is 6-8 hours, single dose is 200-400 mg, daily dose is 2400 mg;
• diclofenac - acts for 8-12 hours, a single dose is 50-100 mg, a daily dose should not exceed 150 mg;
• indomethacin – duration of action is from 6 to 12 hours, a single dose is in the range of 200-400 mg, the highest daily dose is 2400 mg;
• naproxen – used 250-1000 mg at a time, but not more than 1200 mg per day, valid for 12 hours.

Non-selective NSAIDs can have significant side effects during long-term treatment of arthrosis. If there is a high risk of complications, doctors at the Yusupov Hospital use selective COX-2 inhibitors to treat arthrosis: meloxicam 7.5-15 mg once daily, nimesulide 100-200 mg twice daily, celecoxib 100-400 mg once daily . For the treatment of osteoarthritis, NSAIDs are used only during periods of increased pain in minimally effective doses.

Adverse effects of NSAIDs

Even short-term use of NSAIDs in a certain proportion of patients leads to the development of serious side effects. The most common adverse effects of NSAIDs are:

• damage to the gastrointestinal tract;
• violation of platelet aggregation (sticking);
• kidney damage;
• negative effect on the circulatory system.

The side effects of NSAIDs are associated with the suppression of the activity of the “physiological” isomer of COX (COX-1). Other unwanted effects are less common. Most often, in elderly people suffering from concomitant diseases, long-term use of NSAIDs develops coronary heart disease, diabetes mellitus, and renal failure.

The risk of developing serious complications in a number of NSAIDs increases as follows: ibuprofen, diclofenac, naproxen, indomethacin. For most NSAIDs, the risk of gastrointestinal bleeding becomes maximum on average by the eighty-fourth day of treatment, for indomethacin - during the first seven days. Endoscopic features of NSAID gastropathy, which make it possible to distinguish it from ulcers associated with Helicobacter pylori, are the predominant localization of damage in the antrum of the stomach, moderate or minimally expressed signs of inflammation of the mucous membrane.

The relative risk of developing serious complications from the gastrointestinal tract occurs in the following cases:

• availability of information about previously diagnosed peptic ulcer disease;
• use of high doses of NSAIDs;
• simultaneous use of NSAIDs of various groups (including low doses of aspirin);
• elderly patient (over 70 years old);
• taking anticoagulants and high doses of glucocorticoid hormones.

If there is a risk of developing digestive complications from NSAIDs, doctors at the Yusupov Hospital prescribe synthetic prostaglandins and proton pump inhibitors to patients. Histamine H2 receptor blockers are effective in treating NSAID-induced ulcers and erosions of the duodenum, but not the stomach. Proton pump inhibitors appear to be more effective than histamine receptor blockers and misoprostol. The course of therapy with proton pump inhibitors should be at least four weeks. For large sizes and localization of ulcers in the stomach, it varies from 8 to 12 weeks. Patients take “gastroprotectors” throughout the entire duration of the NSAID course.

An increased risk of developing cardiovascular pathology is observed when patients with arthrosis take naproxen, celecoxib, ibuprofen, diclofenac and rofecoxib. Indomethacin, naproxen, piroxicam in moderate therapeutic doses and ibuprofen in high doses reduce the effectiveness of diuretics, beta blockers, and ACE inhibitors. When using non-selective NSAIDs (indomethacin, ibuprofen, piroxicam, pyrazolone, aspirin) and non-narcotic analgesics (analgin, phenacetin, paracetamol), acute kidney damage (nephropathy) and acute renal failure develop.

NON-STEROID ANTI-INFLAMMATORY DRUGS IN OSTEOARTHROSIS THERAPY

The paper deals with drug therapy for osteoarthrosis, gives data on the safe use of various nonsteroidal antiinflammatory agents in terms of the patient`s age and the need for their long-term use, and shows the prospects for improving the pharmacokinetic properties of these drugs .

D.E. Karateev, Ph.D. honey. Sciences, senior researcher at the Institute of Rheumatology (Dir. - Academician of the Russian Academy of Medical Sciences V.A. Nasonova) RAMS, Moscow D.Ye. Karateyev, Candidate of Medical Sciences, Senior Researcher, Institute of Rheumatology, Russian Academy of Medical Sciences (Director VA Nasonova, Academician, Russian Academy of Medical Sciences), Moscow

ABOUT

Steoarthrosis (OA) is the most common disease of the musculoskeletal system [1], which has important social significance. Most patients with OA turn to a doctor for help with lesions of the load-bearing joints (knee and hip), causing pain and limitation of movements, which sharply reduces the quality of life. Knee OA is the main cause of pain and functional impairment in old age [2]. In OA, degeneration of articular cartilage, which is the main symptom of the disease, is naturally associated with the occurrence of secondary inflammation of the synovial membrane [1, 3]. Pain, the main clinical manifestation of OA, is associated with the development of secondary synovitis, which in turn enhances the processes of cartilage degradation. In this regard, in the English-language literature the term “osteoarthritis” is used to denote the nosology, which emphasizes the importance of the inflammatory component in this disease.

An example of osteoarthritis. Heberden's nodes (distal interphalangeal joints) and Bouchard's nodes (proximal interphalangeal joints).

Nonsteroidal anti-inflammatory drugs (NSAIDs) are currently the mainstay of treatment for pain in OA [4]. It is difficult to find an OA patient who does not receive one or another drug of this group at least occasionally. It has been shown that NSAIDs in OA in most cases provide a more pronounced analgesic effect than non-narcotic analgesics, such as paracetamol [5]. The global pharmaceutical industry provides doctors with a wide selection of NSAIDs with different chemical structures [6, 7]. NSAIDs are characterized by an individual reaction to the drug, as well as a fairly high frequency of side effects from the gastrointestinal tract (GIT). The question of the disadvantages and advantages of this or that group of NSAIDs still remains open.

An example of osteoarthritis. Heberden's nodes (distal interphalangeal joints) and Bouchard's nodes (proximal interphalangeal joints). In Russia, as well as throughout the world, the NSAIDs presented in the table are most often used for the treatment of OA. When choosing a NSAID for the treatment of a patient with OA, the doctor must take into account the following important points: 1. The effect of NSAIDs on the gastrointestinal tract 2. The effect of NSAIDs on articular cartilage 3. Age characteristics of patients with OA 4. The need and possibility of long-term use of NSAIDs 5. Possibilities for improving the effectiveness and tolerability of NSAIDs

Table. NSAIDs most commonly used to treat OA

Effect on the gastrointestinal tract

Currently, it can be considered proven that taking large doses of NSAIDs (for example, in rheumatoid arthritis) often causes erosive and ulcerative damage to the gastrointestinal tract, primarily the gastric mucosa (according to Yu. V. Muravyov et al., up to 40% of the total patients who underwent gastroscopy). Erosive and ulcerative damage to the gastrointestinal mucosa is a characteristic consequence of the use of NSAIDs, directly related to their mechanism of action – inhibition of cyclooxygenase-1 [8]. A large number of clinical trials have been conducted around the world regarding the comparative safety of various NSAIDs, and these studies cannot be considered complete. However, by summing up the data from various clinical trials, a fairly definite picture can already be obtained. According to the UK Medicines Safety Committee and a number of other studies [9], in order of increasing relative risk of developing adverse reactions from the gastrointestinal tract, the most common NSAIDs in our country are: 1) ibuprofen; 2) diclofenac; 3) flurbiprofen; 4) naproxen; 5) ketoprofen; 6) piroxicam; 7) indomethacin. Thus, ibuprofen is most well tolerated, and gastrointestinal tract damage occurs most often during treatment with indomethacin.

Scheme: pathological changes in the joint with osteoarthritis

Cartilage degradation

A strong argument against long-term use of NSAIDs in patients with OA is the potential negative impact of these drugs on cartilage. Particular attention should be paid to the fact that, while relieving pain and synovitis, NSAIDs do not delay degenerative changes in cartilage and bone. There are a number of reports that long-term use of NSAIDs may contribute to the progression of cartilage degradation [1]. At the same time, only with the use of indomethacin can increased cartilage degradation and progression of the pathological process in the joints be considered proven [10 – 12]. This mainly concerns OA of the hip joint. The presence of a negative effect of NSAIDs on the progression of OA for other NSAIDs is highly controversial. Special studies have shown that tiaprofenic acid, unlike indomethacin, does not cause worsening of the X-ray picture in gonarthrosis, even with long-term use [35]. Apparently, derivatives of arylpropionic acid (ibuprofen, etc.) do not have a negative effect on cartilage.

Taking into account the age characteristics of patients with OA

The issue of tolerability of NSAIDs is especially important considering that OA usually occurs in old age, when the pharmacokinetics of various drugs may change, primarily due to changes in liver and kidney function. Thus, it has been shown that a number of drugs, such as indomethacin, diflunisal, naproxen and ketoprofen, can accumulate with an increased likelihood of toxic reactions in elderly patients; this is associated with age-related decline in renal function [13]. On the other hand, not all drugs are tolerated worse by older patients. There is evidence that the pharmacokinetics of ibuprofen does not change in old age against the background of age-related changes in liver function, in contrast to a number of other drugs, such as sulindac [14]. There is evidence in the literature of better tolerability of flurbiprofen (flugalin), in particular with regard to the effect on renal function, compared with piroxicam in patients with rheumatoid arthritis over the age of 60 years [15].

The need and possibility of long-term use of NSAIDs

There is a fairly widespread belief that NSAIDs should be prescribed only in short courses, for a maximum of several weeks, to relieve pain. At the same time, a characteristic feature of OA is the progressive degeneration of cartilage in elderly and senile people, clinically manifested by pain, stiffness and limitation of movements in the affected joints, and as synovitis progresses, the symptoms of synovitis and, accordingly, the pain syndrome become more and more persistent. A clinical study (part of an extensive multicenter trial) was conducted at the Institute of Rheumatology of the Russian Academy of Medical Sciences to study the effectiveness and tolerability of flurbiprofen (flugalin) during continuous long-term (12 months) use in patients with OA [16 – 18]. This study led to the conclusion that flugalin is a fairly effective drug for the relief of pain in OA, with satisfactory tolerability. Judging by the dynamics of the pain syndrome in our patients, in most patients it is possible to achieve a stable reduction in the level of pain in the joints with relatively long-term (3-6 months) use of the drug, especially in cases of clearly clinically detectable secondary synovitis. In this case, the doctor can make a judgment about the effectiveness and tolerability of flugalin over a shorter (1–3 months) observation period. Provided there were no side effects in the first 3–4 months, longer (6–12 months) use of the drug was not accompanied, obviously, by a significant increase in the risk of developing complications from the gastrointestinal tract.

Possibilities for improving the effectiveness and tolerability of NSAIDs Long-acting forms of NSAIDs

One way to improve the pharmacokinetic parameters of NSAIDs is the use of prolonged forms (retard). This allows you to maintain a sufficiently high level of the drug in the blood for a longer period, reduce the number of drug doses per day and achieve some improvement in gastrointestinal tolerability. The most well-proven long-acting forms of diclofenac (Voltaren-retard), ibuprofen (Brufen-retard) and flurbiprofen (flugalin-retard). Ibuprofen showed higher efficacy and better tolerability of the prolonged form compared to the conventional tablet form of the drug in OA and rheumatoid arthritis [19, 20]. Our studies [16 – 18] have demonstrated that the long-acting form of flurbiprofen (flugalin-retard) provides a slightly more pronounced analgesic effect in OA than the short-lived form of the drug (which is obviously due to a more gradual decrease in the concentration of the drug in the blood after a single dose). In addition, there was a clear trend towards better tolerability of the prolonged form from the gastrointestinal tract. For patients, the use of flugalin retard was significantly more convenient, since it allowed them to take the medicine once a day.

Combinations with gastroprotectors

Currently, attempts are being made to reduce the risk of developing gastropathy during the treatment of NSAIDs by combining them with so-called gastroprotectors - drugs used to treat gastric and duodenal ulcers that have a preventive effect. The most famous drug is arthrotec - a combination of diclofenac or misoprostol (Cytotec), which is close in structure to natural prostaglandin E1, which stimulates mucus formation and suppresses the secretion of gastric juice. There are a number of encouraging reports about a decrease in the incidence of erosive and ulcerative lesions of the gastrointestinal tract during treatment with arthrothecema, but this cannot be considered an established fact. There is evidence that in OA, arthrotec is not significantly different from diclofenac in either effectiveness or tolerability [21]. Therefore, the feasibility of the combination of diclofenac + misoprostol still requires confirmation.

Cyclooxygenase-2 inhibition

Another promising direction to improve the tolerability of NSAIDs is the development of drugs that selectively inhibit cyclooxygenase-2. According to modern concepts, NSAIDs have a number of pharmacological effects. The main one, obviously, is, as was shown by J. Vane in 1971, the inhibition of prostaglandin synthetase (cyclooxygenase), an enzyme that catalyzes the conversion of arachidonic acid into prostaglandins, which are mediators of inflammation. In most drugs from the NSAID group, this mechanism also leads to inhibition of the synthesis of “useful” prostaglandins that regulate the level of acidity of gastric juice, the functioning of the gastric mucous barrier, and have a vasodilator effect, which leads to the possibility of unwanted reactions. It is now known that there are 2 isoforms of cyclooxygenase (COX) – cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). COX-1 is a constitutional, “useful” enzyme that synthesizes thromboxane A2, prostaglandin E2, prostacyclin, which are involved in the most important physiological processes. COX-2 is an “inducible” enzyme that catalyzes the synthesis of prostaglandins involved in the inflammatory process [22]. Obviously, to obtain an anti-inflammatory effect, it is desirable to have a drug that inhibits the synthesis of “pathological” COX-2 and does not affect the “physiological” COX-1. All commonly used NSAIDs inhibit both COX-2 and COX-1. In recent years, drugs such as meloxicam and nimesulide have been synthesized, which are capable of inhibiting COX-2 significantly more pronounced than COX-1 [23, 24]. A number of authors have shown that these drugs are likely to be better tolerated by patients than traditional NSAIDs, and this information seems more reliable for meloxicam. If the results of preliminary studies are confirmed by clinical practice, doctors and patients will be able to obtain a safe pain reliever and anti-inflammatory drug. However, clinical data on efficacy and safety do not appear to directly correlate with the degree of selectivity of COX-2 inhibition. Thus, the question of the advantages of meloxicam and nimesulide over other NSAIDs remains open. So, based on the above data, an ideal NSAID for the treatment of OA should have the following properties: 1) good analgesic effect; 2) low incidence of gastrointestinal lesions; 3) no negative effect on cartilage; 4) convenient dosage form. Apparently, at present these requirements are most accurately met by derivatives of arylpropionic acid. Drugs in this group, primarily ibuprofen, are considered classic for the treatment of OA, since they have a good analgesic effect and satisfactory tolerability. Ibuprofen (Brufen) is the standard for a well-tolerated NSAID, which is reflected in the fact that most countries allow the drug to be sold over the counter [25]. According to a number of studies [26], the use of ibuprofen is associated with the lowest risk of developing gastrointestinal ulcers compared to all other NSAID drugs. All over the world, ibuprofen is widely used for the treatment of patients with OA, as it has a good analgesic effect and quite satisfactory tolerability. However, it has a less pronounced anti-inflammatory effect, although in some cases it is used to treat inflammatory diseases of the joints, such as rheumatoid arthritis. Compared to ibuprofen, flurbiprofen (flugalin) is a next-generation drug that has a more powerful anti-inflammatory effect, which allows it to be used in lower doses. Both drugs have been used to treat OA for several decades. During this time, numerous clinical trials have been conducted that have demonstrated fairly high clinical efficacy, as well as quite satisfactory tolerability. In terms of tolerability, both ibuprofen and flurbiprofen were superior to drugs such as indomethacin, diclofenac, naproxen and acetylsalicylic acid in a number of studies [27 – 30]. Our studies [16 – 18] showed the possibility and relative safety of long-term (many months) administration of a maintenance dose of flurbiprofen. Moreover, both ibuprofen and flurbiprofen are available in a wide range of dosage forms, including long-acting ones, which provide a good clinical effect when taken once a day. If it is necessary to obtain a more pronounced anti-inflammatory effect (for persistent secondary synovitis, periarthritis), it is advisable to use diclofenac (Voltaren, Diclonate, Naklofen), which has pronounced anti-inflammatory activity, which is also well tolerated and has a variety of dosage forms - from fast-acting to long-acting. At the same time, it should be noted that NSAIDs are characterized by an individual patient’s reaction to the drug, and therefore other drugs from this group can be extremely useful for a number of patients.

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