“Reduce the pain!” Almost every seventh patient visits a doctor with complaints of joint pain. Joint pains are found in various diseases of the joints, spine, muscles, ligaments and connective tissue. Rheumatic diseases cause severe pain, limited mobility, and with progression can lead to severe deformity of the joints, with the loss of their function and a decrease in the quality of life of patients. The most common rheumatic diseases are acute and chronic arthritis, degenerative changes in the joints of the limbs and spine (for example, arthrosis or osteochondrosis), as well as damage to the periarticular tissues, in particular, epicondylitis or periarthritis. Given that there is no etiotropic treatment of rheumatic diseases today, the role of symptomatic drug therapy remains extremely important. Phenylbutazone, then indomethacin, and in the mid-1970s, took the leading place in the market for antirheumatic drugs. appeared diclofenac (Voltaren ), which has become in more than 120 countries around the world a symbol of the treatment of rheumatic diseases. Research to create new products for the treatment of rheumatic diseases is a traditional activity of Novartis (and its predecessor companies). The first milestone in the development of antirheumatic therapy was phenylbutazone, and in 1974 the company began to produce Voltaren , which today remains the most common and effective drug. In 1966, Dr. Alfred Sallmann obtained the highly active substance GP 45840 in the research laboratory of the Geigy company (Geigy), which entered the history of rheumatology under the name “diclofenac”. In animal experiments, it was shown that this active substance has pronounced analgesic, anti-inflammatory and antipyretic properties . After conducting a number of clinical studies, which showed high efficacy and good tolerability of this nonsteroidal agent for treating rheumatic diseases, the drug with the trade name Voltaren has taken its place in the drug market. Despite the fact that in the future other companies and researchers created a large number of similar substances, none of them are more effective than diclofenac.
Strong COX – 2 inhibitor Like other NSAIDs, diclofenac inhibits cyclooxygenase (COX) activity. This enzyme is involved in the synthesis of certain substances in the body (prostaglandins). Prostaglandins are important for the development of inflammation, the occurrence of pain and fever. After the discovery of COX-1 and COX-2 isoenzymes, it became clear that the blockade of COX-2 plays a crucial role in combating inflammation and pain. It should be noted that even in comparison with modern selective COX-2 blockers, diclofenac still remains one of the most active inhibitors of COX-2 [3,4,5] (Fig. 1), which explains its pronounced analgesic and antipyretic effect and therefore, high clinical efficacy. From a pharmacological point of view, this suggested that NSAIDs with acid properties have a more pronounced anti-inflammatory effect due to their ability to accumulate in a higher concentration in the zone of inflammation . Diclofenac is a derivative of phenylacetic acid, which distinguishes it from other non-acidic COX-2 inhibitors. Good control of NSAIDs is often divided by the time of their half-life of plasma (ERW) . Substances with a long half-life have the advantage that they can be taken once a day; however, the ERW of such drugs may vary significantly between different patients. In addition, there is a risk of cumulation of drugs. Usually, long-term elimination is a consequence of significant enterohepatic recirculation, in which there is a tendency to an increased risk of ulceration in the lower intestine . On the contrary, the concentration of NSAIDs with shorter ERW (t50% = 1–2 hours) is easier to control; these drugs are rapidly eliminated, which makes it possible to assign them even to patients with moderately impaired renal and hepatic function. The short duration of the stay of diclofenac in the body also ensures good tolerability of the drug and reduces the risk of drug interactions. Although diclofenac (Voltaren ) refers to drugs with short ERW, the duration of the anti-inflammatory action of Voltaren exceeds the time it circulates in blood plasma due to redistribution into inflammatory tissues.In conjunction with this enzyme, the active substance is not detected in the plasma, and the synthesis of prostaglandins remains blocked. Therefore, for the relief of pain in most cases a single dose of an adequate dose (up to 200 mg) is sufficient. For adequate penetration into the synovial fluid (inflamed tissue), it is enough to take enteric-coated tablets in a sufficient dose. Peak plasma concentration provides admission to the target tissue, on the one hand, does not overload (does not induce) liver enzymes, on the other. In this regard, the justification of the lek forms with delayed release is not always justified. A wide range of indications for use “Rheumatic” indications for diclofenac include acute and chronic diseases of the joints, in particular, exacerbation of arthrosis and spondyloarthrosis, extra-articular lesions, including tendinitis, tendovaginitis, bursitis and myositis. Also, diclofenac is used for pain due to swelling and inflammation in injuries and operations. In the management of patients with pain in cancer (WHO), diclofenac represents the first stage of therapy. A large number of indications for prescription is due to the variety of forms of drug delivery: the active substance Diclofenac sodium can be produced in the form of pills, resistant to gastric juice, pills with a slow release, in suppositories or solutions for injection – as well as a wide range of dosages (from 25 mg / day to 150 mg / day). New forms of drugs meet the needs of the doctor and patient to the greatest extent. New forms of drugs For a more than 25-year history of the form of release of diclofenac have undergone significant changes. Soluble Voltaren dispersion tablets (Voltaren Dispers) provide a very rapid onset of drug action (maximum after 20 minutes) , which made it possible to call this form “oral injection”. The maximum concentration of a substance in plasma is reached as quickly as after injection, and much sooner than after ingestion of pills or retard forms resistant to gastric juice. Another new form was Voltaren Resinate (Voltaren Resinat), the active substance of which is diclofenac – cholestyramine, which acts on the principle of ion exchange resin. At the same time, along with the rapidity of development of the effect, the long-term effect of the drug is provided. Capsules containing 75 mg of Diclofenac Resinate should be taken no more than 2 times per day; This allows you to maintain an effective concentration of diclofenac in the blood, which leads to almost complete blockade of the formation of PGE2 in tissues. Controlled release of diclofenac by the ion-exchange mechanism allows to avoid excessively high concentrations of the drug in the blood, which ensures good tolerability of diclofenac with prolonged use. Another major milestone was the development in 1986 of the first form of diclofenac for local use – Voltaren emulgel (Voltaren Emulgel). The drug contains diclofenac – diethylammonium, modified specifically for external use, which in the form of a patented form – gel – emulsion, combining the properties of cream and gel, provides the most effective topical treatment of pain, inflammation or edema of subcutaneously located target tissues. Pharmacological studies on volunteers showed that the percutaneous use of Voltaren emulgel allows to achieve an effective concentration of diclofenac in the target tissue under the application site, for example, in muscle, synovial membrane or synovial fluid. The closer to the skin is the target tissue, the higher is the concentration of the drug in it . Controlled clinical studies and practical experience in the use of a large number of patients confirmed the good clinical efficacy of diclofenac. In a recent, not yet published double-blind study, Voltaren emulgel was shown to be at least as effective for osteoarthritis of the joints of the fingers and toes as oral ibuprofen (1200 mg / day). The relatively low concentration of diclofenac in plasma, when applied topically, plays a decisive role in ensuring the excellent tolerability of Voltaren emulgel, due to which it serves as the drug of choice for the treatment of elderly patients with localized inflammatory or degenerative rheumatic diseases. Voltaren disperse is the drug of choice for quick relief of rheumatic pains; on the contrary, Voltaren Resinate is preferably used for long-term therapy of the chronic process. Like Voltaren emulgel, both of these new forms of the preparation contain not diclofenac sodium, but special, optimized modifications of diclofenac. These three drugs allow the doctor to select NSAID therapy that best suits the specific needs of the patient. In addition to efficacy and portability, an important role is played by the price of the drug – it is often lower than the price of the corresponding generic.