The relationship between pain and inflammation has long been known. Today, the most common drugs for pain relief are drugs that have both anti-inflammatory and analgesic effects – non-steroidal anti-inflammatory buy diclofenac online (NSAIDs).
The History of the Creation of Diclofenac
The prototype of modern NSAIDs was acetylsalicylic acid, which at the end of the XIX century. first synthesized by a young scientist Felix Hoffman. Its chemical structure and properties became the benchmarks that helped in the development of new representatives of this class of drugs (initially they were called “aspirin-like”). A powerful incentive for the development of new, “non-salicylate” NSAIDs was not so much the lack of effectiveness of acetylsalicylic acid, as the toxicity of its high doses.
In 1966, during the implementation of a program to develop an anti-inflammatory drug with improved biological properties, more than 200 amino-acetic acid analogues were synthesized in the Geigy research laboratory to create a molecule with the required parameters, among which sodium diclofenac showed the most interesting results: [(2,6 dichlorophenyl) -amino] -phenyl-acetic acid.
Initially, diclofenac was used mainly in the treatment of rheumatological diseases, where both components are important: a pronounced anti-inflammatory and potent analgesic effect, but subsequently the area of application of the drug significantly expanded. Currently, diclofenac is used in surgery, traumatology and sports medicine (with damage to the musculoskeletal system, soft tissue damage (bruises, sprains), for postoperative pain relief), in neurology (for the treatment of back pain, tunnel syndromes, migraines), gynecology for dysmenorrhea, adnexitis, in oncology as a means of first-stage anesthesia for the WHO ladder. Intramuscular administration of diclofenac sodium is an effective method of dealing with renal and hepatic colic. A special dosage form of diclofenac in the form of drops has found application in ophthalmology. General practitioners also prescribe diclofenac for various pain syndromes.
Mechanism of Action of Diclofenac
The analgesic effect of diclofenac is due to several mechanisms. The main mechanism of action is the suppression of cyclooxygenase (COX) – an enzyme that regulates the conversion of arachidonic acid to prostaglandins – mediators of inflammation, pain, fever.
Diclofenac and COX Selectivity
In the early 90s of the twentieth century. two isoforms of the COX enzyme, COX-1 and COX-2, were found. Most of the positive effects of NSAIDs (suppression of inflammation, pain, fever) are associated with inhibition of COX-2, and the development of adverse reactions (mainly in the form of lesions of the gastrointestinal tract (GIT) – with suppression of COX-1 synthesis.
However, there are some exceptions to this rule. It has been shown that COX-1 may also play a role in the development of the inflammatory process. COX-1 together with COX-2 is produced by the synovial membrane in patients with rheumatoid arthritis (RA). Probably, this is associated with lower efficacy of selective COX-2 in some pain syndromes. In recent studies, an increased risk of cardiovascular complications was found when using highly selective COX-2 inhibitors.
Diclofenac inhibits both of the COX isoenzyme, but to a greater extent – COX-2. Inhibition of COX-1 in diclofenac is less pronounced than in ibuprofen and naproxen, and therefore diclofenac less frequently causes damage to the gastrointestinal tract. At the same time, inhibition of COX-1 (although to a lesser extent than in non-selective NSAIDs) may explain the greater efficacy of diclofenac compared with selective COX-2 inhibitors in a situation when COX-1 is involved in the pathogenesis of the disease (for example, in RA) . Inhibition of COX-2 in diclofenac is less pronounced than in etoricoxib and rofecoxib, which leads to a reduction in the risk of cardiovascular complications. This balanced effect of diclofenac provides a high therapeutic activity with good tolerability of treatment.
Other Mechanisms of Diclofenac Analgesic Action
In addition to inhibition of prostaglandins, other mechanisms of action of diclofenac have been identified. In an experimental study, it was shown that diclofenac sodium can significantly inhibit the migration of leukocytes to the inflammatory focus. To a certain extent, the drug can also affect the cytokine balance, reducing the concentration of interleukin-6 and increasing the content of interleukin-10. Such a change in the ratio of these products helps to slow the secretion of anti-inflammatory factors. The decrease in the production of free oxygen radicals, which occurs under the influence of diclofenac sodium, can also lead to a decrease in the activity of the inflammatory process and the limitation of its damaging effect on the tissue.
In addition to the pronounced anti-inflammatory activity of the drug has a powerful analgesic potential, not related to its effect on inflammation. It has a complex effect on various mechanisms of perception of pain, providing effective suppression of pain syndrome of various etiologies; It has both central and peripheral antinociceptive effects.
The central analgesic activity of diclofenac sodium is mediated by opioid receptors, as evidenced by the fact that this effect is blocked by naloxone. Apparently, this is due to the effect of diclofenac sodium on tryptophan metabolism. After the introduction of the drug in the brain, the concentration of tryptophan metabolites, which can reduce the intensity of pain, significantly increases.
The local antinociceptive effect of the drug is probably related not only to the suppression of prostaglandin synthesis, since in several experimental models of pain syndrome, local application of prostaglandin synthesis inhibitors such as indomethacin and celecoxib, unlike diclofenac sodium, did not allow for significant analgesic effect. The peripheral analgesic effect of diclofenac sodium is not associated with the opioid effect, since it is not eliminated by naloxone. At the same time, the use of compounds blocking the formation of nitric oxide (NO) and the activation of guanylate cyclase, suppressed the analgesic effect of diclofenac sodium. Inhibitors of various types of potassium channels also had a similar effect. In rat cerebellum cell culture, diclofenac sodium increased the activity of potassium channels, increasing the yield of potassium from the cell. These results suggest that the peripheral antinociceptive effect of this drug may be associated with the activation of several types of potassium channels that occur with the participation of NO and guanosyncyclo monophosphate (cyclo-GMP).
Thus, the analgesic effect of diclofenac may be due to its effect on various levels and links of the pathogenesis of the pain syndrome. In addition to the analgesic effect associated with reducing inflammation in the damage zone by inhibiting prostaglandins (COX-1 and COX-2), diclofenac can reduce pain, reducing inflammation through other mechanisms, affecting potassium channels at the peripheral level, and also reduce the perception of pain through central mechanisms (by increasing the synthesis of the precursor of serotonin – tryptophan) in the brain tissue.
Indications for use diclofenac
Despite the wide range of existing NSAIDs and the creation in recent years of a new class of symptomatic anti-inflammatory drugs (selective COX-2 inhibitors), diclofenac sodium remains the most popular drug among NSAIDs.
The use of diclofenac in rheumatology
From the very beginning of its appearance, diclofenac has found wide application in rheumatology. An important feature that allowed him to oust other drugs from the NSAID group that had been used before was his high analgesic and analgesic activity along with good tolerability.
The effect of diclofenac is manifested in reducing the duration of morning stiffness, reducing pain (at rest and when moving), reducing swelling, swelling of the joints, as well as improving the functional ability of the joints, which increases the volume of movement. Diclofenac is the drug of choice for most rheumatological diseases and is used to treat inflammatory and degenerative rheumatic diseases (arthritis, arthrosis, etc.).
The use of diclofenac in general medical practice, orthopedics, traumatology, sports medicine
The most common in general medical practice are disorders of the musculoskeletal system. Its pathology is diverse in etiology and pathogenesis. Pain can be caused by trauma, degenerative processes, inflammation, dysplasia, trophic changes (osteoporosis). The mechanisms of disease development can be inflammatory, mechanical, neurogenic, etc. The pronounced analgesic effect of diclofenac with moderate and severe pain, inflammatory processes occurring after operations and injuries, rapid relief of spontaneous pain and pain during movement, reduction of inflammatory edema at the wound site made this drug one of the most necessary for the treatment of disorders of the musculoskeletal system, which are found in general practice, orthopedics, traumatology, sports medicine, nevrol ogii.
In the treatment of orthopedic and traumatic injuries, the form of release of the drug also matters. The possibility of combining topical and systemic forms of diclofenac allows for maximum efficiency while minimizing possible side effects. Local forms are most widely used for diseases of extra-articular tissues (tendovaginitis, bursitis, rheumatic affection of soft tissues), injuries to tendons, ligaments, muscles and joints. Systemic forms, such as tablets, suppositories, injection solutions, for massive injuries (combined and combined injuries, postoperative conditions, head injuries, fractures of large bones, etc.).
The use of diclofenac in neurology
Diclofenac is widely used for the relief of pain syndromes in neurological practice. It is indicated for the treatment of acute back pain, with tunnel syndromes (carpal tunnel syndrome, cubital canal syndrome, etc.), with migraine.
The duration of use and the method of administration of the drug depend on the intensity of the pain syndrome. In moderate pain syndromes that do not limit the patient’s motor capabilities, applications to painful areas (spastic muscle) of gels and ointments containing diclofenac sodium are possible within 7-10 days. With intense pain, significantly limiting the movement of the patient within the premises, the injection method of administration of diclofenac sodium is used for 3-7 days, with a further transition to the oral form. There are reports of higher efficacy of phonophoresis with diclofenac compared with the use of the drug in the form of an ointment.
The use of diclofenac in gynecology
The ability to eliminate pain and reduce the severity of blood loss in primary dysmenorrhea allowed the use of diclofenac in gynecological practice. In primary dysmenorrhea, the daily dose is selected individually, usually it is 50-150 mg. The initial dose should be 50-100 mg; If necessary, for several menstrual cycles, it can be increased to 150 mg / day. Reception of diclofenac should be started when the first symptoms appear. Depending on the dynamics of the clinical symptoms, treatment can be continued for several days. Diclofenac can also be used in inflammatory diseases of the pelvis, including adnexitis.
Dosage and Administration: which Dosage form to Choose?
The undoubted advantage of diclofenac is the variety of dosage forms, including tablets (quick and retarding action), solution for parenteral administration, suppositories, as well as forms used for local therapy: ointments, creams, gels, spray, which creates convenience when selecting an individual dose and method use of the drug. The ability to combine different routes of administration in the same patient reduces the risk of adverse reactions.
Diclofenac tablet form
Tablets of diclofenac are available in various dosages. The dose and mode of use of the drug for each patient is set individually, taking into account the severity of the disease. The average recommended dose for adults is 100-150 mg / day. The maximum daily dose is 200 mg. In relatively mild cases of the disease, as well as for long-term therapy, a daily dose of 75-100 mg may suffice.
The daily dose should be divided into several doses. If necessary, relief of night pain or morning stiffness in addition to taking the drug during the day, you can prescribe diclofenac in the form of candles before bedtime; at the same time the daily dose should not exceed 150 mg. Upon reaching the clinical effect, the dose is reduced to the minimum maintenance.
Only 25 mg tablets are prescribed to children aged 6 to 15 years (inclusive). The daily dose is 0.5-2 mg / kg of body weight (in 2-3 doses, depending on the severity of the disease).
Adolescents aged 16 to 18 years, you can assign tablets of 50 mg, which should be washed down with plenty of fluids, preferably before meals. Tablets can not be divided or chewed.
Diclofenac in the form of tablets with prolonged action
A special form of the drug is diclofenac in the form of tablets with prolonged action. As a result of the slow release of the active substance when taking retardirovannyh forms of diclofenac sodium, the effect comes later, but lasts longer. These features of pharmacokinetics make it possible to achieve a reduction in the number of doses (1-2 times per day instead of 3-4 times) while maintaining a stable high concentration of the drug in the focus of inflammation. This makes it preferable to use diclofenac in retard form when long-term administration is necessary (for chronic pain syndromes, mainly in rheumatological practice).
The recommended starting dose for adults is 75 mg, that is, 1 retard tablet per day. The same dose is used in relatively mild cases of the disease, as well as for long-term therapy. In cases where the symptoms are most pronounced at night or in the morning, retard tablets should be taken at bedtime.
Tablets are swallowed whole, preferably with meals. If necessary, increase the dose additionally take 1-2 tablets of diclofenac 25 mg. The maximum daily dose is 200 mg.
Retard tablets should not be prescribed for children and adolescents under 18 years of age.
Diclofenac in the form of rectal suppositories
Diclofenac dosage form in the form of suppositories has several advantages. Candles do not cause those complications that are possible with parenteral administration of drugs (the development of muscle necrosis, infiltrates and suppurations at the injection site). Candles are advisable to appoint when it is impossible to take the drug orally (in debilitated patients, in the presence of strictures of the esophagus, etc.). When taken per os, diclofenac has a direct damaging effect on the cells of the gastric mucosa. With other methods of administration (suppositories, ointments) the risk of damage to the gastrointestinal mucosa is preserved, but significantly lower. That is why in the presence of signs of lesions of the stomach and duodenum, preference is given to the form of diclofenac in the form of candles.
Very often suppositories are used in combination therapy: during the day the patient receives injections or tablets, and before going to bed – candles, which creates the best therapeutic effect due to a more uniform and long-lasting maintenance of the drug concentration in the blood. In this case, the total daily dose should not exceed 150 mg.
For children aged 6 to 15 years (inclusive), only suppositories of 25 mg should be prescribed. The daily dose is 0.5-2 mg / kg body weight (depending on the severity of the symptoms, it should be divided into 2-3 doses). For the treatment of RA, the daily dose may be increased to a maximum of 3 mg / kg (in several injections). Adolescents aged 16 to 18 years old can also be given suppositories of 50 mg.
Suppositories are introduced into the rectum, if possible deeply, preferably after prior cleansing of the intestine. They should not be cut into pieces, as this may lead to further disruption of the distribution of diclofenac.
Diclofenac solution for injection
Diclofenac in the form of injections is preferably used when a fast anesthetic effect is needed, usually with more severe acute pain (renal or hepatic colic, acute pain associated with soft tissue injuries (contusion, stretching), acute back pain, postoperative pain. Usually prescribed 1 ampoule per day, however, in severe cases, you can apply 2 injections per day with an interval of several hours, alternating the injection site.The use of injections can be combined with other dosage forms of diclofenac. arenteralnogo of application should not exceed two days, if necessary, the treatment is continued using diclofenac in the form of tablets or rectal suppositories.
When administered intramuscularly, the drug is injected deep into the upper outer quadrant of the buttocks; during the day, use no more than 2 ampoules (150 mg). In renal and hepatic colic, diclofenac is usually combined with antispasmodics. With a pronounced muscle component in back pain, administration of diclofenac is combined with the use of muscle relaxants.
A combination of two or more NSAIDs should be avoided, since their effectiveness remains unchanged and the risk of side effects increases.
Diclofenac in the form of means for external (local) use
The undesirable effect of NSAIDs on the body is sharply limited, if they are used in the form of local applications. The dosage form for such therapy is a mixture of the active drug with a base that provides absorption under the skin. This method of treatment allows you to enter the drug directly into the lesion. At the same time, the impact on other organs and tissues is minimal.
Abroad there are dosage forms in the form of plates for gluing to the skin, containing 1.3% diclofenac epolamine. This form first appeared in Switzerland in 1993. At present, diclofenac in the form of plates is registered in 43 countries of the world. This form of the drug is intended primarily for those who can not take it orally because of contraindications. It is used 2 times a day for damage to soft tissues (bruise, stretching, compression), while maintaining the integrity of the skin. Plates are convenient for use, but their cost is higher compared to other dosage forms.
These drugs are convenient for use and easily dispensed. After application to the skin, the active compound accumulates in regional soft tissues, and no more than 6% of the active substance enters the bloodstream. At the same time, the content of the drug in the muscles in the area of application is approximately three times its level in the distant muscle tissue. This makes the use of diclofenac gel forms preferable for a wide range of musculoskeletal disorders. Gel forms of diclofenac are non-prescription drugs and are very popular.
Diclofenac as part of combined pain relief medications
There are also dosage forms (ointments, gels) in which diclofenac is one of the main components. The combination of several drugs with different mechanisms of action allows to increase the effectiveness of therapy.
Safety of Use
Diclofenac has an optimal combination of analgesic and anti-inflammatory effects and is well tolerated, therefore, in the absence of contraindications, it can be used for a long period. Studies have confirmed that treatment with diclofenac in fairly high doses (150 mg) with long-term use (up to 8 months or more) was well tolerated by patients. Of course, diclofenac, like any NSAIDs, can have side effects and contraindications. However, side effects, among which ulceration of the gastrointestinal tract mucous membrane is the first to be noted, develop more often in people with risk factors.
The risk factors for lesions of the gastrointestinal mucosa include:
- age over 65 years;
- a history of peptic ulcer disease;
- food intake that increases gastric secretion (spicy, fatty, salty foods);
- large doses or simultaneous administration of several NSAIDs;
- concomitant glucocorticoid therapy;
- the female gender, since women are more sensitive to this group of drugs;
- alcohol intake;
- availability of Helicobacter pylori.
In this regard, treatment should begin with the lowest recommended dose, especially in risk groups. In individuals belonging to such groups, the daily dose of diclofenac should not exceed 100 mg, preference should be given to short-acting diclofenac dosage forms and prescribe it either 50 mg 2 times a day, or 25 mg 4 times a day.
Diclofenac should be taken after meals. With long-term use it is necessary to refrain from drinking alcohol, since diclofenac, like alcohol, is metabolized in the liver. If complaints arise from the gastrointestinal tract, esophagogastroduodenoscopy should be performed, and for systematic administration of diclofenac, this procedure should be prescribed every 4-6 months, since NSAID gastropathy is often asymptomatic – “dumb.”
If necessary, long-term use of diclofenac, which is especially important in rheumatology, it is advisable to appoint it along with misoprostol, which protects the gastric mucosa from damage.
In patients with hypertension, it is necessary to control the level of blood pressure, in patients with bronchial asthma while receiving diclofenac exacerbation may be observed. In patients with chronic liver and kidney diseases, small doses of the drug are used, controlling the level of liver enzymes.
Before prescribing diclofenac, the doctor needs to clarify whether the patient is taking any other drugs due to concomitant diseases in order to avoid possible complications when using diclofenac in combination with other drugs. It is known that diclofenac increases the plasma concentration of digoxin, lithium, cyclosporin A, is nephrotoxic, increases the toxicity of methotrexate. Against the background of potassium-saving diuretics, diclofenac increases the risk of hyperkalemia, and against the background of anticoagulants, the risk of bleeding. Diclofenac reduces the effect of diuretics, hypotensive and hypnotic drugs. The simultaneous intake of antidiabetic agents can lead to both hypokalemia and hyperkalemia.
After the introduction of diclofenac into clinical practice more than 30 years have passed. During this time, many new NSAIDs have emerged, which greatly expanded the possibilities of providing effective care to patients, since the individual response to treatment is very variable. However, diclofenac occupies a special place in this medical arsenal. The combination of high efficiency, good tolerability and a variety of dosage forms of the drug allow you to choose the optimal therapy for a wide range of pain syndromes.