Ibuprofen is an anti-inflammatory drug with a wide range of indications 

Ibuprofen is rightfully considered the most effective and common remedy for treating the symptoms of colds and acute respiratory viral infections. Some patients successfully relieve fever with its help and consider it an antipyretic, while others relieve serious pain of a chronic nature, for example, in the spine. The fact is that Ibuprofen has three properties at the same time: anti-inflammatory, analgesic and antipyretic.

Ibuprofen

Indications for use

Ibuprofen belongs to the group of non-steroidal anti-inflammatory drugs (NSAIDs) - derivatives of phenylpropionic acid. In the instructions for tablets and capsules for adults, we see primarily prescriptions related to the symptomatic treatment of diseases of the joints or spine (rheumatoid arthritis, osteoarthritis, bursitis, sciatica), the fight against pain from injuries, myalgia and neuritis. In children's forms, we find the following indications: sore throat, pain with otitis media, teething, reduction of fever during ARVI or influenza, relief of symptoms of fever during childhood infections and post-vaccination reactions.

Of course, the indications are not limited to those mentioned above. We list here the most common types of pathologies where Ibuprofen does an excellent job eliminating inflammation and pain:

• Pathologies of the musculoskeletal system, pain relief: ankylosing spondylitis, radiculitis, spinal osteochondrosis, exacerbation of gout, polyarthrosis, psoriatic arthritis, tendinitis, inflammation of soft tissues in injuries, back pain, joint pain, trauma, sprains, dislocations, myalgia of various types .
• Diseases of the peripheral nervous system: neuralgia and neuritis.
• Gynecology: primary dysmenorrhea, secondary dysmenorrhea, pain during painful menstruation, with adnexitis.
• Relief of various types of pain: toothache, headache, migraine, sore throat, ear pain with otitis media, muscle pain.
• Use as an antipyretic for fever, flu, ARVI and colds. Increased temperature in infectious and inflammatory diseases.
• Relief after vaccination, including against coronavirus.

ASA - acetylsalicylic acid

Gastrointestinal tract - gastrointestinal tract

IHD - coronary heart disease

LS - medicines

NSAIDs - non-steroidal anti-inflammatory drugs

COX - cyclooxygenase

PG - prostaglandin

TxA2 - thromboxane

It is difficult to imagine modern clinical practice without the use of various nonsteroidal anti-inflammatory drugs (NSAIDs). In Ancient Greece, more than 3.5 thousand years ago, Hippocrates used willow bark extract as an antipyretic and analgesic. Much later, in the 17th century, a substance was isolated from it, which was called salicylic acid (from the Latin salix - willow). At the end of the 19th century, the production of salicylic acid and acetylsalicylic acid (ASA) began in Germany. Currently, more than 20 different representatives of this group are known in clinical practice, differing in chemical structure, features of the mechanism of action, indications for use and tolerability.

Mechanism of action of NSAIDs.

NSAIDs inhibit the synthesis of prostaglandins (PGs), which are important physiological and pathological mediators.
PGs are involved in processes such as pain, inflammation, tumorigenesis, osteoporosis, regulation of body temperature (hyperthermia) and kidney function, etc. From arachidonic acid, with the participation of the enzyme cyclooxygenase (COX), PGH2 is formed, which is the precursor of PGs such as thromboxane (TxA2), prostacyclin, or PGI2, D2, E2 and F2 (see figure).

Figure 1. Mechanism of action of NSAIDs [2, 3]. Two main isoforms of COX are known: COX-1 and COX-2. The issue of isolating the third isoform, COX-3, as a variant of COX-1 under experimental conditions, remains unresolved [1]. The first isoform (COX-1) is synthesized constantly and works according to a universal mechanism, i.e. regardless of in which organ or tissue the synthesis occurs. The synthesis of the second isoform (COX-2) is stimulated by various inflammatory factors (lipopolysaccharides, interleukins, tumor necrosis factor α) in various cells of the human body, such as endothelium, osteoclasts, synoviocytes, monocytes and macrophages [2].

The main pharmacodynamic properties of NSAIDs - anti-inflammatory, antipyretic and analgesic effects - are achieved through inhibition of COX-1 and COX-2. It is the inhibition of COX-1 and COX-2 that causes the main adverse reactions associated with the use of NSAIDs. Prostaglandins PGE2 and PGI2, which are synthesized with the participation of COX-1 in the gastrointestinal tract (GIT), are cytoprotectors of the mucous membrane by reducing the secretion of hydrochloric acid by parietal cells of the stomach, improving blood flow and stimulating mucus production. In addition, with the participation of COX-1, TxA2 is synthesized in platelets, which have vasoconstrictive and proaggregant properties. NSAIDs, by blocking the synthesis of COX-1, can lead to damage to the mucous membrane of the stomach and intestines and disruption of platelet aggregation. Thus, NSAIDs increase the risk of developing severe gastrointestinal diseases such as inflammation, bleeding and penetration of the stomach or intestines. The risk of developing such complications is higher in older people and does not depend on the duration of drug use [4].

The classification of NSAIDs is presented in table. 1.

Among representatives of NSAIDs, there are differences in the chemical structure, features of action and the degree of inhibition of COX-1 and COX-2.
The selectivity of NSAIDs for COX isoforms is usually assessed by the ratio of the degree of inhibition of COX-1 to COX-2 (selectivity coefficient). Selective COX-2 inhibitors are those NSAIDs that have this coefficient of more than 5, highly selective inhibitors - if this coefficient is more than 50 (see Table 1)
. NSAIDs with high selectivity for COX-2 are called coxibs (from the English - cyclo-oxygenase, abbreviated version of COX).

Clinical pharmacology of ibuprofen.

One of the NSAIDs widely used in clinical practice is ibuprofen, which was synthesized by S. Adams and D. Nicholson in Great Britain in 1962. In the Russian Federation it is registered under the trade name Nurofen (original drug). It has pronounced anti-inflammatory, analgesic and antipyretic effects, which, combined with good tolerability, predictability of side effects and low risk of complications, has led to its widespread use in clinical practice.

According to the chemical structure, ibuprofen is a derivative of propionic acid; according to the mechanism of action, it is a non-selective inhibitor of COX-1 and COX-2, lipoxygenase involved in the synthesis of pro-inflammatory leukotrienes [6].

Ibuprofen is a racemic mixture of two optical left- and right-handed isomers, the S (+) and R (–) enantiomers. The clinical effectiveness of ibuprofen is mainly due to the action of the S (+) form, but the presence of the R (–) isomer explains some of the anti-inflammatory properties of ibuprofen [7].

Variety of dosage forms of ibuprofen.

Modern possibilities for the use of ibuprofen are associated with advances in the field of pathophysiology of diseases and the development of new dosage forms of this drug. Currently, ibuprofen is presented in a variety of dosage forms on the drug market.

Not only oral administration of ibuprofen is possible, but also its topical use in the form of a gel, rectal (in the form of suppositories) and parenteral (in the form of solutions for intravenous administration) (Table 2).

Modern technologies have made it possible to develop new dosage forms - capsules containing ibuprofen solution (Nurofen Ultracap) and ibuprofen derivatives - sodium dihydrate and lysinate. The advantages of the lysine salt of ibuprofen are the speed of dissolution of this compound, increased bioavailability and the speed of onset of maximum concentration in the blood plasma (Nurofen Express) [8-10].

In clinical practice, new dosage forms with modified release are also presented, i.e. with a mechanism and nature of release of the drug substance changed in relation to the usual form. Forms of ibuprofen are known as immediate release (IR) and sustained release (SR).

Pharmacokinetics of ibuprofen.

The main pharmacokinetic parameters of ibuprofen, in particular the concentration of enantiomers in plasma or the area under the pharmacokinetic curve, depend on the dosage form and dose of ibuprofen
(see Table 2)
.

When taken orally, ibuprofen is rapidly absorbed from the upper small intestine. The bioavailability of ibuprofen as a weak acid when taken orally averages 80%. Eating generally reduces the rate of absorption of ibuprofen, but certain foods and drinks (eg, Coca-Cola) have been shown to increase the rate of absorption. The time to reach the maximum concentration of ibuprofen isomers in plasma or serum averages 1-2 hours and depends on the dosage form of ibuprofen (see Table 2)

. Based on the rate of absorption, dosage forms of ibuprofen can be distributed in ascending order: ibuprofen tablets → ibuprofen suspension → ibuprofen solution. Rapid absorption of ibuprofen from liquid forms (suspension, solution) provides a faster analgesic and antipyretic effect.

After oral administration of 40-60% of the R (-) form, ibuprofen is metabolized in the intestines and liver into the S (+) form. Further biotransformation of ibuprofen takes place in 2 phases. I - phase of oxidative reactions is associated with a system of microsomal enzymes of cytochrome P-450 (2C9, 2C8 and 2C19), which ensure the formation of inactive carboxyl and phenolic compounds. Differences in genotypes of the P-450 2C9 system lead to differences in the metabolism of ibuprofen, an increase in the area under the pharmacokinetic curve and changes in hepatic clearance [7]. Phase II of ibuprofen metabolism includes the formation of inactive glucuronic and taurine compounds, which are subsequently excreted primarily through the kidneys. Impaired liver function due to liver cirrhosis leads to a slower inversion of the R (–) form of ibuprofen to the S form (+), as well as an increase in half-life to 3.4 hours. Impaired renal function also reduces the rate of elimination of ibuprofen metabolites.

Ibuprofen has a high degree of binding to plasma albumin (90-99%). In adults, ibuprofen, when taken orally and intravenously, has a short half-life of about 2 hours. Ibuprofen penetrates well into the synovial fluid of inflamed joints, which provides analgesic and anti-inflammatory effects. The antipyretic effect of ibuprofen is due to inhibition of PGE2 synthesis in the central nervous system. Ibuprofen is a lipophilic substance, but only its free (not bound to albumin) fraction penetrates the blood-brain barrier.

With topical application of ibuprofen, there is a slight decrease in the systemic bioavailability of the drug to 14-30% of that when taken orally [12], while after topical application, higher concentrations are observed in subcutaneous and soft tissues, including muscle [13]. A number of studies in patients of different categories have shown that the effectiveness of topical application of ibuprofen (5% gel) and ibuprofen (1200 mg/day) taken orally both for acute traumatic injuries of soft tissues and for chronic pain syndrome is the same, and the tolerability of topical forms is better [12, 14, 15].

The pharmacokinetic curve indicators for rectal use are comparable to the pharmacokinetic data for oral administration of the drug. Absorption during rectal administration of ibuprofen is characterized by a high degree of bioavailability and rapid onset of maximum plasma concentration. In addition, the peculiarities of the blood supply to the rectal area lead to the fact that only part of the drug is metabolized in the liver, which leads to an increase in the half-life.

Pharmacokinetics indicators do not differ significantly between men and women, and in different age groups. Pharmacokinetic parameters in children over 2 years of age and adolescents do not differ from those in adults. The only exceptions are children under 2 years of age, whose metabolism of ibuprofen is significantly lower than that of adults, which requires the correct dosage regimen of the drug depending on the child’s body weight. With increasing age, there is a slight increase in half-life, which reflects age-related changes in metabolism and clearance, however, in older people, the elimination of ibuprofen does not undergo significant changes.

Safety of ibuprofen.

The development of selective COX-2 inhibitors was aimed at overcoming the limitations of the use of NSAIDs due to the risk of developing adverse gastrointestinal reactions. However, during the introduction of coxibs into clinical practice, another safety problem arose with long-term use - an increased risk of developing cardiovascular thrombotic complications, myocardial infarction and stroke [16]. The increase in the risk of thrombotic complications in the presence of selective COX-2 inhibitors is based on an imbalance between thromboxane and prostacyclin, which regulate endothelial function and platelet aggregation. Selective coxibs, due to the selective blockade of COX-2, upset the balance between the levels of thromboxane and prostacyclin, which is the basis for the development of thrombotic complications [2]. However, the results of subsequent clinical observations showed that the use of non-selective NSAIDs also increases the risk of developing cardiovascular complications [17, 18]. Current international recommendations, based on the results of long-term clinical studies, limit the use of both coxibs and non-selective NSAIDs in patients with coronary heart disease (CHD), stroke, or at high risk of developing CHD [3, 5].

Another undesirable reaction due to long-term use of NSAIDs is impaired renal function, since both COX isoforms play a significant role in the regulation of kidney function. PGs regulate vascular tone and maintain normal blood flow, which is necessary to maintain normal kidney function. It is now known that inhibition of COX-1 leads to a decrease in glomerular filtration rate, and inhibition of COX-2 slows down sodium reabsorption in healthy volunteers and elderly people. According to a meta-analysis, selective COX-2 inhibitors increase the risk of developing renal failure and arrhythmia [2, 19].

Ibuprofen has an extensive evidence base for safety, due to which it is available over-the-counter (in dosages less than 1200 mg) in many countries around the world.

The safety of ibuprofen has been demonstrated in many large clinical studies. Of greatest interest is a multicenter randomized study conducted in 1999 in France with the participation of 8677 patients (PAIN study), the purpose of which was to compare the effectiveness and tolerability of over-the-counter analgesics: ASA, paracetamol and ibuprofen. It has been shown that ibuprofen (at a dose of less than 1200 mg) is tolerated as well as paracetamol, which was previously considered the standard of safety, and compared to ASA, it causes a significantly lower incidence of adverse reactions [20].

When comparing the frequency of adverse gastrointestinal reactions, it was noted that ibuprofen is characterized by high safety due to the presence of a low-active enantiomer R, which competes with the active form S for the active center of COX-1, which is responsible for the synthesis of PGs, which provide protection to the gastrointestinal mucosa. In addition, the short half-life of ibuprofen may also provide safety advantages for this drug.

Ibuprofen does not form toxic metabolites, its toxicity after accidental or intentional overdose is lower and it has a relatively higher therapeutic index (about 4 times higher than paracetamol). The development of Reye's syndrome (acute hepatic encephalopathy in children while taking ASA) is also uncharacteristic of ibuprofen [14, 21].

Clinical effectiveness of ibuprofen.

Ibuprofen is an effective analgesic for acute pain syndrome of various origins. At a dose of 400 mg, it has repeatedly proven its advantage over placebo in postoperative, toothache, sore throat, dysmenorrhea, tension headaches and migraines, soft tissue trauma, neuralgia and myalgia, as well as a number of other conditions accompanied by severe pain.

For headaches, ibuprofen as a first-line drug is included in the list of analgesics recommended by WHO, as well as the European Federation of Neurological Societies (EFNS) for the treatment of mild to moderate migraine attacks (class A) [22, 23]. The effectiveness of ibuprofen in the treatment of cephalgia has been proven in many placebo-controlled clinical trials, as well as several meta-analyses, including in children and adolescents [24-28].

At a dose of 200-400 mg, ibuprofen is the “gold standard” for the treatment of moderate pain in people with postoperative dental pain [29]. A meta-analysis demonstrated the high effectiveness of ibuprofen compared with placebo across 72 studies. Ibuprofen significantly reduced pain in all patients - by at least 50% for an average of 4.7 hours. Repeated analgesia was required in only 48% of patients taking ibuprofen at a dose of 200 mg, and in 42% - at a dose of 400 mg [30] . Another meta-analysis based on 33 studies found an advantage of ibuprofen (400 mg) in relieving pain after tooth extraction compared to paracetamol (1000 mg), as well as a combination of paracetamol (600-650 mg) and codeine (60 mg) [31].

The issue of choosing an effective and safe NSAID in pediatric practice is especially acute, due to the fact that fever and pain are leading in a number of diseases, including respiratory infections, which are most common in young children. Large multicenter randomized studies have shown that among all analgesic-antipyretic drugs, ibuprofen and paracetamol are the safest drugs. Thus, a meta-analysis combining 24 randomized and 12 observational studies from 1950 to 2008 did not show statistically significant differences in the incidence of adverse reactions of the gastrointestinal tract and kidneys, as well as in the effect on the course of bronchial asthma when taking ibuprofen, paracetamol and placebo [32]. The largest systematic review of data on the effectiveness and safety of ibuprofen compared with paracetamol in the treatment of fever and pain in children and adults was conducted in 2010. It included 85, including large randomized trials in the period 2008-2009. The authors concluded conclusion that ibuprofen is more effective than paracetamol in the treatment of fever and pain in all age groups with equal safety [33].

According to WHO recommendations, ibuprofen at a dose of 5-10 mg/kg, along with paracetamol, is the drug of choice as an antipyretic and analgesic (for mild to moderate pain) in children from 3 months. No other NSAIDs can be recommended for use in pediatric practice due to the lack of the necessary evidence base for their effectiveness and safety [34, 35].

Currently, ibuprofen is also the only drug listed by the WHO for the treatment of patent ductus arteriosus in newborns [36]. Potential new indications for the use of ibuprofen are being studied.

Cystic fibrosis.

Several clinical studies have demonstrated the effect of ibuprofen on slowing the progression of the pulmonary process (slowing the decline in forced expiratory volume in 1 second) in patients with cystic fibrosis with long-term use in various age groups [37-39]. The results obtained are likely due to a decrease in the influx of polymorphonuclear cells into the lungs and, consequently, the inflammatory process [40]. Despite the fact that large doses of ibuprofen were used, the risk of developing adverse gastrointestinal reactions remained low [37, 38].

Parkinson's disease.

It is believed that one of the key links in the pathogenesis of Parkinson's disease is neuroinflammation. Based on this assumption, several studies have been conducted to determine the role of NSAIDs in the development of the disease. A 2010 meta-analysis of 7 large epidemiological studies demonstrated a reduction in the risk of developing Parkinson's disease by 15% in the overall group of patients taking NSAIDs, and by 29 and 21%, respectively, with regular and long-term use of NSAIDs. The strongest neuroprotective effect was observed with ibuprofen, which was confirmed by a number of other studies [41–43].

Mammary cancer.

Currently, there is great interest in the positive effects of NSAIDs, primarily ASA and ibuprofen, on the risk of developing various types of cancer [44–46]. Based on the results of a meta-analysis (38 studies, n=2,788,715), conclusions were drawn about the possible oncoprotective effect of NSAIDs, primarily ibuprofen (relative risk 0.79 with a 95% confidence interval from 0.64 to 0.97) in relation to the development of breast cancer [ 47]. Another meta-analysis (26 studies, n=528,705) showed similar results [48]. Perhaps, after large placebo-controlled studies, the use of ibuprofen will be recommended as a preventive measure for cancer.

Thus, when prescribing therapy, it is important to choose a time-tested remedy. More than 40 years of experience with the use of ibuprofen in widespread clinical practice in almost 80 countries as an over-the-counter drug is a clear example of its effectiveness and safety [49].

What forms does Ibuprofen come in?

In pharmacies you can find four dosage forms of the drug:

• If there are no contraindications related to the gastrointestinal tract, then people usually choose tablets or capsules.
• In cases where there is a stomach disease in the acute stage or the patient for some reason cannot swallow a tablet, suppositories are prescribed.
• Syrups are prescribed to infants. Most pediatricians prefer to reduce fever using Ibuprofen rather than Paracetamol, since the former acts faster and longer, and also has a lower safety profile due to the absence of toxic metabolites.
• For pain in the joints, muscles, back, and injuries, the ointment is ideal.

Ibuprofen CAPS - analgesic and antipyretic agent

Undesirable effects can be minimized by using a low effective dose for the short time needed to control symptoms.

The drug is prescribed with caution to elderly patients, as they are more likely to experience adverse side reactions to NSAIDs, mainly gastrointestinal bleeding and perforation, which can lead to a sharp deterioration of the condition.

Respiratory system:

Caution should be exercised when using the drug in patients with bronchial asthma and other obstructive pulmonary diseases due to the risk of bronchospasm.

Other NSAIDs:

The simultaneous use of Ibuprofen CAPS and other NSAIDs, including selective cyclooxygenase-2 inhibitors, should be avoided.

Systemic lupus erythematosus, as well as mixed connective tissue diseases, increase the risk of aseptic meningitis.

Kidneys:

The drug is used with caution in case of renal failure, because Renal function may deteriorate.

Liver:

The drug should be used with caution in cases of liver dysfunction.

Cardiovascular and cerebrovascular effects:

The drug is prescribed with caution to patients with heart failure, arterial hypertension, and bleeding disorders.

Clinical trials and epidemiological data suggest that ibuprofen, especially at high doses (2400 mg daily) and long-term treatment, may be associated with a small increased risk of arterial thrombotic complications (eg, myocardial infarction or stroke). In general, epidemiological studies do not suggest that low doses of ibuprofen (eg, ≤1200 mg daily) are associated with an increased risk of myocardial infarction.

Female fertility disorders:

There is limited evidence that drugs that inhibit cyclooxygenase/prostaglandin synthesis may impair female fertility by affecting ovulation. This phenomenon is reversible when the drug is discontinued.

Gastrointestinal tract:

Patients with diseases of the gastrointestinal tract (ulcerative colitis, Crohn's disease) should be prescribed NSAIDs with caution due to a possible exacerbation of these diseases.

Patients with a history of gastrointestinal toxicity, especially the elderly, should report any unusual abdominal symptom (especially gastrointestinal bleeding), especially if the symptom is observed during the initial phase of taking the drug.

If patients develop gastrointestinal bleeding while taking the drug, the drug should be stopped immediately.

Caution should be exercised in patients receiving concomitant medications that may increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants such as warfarin, selective serotonin reuptake inhibitors, or antiplatelet agents such as aspirin.

Dermatological:

Serious skin reactions, some fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported very rarely in association with the use of NSAIDs. Ibuprofen CAPS should be discontinued at the first appearance of skin rash, mucosal lesions, or any other signs of hypersensitivity.

Instructions for taking Ibuprofen for adults and children.

• A single dosage for an adult is 200 mg; in case of severe pain, you can take 400 mg, the dosage frequency is 3-4 times a day, but not more than 1200 mg per day.
• A single dose for a child over 6 years old is 200 mg, can be taken 3-4 times a day. The maximum dosage for children per day differs by age as follows: for children 12-17 years old - 1000 mg; for children aged 6 to 12 years - 800 mg.

Ibuprofen Welfarm for adults

How many days can you take Ibuprofen?

The drug is taken for 2-3 days; if the patient’s condition does not improve or becomes worse, it is necessary to stop taking it and consult a doctor.

The effect of ibuprofen on the fetus

Scientists from Harvard University (USA) conducted studies that examined the connection between the use of ibuprofen during pregnancy and nervous disorders in children at an early age. Thus, in a study involving 1,225 pairs of mothers and children, scientists assessed the use of ibuprofen, as well as paracetamol, in early and middle pregnancy and in newborns. This experiment showed that prenatal and postnatal exposure to ibuprofen and paracetamol leads to behavioral disturbances in children and hyperactivity as they grow older.

Ibuprofen for children

Ibuprofen in the form of syrup for children is used from the age of 3 months and can begin to act within 15 minutes. The tablets take effect within 30 minutes.

How to use baby syrups?

Children's syrups are usually made using fruit fillings and therefore children take them with pleasure. For the little ones there is a measuring syringe complete with syrup, where 1 ml contains a certain dose of Ibuprofen.

It is necessary to follow the manufacturer's instructions, the maximum daily dosage for a child is 30 mg per 1 kg of body weight, the interval between doses is from 6 to 8 hours. As we noted earlier, the duration of treatment should not exceed 3 days. Syrups are popular and therefore they are often designed for use up to 12 years, although tablets can also be used from 6 years.

The dose of syrup for a child can be determined from the table.

Ibuflex 400 tablets p/o 400 mg No. 10x2

Name

Ibuflex 400.

Release forms

Pills.

INN

Ibuprofen.

FTG

Npvp.

Description

Film-coated tablets, white or white with a grayish tint, oval, biconvex.

Compound

For one tablet: active substance: ibuprofen – 400 mg; excipients: microcrystalline cellulose, anhydrous colloidal silicon dioxide, magnesium stearate, corn starch, coating (composition of the mixture for coating Opadry II white (85F18422): polyvinyl alcohol, macrogol 3350, talc, titanium dioxide).

Pharmacotherapeutic group

Non-steroidal anti-inflammatory drugs. Propionic acid derivatives. Ibuprofen.

Indications for use

Headache, migraine, toothache, neuralgia, muscle and joint pain, menstrual pain. Ibuflex 400, as an analgesic and anti-inflammatory agent, is prescribed for the treatment of rheumatoid arthritis (including juvenile rheumatoid arthritis or Still's disease), ankylosing spondylitis, osteoarthritis and other non-rheumatoid (seronegative) arthropathies. Ibuflex 400 is prescribed for the treatment of periarticular diseases such as glenohumeral periarthritis, bursitis, tendinitis and tenosynovitis.

Directions for use and dosage

Inside. In order to minimize the risk of adverse reactions, ibuprofen should be taken in the minimum effective dose and for the shortest period necessary to achieve a clinical effect. If symptoms persist or worsen while using the drug, you should consult a doctor. Ibuflex 400 should be taken during or after meals, without chewing, with a glass of water. The dosage regimen is set individually depending on the indications. For adults and children over 12 years of age, the drug is usually prescribed at an initial dose of 400 mg 1-2 times a day. To achieve a rapid therapeutic effect, the dose can be increased to 400 mg 3 times a day. Once the therapeutic effect is achieved, the daily dose is reduced to 600-800 mg. The interval between taking tablets should be at least 4 hours. Do not take more than 3 tablets in 24 hours. The medicine should not be used for more than 7 days or in higher doses without consulting a doctor. Elderly patients: Elderly people are at increased risk of serious adverse reactions. If NSAID use is necessary, the lowest effective dose should be used for the shortest possible duration. During NSAID therapy, the patient should be regularly monitored for gastrointestinal bleeding. Children: Contraindicated in children under 12 years of age. Patients with renal failure: In patients with mild to moderate renal impairment (creatinine clearance 30-80 ml/min), no dose reduction is required. In severe renal failure (creatinine clearance less than 30 ml/min), ibuprofen is contraindicated. Patients with hepatic impairment: In patients with mild to moderate hepatic impairment, no dose reduction is required. In severe liver failure, ibuprofen is contraindicated.

Side effect

From the gastrointestinal tract: the most commonly observed adverse reactions are gastrointestinal disorders. Peptic ulcers, perforations, or gastrointestinal bleeding may occur, sometimes fatal, especially in the elderly. The following adverse reactions have been reported after the use of ibuprofen: nausea, vomiting, diarrhea, flatulence, constipation, dyspepsia, abdominal pain, melena, hematemesis, ulcerative stomatitis, gastrointestinal bleeding and exacerbation of colitis and Crohn's disease. Less common cases of gastritis, duodenal ulcers, gastric ulcers and perforation of the gastrointestinal tract were observed. From the immune system: hypersensitivity reactions have been observed after the use of NSAIDs, which include: nonspecific allergic reaction and anaphylaxis, respiratory tract reactivity, including asthma, exacerbated asthma, bronchospasm or shortness of breath, or various skin manifestations, including various types of rashes, itching, urticaria, purpura , angioedema and very rarely erythema multiforme; bullous dermatoses (including Stevens-Johnson syndrome and toxic epidermal necrolysis). From the cardiovascular system: edema, hypertension and heart failure have been reported in association with the use of NSAIDs. Clinical studies suggest that use of ibuprofen, especially at high doses (2400 mg/day), may lead to a small increase in the risk of arterial thrombotic conditions such as myocardial infarction or stroke. Infectious and parasitic diseases: rhinitis and aseptic meningitis (especially in patients with existing autoimmune disorders such as systemic lupus erythematosus and mixed connective tissue diseases) with symptoms of a stiff neck, headache, nausea, vomiting, fever or confusion. Cases of exacerbation of inflammatory processes of infectious origin associated with the use of NSAIDs have been described. If signs of infection appear or worsen while taking ibuprofen, you should contact your doctor immediately. From the skin and subcutaneous tissue. In exceptional cases, chickenpox can cause severe skin infections and soft tissue complications. Possible side effects associated with the use of ibuprofen are listed according to the classification of undesirable side effects in accordance with the damage to organs and organ systems and the frequency of their development: very common (≥1/10), frequent (≥1/100 to

Contraindications

• Hypersensitivity to any of the ingredients included in the drug. • History of hypersensitivity to acetylsalicylic acid or other NSAIDs (eg asthma, rhinitis, angioedema, urticaria). • Erosive and ulcerative diseases of the gastrointestinal tract (including peptic ulcer of the stomach and duodenum in the acute stage, Crohn's disease, ulcerative colitis). • History of bleeding or perforation of a gastrointestinal ulcer associated with previous NSAID therapy. • Hemophilia and other bleeding disorders (including hypocoagulation), hemorrhagic diathesis. • Patients with impaired renal function with a decrease in glomerular filtration rate less than 30 ml/min. • Severe liver failure. • Severe heart failure (NYHA class IV). • III trimester of pregnancy. • Children under 12 years of age.

Overdose

Symptoms Nausea, vomiting, epigastric pain, diarrhea, tinnitus, headache, gastrointestinal bleeding. In severe poisoning, toxic damage to the central nervous system is observed, which manifests itself as drowsiness, sometimes an excited state and disorientation or coma. Sometimes patients develop seizures. In more severe poisoning, metabolic acidosis, increased prothrombin time, acute renal failure or liver damage may occur. In patients with bronchial asthma, an exacerbation of its symptoms is possible. Treatment Treatment should be symptomatic and supportive and include airway management, monitoring of cardiac function and vital signs until the patient's condition returns to normal. Oral activated charcoal or gastric lavage is recommended within 1 hour of taking a potentially toxic dose of ibuprofen. If bronchial asthma worsens, bronchodilators should be used. Other treatment may be prescribed based on the patient's clinical symptoms. Precautions Undesirable effects can be minimized by selecting the minimum effective dose for the short time necessary for the disappearance of symptoms. Elderly People Elderly people have an increased incidence of adverse reactions to NSAIDs, especially gastrointestinal bleeding and perforation, which can be fatal. Gastrointestinal bleeding, ulceration and perforation Gastrointestinal bleeding, ulceration or perforation, which can be fatal, has been reported with any NSAID, at any stage of treatment, with or without previous symptoms. The risk of bleeding, ulceration, or gastrointestinal perforation increases with increasing doses of NSAIDs in patients with a history of peptic ulcers, especially those complicated by bleeding or perforation, and in the elderly. These patients are advised to take the drug at the minimum effective dose necessary to relieve symptoms. Combination therapy with protective agents (eg, proton pump inhibitors, misoprostol) should be considered for these patients, as well as for patients who require acetylsalicylic acid or other drugs that may increase the risk of gastrointestinal bleeding. Patients with a history of gastrointestinal disease, especially the elderly, should report any unusual abdominal symptoms (primarily gastrointestinal bleeding), especially during the initial stages of treatment. Particular attention should be paid to patients simultaneously taking medications that can increase the risk of ulceration or bleeding: oral corticosteroids, anticoagulants, warfarin, selective serotonin reuptake inhibitors, antiplatelet agents such as acetylsalicylic acid. If there is bleeding or ulceration in the gastrointestinal tract, patients taking ibuprofen should immediately stop taking the drug. NSAIDs are prescribed with caution to patients with ulcerative colitis, Crohn's disease, due to the risk of exacerbation of these conditions. Respiratory impairment Ibuflex 400 should be used with caution in patients suffering from bronchial asthma or with a history of bronchial asthma, since NSAIDs can cause bronchospasm in such patients. Cardiovascular and cerebrovascular effects Appropriate monitoring and advice are required in patients with hypertension and/or moderate heart failure, as fluid retention and edema are possible with the use of NSAIDs. Clinical trial results suggest a possible association between ibuprofen, particularly at high doses (≥2400 mg daily), with a small increased risk of arterial thrombotic events (eg, myocardial infarction and stroke). Epidemiological studies do not suggest an association between low-dose ibuprofen (≤1200 mg per day) and an increased risk of arterial thrombotic events. In patients with uncontrolled hypertension, NYHA class II-III congestive heart failure, established coronary artery disease, peripheral arterial disease and/or cerebrovascular disease, ibuprofen should be prescribed only after a careful benefit-risk assessment, and high doses of ibuprofen should be avoided. (≥2400 mg/day). Renal impairment Like other NSAIDs, long-term use of ibuprofen has been associated with renal capillary necrosis and other renal pathological changes. There is an increased risk of developing renal complications in patients for whom prostaglandin synthesis plays a compensatory role in maintaining renal blood flow (state of dehydration, impaired renal and liver function, heart failure, severe atherosclerosis, taking diuretics, ACE inhibitors, old age). The following precautions are recommended for patients at risk: - monitoring of renal function when prescribed to elderly patients, patients with arterial hypertension and diabetes mellitus during the first week of administration in case of appointment for more than one week; - ensuring monitoring of serum creatinine after 48-72 hours from the start of treatment in patients with chronic heart failure class III according to the NYHA classification, and chronic renal failure with a glomerular filtration rate of less than 60 ml/min; SLE and mixed connective tissue diseases Patients with systemic lupus erythematosus (SLE) and mixed collagen disease may be at increased risk of aseptic meningitis. Skin reactions Serious skin reactions have been reported with the use of ibuprofen. You should immediately stop taking Ibuflex 400 and consult a doctor if you experience skin rashes, mucous membrane lesions, blisters or other signs of allergy, as these symptoms may be the first signs of a serious skin reaction. Hematological effects Ibuprofen, like other NSAIDs, may interfere with platelet aggregation and prolong bleeding time in healthy individuals. Aseptic meningitis In patients treated with ibuprofen, aseptic meningitis has been observed in rare cases. Patients with systemic lupus erythematosus and mixed collagenosis are most susceptible to it; however, cases of the disease have also been reported in patients without chronic diseases. Impaired female fertility Ibuprofen, by inhibiting the synthesis of cyclooxygenase and prostaglandins, can affect ovulation and impair female reproductive function. Reversible after discontinuation of treatment.

Use during pregnancy or breastfeeding

Pregnancy Inhibition of prostaglandin synthesis may negatively affect pregnancy and/or embryo/fetal development. Data from epidemiological studies indicate an increased risk of miscarriage, congenital heart defects and gastrointestinal defects after the use of prostaglandin synthesis inhibitors in early pregnancy. The risk is believed to increase with increasing dose and duration of therapy. In animals, administration of a prostaglandin synthesis inhibitor led to an increase in pre- and postimplantation mortality of the embryo and fetus. In addition, an increase in the incidence of various malformations, including cardiovascular diseases, was observed in animals after receiving a prostaglandin synthesis inhibitor during organogenesis. Ibuprofen should not be used in the first and second trimester of pregnancy, unless absolutely necessary. If ibuprofen is used by a woman who is trying to become pregnant or during the first and second trimesters of pregnancy, the lowest dose possible should be used for the shortest period of time. During the third trimester of pregnancy, all prostaglandin synthesis inhibitors can have the following effects: on the fetus: - cardiopulmonary toxicity (with premature closure of the ductus arteriosus and the development of pulmonary hypertension), - renal dysfunction, which can progress to renal failure, with the development of oligohydramnios; on the mother at the end of pregnancy and the newborn: - possible increase in bleeding time, an antiplatelet effect that can develop even at very low doses, - inhibition of uterine contractions, which leads to a delay or increase in the duration of labor. Due to the above actions, ibuprofen is contraindicated in the third trimester of pregnancy. Lactation In limited studies, ibuprofen has been found in very low concentrations in human milk. There are no known cases of its negative effects on a breastfeeding child, but breastfeeding should, if possible, be stopped while taking ibuprofen.

Impact on the ability to drive vehicles and other potentially dangerous mechanisms

After taking NSAIDs, side symptoms such as dizziness, drowsiness, fatigue and blurred vision may occur. If these symptoms appear, patients should refrain from driving vehicles and other potentially dangerous mechanisms.

Interaction with other drugs

Ibuprofen, like other NSAIDs, should not be used in combination with: - acetylsalicylic acid (aspirin), due to a possible increase in the development of adverse events. Laboratory studies suggest that ibuprofen, when used concomitantly with low doses of acetylsalicylic acid, may competitively inhibit platelet aggregation. Although the admissibility of extrapolation of these data to clinical practice remains uncertain, the possible effect of regular long-term use of ibuprofen on reducing the cardioprotective effect of low doses of acetylsalicylic acid cannot be excluded. The effect of occasional use of ibuprofen on the cardioprotective properties of acetylsalicylic acid seems unlikely; - other NSAIDs, especially selective cyclooxygenase-2 inhibitors. This may increase the risk of side effects. Ibuprofen should be used with caution in combination with the following drugs: - anticoagulants: NSAIDs may enhance the effect of anticoagulants such as warfarin; - diuretics, ACE inhibitors, beta blockers and angiotensin II antagonists: NSAIDs may reduce the effectiveness of diuretics and other antihypertensive drugs. In some patients with impaired renal function (for example, in dehydrated patients or in elderly patients with limited renal function), co-administration of ACE inhibitors, beta blockers or angiotensin II antagonists, as well as substances that inhibit the cyclooxygenase system, may cause a further decrease in renal function (up to acute renal failure), which is usually reversible. Therefore, the combination should be used with caution, especially in the elderly. Patients should receive sufficient fluids. Renal function should be periodically monitored closely both after initiation of co-therapy and subsequently. - corticosteroids: increased risk of gastrointestinal ulcers and bleeding; - antiplatelet agents and selective serotonin reuptake inhibitors: increased risk of gastrointestinal bleeding; - cardiac glycosides: NSAIDs can worsen heart failure, reduce the glomerular filtration rate and increase the level of glycosides in the blood plasma; - lithium: there is evidence that NSAIDs can cause an increase in the concentration of lithium in the blood plasma; - methotrexate: there is evidence that NSAIDs can cause an increase in the concentration of methotrexate in the blood plasma; - cyclosporine: increased risk of nephrotoxicity; - mifepristone: a decrease in the effectiveness of the drug could theoretically occur due to the antiprostaglandin properties of NSAIDs. Limited data suggest that coadministration of NSAIDs on the day of prostaglandin use does not adversely affect mifepristone or prostaglandins on cervical dilatation or reduce the clinical effectiveness of medical termination of pregnancy; - tacrolimus: there may be an increased risk of nephrotoxicity with simultaneous use of NSAIDs with tacrolimus; - zidovudine: increased risk of hematological toxicity with combined use of zidovudine and NSAIDs. There is evidence of an increased risk of hemarthrosis and hematoma in HIV-infected patients with hemophilia when treated concomitantly with zidovudine and ibuprofen; - quinolone antibiotics: patients taking ibuprofen and quinolone antibiotics concomitantly may have an increased risk of seizures; - sulfonylureas: NSAIDs may enhance the effect of sulfonylureas. There have been rare reports of hypoglycemia in patients taking sulfonylureas and ibuprofen concomitantly; - aminoglycosides: NSAIDs may reduce the excretion of aminoglycosides; - plant extracts: ginkgo biloba may increase the risk of bleeding when used simultaneously with NSAIDs; - CYP2C9 inhibitors: Concomitant use of ibuprofen with CYP2C9 inhibitors may increase the exposure time of ibuprofen (a CYP2C9 substrate). In a study with voriconazole and fluconazole (CYP2C9 inhibitors), an increase in S(+)-ibuprofen exposure of approximately 80-100% was noted. The dosage of ibuprofen should be reduced when co-administered with CYP2C9 inhibitors, especially when high doses of ibuprofen are used with voriconazole or fluconazole.

Storage conditions

Store at a temperature not exceeding 25 °C, protected from light. Keep out of the reach of children.

Best before date

Shelf life: 2 years. Do not use after expiration date!

Vacation conditions

By doctor's prescription.

Package

10 tablets each in a blister pack made of PVC polymer film and aluminum foil. One, two, three or five blister packs along with instructions for use are placed in a cardboard pack.

Buy Ibuflex 400 tablet p/o 400 mg in container pack No. 10x2 in the pharmacy

Price for Ibuflex 400 tablet p/o 400 mg in container pack No. 10x2

Instructions for use for Ibuflex 400 tablet p/o 400 mg in container pack No. 10x2

Ibuprofen ointment 5%

The drug is widely used as an external agent. Ointments and gels are produced in pure form or with the addition of cooling agents.

The ointment helps with arthritis, sprains, pain from damaged ligaments, back pain, sports injuries, and neuralgia.

How to use Ibuprofen ointment?

Usually the ointment is prescribed to adults and children over 14 years of age.

The dosage depends on the manufacturing company. A gel from 4 to 10 cm approximately contains 50 – 125 mg of the drug and this is a single dose. The product should be gently rubbed into the skin. Reapply no earlier than after 4 hours. The maximum daily dose is 500 mg.

Ibuprofen ointment

Ibuprofen in the practice of a general practitioner: possibilities for relieving pain syndromes

Pain syndromes of various origins are often encountered in the daily practice of a general practitioner, which determines the growing need for effective painkillers. According to the independent research center DSM Group, an analysis of the pharmaceutical market in 2012 showed that painkillers were one of the most popular groups of pharmaceuticals [1]. Analgesics are the most widely demanded category of drugs in the pharmaceutical market [2].

The feeling of pain is familiar to every person. There are probably no people who would not experience a feeling of pain during their lives. The variety of causes of pain determines the high frequency of patients visiting a doctor for this reason. It should be noted that the prevalence of pain syndromes in recent years, despite the development of pharmacy, has not decreased at all [3], on the contrary, there is even a tendency towards its increase, especially for chronic pain [4].

Verification of the cause of pain is one of the keys to its successful treatment. Among pain syndromes, the largest percentage is headaches, the prevalence of which reaches 90% in the population. Among them, tension headaches (up to 60%) and migraines (up to 23%) undoubtedly dominate. A global health survey conducted in 54 countries with 27,000 respondents found that headaches were the most common reason for seeking medical care and taking medications (Figure 1). The prevalence of primary headache in Russia (2725 respondents from 35 cities) reaches 62.9% with some predominance in the urban population, and more than 10% have headaches for more than 15 days a month. 68.1% of respondents indicated self-use of over-the-counter medications [5]. Headaches are the most common health complaint among drug users around the world.

The top ten complaints, along with headaches, also include back pain, sore throat and other types of pain. About 20% of the adult population suffers from recurrent back pain lasting more than three days, of which 20% have pain that lasts more than a month and is chronic. An equally acute problem is muscle pain, which generally occurs in 30–85% of the population. In this case, myalgia can accompany vertebrogenic back pain (in 60% of patients), but can also be primary [6].

The increase in the prevalence and incidence of pain syndromes is associated with both lifestyle changes and the general aging of the population (Fig. 2).

The main trend in patient preferences is the possibility of self-medication, i.e., independent choice of anesthetic. Therefore, as data from epidemiological studies show, most patients with the most common forms of pain syndromes remain outside the attention of specialists. Thus, only about 10% of patients with back pain seek help from specialists. A similar situation occurs with headaches. Thus, among patients with one of the most common forms of cephalgia - migraine - only 1/6 of them turn to specialists, the rest of the patients are outside their field of vision, preferring to be treated independently [6].

Economic burden of pain syndromes

The increasing prevalence of pain syndromes in the population is a significant burden for workers, employers and society, leading to loss of profits and additional costs and payments [8]. A paradox in the pharmacoeconomics of pain is that cost is a potential barrier to optimal pain management, with even suboptimal pain management showing an increase in overall healthcare costs [9].

Thus, in the USA alone, annual costs aimed at pain relief, as well as legal costs and compensation associated with pain syndrome, are estimated at almost 100 billion US dollars [10]. And, for example, in Sweden, the average annual cost of treating diseases associated with chronic pain syndrome (n = 840,000) is 6,400 euros per patient. The majority of costs (59%) are indirect costs (sick leave payments and early retirement), while the cost of analgesics is only about 1%. Overall, the socioeconomic burden of diseases associated with chronic pain syndrome in Sweden alone reaches 32 billion euros per year [11].

Nonsteroidal anti-inflammatory drugs (NSAIDs)

Practical experience shows that NSAIDs are most often used to relieve subjective pain. The presence of universal mechanisms of pain makes it possible to use drugs from this group in various clinical situations. In Europe, NSAIDs are prescribed by 82% of general practitioners and 84% of rheumatologists in polyclinics; in hospitals they are used in 20% of patients [12].

Thanks to the studied analgesic, anti-inflammatory, and antipyretic mechanisms of action, various representatives of NSAIDs have found wide practical use.

NSAIDs are able to relieve pain of various localizations - in the musculoskeletal system, headaches, dental pain, menstrual pain. In addition, all NSAIDs have antipyretic and anti-inflammatory properties. The variety of therapeutic effects of NSAIDs, as well as the high prevalence of clinical situations in which they are effective, make drugs in this group the most frequently prescribed to patients. The need for NSAIDs is especially increasing in older people, who often have concomitant diseases.

The main effects of NSAIDs are associated with the mechanism of suppression of the activity of cyclooxygenase (COX), an enzyme that regulates the conversion of arachidonic acid into prostaglandins, prostacyclin and thromboxane. Differences in the severity of anti-inflammatory, analgesic effects and toxic effects of drugs of this class are associated with their different ability to influence two isoforms of COX - COX-1 and COX-2. The analgesic and anti-inflammatory effects are mainly associated with the inhibition of COX-2, and the development of side effects is associated with the suppression of COX-1. Therefore, the choice of a specific representative is determined by its ability to predominantly influence COX-2.

Analgesic efficacy profile of ibuprofen

One of the most well-known representatives of the NSAID class is ibuprofen, which has been successfully used in clinical practice for more than 30 years and for more than 10 years in over-the-counter form (Nurofen). The high clinical effectiveness of this drug is confirmed by the high demand for it among consumers. Thus, only in the last six months, in terms of share of sales value in Russia, the drug Nurofen has moved from 8th to 3rd place, while occupying a leading position in Moscow [13].

The analgesic effectiveness of ibuprofen has been convincingly proven in various models of pain: toothache [14–16], headache [17–23], sore throat [14], musculoskeletal pain [14–16], etc.

Toothache is well recognized and sensitive enough to evaluate the analgesic effect of drugs. Ibuprofen at a dosage of 200–400 mg is the “gold standard” for the treatment of moderate pain in postoperative dental pain [14]. A meta-analysis demonstrated that ibuprofen was more effective than placebo across 72 studies. Ibuprofen significantly reduced pain in all patients by at least 50%, for an average of 4.7 hours. Repeated analgesia was required in only 48% of patients taking ibuprofen at a dose of 200 mg and in 42% of patients taking ibuprofen at a dose of 400 mg [15]. Another meta-analysis, based on 33 studies, found an advantage of ibuprofen (400 mg) in relieving pain after tooth extraction compared to paracetamol (1000 mg), as well as a combination of paracetamol (600-650 mg) and codeine (60 mg) [ 16].

For headaches, ibuprofen as a first-line drug is included in the list of analgesics recommended by WHO, as well as the European Federation of Neurological Societies (EFNS) for the treatment of mild to moderate migraine attacks (class A) [17, 18]. The effectiveness of ibuprofen in the treatment of cephalgia has been proven in many placebo-controlled clinical trials, as well as several meta-analyses, including in children and adolescents [19–23].

For sore throat due to tonsillopharyngitis, a double-blind, randomized, multicenter study compared the analgesic efficacy of ibuprofen (400 mg) or paracetamol (1000 mg). The severity of pain when swallowing, difficulty swallowing, and changes in pain intensity were assessed every 6 hours after taking the first dose of drugs. Ibuprofen, compared with paracetamol, was significantly more effective in influencing the severity of pain and difficulty swallowing, while the effect of ibuprofen began significantly earlier than that of paracetamol. Treatment tolerability was comparable in both groups, and no serious side effects were observed during the study. Thus, the study showed that ibuprofen is a more effective alternative to paracetamol in the treatment of sore throat [24].

Ibuprofen, having high efficiency and low toxicity, is widely used in the long-term treatment of various inflammatory and degenerative diseases of the musculoskeletal system.

The effectiveness of ibuprofen and its benefits have been repeatedly demonstrated in large-scale studies. An illustrative example is the multicenter randomized IPSO (Ibuprofen, Paracetamol Study in Osteoarthritis) study conducted in 2004 involving 222 patients suffering from osteoarthritis (OA) of the hip (30% of patients) or knee (70%) joint. For two weeks, the WOMAC (Western Ontario and McMaster Universities osteoarthritis index) scale assessed the effect of ibuprofen (400–1200 mg/day) and paracetamol (1000–3000 mg/day) on the severity of pain and joint syndromes. The results of the study showed a greater reduction in pain in the first 6 hours after taking the drug and a more pronounced further reduction within 14 days in the ibuprofen group compared to paracetamol. The authors concluded that ibuprofen with a single (400 mg) or multiple (up to 1200 mg) dose has a better efficacy/safety ratio than paracetamol [25]. The greater effectiveness of NSAIDs, including ibuprofen, compared with paracetamol in the treatment of OA was also demonstrated in a Cochrane review [26].

According to current recommendations, the use of NSAIDs as symptomatic treatment is recommended for all patients with rheumatoid arthritis (RA). Patients with OA are recommended to take NSAIDs only during periods of increased pain and in lower dosages than for inflammatory arthritis [27, 28].

Ibuprofen can be used both in monotherapy and as part of combination therapy in combination with other drugs. Thus, adding the centrally acting muscle relaxant tizanidine to ibuprofen can not only increase the effectiveness of therapy, but also reduce the incidence of adverse events from the use of NSAIDs. Tizanidine has a protective effect on the gastric mucosa from the effects of NSAIDs [29]. This effect was convincingly demonstrated in the work of Berry H. et al., which studied the addition of tizanidine 4 mg to ibuprofen 400 mg three times daily in patients with acute low back pain. The overall effectiveness of treatment in both groups was almost the same, but the safety of treatment was higher with the combined use of ibuprofen and tizanidine. Patients receiving ibuprofen/tizanidine combination therapy reported significantly less gastrointestinal (GIT) side effects compared to the placebo/ibuprofen group (p < 0.002) [30].

Topical forms of ibuprofen

The high demand for ibuprofen drugs is also due to the variety of its dosage forms. In patients with acute or chronic muscular-articular pain, especially with local damage to the musculoskeletal system and traumatic lesions of soft tissues, local use of NSAIDs in the form of gels and ointments is possible, which reduces the systemic effect and, consequently, adverse reactions.

The effectiveness of this dosage form is not inferior to the tablet form. A number of studies have shown that ibuprofen, regardless of the dosage form, is a highly effective NSAID with a good safety profile.

The widespread use of topical forms of ibuprofen is due to the fact that in patients taking oral forms of NSAIDs for a long time, erosive and ulcerative lesions of the gastrointestinal mucosa, including perforation and bleeding, can develop in 22–68% of cases. Moreover, up to 30% of additional costs in the treatment of arthritis can be attributed to the treatment of gastrointestinal side effects caused by taking oral NSAIDs [31, 32]. Given that topical NSAIDs are as effective as oral NSAIDs, their more favorable tolerability profile makes them preferable in certain clinical situations, such as knee pain. Thus, administration of oral and topical forms of ibuprofen has an equivalent effect on knee pain over the course of a year. Due to a more favorable tolerability profile, topical forms of NSAIDs can be prescribed as an alternative to oral forms [33]. Based on the results of a Cochrane review of 47 studies, the authors concluded that when using topical forms of NSAIDs, there is a good effect compared to enteral use and a significantly lower number of complications [34].

The same effectiveness of using a topical form of ibuprofen (5% gel) and oral ibuprofen 400 mg (1200 mg per day) has also been proven for acute soft tissue injury for at least 7 days. In both groups, complete improvement was observed between days 3 and 6 of therapy. It should be noted that the treatment was well tolerated in both groups (the identified cases of adverse events were not related to the treatment) [35].

While topical ibuprofen costs slightly more than oral ibuprofen, overall treatment costs are reduced by reducing the incidence of side effects, as shown in the TOIB study (Topical or oral ibuprofen for chronic knee pain in older people) [36]. .

Safety profile of ibuprofen therapy

The main concern for patients with chronic pain is the safety of the drug used over long-term use. It's no secret that the main serious side effect of all NSAIDs is gastrointestinal bleeding (GI bleeding). Many studies indicate that low dose ibuprofen use (up to 1200 mg/day) causes only minimal damage to the gastrointestinal mucosa, even with long-term use. Ibuprofen, as a drug with well-studied pharmacological effects, is considered the “gold standard” for safety of use, which is especially important in the treatment of patients with chronic pain syndromes. Ibuprofen in low doses (800–1200 mg per day) is approved for over-the-counter use in many countries and has a good safety profile comparable to paracetamol.

Increasing the recommended doses (up to 1800–2400 mg per day) is used in the long-term treatment of rheumatic and some other diseases of the musculoskeletal system. Based on a meta-analysis of observational epidemiological studies from 2000–2008. The influence of various NSAIDs on the risk of bleeding from the upper gastrointestinal tract has been established. As initially expected, the lowest incidence of GI bleeding was observed in the coxibs group (hazard ratio (RR) 1.88; 95% confidence interval (CI) 0.96–3.71), among non-selective NSAIDs, the best results were obtained with ibuprofen ( RR 2.69; 95% CI 2.17–3.33), the greatest risk was observed with ketorolac (RR 14.54; 95% CI 5.87–36.04) and piroxicam (RR 9.94; 95% CI 5.99–16.50). The authors concluded that the frequency of bleeding depends on several factors: the selectivity of the drug with respect to COX, the dosage and duration of use, as well as the half-life or use of a prolonged form of the drug [37]. Similar results were demonstrated in a number of earlier meta-analyses, according to which ibuprofen was characterized by the lowest risk of GI bleeding compared with diclofenac, naproxen, indomethacin, piroxicam and ketoprofen [37–40].

The dose-dependent effect of ibuprofen on the occurrence of serious gastrointestinal complications has been confirmed in a number of other studies. The risk of serious gastrointestinal adverse events with NSAIDs is relatively low, occurring in 1% of patients per year, primarily when used in high doses for long-term treatment of chronic conditions. The incidence of side effects when using ibuprofen in recommended doses in children and adults is comparable to that of paracetamol. Of all NSAIDs, ibuprofen appears to have one of the best gastrointestinal safety profiles [41, 42].

We can clearly conclude that ibuprofen has the best safety profile in relation to the gastrointestinal tract among non-selective NSAIDs, as well as a relatively low risk of developing cardiovascular complications with long-term use.

In accordance with existing recommendations, no advantages in the effectiveness of various NSAIDs, including selective ones, have been reliably identified in the treatment of rheumatic diseases, therefore the choice of drug should be made based on its safety profile and the individual characteristics of the patient. Coxibs are contraindicated in patients at high risk of cardiovascular complications. To reduce the risk of gastrointestinal complications, it is recommended to use misoprostol or proton pump blockers in conjunction with non-selective NSAIDs.

Currently, the first large randomized trial (n = 20,000 patients) is being conducted to establish the safety profile of celecoxib, ibuprofen and naproxen in patients suffering from OA or RA at high risk of developing cardiovascular complications [43]. This study will provide clearer recommendations regarding administration in these patients.

Conclusion

Thus, clinical experience with the use of ibuprofen for the most common forms of pain syndromes demonstrates its effectiveness not only as a means for relieving painful episodes, but also for the course treatment of chronic pain. An additional advantage of this drug is its existence in several dosage forms.

The use of ibuprofen (Nurofen) meets modern standards of pain therapy. Ease of use, variety of dosage forms of the drug and its availability determine high patient compliance with the prescribed therapy, which is the key to successful treatment.

More than 50 years of successful use of ibuprofen in widespread clinical practice in more than 80 countries as an over-the-counter drug serves as a clear example of its high profile of effectiveness and safety [44].

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T. E. Morozova, Doctor of Medical Sciences, Professor S. M. Rykova, Candidate of Medical Sciences

GBOU VPO First Moscow State Medical University named after. I. M. Sechenova Ministry of Health of the Russian Federation, Moscow

Contact information for authors for correspondence

Side effect

• Like all medications, Ibuprofen can cause allergic reactions: skin itching, urticaria, Quincke's edema, anaphylactic reactions, incl. anaphylactic shock. In this case, you should stop taking the drug and consult a doctor.
• The following side effects may be observed on the part of the digestive system: pancreatitis, nausea, vomiting, erosive and ulcerative lesions of the gastrointestinal tract, stomach and abdominal pain, stomatitis, liver dysfunction, hepatitis.
• Genitourinary system: polyuria, renal dysfunction, renal failure, edema, cystitis, nephrotic syndrome, interstitial nephritis.
• Nervous system and sensory organs: irritation and dry eyes, ringing in the ears, hallucinations, psychomotor agitation, confusion, headaches, anxiety, irritability.
• Respiratory system: allergic rhinitis, bronchospasm, shortness of breath.
• Cardiovascular system: agranulocytosis, leukopenia, increased pulse, hypertension, heart failure.

Ibuprofen for pregnant women: can it be taken and how does it affect the fetus?

The inhibition of the synthesis of prostaglandins (physiologically active substances), which is caused by ibuprofen, can negatively affect the course of pregnancy, as well as the development of the embryo or fetus.
Epidemiological studies have shown that use of the drug in early pregnancy increases the risk of miscarriage, as well as the occurrence of such pathologies in the embryo as:

• gastroschisis - a defect in the anterior wall of the intestine, as a result of which the intestines and other abdominal organs fall out of the cleft;
• cardiovascular pathologies (heart malformations).

Also, according to research, a negative effect on female fertility (ability to bear children) was found - there is a decrease in the ability to conceive.

These pathologies depend on the dosage and duration of taking the drug.

Therefore, ibuprofen is not recommended to be taken during the first and second trimesters of pregnancy. An exception can be made only in cases where it is absolutely necessary, but in each case the intake should be carried out only under the strict supervision of a doctor.

If, however, the need to take the drug arises in the first and second trimester of pregnancy or during the period when a woman is trying to become pregnant, then it is necessary to take only the minimum dose of ibuprofen and only for the shortest period of time.

Ibuprofen as an analgesic and antipyretic is not the drug of choice for pregnant women, as it is unsafe for the fetus. However, severe, constant pain that cannot be relieved during pregnancy leads to anxiety, depression and even increased blood pressure, which can ultimately lead to the threat of premature birth. In connection with this factor, taking into account the benefits for the mother and the risk for the fetus from taking the drug, ibuprofen is allowed for use in emergency cases, after consulting a doctor in the first and second trimesters of pregnancy.

During the third trimester of pregnancy, the use of ibuprofen must be stopped (especially after the 31st week), since during this period the drug poses the greatest danger to the fetus. The following pathologies may occur in a child:

• impaired renal function, which can lead to chronic diseases and even renal failure;
• premature closure of the ductus arteriosus (the vessel connecting the thoracic aorta to the pulmonary artery);
• pulmonary hypertension.

For the mother, the course of pregnancy and childbirth, the risks are also great. The following conditions may occur:

• increase in the degree and time of bleeding during childbirth;
• antiplatelet effect, which is possible even at very low doses;
• a decrease in the activity of uterine contractions, which can lead to a delay in labor or an increase in the duration of labor.

Contraindications:

• Hypersensitivity to the components of the drug.
• Bleeding disorders, hemophilia.
• Hematopoietic disorders.
• Erosive and ulcerative lesions of the gastrointestinal tract in the acute stage, bleeding in the gastrointestinal tract.
• Kidney or liver failure.
• Severe heart failure.
• The period after coronary artery bypass surgery.
• “Aspirin triad” (aspirin intolerance, nasal polyps and bronchial asthma).
• Diseases of the optic nerve.
• Caution should be exercised when taking other NSAIDs.
• Simultaneous use of medication and alcoholic beverages is not recommended.

Features of application

Patients with a history of gastrointestinal disorders, especially elderly patients, should report any unusual gastrointestinal symptoms (primarily bleeding), especially gastrointestinal bleeding at the beginning of treatment.

If gastrointestinal bleeding or ulceration occurs in patients receiving ibuprofen, treatment should be discontinued.

Pregnant

Ibuprofen should not be taken during the first two trimesters of pregnancy unless absolutely necessary.

Ibuprofen is contraindicated in the third trimester of pregnancy.

Children

Do not use in children under 12 years of age and weighing <40 kg.

Drivers

Adverse effects such as dizziness, drowsiness, fatigue and blurred vision may occur after taking NSAIDs. If such phenomena occur when using NSAIDs, patients should not drive vehicles or operate other machinery.

special instructions

• Ibuprofen is prescribed in a short course - three days. If therapy lasts 10 days or more, you should consult a doctor.
• Elderly patients need to carefully monitor the tolerability of the drug, as they are more likely to experience side effects.
• May temporarily reduce female reproductive function (the effect disappears after discontinuation).
• It may affect the ability to drive vehicles, so if the patient notices lethargy or drowsiness, he should refrain from driving vehicles and other activities where reaction speed is required.

Ibuprofen for children

The effect of ibuprofen on pregnant women with hypertension

During an experiment, Christina Penfield, associate professor of maternal and fetal medicine at New York University Medical Center, discovered the effect of ibuprofen in pregnant women suffering from blood pressure. These studies involved 2 groups of women who received pain relief with ibuprofen or paracetamol after childbirth. The experiment revealed that a group of pregnant women with hypertension who took ibuprofen did not have an increase in blood pressure compared to women who did not take this NSAID.

Be careful!

Avoid taking ibuprofen during pregnancy. If there is still a need to reduce fever or pain, be sure to consult with your doctor about which medication will have minimal risks for the fetus and the course of pregnancy.

Interaction with other drugs

Ibuprofen was created back in 1953 and is therefore well studied. Here we will briefly list its interactions with common drugs - this is mainly a group of cardiovascular drugs, some antibiotics. A complete list of drug interactions should be read in the instructions for the drug.

• Reduces the effect of ACE inhibitors, beta-blockers and some diuretics, such as furosemide.
• The effect may be enhanced when taken with anticoagulants.
• The activity of amlodipine decreases.
• Caution should be used when taking warfarin, methotrexate and lithium together.
• Interactions have been noted with cardiac glycosides, quinolone antibiotics, ethanol, barbiturates, rifampicin, phenylbutazone, cyclosporine, mifepristone, tacrolimus, zidovudine, cefoperazone, cefotetan, valproic acid.