Nonsteroidal anti-inflammatory drugs-a collection of clones or a community of bright individuals? The view of a clinical pharmacologist
Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most commonly used drugs among both prescription drugs and over-the-counter medications, i.e. used by patients themselves for self-medication without a doctor's prescription. The frequency of use of NSAIDs in clinical practice is due to the spectrum of their pharmacological effects: analgesic, anti-inflammatory, antipyretic, antiplatelet (acetylsalicylic acid). However, a wide range of therapeutic effects and high clinical efficacy have a downside: NSAIDs are included in the group of drugs that most often cause undesirable drug reactions (NLR) associated with toxic effects, hypersensitivity, drug and food interactions. Therefore, the clinician faces a difficult task: the selection of NSAIDs for a specific patient.
The choice of a drug is carried out according to a certain algorithm.
Determination of the indication for the use of the drug, which is due to the clinical diagnosis of the patient: the underlying disease, the presence of comorbid pathology, complications, concomitant diseases. Of great importance is the assessment of risk factors for the development of complications of drug therapy: an allergic history; previously detected symptoms of drug intolerance; concomitant therapy, including the use of herbal medicines, vitamin preparations, over-the-counter drugs, dietary supplements; dietary preferences of the patient, alcohol abuse, smoking.
After determining the indication ("problem" of the patient), the doctor selects a group of drugs and a specific drug within this group, based on the criteria of effectiveness, safety, cost and ease of use.
Having decided on the choice of a specific drug, the doctor chooses the mode of use of the drug: dose, frequency of use, duration of therapy.
The doctor explains to the patient in an accessible form what is wrong with him and why there are symptoms that bother him, provides information about possible non-drug methods of correcting the pathological condition, explains to the patient why this drug is chosen and what the patient should pay attention to when using this drug, if any symptoms appear, he should immediately consult a doctor and even stop taking the drug. Almost 50% of cases of pharmacotherapy inefficiency are caused by low patient compliance, which is why it is so important to achieve cooperation with the patient, compliance with the rules of drug therapy.
The doctor himself in the course of treatment evaluates the effectiveness and safety of the pharmacotherapy, decides on the indications for the appointment of protective therapy, discontinuation/prolongation of treatment when the goal is achieved or changing the drug if it is ineffective.
The implementation of this algorithm is possible only if the doctor is well aware of the indications for use and the clinical and pharmacological properties of the selected drug.
Features of the use of NSAIDs in clinical practice
As mentioned above, the main pharmacodynamic effects of NSAIDs are analgesic, anti-inflammatory, and antipyretic. Thus, drugs of this group are used for diseases of the musculoskeletal system, joints, postoperative pain, tension headache, migraine, dysmenorrhea, renal and hepatic colic, chronic pain syndrome, colds, fever.
The efficiency of a drug is determined by several factors: mechanism of action, oral bioavailability (the percentage of the dose received by the blood system), peculiarities of metabolism, the concentration in the blood and tissues of the body, speed of development, the therapeutic effect and duration of retention. The safety of the use of the drug depends on the mechanism of action and features of metabolism, excretion of the drug, its ability to enter into drug interactions.
The mechanism of action of NSAIDs is due to their ability to inhibit the enzyme cyclooxygenase-2 (COX-2) in inflammation (Fig. 1). It is the COX-2 participates in the formation of proinflammatory prostaglandins, which potentiate the activity of mediators of inflammation (histamine, serotonin, bradykinin) that activate pain receptors; involved in control of activity of the center thermal regulation, promote cell proliferation, mutagenesis, and destruction. At the same time, NSAIDs also block cyclooxygenase-1 (COX-1), which is present in all organs and provides normal physiological processes (synthesis of protective gastric mucus, some stages of hematopoiesis, filtration and reabsorption in the kidneys). There is also a "constitutive" COX-2, which is found in high concentrations in the brain, bones, organs of the female reproductive system, kidneys, ensuring their normal functioning.
Additional mechanisms of anti-inflammatory action of NSAIDs are:
inhibition of interleukin-1 activity synthesis;
suppression of neutrophil function and interaction of leukocytes with vascular endothelium;
inhibition of activation of NF-kb (transcription factor), which regulates the synthesis of "pro-inflammatory" mediators;
activation of PPARs (peroxisoma proliferator activated receptors).
Reduced synthesis of "useful" prostanoids underlies the mechanisms of NLR development when using NSAIDs.
NSAIDs can be divided into two groups: non-selective COX inhibitors (ibuprofen, diclofenac, naproxen, etc.) and selective COX-2 inhibitors (meloxicam, nimesulide, coxibs). When using drugs of the second group, NSAIDs-gastropathies and NSAIDs-enteropathies, gastrointestinal bleeding, are much less likely to develop, but the risk of complications from the cardiovascular system increases. The effect of NSAIDs increases with an increase in the dose of the drug, while at maximum doses, the selectivity of the action of selective NSAIDs decreases.
It should also be noted that when using medium and high doses of various NSAIDs, their effectiveness is comparable, which follows from the results of multicenter clinical studies that compared the analgesic and anti-inflammatory effects of NSAIDs in injuries, operations and diseases of the musculoskeletal system. For example, a meta-analysis of data from 29 randomized clinical trials (n=18,000) evaluated the effectiveness of various NSAIDs in osteoarthritis. Differences in the severity of pain reduction (in millimeters of visual analog scale) between NSAIDs and placebo were: for naproxen 1000 mg/day 12.9 (95% confidence interval (CI) 8.2-17.7), ibuprofen 2400 mg/day 9.0 (95% CI 5.0-13.1), diclofenac 16.2 (95% CI 11.7-20.6), celecoxib 200 mg 14.7 (95% CI 12.1-17.3), etoricoxib 30 mg 14.2 (95% CI 12.6-16.8), etoricoxib 60 mg 16.2 (95% CI 12.7-19.8).
It is believed that intravenous or intramuscular administration of the drug provides a faster and more pronounced therapeutic effect than oral administration of the drug. However, this position is not supported by the data of clinical studies. In a systematic review of 26 RCTs (n=2225), the efficacy of NSAIDs in parenteral, rectal, and oral administration was analyzed. Indications for the appointment of NSAIDs were musculoskeletal diseases, postoperative pain, dysmenorrhea, renal colic. There were no significant differences in the analgesic effect of different dosage forms of NSAIDs, with the exception of renal colic, in which a significant advantage of intravenous NSAIDs compared to oral administration was shown.
Thus, we can draw the following conclusions .
All NSAIDs in adequate anti-inflammatory (medium and maximum) doses with long-term use have equal analgesic potential (level of evidence 1a).
The effectiveness of NSAIDs depends on the dose. The use of higher doses allows for a more pronounced analgesic and anti-inflammatory effect (level of evidence 1b).
There is no evidence that the use of NSAIDs in the form of injections or instant forms for oral administration has an advantage over oral forms when treatment is carried out for more than 1 day (level of evidence 1b).
Risk of adverse drug reactions when using NSAIDs
Since the effectiveness of NSAIDs is comparable in therapeutic doses, choosing NSAIDs for a particular patient is based on the possible risks of developing NLR. Risk factors for the development of NLR when using NSAIDs are: age over 60 years, overweight, smoking, a history of gastric and duodenal ulcer, venous thrombosis and thromboembolism, CHD, cerebrovascular disease, peripheral atherosclerosis, arterial hypertension, lipid metabolism disorders, diabetes mellitus, bowel, liver, kidney, blood diseases, congestive heart failure, chronic alcohol addiction intoxication, concomitant use of drugs that interact with NSAIDs, lactation. For a more differentiated choice of NSAIDs, a special algorithm was proposed, which implies the appointment of selective NSAIDs to patients with risk factors for gastrointestinal complications and the use of NSAIDs with less pronounced toxic effects on the cardiovascular system in patients with high cardiovascular risk, as well as the appointment of protective therapy.
According to the Russian recommendations on the rational use of NSAIDs:
the main method of preventing the development of NLR when using NSAIDs is to take into account risk factors, correct them (if possible) and prescribe NSAIDs with a more favorable profile of gastrointestinal (gradation of recommendation A) and cardiovascular safety (gradation of recommendation B);
an additional method of preventing complications from the upper gastrointestinal tract is the appointment of proton pump inhibitors (PPIs) (gradation of recommendation A);
an additional method of preventing complications from the upper gastrointestinal tract, small and large intestine can be the appointment of rebamipid (gradation of recommendation B);
There are no effective medical methods of nephro-and hepatoprotection to reduce the risk of NSAID-associated complications.
Ibuprofen + paracetamol combination: pharmacokinetics, efficacy and safety aspects
NSAIDs containing ibuprofen, which was synthesized in 1961 and is still considered the "gold standard" analgesic, are widely distributed on the Russian market. It is also the safest non-selective NSAID for the development of NSAID-gastropathies. Ibuprofen is approved for over-the-counter use and is available in a variety of dosage forms. So, in the line of drugs under the trade mark Nurofen , coated tablets are presented; capsules containing a liquid active substance that is absorbed and reaches its maximum concentration in the blood faster than when taking the tablet form. Ibuprofen is available in the dosage form of a suspension that does not contain sugar and alcohol, for oral administration for children aged 3 months to 12 years.
For ibuprofen, as for most analgesics, the speed and completeness of the onset of an analgesic effect is determined by the time the maximum concentration in the blood plasma is reached after oral administration. This means that dosage forms that provide faster absorption also have a faster and more pronounced therapeutic effect. Ibuprofen is contained in the composition of medicines in the form of weak acid or salts. It is known that salts, such as the sodium salt of ibuprofen, which is part of a number of drugs of the Nurofen line, are absorbed faster than ibuprofen in the form of free acid. In a study by P. V. Dewland et al. (2009) studied the bioavailability of ibuprofen after oral administration of its two forms acid and sodium salt to healthy volunteers. The authors found that the rate of absorption of the sodium salt of ibuprofen, estimated by the time of reaching the maximum concentration in blood plasma, is significantly higher (i.e. it is absorbed 2 times faster than the acidic form), and its concentration is significantly higher. At the same time, there was no increase in the risk of developing NLR.
To achieve a rapid onset of analgesia, it is advisable to use dosage forms with a higher absorption rate and, therefore, a faster achievement of the maximum concentration in plasma. Moore et al. (2013) published a systematic review that demonstrated a significant advantage of fast-acting forms of ibuprofen over standard ones in providing an analgesic effect. The authors analyzed the results of 30 clinical studies involving 1015 patients and clearly showed that when using fast-acting forms of ibuprofen, maximum plasma concentrations are reached on average in 50 minutes, while for standard forms-within 90 minutes. At the same time, the analgesic effect not only occurs faster, but is also accompanied by more pronounced anesthesia for 6 hours. There were strong correlations between faster reduction of pain intensity in the period of 0-60 minutes and more pronounced analgesia in the range of 0-6 hours. In general, the effectiveness of the fast-acting form of ibuprofen at a dose of 200 mg was the same as that of the standard form at a dose of 400 mg, but fewer repeated analgesics were required with comparable pharmacotherapy safety.
The Drug Nurofen Intensive is a combination of ibuprofen 200 mg and paracetamol 500 mg, which differ in their action, which suggests that when they are combined, due to the peculiarities of the mechanisms of action of the two components, the analgesic effect is summed up. Ibuprofen is an inhibitor of COX-1 and COX-2; its analgesic effect is realized by inhibiting action at the peripheral level, antipyretic-is associated with central inhibition of prostaglandin synthesis in the hypothalamus. Ibuprofen also inhibits the migration of white blood cells to the site of inflammation and reversibly suppresses platelet aggregation. Paracetamol is a non-selective inhibitor of COX-2, mainly in the central nervous system (CNS), stimulates the activity of the descending serotonin pathways, which leads to the relief of pain impulse transmission in the spinal cord; the analgesic effect of acetaminophen is associated with the effect on the cannabinoid system of the CNS.
The combination of ibuprofen 200 mg + paracetamol 500 mg has a more pronounced analgesic effect than monopreparations of ibuprofen and paracetamol alone and even combined drugs containing codeine. A double-blind randomized study of 678 participants found that the combination of ibuprofen 200 mg + paracetamol 500 mg provided statistically significantly more effective pain relief than combined codeine-containing drugs.
Taking into account the fact that paracetamol slowly dissolves in an alkaline environment, but quickly in an acidic one, while ibuprofen on the contrary, their reception separately leads to the fact that their absorption occurs in different parts of the gastrointestinal tract: paracetamol mainly in the stomach, ibuprofen in the intestines. In the production of Nurofen The modern synchrotechtm technology was used intensively, which made it possible, thanks to the use of a unique capsule membrane, to optimize the dissolution of the drug with a rapid and simultaneous release of active active substances.
Tanner et al. (2010) showed that the tmax of paracetamol when using a combination of paracetamol and ibuprofen was significantly lower than when using paracetamol alone (average difference of 10 min; p<0.05), otherwise the pharmacokinetic parameters of paracetamol and ibuprofen were comparable to those of monopreparations or a combination of paracetamol and ibuprofen. The average plasma concentrations of both drugs were also higher after taking a combination of ibuprofen and paracetamol compared to those after taking ibuprofen or paracetamol in the form of monopreparations. Mean plasma levels after 10 and 20 minutes were 6.64 mcg / ml and 16.81 mcg/ml, respectively, for ibuprofen when administered orally with the combination drug, compared with 0.58 mcg/ml and 9.00 mcg/ml, respectively, for the monopreparation. For paracetamol, the average plasma levels after 10 and 20 minutes were 5.43 mcg / ml and 14.54 mcg/ml, respectively, for the combination, compared with 0.33 mcg/ml and 9.19 mcg/ml, respectively, for the monopreparation.
A pronounced analgesic effect when using a combination of ibuprofen and paracetamol developed after 15 minutes and reached a maximum after 40 minutes with a duration of up to 8 hours.
Safety of the combination of ibuprofen and paracetamol
It has already been noted that ibuprofen in medium therapeutic doses (600-1200 mg/day) has low gastrotoxicity. Paracetamol is a central analgesic and does not cause NSAID-gastropathy. Table 4 shows a comparison of the activity of a number of NSAIDs with respect to the selectivity of COX-1/COX-2.
If we talk about the risk of developing cardiovascular complications when using a combination of paracetamol and ibuprofen, it is also low. However, it should be remembered that ibuprofen reduces the antiplatelet effect of acetylsalicylic acid and their combined use is not recommended.
The use of combinations of ibuprofen and paracetamol is contraindicated: of prehyperfunctions to ibuprofen, paracetamol or other components of the drug, while the use of other drugs, containing paracetamol, in case of full or partial combination of bronchial asthma, recurrent polyposis of the nose and paranasal sinuses, in case of intolerance to acetylsalicylic acid or other NSAIDs, erosive-ulcerative diseases of the digestive tract, peptic ulcer bleeding (active or in history), perforation of ulcers of the gastrointestinal tract, triggered by taking NSAIDs, severe heart failure, severe hepatic insufficiency or liver diseases in the active phase. The combination of ibuprofen and paracetamol is not prescribed for patients with severe renal insufficiency (creatinine clearance less than 30 ml/min), with confirmed hyperkalemia, decompensated heart failure and during the period of coronary artery bypass grafting, with cerebrovascular or other bleeding, in the third trimester of pregnancy, with hemophilia and other blood clotting disorders and hemorrhagic diathesis, as well as with the genetic absence of glucose-6-phosphate dehydrogenase. The combination of ibuprofen and paracetamol is contraindicated in persons under 18 years of age.
In general, the combination of ibuprofen and paracetamol is well tolerated, NLR is rare, usually mild and comparable in frequency to placebo.
Thus, NSAIDs remain one of the most widely used groups of drugs. The choice of NSAIDs is based on the individual characteristics of the patient, the risk factors for the development of complications of drug therapy. A patient who regularly takes NSAIDs needs to be monitored for early detection of the development of NLR. The combination of ibuprofen with paracetamol allows you to increase the therapeutic result without increasing the risk of side effects.