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Introduction
Nociceptive pain is one of the common clinical syndromes encountered by doctors of many specialties.
The most widely used drugs in the treatment of pain are from the group of nonsteroidal anti-inflammatory drugs (NSAIDs). Despite the presence of a seemingly huge arsenal of painkillers, the treatment of acute and chronic pain syndrome presents certain difficulties for practicing doctors due to the development of side effects. Thus, the currently available information about the unsafety of long-term use of NSAIDs leads to the need to search and develop new dosage forms and ways of their use. This review is devoted to this urgent problem and the search for ways to solve it.
NSAIDs have long taken a strong place in medical practice and are used for various pathologies. From a clinical point of view, they have some common properties:
anti-inflammatory effect;
analgesic and antipyretic effect;
inhibitory effect on platelet aggregation;
good tolerance.
Nonsteroidal anti-inflammatory drugs
Nonsteroidal anti-inflammatory drugs (NSAIDs) are a group of non-hormonal drugs that have an anti-inflammatory effect.
The drugs listed below are most often used in pediatric practice.
Aspirin, analgin, diclofenac, ibuprofen, ketoprofen, napraxen, piroxicam, meloxicam, nimesulide
Available in tablets, capsules, injection solutions, ointments, gels, suppositories (suppositories).
What are non-steroidal anti-inflammatory drugs and how do they work?
NSAIDs have anti-inflammatory, analgesic and antipyretic effects. The main mechanism of action is inhibition of prostaglandin formation. Prostaglandins are tissue hormones that promote the development of inflammation and accompanying pain.
What are non-steroidal anti-inflammatory drugs used for?
The drugs are intended to relieve pain of various types.
Non-steroidal anti-inflammatory drugs are indicated for inflammatory diseases of the joints (rheumatoid arthritis, rheumatism, ankylosing spondylitis, chronic gouty arthritis), degenerative diseases (deforming osteoarthritis, osteochondrosis), lumbago, sciatica, neuralgia, myalgia, diseases of extra-articular tissues (tenosynovitis, bursitis, rheumatic soft tissue tissues), post-traumatic pain syndrome accompanied by inflammation, postoperative pain, acute attack of gout, migraine attacks, renal and hepatic colic, infections of the ENT organs, residual effects of pneumonia. Locally - injuries of tendons, ligaments, muscles and joints (to relieve pain and inflammation during sprains, dislocations, bruises), localized forms of soft tissue rheumatism (elimination of pain and inflammation).
What should you tell your doctor before starting treatment with non-steroidal anti-inflammatory drugs?
- The patient has a peptic ulcer of the stomach and/or duodenum
- The patient has chronic kidney or liver disease
- The patient has ever had a reaction to salicylates or any other drug
- That the patient is taking any other medications, including over-the-counter medications, vitamins
- About pregnancy or breastfeeding
What are the rules for taking non-steroidal anti-inflammatory drugs?
- Take the drug as prescribed by your doctor.
- NSAIDs are taken 1-2 hours after meals with plenty of water.
- Never take non-steroidal anti-inflammatory drugs in a dose greater than prescribed by your doctor. If you have taken an excessive dose, consult a doctor immediately or call an ambulance.
- During treatment, carry the medication package with you and maintain a constant supply of the drug.
- This medicine is prescribed only for you. Never give it to other people, even if you think they have a similar disease.
- With long-term use of nonsteroidal anti-inflammatory drugs, regular monitoring of parameters reflecting liver and kidney function, as well as peripheral blood parameters, should be carried out.
What to do if you miss a dose?
- Take the missed dose of medication as soon as you remember.
- If you miss a dose and it is already time for your next dose, continue taking your NSAIDs as usual.
- Do not take a double or extra dose of the drug.
What is needed for treatment to be effective and safe?
- Visit your doctor regularly to evaluate the effectiveness of your treatment.
- If you do not feel any improvement while taking the drug, discuss this with your doctor.
- If you need to take nonsteroidal anti-inflammatory drugs along with other medications, be sure to discuss this with your doctor.
What problems can cause taking non-steroidal anti-inflammatory drugs?
- Disorders of the gastrointestinal tract function may appear (abdominal pain, constipation, heartburn, nausea), but often they are not so severe as to interrupt treatment.
- Long-term therapy with large doses increases the risk of side effects from the gastrointestinal tract (as an exception, peptic ulcers or bleeding may occur).
- Rarely, rash, itching, swelling, feeling of fatigue, and dizziness appear.
- There may be an increase in the activity of liver enzymes.
- Gel and ointment sometimes cause redness, itching and a burning sensation at the site of application.
How to properly store non-steroidal anti-inflammatory drugs?
- The drug should be stored in a dry place, out of reach of children, at a temperature not exceeding 25 degrees.
- Never use the drug after the expiration date.
Mechanisms of action of NSAIDs
NSAIDs affect various pathogenetic components of the inflammatory process. Despite the fact that, due to differences in the chemical structure, the effect on certain links differs, for these drugs the main mechanisms of action are similar:
decrease in capillary permeability;
stabilization of lysosomal membranes;
inhibition of the production of macroergic compounds (ATP);
inhibition of synthesis or inactivation of inflammatory mediators.
According to modern concepts, the key and most general mechanism of action of NSAIDs is their inhibition of the biosynthesis of prostaglandins (PG) from arachidonic acid due to inhibition of the enzyme cyclooxygenase (COX) [1].
One of the initial mechanisms of cellular response during inflammation is the release of arachidonic acid from membrane phospholipids, which is quickly metabolized by COX enzymes, lipoxygenase and the cytochrome P-450 system [2]. The main pathways of arachidonic acid metabolism are presented in Figure 1.
One of the most important achievements of pharmacology was the discovery of the existence of two main isoforms of COX: COX-1 and COX-2. COX-1 is a structural enzyme, synthesized in most cells of a healthy body (excluding red blood cells) and catalyzes the formation of physiological PGs, thromboxane and prostacyclin, which occupy an important place in the regulation of a number of physiological processes in the body, such as blood coagulation, regulation of vascular tone, protection of the mucosa gastrointestinal tract (GIT), bone metabolism, growth of nervous tissue, pregnancy, provision of renal blood flow, processes of regeneration and apoptosis. The existence of another COX isoform, COX-3, is also suggested. The putative COX-3 is expressed in the brain, also affects the synthesis of PG and is involved in the development of pain and fever, however, unlike other isoforms, it does not affect the development of inflammation. The activity of COX-3 is inhibited by acetaminophen (paracetamol), which has a weak effect on COX-1 and COX-2.
According to the accepted concept, inhibition of COX-2 is the most important aspect of the mechanism of anti-inflammatory action of NSAIDs, and suppression of COX-1-dependent PG synthesis is associated with the main side effects of NSAIDs (damage to the gastrointestinal tract, platelet aggregation, disturbances of renal blood flow, etc.). Various representatives of NSAIDs differ not only in their chemical structure and pharmacodynamics, but also in their effects on various COX isoforms [3].
Classification of NSAIDs by mechanism of action (inhibitory activity against different COX isoforms):
Selective COX-1 inhibitors:
acetylsalicylic acid in low doses (up to 325 mg).
Non-selective inhibitors of COX-1 and COX-2:
amtolmetin guacil, aceclofenac, acemetacin, acetylsalicylic acid, benzydamine, dexketoprofen, diclofenac, ibuprofen, indomethacin, ketoprofen, ketorolac, lornoxicam, metamizole sodium, methyl salicylate, naproxen, piroxicam, propyphenazone, tenoxicam, phenazone, phenylbutazone, fl urbiprofen, choline salicylate, etodolac, etofenamate.
Selective COX-2 inhibitors:
meloxicam, nimesulide.
Highly selective COX-2 inhibitors:
parecoxib, celecoxib, etoricoxib [4].
Side effects of NSAIDs
When discussing the use of NSAIDs, it is necessary to take into account the problem of side effects.
The structure-modifying properties of NSAIDs appear when they are taken over a long period of time in therapeutic doses. In this situation, the risk of developing complications specific to this class, mainly in the form of disturbances in the structure and function of the gastrointestinal tract and cardiovascular system (CVS), may become the main factor limiting the therapeutic potential of these drugs (Table 1) [5]. The most important complications include the so-called NSAID gastropathy (pathology of the upper gastrointestinal tract, manifested by clinically significant ulcers, bleeding and perforation) and cardiovascular accidents (myocardial infarction, ischemic stroke and sudden coronary death). Among these complications, NSAID-associated gastropathy has the greatest practical importance. This is a serious medical and social problem given the widespread use of NSAIDs [6].
Nephrotoxicity is the second most important group of adverse drug reactions of NSAIDs, which develops as a result of systemic non-selective suppression of prostaglandin synthesis, which leads to narrowing of the lumen of blood vessels and a decrease in renal blood flow. As a result, renal ischemia quickly develops, the glomerular filtration rate decreases, and the volume of diuresis decreases. There is a disturbance in water-electrolyte metabolism, which causes water retention in the body, edema, hypernatremia, hyperkalemia, the level of creatinine in the serum increases, and blood pressure rises. Hepatotoxicity with NSAIDs is rare. According to various estimates, in 1–4% of cases there is an asymptomatic moderate increase in the level of liver transaminases (ALAT, AST) [6].
Use of NSAIDs for musculoskeletal pain
Diseases characterized by the development of musculoskeletal pain (MSP) represent one of the main medical and social problems. This pathology is a source of suffering and social losses for millions of people, one of the common causes of short-term or permanent disability and a serious burden for the state and society, which are forced to spend huge amounts of money on diagnosis, treatment and care of patients. Patients need adequate medical care, first of all, quick and complete pain relief [7].
MPS is extremely common and accounts for approximately one third of all acute and chronic pain syndromes. Their localization is very diverse, but most often it is the lumbar and sacral spine, lower leg, shoulder girdle and neck. Moreover, in half of patients with MBS, pain occurs in several areas simultaneously [8].
MPS is characterized by both acute and chronic pain syndromes. The initial pain that occurs is usually acute, sharp, intense, and it goes away when the irritant is eliminated and the damaged tissue or organ is restored. This pain warns the body of danger, performs a protective function and ensures the activation of systems aimed at eliminating the damaging factor. In some cases, pain does not occur in response to damage: often it has already been eliminated, but the pain remains, no longer being a protective, but a damaging factor in the body. Chronic pain often becomes an independent disease, being the only symptom that bothers the patient for a long time, and often its cause cannot be determined. Chronic pain affects an average of 15–20% of the population, and most often this pain is associated with musculoskeletal problems [9].
Adequate medicinal pain relief not only alleviates the patient’s condition, but also facilitates a faster return to his usual level of daily activity. The key direction of symptomatic and pathogenetic treatment of back pain is the use of NSAIDs (Table 2) [10–12].
A feature of modern NSAIDs is the existence of a variety of dosage forms (tablets, suspensions), including for topical use in the form of ointments, gels, sprays, as well as suppositories and preparations for parenteral administration. However, their prescription requires a lot of attention and knowledge from the doctor in order to individually select an effective and safe remedy among many drugs [13].
NSAIDs for topical use
Since the use of NSAIDs orally or parenterally is often accompanied by the development of side effects and complications in patients, more attention is currently focused on topical NSAIDs. The ability to use drugs locally (externally) allows the active substance to be delivered as close as possible to the source of pain without causing systemic effects, which significantly reduces the risk of side effects and complications.
The transdermal route of administration has many advantages over other forms of drug delivery:
reduces the risk of side effects due to the fact that the drug reaches the bloodstream, bypassing the gastrointestinal tract and the first passage through the liver;
expands the possibilities of using drugs with a short half-life as a result of their continuous long-term intake into the patient’s body;
allows you to reduce the daily and course doses of the drug due to a decrease in the metabolism of the drug when passing through the liver;
provides the opportunity to use medications that irritate the gastric mucosa;
ensures painlessness and ease of use of medications. Patients can self-administer medications at home (as opposed to nursing-assisted injections and intravenous administration) [14].
Treatment options for chronic pain have expanded with the development of transdermal therapeutic systems (TTS), which provide a simple, convenient, and safe dosage form of drug administration. Several classifications of TTS can be distinguished. S.S. Khmelevskaya et al. propose to use a classification similar to the classification of ophthalmic drugs of this type:
matrix (with drug release through diffusion);
erosive (drug release is carried out by diffusion with simultaneous erosion of the therapeutic system);
reservoir (with diffusion of the active ingredient through membranes), osmotic mini-pumps.
Literary sources also provide another classification of TTS:
TTC - medicinal films (DP).
TTC - ointments, gels, pastes.
TTC - discs, patches [15].
When using a patch form of TTC, the goal of prolonged action of the drug is achieved. In this case, the dose and absorption surface are set quite accurately, which significantly distinguishes them from ointments, creams, and gels [16].
The use of TTS has many undeniable advantages and obvious advantages over other dosage forms:
makes it possible to strictly control the total concentration of the active substance in the patient’s body and its delivery rate;
ensures a more uniform supply of the drug, thereby significantly reducing fluctuations in the concentration of the drug in the blood and associated adverse reactions, which is especially important for drugs with a low therapeutic index;
allows you to increase the duration of exposure to medicinal substances that have a short half-life due to continuous long-term entry into the body;
ensures prolonged action of the drug, which reduces the cost of treatment and reduces the frequency of administration;
is the most non-invasive method of drug delivery;
makes it possible to more correctly dosage the drug; at the same time, the risk of overdose is minimized, since the entire dose of the drug is outside the body, and treatment can be interrupted if necessary;
facilitates the process of drug therapy, preventing the possibility of missing a drug dose, especially when long-term treatment of patients with chronic diseases is necessary [17].
TTC delivery of NSAIDs is widely used in foreign practical medicine.
In Russia today, the State Register of Medicines lists 35 trade names of medicines produced in the form of TTC, mostly foreign-made. Of these, only 4 are NSAIDs: 3 TTC containing diclofenac, and 1 TTC containing ketoprofen.
Hormonal ointments
When there is no positive dynamics from the use of non-hormonal ointments, specialists resort to hormonal drugs. Their main components are glucocorticosteroids - hormones that are produced by the adrenal glands in the human body. The mechanism of action of such drugs is based on the effect on the metabolism of proteins and carbohydrates. Hormonal ointments restore the level of cortisone, with a deficiency of which the body becomes unable to cope with inflammatory processes.
Depending on the degree of impact on the skin, hormonal ointments are divided into several categories:
- weak,
- average,
- strong,
- very strong.
The latter are used only for the most severe forms of dermatitis, so they are never prescribed first. Examples of hormonal ointments:
- Hydrocortisone,
- Celestoderm,
- Akriderm,
- Advantan,
- Elokom,
- Dermovate,
- Fucicort.
The main disadvantages of hormonal ointments in the treatment of dermatitis:
- Addiction. The main disadvantage is that over time the ointment ceases to be effective for treating a particular patient. The same active components of hormonal ointments are addictive.
- Side effects. Due to their hormonal nature, such ointments have many unpleasant side effects. They appear when used incorrectly or for too long. In severe cases, skin atrophy and even adrenal insufficiency may develop.
- Presence of withdrawal syndrome. As in the case of non-hormonal ointments, when using hormonal ointments, you cannot interrupt the course and skip application. The withdrawal syndrome manifests itself especially strongly when abruptly stopping a hormonal drug. This means that symptoms of dermatitis may suddenly return. For this reason, hormonal drugs are discontinued gradually, reducing the dose and number of applications.
Hormonal products can claim to be the best ointments for dermatitis, but only in terms of effectiveness. Yes, they help cope with the symptoms of the disease faster than non-hormonal ones. But at the same time, they can have a short-term effect, require very strict adherence to the treatment regimen, have side effects and a large list of contraindications, which includes:
- venereal diseases;
- tuberculosis;
- pregnancy and lactation;
- herpes;
- bacterial or fungal skin lesions.
