Non-narcotic analgesics - indications for use, effect on the body and possible consequences

Abuse of non-narcotic analgesics

Most of the population does not have a proper understanding of the clinical pharmacology of painkillers. Given the free sale of NSAIDs, people often abuse them without even reading the instructions. Some medications, such as phenacetin and amidopyrine, even cause a mild euphoric effect.

Phenacetin, now banned in the Russian Federation, has the greatest toxicity. When this drug is abused, drug intoxication with psychopathological manifestations has been observed. Consequences included emotional lability, addiction to other substance abuse disorders, and personality changes. The withdrawal syndrome was extremely difficult - with sleep disorders and gastrointestinal dysfunction.

Many “pharmacy drugs” (“Spazmolex”, “Zaldiar”, “Trigan D”) contain paracetamol, which recreational users mistakenly do not pay attention to. Acute overdose of NSAIDs is associated with the rapid development of toxic hepatitis and renal failure, which can be fatal. If you experience a severe headache, confusion, or convulsions, you should immediately call an emergency medical team.

Postoperative pain relief

A. M. Kokhan , anesthesiologist at Medical On Group (Odintsovo, International Medical Center)

After completion of surgery and after the local anesthetics have worn off, one of the main problems in the early postoperative period is pain. For its treatment in modern outpatient practice, non-narcotic analgesics are used, which, in addition to analgesic effects, have antipyretic, anti-inflammatory and desensitizing properties.

Analgesic (“painkiller”, from ancient Greek a? - “without, against” and a?????? - “pain”) - a medicinal substance of natural, semi-synthetic or synthetic origin, intended to relieve pain - analgesia .

Non-steroidal anti-inflammatory drugs (non-narcotic analgesics, non-steroidal anti-inflammatory drugs, NSAIDs, NSAIDs, NSAIDs, NSAIDs) are a group of drugs that have analgesic, antipyretic, desensitizing and anti-inflammatory effects that reduce pain, fever and inflammation.

They are characterized by:

nonspecific anti-inflammatory effect, that is, an inhibitory effect on any inflammatory process, regardless of its etiological and nosological characteristics;
relatively good tolerability associated with their rapid elimination from the body;
in therapeutic doses - an inhibitory effect on platelet aggregation and the interaction of immunocompetent cells;
binding to plasma albumin, and there is competition between different drugs for binding sites.

The use of the term “nonsteroidal” in the name emphasizes their difference from glucocorticoids, which have not only an anti-inflammatory effect, but also other, sometimes undesirable, properties of steroids.

The second name, non-narcotic anti-inflammatory drugs (NSAIDs), is appropriate because these drugs reduce the perception of pain without noticeably disrupting other functions of the central nervous system and are devoid (unlike narcotic analgesics) of psychotropic effects (and therefore the development of a patient’s addiction to them) and depressing effects. on nerve centers, which allows them to be used more widely, for a long time, and also in outpatient practice [1, 2].

In the mechanism of action of non-narcotic analgesics, a certain role is played by the influence on the thalamic centers, which leads to inhibition of the conduction of pain impulses in the cerebral cortex

The main mechanism of action of NSAIDs was discovered by J. Vane et al in 1971. The mechanism of action of NSAIDs is the suppression of prostaglandin (PG) synthesis by inhibiting the activity of cyclooxygenase (COX), a key enzyme in the metabolism of arachidonic acid. Tissue damage is accompanied by a violation of cell integrity. In response to any damage to the cell structure, a cascade of reactions is triggered, leading to the oxidation of arachidonic acid. NSAIDs inhibit the activity of cyclooxygenases, thus affecting the synthesis of prostaglandins, and therefore breaking the chain of the inflammatory reaction [3].

Also in the mechanism of action of non-narcotic analgesics, a certain role is played by the influence on the thalamic centers, which leads to inhibition of the conduction of pain impulses in the cerebral cortex. By the nature of the central action, these analgesics differ from narcotic ones in that they do not affect the ability of the central nervous system to summation of subcortical impulses [4].

Non-narcotic analgesics in their pharmacological properties differ significantly from the analgesics of the morphine group. These drugs are significantly inferior in their analgesic effect to narcotic painkillers. Non-narcotic analgesics do not depress breathing, do not cause euphoria or drug dependence, do not have a hypnotic effect, and do not affect the cough center.

This group of drugs clearly exhibits anti-inflammatory and antipyretic effects that narcotic analgesics do not have. The advantage of these drugs is the absence of a narcotic effect, which has given rise to their widespread use in outpatient practice.

Non-narcotic analgesics are classified according to their chemical structure:

Salicylic acid derivatives: acetylsalicylic acid (aspirin), lysine acetylsalicylate (acelysin), sodium salicylate, methyl salicylate, salicylamide, Viox (difiunisal - a derivative of salicylic acid) - have a prolonged anti-inflammatory and analgesic effect. Representatives of this group are characterized by low toxicity. LD50 (semi-lethal dose - the average dose of a substance that causes the death of half the members of the test group) of acetylsalicylic acid is 120 g. However, they have a noticeable irritant effect (risk of ulceration and bleeding). Drugs in this group are contraindicated in children under 12 years of age.
Pyrazolone derivatives: amidopyrine (aminophenazone), metamizole sodium (analgin), phenylbutazone (butadione), phenazone (antipyrine). The drugs have a small breadth of therapeutic action, inhibit hematopoiesis, and therefore are not prescribed for a long time. Analgin, due to its good water solubility, is used intramuscularly, subcutaneously and intravenously for emergency pain relief and treatment of hyperthermia; amidopyrine increases convulsive readiness in young children and reduces diuresis.
Para-aminophenol derivatives: phenacetin and paracetamol. Representatives of this group lack anti-inflammatory activity, antiplatelet and anti-rheumatic effects. They practically do not cause ulcer formation, do not inhibit kidney function, and do not increase convulsive activity of the brain. Paracetamol is the drug of choice for the treatment of hyperthermia, especially in children. Phenacetin causes nephritis with long-term use.
Derivatives of organic acids: Phenylacetic - diclofenac sodium (ortofen, voltaren). This drug rarely causes ulceration and is used primarily as an anti-inflammatory and antirheumatic agent. Phenylpropionic acid - ibuprofen, naproxen, ketoprofen, pirprofen, tiaprofenic acid (tiaprofen). Ibuprofen is similar to diclofenac; naproxen and pyroprofen provide a greater anti-inflammatory effect; Tiaprofen exhibits greater selectivity in suppressing the synthesis of PG F2-alpha (less likely to have side effects on the bronchi, gastrointestinal tract and uterus). Indoleacetic - methindole (indomethacin), sulindac, selective COX-2 inhibitor - stodolac. Indomethacin is the standard in terms of anti-inflammatory activity (maximum), but interferes with the exchange of brain mediators (reduces the level of GABA) and provokes insomnia, agitation, hypertension, convulsions, and exacerbation of psychoses. Sulindac turns into indomethacin in the patient's body and has a longer and slower effect. Anthranilic (fenamic): mefenamic acid, flufenamic acid. Mefenamic acid is used mainly as an analgesic and antipyretic; Niflumic acid is similar in properties to mefenamic acid; Flufenamova is used as an anti-inflammatory agent (weak analgesic). Pyrrolizine carboxylic acid - ketorolac. Has a pronounced analgesic effect.
Oxicams: piroxicam, tenoxicam, loroxicam (xefocam), selective COX-2 inhibitor meloxicam. The drugs differ in their duration of action (12-24 hours) and their ability to penetrate well into inflamed tissues.
Non-acid derivatives Alkanones: selective COX-2 inhibitors - nabumetone. Sulfonamide derivatives: nimesulide (Nise), rofecoxib, highly active COX-2 inhibitors - celecoxib (Celebrex) [2].

Based on the strength of the anti-inflammatory effect of average doses, NSAIDs are arranged in the following sequence (from maximum at the top to minimum at the bottom):

Indomethacin
Flurbiprofen
Diclofenac sodium
Piroxicam
Ketoprofen
Naproxen
Ibuprofen
Amidopyrine
Aspirin

According to the analgesic effect of average doses, NSAIDs can be arranged in the following sequence (from maximum at the top to minimum at the bottom):

Ketorolac
Ketoprofen
Diclofenac sodium
Indomethacin
Flurbiprofen
Amidopyrine
Piroxicam
Naproxen
Ibuprofen
Aspirin

Most NSAIDs are taken orally. They dissolve well in lipids, poorly in water, and are well absorbed from the gastrointestinal tract in the form of undissociated molecules by passive diffusion.

Bioavailability (in pharmacokinetics and pharmacology in a broad sense, this is the amount of a drug substance reaching the site of its action in the human body - the ability of the drug to be absorbed) of NSAIDs is 70-100%. Since NSAIDs are weak organic acids, their absorption is improved in an acidic environment. A shift in the pH of gastric contents to the alkaline side significantly reduces the rate of absorption. The maximum concentration of most NSAIDs in the blood is reached after 1-2 hours. Food slows down absorption. Water-soluble forms of some drugs (sodium salicylate, diclofenac, metamizole, acetylsalicylic acid) can be administered intravenously or intramuscularly.

Saridon

Consists of paracetamol, propyphenazone and caffeine. The ratio of analgesics in the drug is 5:3. With this ratio, they act as synergists, since paracetamol in this case increases the bioavailability of propyphenazone by one and a half times. Caffeine normalizes cerebral vascular tone, accelerates blood flow, without having a stimulating effect on the central nervous system in the dose used. Therefore, caffeine enhances the effect of analgesics for headaches. In addition, it improves the absorption of paracetamol. Saridon is generally characterized by high bioavailability and rapid development of analgesic effect.

Indications:

Pain syndrome of various localization (headache, toothache, pain in rheumatic diseases, dysmenorrhea, fever).

Dosage:

1-2 tablets 1-3 times a day.

Release form:

Tablets containing 250 mg of paracetamol, 150 mg of propyphenazone and 50 mg of caffeine.

Plivalgin

Available in tablet form, each containing 210 mg of paracetamol and propyphenazone, 50 mg of caffeine, 25 mg of phenobarbital and 10 mg of codeine phosphate. The analgesic effect of the drug is enhanced due to the presence of narcotic analgesics codeine and phenobarbital, which have a sedative effect. The role of caffeine is discussed above.

Indications:

Pains of various localizations (headache, dental, muscle, joint, neuralgia, dysmenorrhea), fever.

Warnings:

With frequent use, especially in high doses, you may feel tired and drowsy. Drug dependence may develop.

Dosage:

1-2 tablets 3-4 times a day [5].

If possible, the simultaneous administration of NSAIDs and diuretics should be avoided due to, on the one hand, a weakening of the diuretic effect and, on the other, the risk of developing renal failure

Main contraindications for use:

Individual intolerance, including in patients with broncho-obstructive syndrome.
Erosion and ulcers of the gastrointestinal tract.
Pregnancy (with the exception of aspirin in small doses as an antiplatelet agent).
Severe dysfunction of the liver and kidneys.
Leuko- and thrombocytopenia.

Approaches to rational prescribing and dosing of NSAIDs:

Before prescribing an NSAID to a patient, it is necessary to decide whether this drug is really indicated for him.
Taking into account modern standards of pharmacotherapy for the existing disease, it is necessary to develop a treatment program with minimally effective doses in the shortest possible time. As a rule, in acute cases, the beginning of treatment (the first hours, days) with high doses with a quick transition to maintenance doses is more effective and safe than uncontrolled long-term use.
NSAIDs are unequal in their damaging effect on the stomach and intestines, liver, kidneys and blood cells, which should be taken into account when planning therapy, especially long-term therapy, and if it is necessary to use these drugs in patients with pathology of the above organs, elderly and senile patients.
Each patient has his own NSAID drug(s) with the best efficacy and safety profile. It is impossible to predict a patient's reaction to a specific drug. The ineffectiveness of one drug does not mean the ineffectiveness of the subgroup as a whole. If long-term treatment is necessary, the optimal drug can be determined using sequential trial treatment with various NSAIDs with a comparative assessment of its results.
When assessing the effectiveness, it is necessary to take into account that the analgesic effect is first noted (after hours of administration), and the manifestation of the anti-inflammatory effect itself is observed later; its assessment should be carried out no earlier than after 2 weeks of regular use (oxicams - after 4 weeks).
As a rule, NSAIDs are used after meals, in a sitting position, with 150-250 ml of boiled water at room temperature.
The time of taking the drug should be associated with the part of the day when the symptoms of the disease are most pronounced. By this time, the peak effect of the drug should be observed. Under this condition, it is not necessary to ensure the effect of the drug throughout the day; “asymmetrical” administration 1-2 times a day is possible.
The simultaneous use of two or more NSAIDs is not advisable due to the lack of evidence of the rationality of such combinations and the presence of data on the competition of various NSAIDs for binding to blood proteins, which may increase the risk of side effects. An exception is possible with a combination of fast- and short-acting dosage forms at different times of the day.

Many drugs prescribed concomitantly with NSAIDs, in turn, can affect their pharmacokinetics and pharmacodynamics

Side effects associated with the main effect of NSAIDs - suppression of prostaglandin synthesis.

Gastrotoxicity - dyspeptic disorders, erosions and ulcers of the stomach and duodenum and subsequent complications in the form of bleeding and perforation. It is necessary to simultaneously prescribe drugs that protect the mucous membrane of the gastrointestinal tract. Misoprostol and proton pump blockers (omeprazole) have the best effect; high doses of H2 blockers (famotidine 40 mg 2 times a day) can be effective.

Nephrotoxicity:

deterioration of renal blood flow with possible deterioration of kidney function, impaired water-electrolyte and nitrogen metabolism, increased blood pressure;
direct damaging effect on the kidney parenchyma such as interstitial nephritis (nephropathy).

Violation of blood coagulation activity - through inhibition of platelet aggregation and prothrombin formation in the liver. These phenomena can contribute to the development of bleeding, primarily from the gastrointestinal tract.

Bronchospasm is more common in patients already suffering from bronchial obstructive syndrome.

Prolongation of pregnancy and delay of childbirth.

Side effects not related to the main effect of NSAIDs - suppression of prostaglandin synthesis

Hematotoxicity - a decrease in the number of red blood cells and leukocytes in the blood, up to aplastic anemia and agranulocytosis. It is most pronounced in pyrazolone derivatives.

Hepatotoxicity is an increase in the activity of liver enzymes in the blood, in rare cases with the development of clinical manifestations of hepatitis.

Allergic reactions are possible, as with the use of any other medications, skin rash, Quincke's edema, anaphylactic shock, Lyell's and Stevens-Johnson syndromes.

The analgesic effect of NSAIDs is enhanced by sedatives; in addition, the effect of NSAIDs is enhanced by antihistamines

Routine safety monitoring of NSAID use:

informing patients about possible side effects and necessary actions if their development is suspected;
systematic monitoring of blood pressure.

The optimal analgesic in the postoperative period is ketorolac, the analgesic activity of which is comparable to 12 mg of morphine. The maximum effect develops within 2-3 hours.

The effect of inhibiting platelet aggregation ceases after 24-48 hours.

Bioavailability in adults is 100%, regardless of the route of administration.

No carcinogenic effect or mutagenicity was detected, and it does not affect fertility. Strengthening and increasing the duration of pain relief is possible by combining the drug with first-generation antihistamines that have a sedative effect [6].

Recommended oral combinations on the first day (no more than 5 days):

Ketorolac 10-20 mg and diphenhydramine 100 mg - 2 times;
Ketorolac 10-20 mg and suprastin 25 mg - 3 times;
Ketorolac 10-20 mg and tavegil 1 mg - 2-3 times;
Ketorolac 10-20 mg and peritol 4 mg - 2-3 times.

In the next day - 1-2 times, depending on the intensity of the pain syndrome, but no more than 5 days.

Table No. 1. Comparative characteristics of the analgesic effect of NSAIDs using the example of aspirin. Drugs of Choice from the Medical Letter, 1995

A drug	Single dose	Interval	Maximum daily dose	Note
Aspirin	Orally 500–1000 mg	4–6 hours	4000 mg	Duration of action after a single dose: 4 hours
Paracetamol	Orally 500–1000 mg	4–6 hours	4000 mg	Equal in effectiveness to aspirin; 1000 mg is usually more effective than 650 mg; duration of action is 4 hours.
Diflunisal	Orally 1st dose 1000 mg, then 500 mg	8–12 hours	1500 mg	500 mg diflunisal > 650 mg aspirin or paracetamol, approximately equal to paracetamol/codeine combination; acts slowly but lasts
Diclofenac-potassium	Orally 50 mg	8 ocloc'k	150 mg	Compare with aspirin, longer action
Etodolac	Orally 200–400 mg	6?8 hours	1200 mg	200 mg is approximately equal to 650 mg aspirin, 400 mg > 650 mg aspirin
Fenoprofen	Orally 200 mg	4–6 hours	1200 mg	Compare with aspirin
Flurbiprofen	Orally 50–100 mg	6?8 hours	300 mg	50 mg > 650 mg aspirin; 100 mg > paracetamol/codeine combinations
Ibuprofen	Orally 200–400 mg	4–8 hours	2400 mg	200 mg = 650 mg aspirin or paracetamol; 400 mg = paracetamol/codeine combinations
Ketoprofen	Orally 25–75 mg	4–8 hours	300 mg	25 mg = 400 mg ibuprofen and > 650 mg aspirin; 50 mg > paracetamol/codeine combination
Ketorolac	Intramuscular 30–60 mg	6 hours	120 mg	Compare with 12 mg of morphine, longer action, course no more than 5 days
Mefenamic acid	Orally 1st dose 500 mg, then 250 mg	6 hours	1250 mg	Comparable to aspirin, but more effective for dysmenorrhea, course no more than 7 days
Naproxen	Orally 1st dose 500 mg, then 250 mg	6–12 hours	1250 mg	250 mg is approximately equal to 650 mg aspirin, slower but longer acting; 500 mg > 650 mg aspirin, quick effect same as aspirin
Naproxen sodium	Orally 1st dose 550 mg, then 275 mg	6–12 hours	1375 mg	275 mg is approximately equal to 650 mg aspirin, slower but longer-lasting action; 550 mg > 650 mg aspirin, the same speed of effect as aspirin

Table No. 2. Effect of NSAIDs on the effect of other drugs. By Brooks PM, Day RO, 1991, with additions

A drug	NSAIDs	Action	Recommendations
Pharmacokinetic interaction
Indirect anticoagulants	Phenylbutazone Oxyphenbutazone	Inhibition of metabolism in the liver, enhancing the anticoagulant effect	Avoid these NSAIDs if possible or closely monitor
Everything, especially aspirin	Displacement from plasma proteins, enhancing the anticoagulant effect	Avoid NSAIDs if possible or closely monitor
Oral hypoglycemic drugs (sulfonylureas)	Phenylbutazone Oxyphenbutazone	Inhibition of metabolism in the liver, increased hypoglycemic effect	Avoid NSAIDs if possible or closely monitor blood glucose levels
Everything, especially aspirin	Displacement from plasma proteins, enhancing the hypoglycemic effect
Digoxin	All	Inhibition of renal excretion of digoxin in case of impaired renal function (especially in young children and the elderly), increasing its concentration in the blood, increasing toxicity. If renal function is normal, interaction is less likely	Avoid NSAIDs if possible, or closely monitor creatinine clearance and blood digoxin concentrations
Aminoglycoside antibiotics	All	Inhibition of renal excretion of aminoglycosides, increasing their concentration in the blood	Strict control of aminoglycoside concentrations in the blood
Methotrexate (high "non-rheumatological" doses)	All	Inhibition of renal excretion of methotrexate, increase in its concentration in the blood and toxicity (no interaction with the “rheumatological” dose of methotrexate is observed)	Simultaneous administration is contraindicated. It is acceptable to use NSAIDs during periods of chemotherapy
Lithium preparations	All (to a lesser extent aspirin, sulindac)	Inhibition of renal excretion of lithium, increase in its concentration in the blood and toxicity	Use aspirin or sulindac if NSAIDs are necessary. Strict control of lithium concentration in the blood
Phenytoin	Phenylbutazone Oxyphenbutazone	Inhibition of metabolism, increased blood concentration and toxicity	Avoid these NSAIDs if possible, or closely monitor phenytoin blood concentrations
Pharmacodynamic interaction
Antihypertensive drugs Beta blockers Diuretics ACE inhibitors*	To the greatest extent indomethacin, phenylbutazone. At the least? sulindak	Weakening the hypotensive effect due to inhibition of PG synthesis in the kidneys (sodium and water retention) and blood vessels (vasoconstriction)	Use sulindac and avoid other NSAIDs if possible for hypertension. Strict blood pressure control. Increased antihypertensive therapy may be required
Diuretics	To the greatest extent indomethacin, phenylbutazone. At the least? sulindak	Weakening of diuretic and natriuretic effects, worsening of heart failure	Avoid NSAIDs (except sulindac) in heart failure, strictly monitor the patient's condition
Indirect anticoagulants	All	Increased risk of gastrointestinal bleeding due to mucosal damage and inhibition of platelet aggregation	Avoid NSAIDs if possible
Higher risk combinations
Diuretics All	All (to a lesser extent sulindac)	Increased risk of developing kidney failure	The combination is contraindicated
Triamterene	Indomethacin	High risk of developing acute renal failure	The combination is contraindicated
All potassium-sparing	All	High risk of developing hyperkalemia	Avoid such combinations or strictly monitor plasma potassium levels

The list of references is in the editorial office

pharmachologic effect

All narcotic analgesics stimulate opioid receptors in the brain and spinal cord, which are responsible for the perception of pain. This stimulation leads to a blockade of the transmission of pain impulses to the pain centers, and also reduces the patient’s perception of pain severity.

In addition to the analgesic - pain-relieving - effect, narcotic analgesics have a sedative (calming) effect (a state of rest), euphoria (a state of causeless high mood with pleasant sensations and freedom from problems and anxieties). This leads to the development of drug addiction - an irresistible desire to take these drugs again and again.

All narcotic analgesics additionally block the cough center in the medulla oblongata, which leads to the development of an antitussive effect.