Analgin is a widely used medication that has an affordable price. It belongs to the group of non-steroidal anti-inflammatory drugs. Its peculiarity is its pronounced analgesic and antipyretic properties.
The drug is produced in ampoules for intramuscular administration and in tablets. The second form is more popular. One tablet of the drug contains 250 or 500 mg of metamizole sodium. The active substance provides a strong analgesic, antipyretic and anti-inflammatory effect. It is quickly absorbed into the gastrointestinal tract and subsequently excreted by the kidneys.
What does analgin help with?
The question of what analgin helps with is very common. The range of applications of this medicinal pain reliever is extremely wide. It can be used to relieve pain of various etiologies, in particular:
- After injury or surgery.
- Caused by spasms of the muscles of internal organs.
- Caused by the development of tumor processes.
As the instructions for Analgin indicate, it is indicated to alleviate the condition of patients with chronic pain of varying intensity. It allows you to stabilize the body’s condition when it is impossible to carry out other effective therapeutic measures. Analgin is used, the instructions for use indicate this, in order to lower high temperatures in infectious diseases, if this has not been achieved with other antipyretic drugs.
It is quite difficult to list exactly what analgin helps with due to the wide range of uses of the medicine. The most commonly taken tablets are for headaches and toothaches. It has proven its effectiveness in neuralgia and myalgia. In combination with antispasmodic drugs, analgin alleviates the patient's condition with renal and biliary colic.
What we are treated with: Analgin. To numb the pain or defeat the disease
Scientific review of a popular painkiller
Why is one of the most accessible and well-known painkillers in our country dangerous, against what types of pain is it effective, how do medical researchers fight for the lives of patients with pharmaceutical companies and with each other, why Sweden first banned Analgin, then allowed it, and then banned it again, read the material from Indicator.Ru from the section “How we are treated.”
Medicines designed to combat pain, fever and inflammation are among the most sought after on the pharmaceutical market. They are in any medicine cabinet and are often sold without a prescription in Russia, but in reality, many of them can seriously threaten health, especially if you do not first weigh all the pros and cons of such treatment and do not take into account risk factors.
The hero of today’s issue of the “How We Are Treated” column is the familiar Analgin - a cheap and accessible pain reliever and antipyretic. You may be surprised, but it is prohibited for sale in Western Europe and the USA, as well as several other countries.
From what, from what
The active ingredient in Analgin is called metamizole. It was first synthesized in 1920 by Ludwig Knorr, who is also known for discovering and studying several non-steroidal anti-inflammatory drugs, such as antipyrine; He was also interested in the properties of morphine and codeine. At the beginning of the 20th century, there were not as many rules and complex approval procedures for the drug as there are now, so the drug began to be produced just two years after its discovery. In the West, a drug based on metamizole is called Dipirone.
Metamizole molecule. Sulfur atoms are indicated in yellow, carbon in gray, oxygen in red, nitrogen in blue, and hydrogen in white.
Scientists have not fully established the exact mechanism of operation of this molecule, but metamizole presumably blocks the synthesis of prostaglandins in the brain and spinal cord. We have already told the heartbreaking story that the causes of pain and inflammation lie precisely in their incorrect behavior after meeting with the cyclooxygenase sisters in the article about Nurofen. However, Metamizole is not as hardworking as our previous heroes: he does not go to suppress the uprising of dissatisfied prostaglandins personally, but sends his derivatives. It was also not found to be associated with type 1 cannabinoid receptors located in the cells of the central system, which substances from hemp, as well as paracetamol, are blamed for. Although it most likely has some influence on this system. Other authors, on the contrary, argue that, although Analgin himself did not work there, his subordinate metabolites could well act on type 1 cannabinoid receptors at his “guidance.”
The Cochrane Collaboration reviewed our review, which looked at moderate to high quality studies assessing the ability of metamizole to help with post-operative acute pain. Despite the confusion, the review confirms that this drug really works.
The Cochrane Library is a database of the Cochrane Collaboration, an international non-profit organization involved in the development of guidelines from the World Health Organization. The organization's name comes from its founder, the 20th-century Scottish medical scientist Archibald Cochrane, who championed the need for evidence-based medicine and good clinical trials and wrote the book Efficiency and Effectiveness: Random Reflections on Health Care. Medical scientists and pharmacists consider the Cochrane Database to be one of the most authoritative sources of such information: the publications included in it have been selected according to the standards of evidence-based medicine and report the results of randomized, double-blind, placebo-controlled clinical trials.
Compared to placebo, which helped only 30% of patients, a single dose of metamizole 500 mg improved the condition of 70% of study participants. True, the authors still had doubts about comparing the active substance Analgin with other painkillers: the results were too ambiguous, and the patient samples were small.
The effect of Dipiron (Analgin) against acute attacks of pain (for example, after the removal of a wisdom tooth) and in renal colic has also been proven. In the latter case, scientists also proved that intravenous injections help better than intramuscular ones.
Side effects
Analgin can be dangerous in a completely different way: our granulocytes, one of the types of leukocytes, do not like it. Associated with them is a side effect of long-term use of the drug - agranulocytosis, that is, a drop in the level of granulocytes to 5% or even lower.
Granulocytes are granular leukocytes, white blood cells, which are characterized by a clearly visible nucleus and large granules inside. In every cubic millimeter of our blood you can find about 2-6 thousand of these cells. Their goal is to fight infections, or immune protection of the borders of our body. Agranulocytosis may be associated with the effect of Analgin on type 2 cannabinoid receptors.
There is scientific evidence to support this idea. Scientists from Germany, the USA and Italy prove that substances resulting from the breakdown of metamizole are able to bind both cannabinoid receptors. They also prove that these substances react with type 1 and type 2 cyclooxygenases both in vitro and in living tissue.
When the ranks of immune defenders are so thinned out, the body becomes vulnerable to many bacterial and fungal infections. Stomatitis, ulcers of the mucous membranes, fever, pain in the throat and joints are the first unpleasant manifestations of this condition. It can cause swelling of the larynx and even suffocation. This set of clinical signs can confuse the doctor, so it is not always possible to correctly determine the cause of these manifestations.
In case of complications, an atypical form of pneumonia occurs, which is difficult to diagnose due to the absence of cough and sputum, necrotic enteropathy (damage to the intestinal walls, pain and bloating in the abdomen, loose stools), which can lead to the death of the patient if bacteria from his intestines enter the blood . Also, with severe agranulocytosis, toxic hepatitis can develop - severe damage to liver tissue.
However, scientists continue to argue about how often taking Analgin leads to this disease.
The first articles about the dangers of Analgin began to be published back in the late 1960s, and one of them caused a stir among foreign doctors: according to this article, 0.79% of patients taking Dipiron also received agranulocytosis, and a third of patients with agranulocytosis died.
After this, Analgin-Dipirone was banned in the UK. The UK's example was followed by other countries where metamizole-based drugs disappeared from pharmacies in the seventies. At the same time, in Eastern Europe and Latin America, the same drugs were easily and freely sold, considering them to be safe analgesics. Therefore, the Europeans did not calm down and continued to look for evidence that would confirm the involvement of metamizole in the occurrence of agranulocytosis or justify the drug.
An international study was conducted, involving representatives from seven European cities and Jerusalem, but a large-scale search that lasted six years led to a rather modest figure: 1 case in 1.1 million patients per week. It looks like an excellent alibi, if you do not take into account that it included only patients in the hospital, and the controls were patients with agranulocytosis, from whom they were asked whether they drank metamizole. That being said, the case—the metric the scientists used—is quite unusual. If you recalculate the same data for a year, the figure will be completely different - 20,000.
Colleagues from Latin America saw a lot of bias in these studies: in their opinion, the risk estimates for using the drug were greatly overestimated. Thus, doctors from Sao Paulo did not find any particular dangers in the use of this medicine and stated that it, of course, increases the risk of developing agranulocytosis, but so weakly that this can be neglected without leaving people without an accessible medicine.
They also conducted another study, including Mexico and Argentina, but the results were the same. However, the author of the Russian review, Maria Avksentyeva, notes that this study was funded by a corporation that absorbed the producers of metamizole. In both studies, the risk of agranulocytosis was about half a person per million per year.
The Swedes also banned the drug. After a large-scale European project, they returned it to pharmacies again, but not just like that, but for the purpose of study. The indications became narrower: only for short-term use for renal and hepatic colic and acute pain after operations, and then doctors began to record side effects. Then the results convinced Swedish doctors that there was a danger, and in 1999 the drug was banned again.
The Dutch studied the effect of medications on agranulocytosis for 20 years, and they also considered metamizole dangerous for use. Library+will+be+unavailable+on+Saturday+01st+July+from+03.00-09.00+EDT+and+on+Sunday+2nd+July+03.00-06.00+EDT+for+essential+maintenance.++Apologies+ for+the+inconvenience), although in a small number of cases.
In a review from Barcelona doctors, metamizole took fourth place in the list of drugs that increase the risk of agranulocytosis, and for some reason no one is going to ban the winners from this “podium.” Leading the list, by the way, was methimazole, used to correct an overactive thyroid gland (that’s how important it is not to confuse the names).
In recent years, several more articles have appeared on this topic. The authors of another systematic review, examining 22 articles on the side effects of metamizole, also confirmed that the risk of agranulocytosis is increased, although its level varies greatly from one study to another. In another large study of a single dose of metamizole for post-operative pain, researchers assessed the drug's side effects in a group of 1,177 children under six years of age. The drug was administered once and intravenously, and no signs of agranulocytosis were found in patients. The same data for adults is confirmed by a review that assessed data from 79 studies.
Taking into account 77 reports from Switzerland and 1,417 international ones, the World Health Organization also summed up its conclusion: according to the conclusions of its experts, the risk is 0.46-1.63 per million person-days of use.
Thus, most of the results boil down to the fact that you should not use drugs based on metamizole for a long time, although, according to some data, a single dose may be relatively safe. Be that as it may, immigrants from Latin America to the United States continue to take metamizole illegally, swearing at local legislation, and some scientists suggest that the drug has a stronger effect on haplogroups common in Europe, so Latin Americans and Asians get much less.
Indicator.Ru recommends: can be used, but not for a long time
Scientific research data indicates the relative danger of the drug with long-term use, although not all scientists agree with this point of view. At the same time, in many developed countries the drug is either withdrawn from circulation or sold strictly according to a prescription, but in others it is freely sold, as in Russia. What to do? To be on the safe side, it is still better to heed the warnings and if you take Analgin, then do it for acute attacks of pain, but not for protracted, chronic pain. You can also make a choice in its favor if other painkillers do not help or are not suitable, but also do not get carried away with this drug and do not take it for more than a few days in a row.
Chronic use of analgesics can be dangerous: some, like many non-steroidal anti-inflammatory drugs, increase the risk of heart attack and gastrointestinal bleeding, others, like Analgin, can critically reduce the level of immune cells, a type of white blood cell, in the blood. And if this happens, you will become defenseless against a number of serious diseases, which can lead to pneumonia, hepatitis, and death at the end of this epic.
But always remember that numbing the pain does not mean defeating the disease itself. Therefore, it is better to try to find out the cause of the problem and eliminate it, if the pain does not go away after a couple of days, than to drink analgesics for weeks, turning a blind eye to a possible threat to your health not only from them, but also from the fact that while “treating” the symptoms you forget about the disease itself.
And if you still drink Analgin, listen carefully to your health: even severe stomatitis and an increase in temperature can be an alarming sign, after which it is better to go to the doctor and ask for a referral for a blood test so that these same leukocytes can be counted for you.
This article was published in the magazine “Idikator” on June 29, 2017.
Author: Ekaterina Mishchenko
Contraindications and adverse reactions
The main contraindication for taking the drug is hypersensitivity to the active component in its composition. Treatment with the drug in the 1st trimester of pregnancy is strictly prohibited. If possible, you should refrain from taking it during other periods of pregnancy and during breastfeeding until the child reaches 3 months of age. The drug is not prescribed to children under 10 years of age, and before reaching adulthood, when using the medicine, you should first consult a doctor.
Treatment with analgin should be discontinued if hematopoiesis is suppressed. In particular, agranulocytosis, which is characterized by changes in peripheral blood, is a contraindication. This is accompanied by severe symptoms: weakness, bleeding, problems with the digestive system, etc.
It is strictly forbidden to use analgin to relieve acute pain in the abdominal area until the causes of their occurrence are determined. It is also not recommended to use the drug for the following pathologies:
- Kidney or liver failure.
- Anemia.
- Leukopenia.
- Bronchial asthma.
- Pyelonephritis and glomerulonephritis
Failure to comply with contraindications and overdose may result in dangerous allergic reactions. This often manifests itself as a rash on the skin and Quincke's edema. In rare cases, anaphylactic shock, Lyell's syndrome or Stevens-Johnson syndrome develops.
You cannot take analgin for a long time for pain relief. Otherwise, you can provoke blood count violations. The risks of developing leukopenia or thrombocytopenia increase significantly.
Other possible adverse reactions of the body:
- An attack of bronchospasm.
- Reduced blood pressure.
- Malfunction of the kidneys.
If any negative side reactions occur, you should stop taking the drug. It is advisable to inform your doctor about this and consult about a possible replacement of the pain medication.
An overdose is recorded when using the medicine for a week in large doses to relieve pain. In this case, nausea and severe vomiting, decreased blood pressure and shortness of breath, delirium and impaired consciousness, as well as many other dangerous disorders of the body, may occur. You should urgently rinse and take saline laxatives. An increased drinking regimen and intake of absorbents are indicated. In severe cases, hemodialysis will be necessary.
Analgin
The drug contains a pyrazolone derivative, metamizole sodium, which can rarely cause life-threatening shock and agranulocytosis (see section “Side effects”). Patients who experience anaphylactoid reactions in response to the use of metamizole sodium are also at risk of developing them in response to the use of other non-narcotic analgesics/NSAIDs.
Patients who experience anaphylactic or other immune-mediated reactions (eg, agranulocytosis) in response to the use of metamizole sodium are also at risk of developing them in response to the use of other pyrazolones and pyrazolidines.
Agranulocytosis
If signs of agranulocytosis or thrombocytopenia appear (see section “Side Effects”), the drug should be immediately discontinued and a general blood test (with determination of the leukocyte formula) should be performed. Discontinuation of therapy should not be delayed until laboratory results are available.
Pancytopenia
If pancytopenia develops, the drug should be immediately discontinued and a complete blood count should be monitored until its values return to normal (see section “Side Effects”). All patients should be advised to seek immediate medical attention if signs and symptoms suggestive of a blood disorder (eg, weakness, infection, persistent fever, bruising, bleeding, pallor) occur during treatment.
Anaphylactic/anaphylactoid reactions
Before using metamizole sodium, it is necessary to conduct a thorough interview with the patient. If a risk of developing anaphylactoid reactions is identified, the use of the drug is allowed only after a thorough assessment of the possible risks and expected benefits. If a decision is made to use metamizole sodium, the patient must be under strict medical supervision and emergency measures must be prepared.
An increased risk of developing hypersensitivity reactions to metamizole sodium is caused by the following conditions: analgesic bronchial asthma or intolerance to analgesics (urticaria-angioedema type) (see section “Contraindications”); bronchial asthma, especially accompanied by rhinosinusitis and nasal polyposis; chronic urticaria; alcohol intolerance, against the background of which, even when taking a small amount of alcoholic beverages, patients experience sneezing, lacrimation and severe redness of the face.
Alcohol intolerance may indicate a previously unidentified analgesic bronchial asthma).
Anaphylactic shock may occur in susceptible patients, so special caution should be exercised in patients with asthma or atopy.
Severe skin reactions
Life-threatening skin reactions have been described with the use of metamizole sodium: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). If signs of SJS or TEN appear (such as a progressive skin rash, often accompanied by blistering or ulceration of the mucous membrane), treatment with metamizole should be stopped immediately and never restarted. Patients should be educated about the signs and symptoms of these diseases. They should be carefully monitored for skin reactions, especially during the first weeks of treatment.
Isolated hypotensive reactions
Metamizole sodium may cause hypotensive reactions (see also section "Side effects"). These reactions may be dose-dependent. The risk of such reactions is also increased in: pre-existing hypotension, decreased circulating blood volume or dehydration, unstable hemodynamics or acute circulatory disorders (for example, in patients with myocardial infarction or trauma), in patients with high fever. In this regard, such patients should undergo detailed diagnostics and be closely monitored. Preventive measures (eg, cardiovascular resuscitation) may be necessary to reduce the risk of hypotensive reactions.
In patients in whom lowering blood pressure should be avoided at all costs (for example, with severe ischemic heart disease or significant cerebral artery stenosis), metamizole sodium should only be used with careful monitoring of hemodynamic parameters.
Abdominal pain
It is unacceptable to use the drug to relieve acute abdominal pain (until the cause is determined).
Impaired kidney or liver function
In patients with impaired renal or liver function, the use of metamizole sodium is allowed only after a strict assessment of the benefits and risks, observing all the necessary precautions.
Dosage
Only if it is impossible to take pills for any reason, intramuscular or intravenous injections are indicated. A single dose is 1-2 ml of a 50% solution of metamizole sodium. The daily dose should not exceed 4 ml.
To relieve pain, it is recommended to take a 500 mg tablet. For acute pain, the dose can be increased one-time to 2 tablets. You can take no more than 4 tablets per day, divided into 2-3 doses. The duration of therapy should not exceed 5 days. Analgin is taken as an antipyretic for no more than 3 days.
If you follow the dosage recommendations, problems with concentration and reaction speed are completely eliminated. Therefore, when using analgin to relieve pain, there are no restrictions on driving a car. Dangers arise only when large doses are used.
When using the drug, it should be taken into account that the toxic effects can be enhanced by other non-narcotic analgesics. It is also undesirable to use analgin simultaneously with tricyclic antidepressants and contraceptives. Barbiturates and phenylbutazone reduce the effectiveness of the drug, and sedatives and tranquilizers enhance it. The consumption of alcoholic beverages during pain relief with analgin is strictly prohibited.
Metamizole sodium (Dipirone, Analgin) - a pyrazolone derivative with analgesic, antipyretic and anti-inflammatory effects, appeared on the pharmaceutical market in 1921 and was widely used throughout the world as an over-the-counter drug. In the 60s Information has begun to emerge that, like other pyrazolones, metamizole can cause serious adverse reactions, including deaths, primarily due to damage to the hematopoietic system. Agranulocytosis, which develops in some patients with oral and intravenous administration of metamizole sodium, caused its withdrawal from the pharmaceutical market in many countries, but in others it continues to be widely used, incl. and as an over-the-counter product [1].
The drug's manufacturers, the German pharmaceutical companies Hoechst and Boehringer-Mannheim, insisted on the safety of metamizole and argued that myelotoxic reactions with its use are extremely rare. In order to determine the frequency of agranulocytosis, the companies organized a large international epidemiological study - the International Agranulocytosis and Aplastic Anaemia Study (IAAAS) [2]. According to his data, the frequency of agranulocytosis associated with the use of metamizole was approximately 1:1000000. However, the results of the IAAAS study, released in 1986, have been questioned in many publications due to errors in data collection and inadequate supervision. In addition, the calculation of the frequency of the myelosuppressive effect was carried out incorrectly. When calculating, the indicator “one week of use” was used instead of the indicator “number of cases per year” [3]. If we recalculate the results using the last indicator, then 1 case of agranulocytosis occurs per 20 thousand cases of drug use per year, i.e. the complication rate is 1:20,000 [3].
In Germany, according to the IAAAS study, in 1985, about 100 cases of agranulocytosis associated with the use of metamizole were registered. During this period, the drug was prescribed to approximately 3 million patients who received approximately 10 million packages. According to calculations, there was 1 case of agranulocytosis per 30 thousand patients using the drug [4]. These data became the basis for the introduction of regulatory measures. In 1986, the over-the-counter sale of metamizole sodium was banned in Germany, and its use was limited to the following indications [4]:
- acute severe pain due to injury or surgery;
- colic pain;
- pain due to malignant neoplasms or other severe pain, chronic pain in the absence of effect or the presence of contraindications to other therapeutic agents;
- high temperature that cannot be reduced by other means.
Subsequently, all combination drugs containing metamizole sodium were banned in Germany. The reason for the ban was the concern that when prescribing a combination, doctors do not always take into account the risk of complications associated with the individual ingredients included in its composition. In addition, the results of clinical studies have shown that combinations of metamizole sodium with pitofenone and other antispasmodics do not have any advantages compared to metamizole alone.
However, the trade names of combination drugs were so popular that German manufacturers of combinations, having removed the antispasmodic from their composition, retained the popular names of combinations for monocomponent drugs. Moreover, in the instructions of the Hoechst company in the description of the pharmacological properties of monocomponent Baralgan M and Baralgin M, an indication of the antispasmodic effect, which metamizole does not possess, remains. Such information came from India in 1998 at the Internet conference “E-Drugs”. Unfortunately, some popular Russian drug reference books also published it in the same year.
The use of metamizole has been severely restricted or banned in many countries. In particular, in the WHO document “Consolidated list of products whose consumption and/or sale have been banned, withdrawn” , severely restricted or not approved by Governments" 1987) published information that metamizole sodium is prohibited or limited for use in Australia, Norway, the Philippines, the USA, Italy, Denmark, Saudi Arabia, Bangladesh, Germany, Egypt, Israel, Greece, Mexico, Peru, Singapore, Sweden and Venezuela.
The first country to ban the import of metamizole was Australia (1965). In a discussion initiated at the request of the Moldovan drug information center DrugInfo at the E-Drugs conference in 2002, the representative of Australia expressed the opinion that currently few Australian doctors know about the existence of such a drug as metamizole sodium.
In Norway, the use of metamizole was banned in 1976. In 1977, its prescription use was banned in the Philippines. Use (only under close medical supervision) is limited to cases of serious and life-threatening situations when other antipyretic drugs are ineffective. The instructions for use include a warning about the risk of developing fatal agranulocytosis.
That same year, the US Food and Drug Administration (FDA) did not approve the drug, despite its high effectiveness as an analgesic and antipyretic. This decision was due to the fact that fatal agranulocytosis cannot be predicted and prevented even with frequent monitoring of the blood picture, since it can develop within several hours after taking the drug. The FDA has concluded that the potential risks of metamizole significantly outweigh its benefits.
In Kuwait, in 1978, all dosage forms of metamizole were banned, except injectable forms, which can be used in emergency situations. In 1979, injectable drugs containing more than 1 gram of metamizole and its combination drugs for intravenous administration were withdrawn from the market in Italy, and in Denmark all metamizole-containing drugs for systemic use were banned. In 1980, a similar decision was made by Saudi Arabia. However, in the latter case, the reason for the ban was not agranulocytosis, but reports of the development of anaphylactic shock in patients. The possible risk of anaphylactic shock also served as the basis for prohibiting the registration of drugs containing more than 1 g of metamizole in Egypt (1983).
This side effect of metamizole has received much less attention than the inhibitory effect on the bone marrow. However, the results of monitoring adverse reactions in German hospitals indicate that vascular shock caused by metamizole is observed 10 times more often than agranulocytosis [4]. The mortality rate is 30-50%. It is important to note that due to the destruction of vascular endothelial cells caused by their hypersensitivity to metamizole, blood pressure cannot be raised either with the help of blood substitutes or vasoconstrictors. In Germany, one of the reasons for the ban on injectable combination drugs metamizole was the death from anaphylactic shock of the chairman of the Medicines Committee of the German Medical Association, caused by one of them.
Metamizole can cause other side effects associated with immune disorders: hepatitis, alveolitis, interstitial nephritis, pneumonia and serious skin reactions - Lyell's syndrome (toxic epidermal necrolysis) and Stevens-Johnson (erythema malignant exudative erythema) [5]. The authoritative international drug guide MARTINDALE, The Extra Pharmacopoeia (Thirtieth Ed., 1993) states that due to the risk of serious adverse reactions, the use of metamizole is justified only in life-threatening situations when there is no alternative. In many countries where the use of metamizole is limited, it is used for this purpose, for example, to relieve pain in patients with terminal conditions or to treat hyperpyrexia (Table).
In recent years, the list of states in which the use of metamizole sodium is limited or prohibited has been constantly expanding. Regulatory measures have been introduced for metamizole in approximately 40 countries. There are countries where it has never been registered, such as the UK. Among Western European countries, metamizole is relatively widely represented on the pharmaceutical market in France: in the form of a monocomponent drug it is registered under 2 trade names, in the form of combinations - under 5 (of which 2 are combinations with caffeine, 2 with antispasmodics and 1 with codeine). However, in most countries of Western Europe, both monocomponent and combined preparations of metamizole are prohibited.
The world already has experience of “double” prohibition of the drug. Metamizole was present on the Swedish pharmaceutical market from 1934 to 1974. In 1974, on the recommendation of the Medicines Agency, it was voluntarily withdrawn from the market by manufacturers due to side effects and, above all, the risk of agranulocytosis. The incidence of agranulocytosis is estimated to be 1:3000 in Sweden [6].
However, in 1995, taking into account the results of the large epidemiological study mentioned above, the country's regulatory authorities concluded that metamizole is effective, cheap and fairly safe. This was the basis for its re-authorization, subject to careful monitoring of adverse reactions. Metamizole has been approved for the limited indications of short-term control of acute, moderate to severe pain resulting from tissue damage, such as surgery or urinary and biliary colic.
After re-authorization, the Swedish Medicines Agency received 7 reports of agranulocytosis with the use of metamizole, of which in 6 cases the drug was taken orally. According to the Agency's conclusion, the frequency of agranulocytosis was 1:1700, which was significantly higher than expected. In 1999, based on the results of monitoring of adverse reactions, metamizole was again withdrawn from the Swedish pharmaceutical market.
Currently, the Swedish Medicines Agency has published complete data [7], which suggests that agranulocytosis associated with metamizole is even more common - 1: 1439. In total, 52 cases of serious blood damage under the influence of metamizole were registered in the country, 15 of which were fatal Exodus. Agranulocytosis was observed in 43 cases (10 deaths). These data are very close to those obtained in the 50s. regarding aminopyrine.
As follows from the table, metamizole sodium is prohibited not only in Western European countries, North America and Australia. Its use is not approved in many developing countries in Asia, Africa and South America. In general (with different formulations), all drugs and dosage forms of metamizole are prohibited or not approved for use in 19 countries. The only region where metamizole continues to be widely used is Eastern Europe, including the republics of the former Soviet Union and countries that were part of the socialist camp. The exception is the former Czechoslovakia, where the use of all drugs containing metamizole was brought under control back in 1992.
In Mongolia, in addition to commercial preparations of metamizole (Analgin), large packages of it are hand-packed in pharmacies and sold without a prescription. In Croatia, according to B. Vrhovac, theoretically metamizole is a prescription drug, but in practice it can be freely purchased at any pharmacy. An analysis of the medical records of patients who were in one of the hematology departments of a Croatian clinic with a diagnosis of agranulocytosis showed that 25% of patients took metamizole.
In Bulgaria, metamizole (Analgin) is one of the most frequently prescribed drugs, partly due to the fact that the country is one of its main producers. A similar situation has developed in Russia and the republics of the former Soviet Union. The widespread use of metamizole in these countries appears to be based on three interrelated factors: 1) the traditional Eastern European prejudice against opioid analgesics (this problem was encountered during the Bosnian war); 2) historically shaped preferences of physicians and drug consumers; and 3) the strong influence of metamizole manufacturers in this geographic region.
Metamizole is often supplied to former socialist countries as humanitarian aid. Donors say it is an alternative to opioid analgesics, which cannot be donated as humanitarian aid.
In recent years, some positive changes have been observed in the CIS countries and the Baltic republics. Thus, in Armenia, since 2000, registration of tablets and injection solutions of metamizole has been stopped [8]. The latter were replaced with soluble aspirin. However, previously registered metamizole (Analgin) will remain on the market until the expiration of the registration period. Combination drugs containing metamizole are still being registered.
In Lithuania, in September 2000, the State Medicines Control Agency refused, for safety reasons, the re-registration of combination drugs containing metamizole sodium, fenpiverine bromide and pitofenone hydrochloride [9].
In Moldova, the DrugInfo information center is actively fighting for the withdrawal of metamizole, making extensive use of the capabilities of its bulletin [4].
The safety issues of analgin were repeatedly raised by A.V. Astakhova on the pages of the Russian bulletin “Drug Safety” and in other periodicals. As international experience shows, awareness of doctors and drug consumers about serious adverse reactions of metamizole can lead to a significant reduction in the volume of its consumption.
Thus, a retrospective analysis of outpatient charts conducted in one of the medical institutions in Cameroon showed that in 1992, Dipirone (metamizole) was contained in 48% of prescriptions. At the end of 1992, an independent bulletin (Precriber's bulletin) published a large review of Dipirone. This newsletter number was sent to all doctors, nurses, midwives and pharmacists. As a result, in 1993, the number of Dipirone prescriptions in the same medical institution decreased to 9% [10]. Consideration of metamizole, in particular, combination drugs containing it, is in the plans of the Russian Pharmacological Committee. In particular, the Committee decided to prohibit the over-the-counter release of Analgin for use by people under 15 years of age. However, along with regulatory measures, a lot of educational work should be carried out in this direction, since, as mentioned above, there are powerful factors that counteract the introduction of restrictions on the use of analgin in Russia. The latest attempts to keep metamizole on the Eastern European market include the theory of ethnic differences in reactions to the drug.
