Analgin tablets cancelled! The rise and fall of the "miracle antipyretic drug" over the past century

The "miracle antipyretic drug" Analgin has always been controversial because of its frequent and serious side effects. Recently, the State Food and Drug Administration officially included "Analgin Tablets" in the list of drug registration certificates that have been cancelled. Let's take a look at the century-old history of Analgin.

On November 12, the State Drug Administration issued the Notice on Cancelling the Registration Certificates of 34 Drugs Including Mercurochrome Solution (No. 132 of 2021). The Notice canceled the registration certificates of 34 drugs including Mercurochrome Solution, among which Analgin Tablets was on the cancellation list.

Once upon a time, this flat white tablet packed in a plastic bag became the Chinese people's first choice "magic drug" for reducing fever and relieving pain because of its quick effect and low price.

In 1952, it was successfully developed by Shanghai Wuzhou Pharmaceutical Factory. After it was launched in China, it was once as famous as aspirin and acetaminophen (i.e. paracetamol). After nearly 70 years of use, the drug was "sentenced to death". The State Food and Drug Administration issued two important notices in March 2020, requiring the immediate suspension of the production, sale and use of Analgin Injection, Analgin Chlorpromazine Injection, Children's Analgin Enema Solution, Analgin Drops, Analgin Nasal Drops, Analgin Solution Tablets for Nasal Drops, and Children's Antipyretic Suppositories in my country, and revised the instructions for Analgin related varieties. Two consecutive heavy announcements about "Analgin" suddenly made this "old drug" that has been silent for many years popular. Next, let's take a look at the things about Analgin.

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Obvious advantages

It was popular for a while, but was later banned in many countries

Metamizole is a veritable old drug. It has been exactly 100 years since its initial discovery. In this century, Metamizole has also had a rough fate and experienced the ups and downs of "life". As early as 1920, the German Hoechst AG company synthesized an antipyretic analgesic, which is now Metamizole Sodium. Two years later, Germany launched it on the market as a non-narcotic analgesic.

As a pyrazolone antipyretic analgesic, Analgin is a compound of aminopyrine and sodium sulfite, which has analgesic, anti-inflammatory and anti-rheumatic effects. It is mainly used to relieve fever during high fever, and can also be used for headaches, migraines, muscle pain, joint pain and dysmenorrhea, etc. It can also be used for acute rheumatic arthritis. Since its launch, Analgin has been popular in countries around the world as an over-the-counter "fever-reducing magic drug" and has been widely used for half a century.

Compared with aspirin, which was launched earlier, or acetaminophen, which was launched later, analgin seems to have obvious advantages. In addition to its similar antipyretic and analgesic effects, analgin generally does not cause severe renal damage, nor does it cause the Reye's syndrome unique to aspirin when used by children. It also does not cause drug-induced hepatitis or even fulminant liver failure after overdose like acetaminophen.

However, the good times did not last long. With the widespread use of analgin, its serious side effects continued to emerge, which laid the groundwork for various countries to gradually ban its use.

▲There are many cases of skin rashes and anaphylactic shock caused by Analgin (picture from the Internet)

The most obvious adverse reaction is in the blood system, which may cause severe agranulocytosis, which develops rapidly and is life-threatening in severe cases. In the 1920s, aminopyrine was found to cause granulocytopenia, and analgin is composed of aminopyrine and sodium sulfite. Based on this, it is estimated that the incidence of granulocytopenia caused by analgin is 1/120, that is, one person will experience granulocytopenia for every 120 people taking analgin.

By the 1930s, Sweden had already had reports of adverse reactions related to analgin. In March 1974, data showed that the incidence of analgin-induced granulocytopenia was 1/3000. Although this was lower than the previously predicted incidence, Sweden still removed all analgin-containing drugs from the market. Then in 1977, also in view of the potential serious adverse reactions of analgin-induced granulocytopenia, the U.S. Food and Drug Administration (FDA) required the ban of all dosage forms of analgin that had been on the market. Subsequently, more than 30 countries, including Australia, Japan, and Iran, have banned or restricted the use of analgin.

To make matters worse, in addition to serious adverse reactions in the blood system, analgin can also cause serious allergic reactions, such as severe drug rash, anaphylactic shock, etc.

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Due to national conditions,

Domestic use for nearly 70 years

As a long-established antipyretic and analgesic, the star drug Analgin has been almost the first choice for Chinese people to reduce fever for a long time. Until 1997, the production and sales volume of Analgin in my country still ranked among the top antipyretic and analgesic drugs. It was during this period that some developed countries abroad began to ban the use of Analgin, but there are still many countries in the world that use Analgin. Domestic Analgin pharmaceutical factories also began to export the drug and became a major exporter after Germany. It is mainly exported to Germany, Denmark, the Netherlands and other countries. The amount of re-export trade through Hong Kong is also very large, and my country has also rapidly emerged a number of pharmaceutical factories producing Analgin.

In fact, when some developed countries announced the ban on the use of analgin, my country's Ministry of Health had already begun to pay attention to the adverse reactions of analgin. In 1982, my country's Ministry of Health issued the "Notice on the Elimination of 127 Drugs", which listed compound analgin tablets as eliminated drugs, but did not restrict the tablets, drops and injections of analgin.

As a well-known antipyretic drug, even those born after the 1990s are familiar with it. Take the author as an example. When I had a fever as a child, I usually went to the village clinic for treatment. The antipyretic drug prescribed by the doctor was Analgin. This phenomenon is particularly obvious in the vast rural areas. Even today when the pharmaceutical industry is strong, large bottles of Analgin tablets can still be seen in primary medical institutions.

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Behind the disabled

A high incidence of adverse reactions

Since the elimination of compound analgin tablets in 1982, nearly 40 years have passed. The national authorities have never taken further restrictive actions on analgin, but this does not mean that analgin will not cause adverse reactions.

On the contrary, with the continuous improvement of the national adverse reaction monitoring system, the adverse reactions of analgin have become more and more obvious.

As early as 1986, Chen Mulian and other researchers had reported a case of adverse reactions of anemia caused by analgin. In 1987, Zhang Tianfeng reported a case of acute aplastic anemia caused by analgin; Song Fulian reported two cases of fetal death in pregnant women after taking analgin tablets. In 1994, Xie Ruding reported a case of coma and limb necrosis caused by oral analgin. There are many such case reports, and I will not go into details one by one.

In addition to individual case reports, a total of 92 adverse reactions to Analgin were collected in the "Drug Adverse Reaction Monitoring Information Bulletin" (Issue 2) issued by the National Center for Adverse Drug Reaction in 2008. Among them, there were 11 cases of anaphylactic shock, 7 deaths; 16 cases of blood system reactions, 1 death; 31 cases of skin and appendage reactions, 4 deaths; 17 cases of urinary system reactions, 5 deaths; 9 cases of digestive system reactions, 1 death; and 8 cases of severe reactions such as respiratory and cardiac arrest, incontinence, and 1 death.

Therefore, in the eyes of most doctors and pharmacists, Analgin has long been "scared to death". Except for primary medical institutions which are still using it, urban medical institutions have basically abandoned its use.

On March 17, 2020, the State Drug Administration issued the "Announcement on the Cancellation of the Drug Registration Certificates for Analgin Injection and Other Products" (No. 29 of 2020) and the "Announcement on the Revision of the Instructions for Analgin Related Products" (No. 34 of 2020), requiring the cessation of the production, sales and use of Analgin Injection and other products in my country, and revising the instructions for Analgin Tablets, Chongganling Tablets, Chongganling Capsules, Compound Artemisia Analgin Tablets and other products.

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There are many alternative drugs.

Completed historical mission

With the strengthening of the national medicine industry, there are now many types of antipyretic and analgesic drugs on the market with a full range of dosage forms, which can fully meet the needs of patients of all ages.

If you need to reduce fever or relieve pain, you can choose acetaminophen or ibuprofen. These two drugs are also the mainstream antipyretic drugs on the market.

Although acetaminophen may cause severe drug-induced hepatitis, it basically does not occur when adults use it at a regular dose of less than 2g per day. It is also relatively safe for children to use it at a dose calculated based on their weight.

Ibuprofen is a propionic acid derivative. Apart from common gastrointestinal reactions such as nausea and abdominal discomfort, there are basically no serious adverse reactions when used at regular doses.

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Coincidentally,

Those star drugs that have been delisted

It is not just Analgin. In the history of modern drug treatment, many drugs have been withdrawn from the market due to serious or even fatal malformations. Among these drugs, the "Thalidomide Incident" has a particularly far-reaching impact.

Thalidomide, also known as thalidomide, was first marketed in West Germany in 1956 to treat pregnancy reactions and relieve the tension of pregnant women. Due to its good effect in treating morning sickness, it quickly became popular in 17 countries in Europe, Asia, Australia, North America (excluding the United States) and Latin America.

In October 1961, three German doctors reported some cases of phocomelia in children at a meeting of West German gynecologists, which attracted everyone's attention. This was just the beginning. Reports of phocomelia in other places followed one after another. These newborns had very short upper and lower limbs, or even no arms and legs, with their hands and feet directly connected to the body.

▲Analia Munoz (second from left), a survivor of the "Thalidomide Incident" in a BBC report in 2017 (picture from the Internet)

After a long period of epidemiological investigation, it was confirmed that the occurrence of seal foot deformity was related to the mother's use of thalidomide during pregnancy. The investigation found that the drug caused deformities in more than 10,000 people around the world, with 6,000 to 8,000 cases in West Germany alone.

It is worth noting that although the harm caused by the "Thalidomide Incident" was so great, the United States, Switzerland and East Germany, which strictly control the approval of imported drugs, were basically not affected.

In addition, other drugs that have been withdrawn from the market due to serious adverse reactions include clofoquinol, diethyltin disulfide, dinitrophenol and phenylpropanolamine.

In recent years, my country has attached increasing importance to the work of adverse drug reactions, and the monitoring of adverse drug reactions has basically been aligned with international standards. With the continuous accumulation of monitoring data and the increase in alternative drugs, drugs named by domestic or foreign drug regulatory authorities due to adverse reactions may face the risk of being banned or restricted in use, such as rofecoxib, domperidone, and montelukastner.

Written by Zhao Ning (Deputy Chief Pharmacist of Peking University First Hospital, Founder of Internet Pharmacist Group "Yaoshi.com")

Editor/Ji Jingjing New Media Editor/Li Yunfeng

Photo provided by Visual China

Produced by: Science Central Kitchen

Produced by: Beijing Science and Technology News | Science Plus Client

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