Metamizole, or dipyrone, is a
painkiller
An analgesic drug, also called simply an analgesic (American English), analgaesic (British English), pain reliever, or painkiller, is any member of the group of drugs used to achieve relief from pain (that is, analgesia or pain management). It i ...
,
spasm reliever, and
fever reliever that also has
anti-inflammatory
Anti-inflammatory is the property of a substance or treatment that reduces inflammation or swelling. Anti-inflammatory drugs, also called anti-inflammatories, make up about half of analgesics. These drugs remedy pain by reducing inflammation as o ...
effects. It is most commonly given by mouth or by intravenous infusion.
Although it is available over-the-counter
Over-the-counter (OTC) drugs are medicines sold directly to a consumer without a requirement for a prescription from a healthcare professional, as opposed to prescription drugs, which may be supplied only to consumers possessing a valid prescr ...
in some countries, it is banned in others, due to its potential for adverse events, including agranulocytosis
Agranulocytosis, also known as agranulosis or granulopenia, is an acute condition involving a severe and dangerous lowered white blood cell count (leukopenia, most commonly of neutrophils) and thus causing a neutropenia in the circulating blood. ...
.[ A study by one of the manufacturers of the drug found the risk of agranulocytosis within the first week of treatment to be a mere 1.1 in a million, versus 5.92 in a million for ]diclofenac
Diclofenac, sold under the brand name Voltaren, among others, is a nonsteroidal anti-inflammatory drug (NSAID) used to treat pain and inflammatory diseases such as gout. It is taken by mouth or rectally in a suppository, used by injection, or ...
.
It is in the ampyrone
Ampyrone is a metabolite of aminopyrine with analgesic, anti-inflammatory, and antipyretic properties. Its use as a drug is discouraged due to the risk of agranulocytosis. It is used as a reagent for biochemical reactions producing peroxides ...
sulfonate
In organosulfur chemistry, a sulfonate is a salt or ester of a sulfonic acid. It contains the functional group , where R is an organic group. Sulfonates are the conjugate bases of sulfonic acids. Sulfonates are generally stable in water, non-ox ...
family of medicines.
It was patented in 1922 and was first used medically in Germany
Germany,, officially the Federal Republic of Germany, is a country in Central Europe. It is the second most populous country in Europe after Russia, and the most populous member state of the European Union. Germany is situated betwe ...
under the brandname "Novalgin". For many years, it was available over-the-counter
Over-the-counter (OTC) drugs are medicines sold directly to a consumer without a requirement for a prescription from a healthcare professional, as opposed to prescription drugs, which may be supplied only to consumers possessing a valid prescr ...
in most countries, before its withdrawal due to severe adverse effects. Metamizole is marketed under various trade names.
Medical uses
It is primarily used for perioperative
The perioperative period is the time period of a patient's surgical procedure. It commonly includes ward admission, anesthesia, surgery, and recovery. Perioperative may refer to the three phases of surgery: preoperative, intraoperative, and posto ...
pain, acute injury, colic
Colic or cholic () is a form of pain that starts and stops abruptly. It occurs due to muscular contractions of a hollow tube ( small and large intestine, gall bladder, ureter, etc.) in an attempt to relieve an obstruction by forcing content out ...
, cancer pain, other acute/chronic forms of pain and high fever unresponsive to other agents.[
]
Special populations
Its use in pregnancy is advised against, although animal studies are reassuring in that they show minimal risk of birth defects. Its use in the elderly and those with liver or kidney impairment is advised against, but if these groups of people must be treated, a lower dose and caution is usually advised. Its use during lactation is advised against, as it is excreted in breast milk.[
]
Adverse effects
Metamizole has a potential of blood-related toxicity (blood dyscrasia
In medicine, both ancient and modern, a dyscrasia is any of various disorders. The word has ancient Greek roots meaning "bad mixture". The concept of dyscrasia was developed by the Greek physician Galen (129–216 AD), who elaborated a model of h ...
s), but causes less kidney
The kidneys are two reddish-brown bean-shaped organs found in vertebrates. They are located on the left and right in the retroperitoneal space, and in adult humans are about in length. They receive blood from the paired renal arteries; blood ...
, cardiovascular
The blood circulatory system is a system of organs that includes the heart, blood vessels, and blood which is circulated throughout the entire body of a human or other vertebrate. It includes the cardiovascular system, or vascular system, tha ...
, and gastrointestinal toxicity than non-steroidal anti-inflammatory drugs
Non-steroidal anti-inflammatory drugs (NSAID) are members of a therapeutic drug class which reduces pain, decreases inflammation, decreases fever, and prevents blood clots. Side effects depend on the specific drug, its dose and duration of ...
(NSAIDs).[ Like NSAIDs, it can trigger bronchospasm or ]anaphylaxis
Anaphylaxis is a serious, potentially fatal allergic reaction and medical emergency that is rapid in onset and requires immediate medical attention regardless of use of emergency medication on site. It typically causes more than one of the follow ...
, especially in those with asthma
Asthma is a long-term inflammatory disease of the airways of the lungs. It is characterized by variable and recurring symptoms, reversible airflow obstruction, and easily triggered bronchospasms. Symptoms include episodes of wheezing, cou ...
.
Serious side effects include agranulocytosis
Agranulocytosis, also known as agranulosis or granulopenia, is an acute condition involving a severe and dangerous lowered white blood cell count (leukopenia, most commonly of neutrophils) and thus causing a neutropenia in the circulating blood. ...
, aplastic anaemia
Aplastic anemia is a cancer in which the body fails to make blood cells in sufficient numbers. Blood cells are produced in the bone marrow by stem cells that reside there. Aplastic anemia causes a deficiency of all blood cell types: red blood c ...
, hypersensitivity reactions (like anaphylaxis
Anaphylaxis is a serious, potentially fatal allergic reaction and medical emergency that is rapid in onset and requires immediate medical attention regardless of use of emergency medication on site. It typically causes more than one of the follow ...
and bronchospasm
Bronchospasm or a bronchial spasm is a sudden constriction of the muscles in the walls of the bronchioles. It is caused by the release (degranulation) of substances from mast cells or basophils under the influence of anaphylatoxins. It causes di ...
), toxic epidermal necrolysis
Toxic epidermal necrolysis (TEN) is a type of severe skin reaction. Together with Stevens–Johnson syndrome (SJS) it forms a spectrum of disease, with TEN being more severe. Early symptoms include fever and flu-like symptoms. A few days later th ...
and it may provoke acute attacks of porphyria
Porphyria is a group of liver disorders in which substances called porphyrins build up in the body, negatively affecting the skin or nervous system. The types that affect the nervous system are also known as acute porphyria, as symptoms are ra ...
, as it is chemically related to the sulfonamide
In organic chemistry, the sulfonamide functional group (also spelled sulphonamide) is an organosulfur group with the structure . It consists of a sulfonyl group () connected to an amine group (). Relatively speaking this group is unreactive. ...
s.[ The relative risk for agranulocytosis appears to greatly vary according to the country of estimates on said rate and opinion on the risk is strongly divided.] Genetics may play a significant role in metamizole sensitivity. It is suggested that some populations are more prone to suffer from metamizole induced agranulocytosis than others. As an example, metamizole-related agranulocytosis seems to be an adverse effect more frequent in British population as opposed to Spaniards.
According to a systematic review from 2016 Metamizole significantly increased the risk of upper gastrointestinal bleeding by a factor ranging from 1.4 to 2.7 (relative risk
The relative risk (RR) or risk ratio is the ratio of the probability of an outcome in an exposed group to the probability of an outcome in an unexposed group. Together with risk difference and odds ratio, relative risk measures the association bet ...
).
Contraindications
Previous hypersensitivity (such as agranulocytosis
Agranulocytosis, also known as agranulosis or granulopenia, is an acute condition involving a severe and dangerous lowered white blood cell count (leukopenia, most commonly of neutrophils) and thus causing a neutropenia in the circulating blood. ...
or anaphylaxis
Anaphylaxis is a serious, potentially fatal allergic reaction and medical emergency that is rapid in onset and requires immediate medical attention regardless of use of emergency medication on site. It typically causes more than one of the follow ...
) to metamizole or any of the excipients
An excipient is a substance formulated alongside the active ingredient of a medication, included for the purpose of long-term stabilization, bulking up solid formulations that contain potent active ingredients in small amounts (thus often referred ...
(e.g. lactose
Lactose is a disaccharide sugar synthesized by galactose and glucose subunits and has the molecular formula C12H22O11. Lactose makes up around 2–8% of milk (by mass). The name comes from ' (gen. '), the Latin word for milk, plus the suffix '' - ...
) in the preparation used, acute porphyria
Porphyria is a group of liver disorders in which substances called porphyrins build up in the body, negatively affecting the skin or nervous system. The types that affect the nervous system are also known as acute porphyria, as symptoms are ra ...
, impaired haematopoiesis
Haematopoiesis (, from Greek , 'blood' and 'to make'; also hematopoiesis in American English; sometimes also h(a)emopoiesis) is the formation of blood cellular components. All cellular blood components are derived from haematopoietic stem cells. ...
(such as due to treatment with chemotherapy
Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs (chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemotherap ...
agents), third trimester of pregnancy (potential for adverse effects in the newborn), lactation, children with a body weight below 16 kg, history of aspirin-induced asthma and other hypersensitivity reactions to analgesics.[
Oral ]anticoagulants
Anticoagulants, commonly known as blood thinners, are chemical substances that prevent or reduce coagulation of blood, prolonging the clotting time. Some of them occur naturally in blood-eating animals such as leeches and mosquitoes, where the ...
(blood thinners), lithium
Lithium (from el, λίθος, lithos, lit=stone) is a chemical element with the symbol Li and atomic number 3. It is a soft, silvery-white alkali metal. Under standard conditions, it is the least dense metal and the least dense solid el ...
, captopril
Captopril, sold under the brand name Capoten among others, is an ACE inhibitor, angiotensin-converting enzyme (ACE) inhibitor used for the treatment of hypertension and some types of congestive heart failure. Captopril was the first oral ACE inh ...
, triamterene
Triamterene (trade name Dyrenium among others) is a potassium-sparing diuretic often used in combination with thiazide diuretics for the treatment of high blood pressure or swelling. The combination with hydrochlorothiazide, is known as hydroch ...
and antihypertensive
Antihypertensives are a class of drugs that are used to treat hypertension (high blood pressure). Antihypertensive therapy seeks to prevent the complications of high blood pressure, such as stroke and myocardial infarction. Evidence suggests tha ...
s may also interact with metamizole, as other pyrazolone Pyrazolone is 5-membered heterocycle containing two adjacent nitrogen atoms. It can be viewed as a derivative of pyrazole possessing an additional carbonyl (C=O) group. Compounds containing this functional group are useful commercially in analgesic ...
s are known to interact adversely with these substances.
Overdose
It is considered fairly safe on overdose, but in these cases supportive measures are usually advised as well as measures to limit absorption (such as activated charcoal
"Activated" is a song by English singer Cher Lloyd. It was released on 22 July 2016 through Vixen Records. The song was made available to stream exclusively on ''Rolling Stone'' a day before to release (on 21 July 2016).
Background
In an interv ...
) and accelerate excretion (such as haemodialysis
Hemodialysis, also spelled haemodialysis, or simply dialysis, is a process of purifying the blood of a person whose kidneys are not working normally. This type of dialysis achieves the extracorporeal removal of waste products such as creatinin ...
).
Physicochemistry
It is a sulfonic acid and comes in calcium
Calcium is a chemical element with the symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar to ...
, sodium
Sodium is a chemical element with the symbol Na (from Latin ''natrium'') and atomic number 11. It is a soft, silvery-white, highly reactive metal. Sodium is an alkali metal, being in group 1 of the periodic table. Its only stable iso ...
and magnesium
Magnesium is a chemical element with the symbol Mg and atomic number 12. It is a shiny gray metal having a low density, low melting point and high chemical reactivity. Like the other alkaline earth metals (group 2 of the periodic ta ...
salt forms.[ Its sodium salt ]monohydrate
In chemistry, a hydrate is a substance that contains water or its constituent elements. The chemical state of the water varies widely between different classes of hydrates, some of which were so labeled before their chemical structure was underst ...
form is a white/almost crystalline powder that is unstable in the presence of light, highly soluble in water
Water (chemical formula ) is an inorganic, transparent, tasteless, odorless, and nearly colorless chemical substance, which is the main constituent of Earth's hydrosphere and the fluids of all known living organisms (in which it acts as a ...
and ethanol
Ethanol (abbr. EtOH; also called ethyl alcohol, grain alcohol, drinking alcohol, or simply alcohol) is an organic compound. It is an Alcohol (chemistry), alcohol with the chemical formula . Its formula can be also written as or (an ethyl ...
but practically insoluble in dichloromethane
Dichloromethane (DCM or methylene chloride, methylene bichloride) is an organochlorine compound with the formula . This colorless, volatile liquid with a chloroform-like, sweet odour is widely used as a solvent. Although it is not miscible with ...
.
Pharmacology
Its precise mechanism of action is unknown, although it is believed that inhibiting brain and spinal cord prostaglandin
The prostaglandins (PG) are a group of physiologically active lipid compounds called eicosanoids having diverse hormone-like effects in animals. Prostaglandins have been found in almost every tissue in humans and other animals. They are derive ...
(fat-like molecules that are involved in inflammation, pain and fever) synthesis might be involved.[ Recently, researchers uncovered another mechanism involving metamizole being a ]prodrug
A prodrug is a medication or compound that, after intake, is metabolized (i.e., converted within the body) into a pharmacologically active drug. Instead of administering a drug directly, a corresponding prodrug can be used to improve how the drug ...
. In this proposal, not yet verified by other researchers, the metamizole itself breaks down into other chemicals that are the actual active agents. The result is a pair of cannabinoid
Cannabinoids () are several structural classes of compounds found in the cannabis plant primarily and most animal organisms (although insects lack such receptors) or as synthetic compounds. The most notable cannabinoid is the phytocannabinoid tet ...
and NSAID arachidonic acid
Arachidonic acid (AA, sometimes ARA) is a polyunsaturated omega-6 fatty acid 20:4(ω-6), or 20:4(5,8,11,14). It is structurally related to the saturated arachidic acid found in cupuaçu butter. Its name derives from the New Latin word ''arachi ...
conjugates (although not in the strict chemical meaning of the word) of metamizole's breakdown products. Despite this, studies in animals have found that the CB1 cannabinoid receptor is not involved in the analgesia induced by metamizole. Although it seems to inhibit fevers caused by prostaglandins, especially prostaglandin E2
Prostaglandin E2 (PGE2), also known as dinoprostone, is a naturally occurring prostaglandin with oxytocic properties that is used as a medication. Dinoprostone is used in labor induction, bleeding after delivery, termination of pregnancy, and ...
, metamizole appears to produce its therapeutic effects by means of its metabolites, especially ''N''-methyl-4-aminoantipyrine (MAA) and 4-Aminoantipyrine (AA).[
]
History
Ludwig Knorr
Ludwig Knorr (2 December 1859 – 4 June 1921) was a German chemist. Together with Carl Paal, he discovered the Paal–Knorr synthesis, and the Knorr quinoline synthesis and Knorr pyrrole synthesis are also named after him. The synthesis in 18 ...
was a student of Emil Fischer
Hermann Emil Louis Fischer (; 9 October 1852 – 15 July 1919) was a German chemist and 1902 recipient of the Nobel Prize in Chemistry. He discovered the Fischer esterification. He also developed the Fischer projection, a symbolic way of dra ...
who won the Nobel Prize for his work on purines and sugars, which included the discovery of phenylhydrazine
Phenylhydrazine is the chemical compound with the formula . It is often abbreviated as . It is also found in edible mushrooms.
Properties
Phenylhydrazine forms monoclinic prisms that melt to an oil around room temperature which may turn yellow ...
. In the 1880s, Knorr was trying to make quinine
Quinine is a medication used to treat malaria and babesiosis. This includes the treatment of malaria due to ''Plasmodium falciparum'' that is resistant to chloroquine when artesunate is not available. While sometimes used for nocturnal leg cr ...
derivatives from phenylhydrazine, and instead made a pyrazole
Pyrazole is an organic compound with the formula C3H3N2H. It is a heterocycle characterized by a 5-membered ring of three carbon
Carbon () is a chemical element with the symbol C and atomic number 6. It is nonmetallic and tetravalent
...
derivative, which after a methylation, he made into phenazone
Phenazone (INN and BAN; also known as phenazon, antipyrine (USAN), or analgesine) is an analgesic (pain reducing), antipyretic (fever reducing) and anti-inflammatory drug. While it predates the term, it is often classified as a nonsteroidal anti- ...
, also called antipyrine, which has been called "the 'mother' of all modern antipyretic analgesics." Sales of that drug exploded, and in the 1890s chemists at Teerfarbenfabrik Meister, Lucius & Co. (a precursor of Hoechst AG
Hoechst AG () was a German chemicals then life-sciences company that became Aventis Deutschland after its merger with France's Rhône-Poulenc S.A. in 1999. With the new company's 2004 merger with Sanofi-Synthélabo, it became a subsidiary of the ...
which is now Sanofi
Sanofi S.A. is a French multinational pharmaceutical and healthcare company headquartered in Paris, France. Originally, the corporation was established in 1973 and merged with Synthélabo in 1999 to form Sanofi-Synthélabo. In 2004, Sanofi-Syn ...
), made another derivative called pyramidon
Aminophenazone (or aminopyrine, amidopyrine, Pyramidon) is a non-narcotic analgesic substance. It is a pyrazolone and a derivative of phenazone, which also has anti-inflammatory and antipyretic properties. While inexpensive and effective, espec ...
which was three times more active than antipyrine.[
In 1893, a derivative of antipyrine, ]aminopyrine
Aminophenazone (or aminopyrine, amidopyrine, Pyramidon) is a non-narcotic analgesic substance. It is a pyrazolone and a derivative of phenazone, which also has anti-inflammatory and antipyretic properties. While inexpensive and effective, especi ...
, was made by Friedrich Stolz
Friedrich Stolz (6 April 1860 – 2 April 1936) was a German chemist and, in 1904, the first person to artificially synthesize epinephrine (adrenaline).
References
*
1860 births
1936 deaths
19th-century German chemists
20th-century Ger ...
at Hoechst.[ Yet later, chemists at Hoechst made a derivative, melubrine (sodium antipyrine aminomethanesulfonate), which was introduced in 1913; finally in 1920, metamizole was synthesized.][ Metamizole is a methyl derivative of melubrine and is also a more soluble prodrug of pyramidon.][ Metamizole was first marketed in Germany as "Novalgin" in 1922.][
]
Society and culture
Legal status
Metamizole is banned in several countries, available by prescription in others (sometimes with strong warnings, sometimes without), and available over the counter
Over-the-counter (OTC) drugs are medicines sold directly to a consumer without a requirement for a prescription from a healthcare professional, as opposed to prescription drugs, which may be supplied only to consumers possessing a valid prescr ...
in yet others.[Department of Economic and Social Affairs of the United Nations Secretaria]
Consolidated List of Products Whose Consumption and/or Sale Have Been Banned, Withdrawn, Severely Restricted or not Approved by Governments Fourteenth Issue (New data only) (January 2005 – October 2008): Pharmaceuticals
United Nations – New York, 2009 For example, approval was withdrawn in Sweden (1974), the USA (1977), and India (2013, ban lifted in 2014).
Although metamizole is banned in the USA, it was reported by small surveys that 28% of Hispanics in Miami
Miami ( ), officially the City of Miami, known as "the 305", "The Magic City", and "Gateway to the Americas", is a East Coast of the United States, coastal metropolis and the County seat, county seat of Miami-Dade County, Florida, Miami-Dade C ...
have possession of it, and 38% of Hispanics in San Diego, CA
San Diego ( , ; ) is a city on the Pacific Ocean coast of Southern California located immediately adjacent to the Mexico–United States border. With a 2020 population of 1,386,932, it is the eighth most populous city in the United States ...
reported some usage.
Amid the opioid crisis
The opioid epidemic, also referred to as the opioid crisis, is the rapid increase in the overuse, misuse/abuse, and overdose deaths attributed either in part or in whole to the class of drugs opiates/opioids since the 1990s. It includes the sign ...
, a study pointed the legal status of metamizole have a relation to the consumption of oxycodone
Oxycodone, sold under various brand names such as Roxicodone and OxyContin (which is the extended release form), is a strong, semi-synthetic opioid used medically for treatment of moderate to severe pain. It is highly addictive and a commonly ...
, showing the use of those drugs were inversely correlated. Its use could be beneficial when adjusted for the addictive-risk of opioids, specially on limited and controlled use of metamizole. A 2019 Israeli conference also justified the approved status as a preventive to opioid dependence, and metamizole being safer than most analgesics for renal impaired patients.
Metamizole is the most sold medication in São Paulo, Brazil
SAO or Sao may refer to:
Places
* Sao civilisation, in Middle Africa from 6th century BC to 16th century AD
* Sao, a town in Boussé Department, Burkina Faso
* Saco Transportation Center (station code SAO), a train station in Saco, Maine, U.S ...
, accounting for 488 tons in 2016.
In 2012, headache accounts for 70% of its use in Indonesia.
In 2018, investigators in Spain looked into Nolotil (as metamizole is known in Spain) after the death of several British people in Spain. A possible factor in these deaths might have been a side effect of metamizole that can cause agranulocytosis
Agranulocytosis, also known as agranulosis or granulopenia, is an acute condition involving a severe and dangerous lowered white blood cell count (leukopenia, most commonly of neutrophils) and thus causing a neutropenia in the circulating blood. ...
(a lowering of white blood cell
White blood cells, also called leukocytes or leucocytes, are the cell (biology), cells of the immune system that are involved in protecting the body against both infectious disease and foreign invaders. All white blood cells are produced and de ...
count).
Brand names
Metamizole is generic, and in countries where it is marketed, it is available under many brand names.[Drugs.co]
Drugs.com international listings for Metamizole
Page accessed June 21, 2015 In Russia, it is commonly sold under the "Analgin" () trade name.
In Romania metamizole is available as the original marketed pharmaceutical product by Zentiva as Algocalmin, as 500 mg immediate release tablets. It's also available as an injection with 1 g of metamizole sodium dissolved in 2 ml of solvent.
In Israel it is sold under the brand name "Optalgin" ( he, אופטלגין), manufactured by Teva.
References
{{Authority control
Analgesics
Antipyretics
CYP3A4 inducers
Drugs with unknown mechanisms of action
Pyrazolones
Sulfonates
Withdrawn drugs