Metamizole

Last updated

Metamizole
Metamizole2DACS.svg
Metamizole monohydrate 3D ball-and-stick.png
Clinical data
Trade names Novalgin, Algocalmin, [1] Analgin, others [2]
Other namesDipyrone (BAN UK, USAN US, Sulpyrine (JAN JP)
AHFS/Drugs.com International Drug Names
Pregnancy
category
  • None assigned; no evidence of teratogenicity in animal studies, but use in the third trimester may cause adverse effects in the newborn or ductus arteriosus (a heart defect) due to its weak NSAID activity. [3] [4]
Routes of
administration 		Oral, IM, IV, rectal
ATC code
Legal status
Legal status
  • AU:Withdrawn
  • BR: OTC (Over the counter)
  • CA:Veterinary only [5]
  • DE:§ 48 AMG/§ 1 MPAV (Prescription only) [6]
  • NZ:Prescription only [7] [8]
  • UK:Withdrawn
  • US:Veterinary only (horses) [9]
  • EU:Legally available [10]
Pharmacokinetic data
Bioavailability 100% (active metabolites) [11]
Protein binding 48–58% (active metabolites) [11]
Metabolism Liver [11]
Elimination half-life 14 minutes (parent compound; parenteral); [4] metabolites: 2–4 h [11]
Duration of action 4–6 h [12]
Excretion Urine (96%, IV; 85%, oral), faeces (4%, IV). [4]
Identifiers
  • [(2,3-Dihydro-1,5-dimethyl-3-oxo-2-phenyl-1H-pyrazol-4-yl)methylamino] methanesulfonic acid
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.000.631 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C13H17N3O4S
Molar mass 311.36 g·mol−1
3D model (JSmol)
  • c1ccccc1N2N(C)C(C)=C(C2=O)N(C)CS(=O)(=O)O
  • InChI=1S/C13H17N3O4S/c1-10-12(14(2)9-21(18,19)20)13(17)16(15(10)3)11-7-5-4-6-8-11/h4-8H,9H2,1-3H3,(H,18,19,20) X mark.svgN
  • Key:LVWZTYCIRDMTEY-UHFFFAOYSA-N X mark.svgN
 X mark.svgNYes check.svgY  (what is this?)    (verify)
Oral solution bottle of dypirone in its packaging (Portuguese lettering) Dipirona PNG.png
Oral solution bottle of dypirone in its packaging (Portuguese lettering)

Metamizole or dipyrone is a painkiller, spasm reliever, and fever reliever drug. It is most commonly given by mouth or by intravenous infusion. [13] [11] [14] It belongs to the ampyrone sulfonate family of medicines and was patented in 1922. Metamizole is marketed under various trade names. [2] [3] It was first used medically in Germany under the brand name "Novalgin", [15] later becoming widely known in Slavic nations and India under the name "Analgin". [16] [17]

Contents

Sale of Metamizole is restricted in some jurisdictions following studies in the 1970s which correlated it to severe adverse effects, including agranulocytosis. [18] Other studies have disputed this judgement, instead claiming that it is a safer drug than other painkillers. [19] [20] Metamizole is popular in many countries, where it is typically available as an over-the-counter medication. [21]

Medical uses

Metamizole, with its potent analgesic (pain relief), antipyretic (fever reduction), and spasmolytic (relax muscle contractions) properties, is utilized in the management of acute pain, fever, and pain caused by muscle spasms. [22]

It is primarily used for perioperative pain, acute injury, colic, cancer pain, other acute/chronic forms of pain and high fever unresponsive to other agents. [4] Metamizole also effectively manages biliary and intestinal colic-like pain, and reduces the spasm of the smooth muscle of the sphincter of Oddi. [23]

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. [4]

Adverse effects

While metamizole is a relatively safe medication, [24] it is not entirely devoid of adverse effects. [24]

Metamizole has a potential of blood-related toxicity (blood dyscrasias), but causes less kidney, cardiovascular, and gastrointestinal toxicity than non-steroidal anti-inflammatory drugs (NSAIDs). [11] Like NSAIDs, it can trigger bronchospasm or anaphylaxis, especially in those with asthma. [14]

Serious side effects include agranulocytosis, aplastic anaemia, hypersensitivity reactions (like anaphylaxis and bronchospasm), toxic epidermal necrolysis and it may provoke acute attacks of porphyria, as it is chemically related to the sulfonamides. [3] [11] [14] 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. [3] [25] [26] Genetics may play a significant role in metamizole sensitivity. [27] 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. [28] An assessment report by the European Medicines Agency remarked that "the potential to induce agranulocytosis may be associated with genetic characteristics of the population studied". [29]

A 2015 meta-analysis concluded that on the evidence available "for short-term use in the hospital setting, metamizole seems to be a safe choice when compared to other widely used analgesics", but that the "results were limited by the mediocre overall quality of the reports" analysed. [30]

A systematic review from 2016 found that metamizole significantly increased the relative risk of upper gastrointestinal bleeding, by a factor of 1.4–2.7 times. [31] A study by one of the manufacturers of the drug found the risk of agranulocytosis within the first week of treatment to be a 1.1 in a million, versus 5.9 in a million for diclofenac.[ medical citation needed ] Therapeutic effect of metamizole on intestinal colic is attributed to its analgesic properties, with no evidence of interference in small bowel or colon motility. [23]

Metamizole has potential for hepatotoxicity. [32]

Contraindications

Previous hypersensitivity (such as agranulocytosis or anaphylaxis) to metamizole or any of the excipients (e.g. lactose) in the preparation used, acute porphyria, impaired haematopoiesis (such as due to treatment with chemotherapy 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. [4]

In 2018, the European Medicines Agency (EMA) reviewed the safety of metamizole and concluded it to be generally safe for the general population. However, they advised against its use in the third trimester of pregnancy or while breastfeeding due to risks of renal impairment or ductus arteriosus to the fetus or infant. [10]

Interactions

A clinically severe interaction has been identified between aspirin and metamizole for patients who regularly take aspirin to manage vascular disease: this interaction occurs due to steric hindrance at the active aspirin binding site of COX-1 by metamizole; to manage this interaction, it is recommended to make a delay between the intake of each of these drugs, with aspirin being taken at least 30 minutes before metamizole. [33]

Known interactions
Drug(s)Interaction/reason for theoretical potential for interaction
Aspirin Platelet aggregation inhibition (PAI) by aspirin; metamizole prevents aspirin from inhibiting COX-1. [33]
Ciclosporin Decreased serum levels of ciclosporin. [4]
Chlorpromazine Additive hypothermia (low body temperature) may result. [4]
Hydroxyethyl starch Acute renal insufficiency. Low evidence, but discouraged simultaneous administration. [34]
Methotrexate Additive risk for haematologic (blood) toxicity. [4] More specifically, bone marrow aplasia. [34]

Oral anticoagulants (blood thinners), lithium, captopril, triamterene and antihypertensives may also interact with metamizole, as other pyrazolones 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) and accelerate excretion (such as haemodialysis). [4]

Physicochemistry

Metamizole is a sulfonic acid and comes in calcium, sodium and magnesium salt forms. [3] Its sodium salt monohydrate form is a white/almost crystalline powder that is unstable in the presence of light, highly soluble in water and ethanol but practically insoluble in dichloromethane. [35]

Pharmacology

Its precise mechanism of action of metamizole is unknown, although it is believed that metamizole generally exerts its action by inhibiting the COX-3 enzyme which is responsible for the biosynthesis of prostaglandins in the central nervous system (CNS)—in the brain and spinal cord. Prostaglandins are lipid compounds that play a role in inflammation, pain, and fever. By inhibiting the COX-3 enzyme in the CNS, metamizole reduces the production of prostaglandins, thereby alleviating pain, reducing fever, and potentially lessening inflammation. [14] [36] Activation of the endocannabinoid and opioidergic systems is also thought to play a role in analgesic effects of metamizole. [37] [20] Metamizole is classified as an atypical nonsteroidal anti-inflammatory drug (NSAID). Unlike typical NSAIDs, metamizole exhibits weak or no anti-inflammatory properties (at least in therapeutic doses), [22] [36] but possesses potent analgesic effects via its action in the CNS: this central action distinguishes it from other NSAIDs, which generally exert their effects peripherally. [36] The inhibition of COX-1 and COX-2 by metamizole is less potent than the inhibition of these enzymes by traditional NSAIDs. [12]

Metamizole is metabolized in the liver, where it is converted into active metabolites through the process of N-demethylation. [38] The mechanism of action of metamizole is believed to be exerted via its active metabolites, specifically, arachidonoyl-4-methylaminoantipyrine (ARA-4-MAA) and arachidonoyl-4-aminoantipyrine (ARA-4-AA). [39] [19] [24] This mechanism of action has been compared to paracetamol and its active arachidonic acid metabolite AM404. The CB1 receptor inverse agonist AM-251 was able to reduce the cataleptic response and thermal analgesia of metamizole. [40] Another study found its antihyperalgesic effect reversed by the CB2 inverse agonist AM-630 [41] Although it seems to inhibit fevers caused by prostaglandins, especially prostaglandin E2, [42] metamizole appears to produce its therapeutic effects by means of its metabolites, especially N-methyl-4-aminoantipyrine (MAA) and 4-aminoantipyrine (AA) which form through the FAAH enzyme to create arachidonoyl-4-methylaminoantipyrine (ARA-4-MAA) and arachidonoyl-4-aminoantipyrine (ARA-4-AA). [4]

Metamizole likely induces the CYP2B6 and CYP3A4 enzymes. [22]

Pharmacokinetics of metamizole's major metabolites [4]
MetaboliteAcronymBiologically active?Pharmacokinetic properties
N-methyl-4-aminoantipyrine2DACS.svg
N-methyl-4-aminoantipyrine
MAAYesBioavailability≈90%. Plasma protein binding: 58%. Excreted in the urine as 3±1% of the initial (oral) dose
4-aminoantipyrine2DACS.svg
4-aminoantipyrine
AAYesBioavailability≈22.5%. Plasma protein binding: 48%. Excreted in the urine as 6±3% of the initial (oral) dose
N-formyl-4-aminoantipyrine2DACS.svg
N-formyl-4-aminoantipyrine
FAANoPlasma protein binding: 18%. Excretion in the urine as 23±4% of the initial oral dose
N-acetyl-4-aminoantipyrine.svg
N-acetyl-4-aminoantipyrine
AAANoPlasma protein binding: 14%. Excretion in the urine as 26±8% of the initial oral dose

History

Ludwig Knorr was a student of Emil Fischer who won the Nobel Prize for his work on purines and sugars, which included the discovery of phenylhydrazine. [1] [43] In the 1880s, Knorr was trying to make quinine derivatives from phenylhydrazine, and instead made a pyrazole derivative, which after a methylation, he made into phenazone, also called antipyrine, which has been called "the 'mother' of all modern antipyretic analgesics." [1] [44] : 26–27  Sales of that drug exploded, and in the 1890s chemists at Teerfarbenfabrik Meister, Lucius & Co. (a precursor of Hoechst AG which is now Sanofi), made another derivative called pyramidon which was three times more active than antipyrine. [1]

In 1893, a derivative of antipyrine, aminopyrine, was made by Friedrich Stolz at Hoechst. [44] : 26–27  Yet later, chemists at Hoechst made a derivative, melubrine (sodium antipyrine aminomethanesulfonate), which was introduced in 1913; [45] finally in 1920, metamizole was synthesized. [20] Metamizole is a methyl derivative of melubrine and is also a more soluble prodrug of pyramidon. [1] [44] : 26–27  Metamizole was first marketed in Germany as "Novalgin" in 1922. [1] [20]

Society and culture

World map of availability of Metamizole (Dipyrone) .mw-parser-output .legend{page-break-inside:avoid;break-inside:avoid-column}.mw-parser-output .legend-color{display:inline-block;min-width:1.25em;height:1.25em;line-height:1.25;margin:1px 0;text-align:center;border:1px solid black;background-color:transparent;color:black}.mw-parser-output .legend-text{} Over-the-counter with limited restrictions. Available, but no data on the requirement of prescriptions. Prescription-only, with fairly limited restrictions on its use. Prescription-only, with extensive restrictions on its use. Banned for human use. It may still be used by veterinary cases in some countries. No data. Metamizole (Dipyrone) Availability World Map.svg
World map of availability of Metamizole (Dipyrone)
   Over-the-counter with limited restrictions.
   Available, but no data on the requirement of prescriptions.
   Prescription-only, with fairly limited restrictions on its use.
   Prescription-only, with extensive restrictions on its use.
   Banned for human use. It may still be used by veterinary cases in some countries.
   No data.

Metamizole is banned in several countries, available by prescription in others (sometimes with strong warnings, sometimes without), and available over the counter in yet others. [18] [46] [47] For example, approval was withdrawn in Sweden (1974), the US (1977), [48] and India (2013, ban lifted in 2014). [49] [17] [50]

Although metamizole is banned in the US because of its risk of agranulocytosis, [51] it was reported by small surveys that 28% of Hispanics in Miami have possession of it, [52] and 38% of Hispanics in San Diego reported some usage. [53]

There were unauthorized sales and use of metamizole in horses in the US. After reviewing trial data on its safety, the FDA approved it for treating fever in equines. [9]

Amid the opioid crisis, a study pointed out that the legal status of metamizole has a relation to the consumption of oxycodone, showing the use of those drugs were inversely correlated. Its use could be beneficial when adjusted for the addictive risk of opioids, especially on limited and controlled use of metamizole. [54] 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. [55]

Metamizole is the most sold medication in São Paulo, Brazil, accounting for 488 tons in 2016. [56] Given this contrasting consumption compared to other countries, the Brazilian Health Regulatory Agency (ANVISA) convened an international panel for evaluating its safety in 2001, and the conclusion was that the benefits substantially outweighed the risks, and imposing restrictions would lead to significant negative consequences to the population. [57] [26] It is also highly popular in Latin America overall. In 2022 in Brazil alone over 215 million doses were administered. [58]

The Bulgarian pharmaceutical Sopharma produces it under the brand Analgin, which as of 2014, has been the top-selling analgesic in Bulgaria for over a decade. [16]

In Germany, the drug is the most commonly prescribed painreliever. [54]

In 2012, headache accounts for 70% of its use in Indonesia. [59]

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 (a lowering of white blood cell count). [60]

Brand names

Metamizole is the international nonproprietary name, and in countries where it is marketed, it is available under many brand names. [2]

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" (Hebrew : אופטלגין), manufactured by Teva.

In Czechia it is available under the brand name "Algifen Neo" in the form of drops containing 500 mg/ml of Metamizole and 5 mg/ml of Pitofenone, manufactured by Teva.

It is known as Sulpyrin and Sulpyrine in South Korea (설피린) and Japan. (スルピリン) [61] [62]

Analgin

Analgin (Russian: Анальгин) is a generic name used in the former USSR pharmacopeia, [63] continuing in use in Slavic nations. A firm in Russia tried unsuccessfully in 2011 to claim the name as their trademark. [64] [65] In Bulgaria, Sopharma succeeded in registering Analgin as a trademark in 2004. [66]

Analgin is also the common term used in the Indian pharmacopeia. [67]

Related Research Articles

<span class="mw-page-title-main">Analgesic</span> Drugs used to achieve relief from pain

An analgesic drug, also called simply an analgesic, antalgic, pain reliever, or painkiller, is any member of the group of drugs used for pain management. Analgesics are conceptually distinct from anesthetics, which temporarily reduce, and in some instances eliminate, sensation, although analgesia and anesthesia are neurophysiologically overlapping and thus various drugs have both analgesic and anesthetic effects.

<span class="mw-page-title-main">Hydrocodone</span> Opioid drug used in pain relief

Hydrocodone, also known as dihydrocodeinone, is a semi-synthetic opioid used to treat pain and as a cough suppressant. It is taken by mouth. Typically, it is dispensed as the combination acetaminophen/hydrocodone or ibuprofen/hydrocodone for pain severe enough to require an opioid and in combination with homatropine methylbromide to relieve cough. It is also available by itself in a long-acting form sold under the brand name Zohydro ER, among others, to treat severe pain of a prolonged duration. Hydrocodone is a controlled drug: in the United States, it is classified as a Schedule II Controlled Substance.

<span class="mw-page-title-main">Nonsteroidal anti-inflammatory drug</span> Class of therapeutic drug for relieving pain and inflammation

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 use, but largely include an increased risk of gastrointestinal ulcers and bleeds, heart attack, and kidney disease.

An antipyretic is a substance that reduces fever. Antipyretics cause the hypothalamus to override a prostaglandin-induced increase in temperature. The body then works to lower the temperature, which results in a reduction in fever.

<span class="mw-page-title-main">Paracetamol</span> Common medication for pain and fever

Paracetamol, or acetaminophen, is a non-opioid analgesic and antipyretic agent used to treat fever and mild to moderate pain. It is a widely used over-the-counter medication. Common brand names include Tylenol and Panadol.

<span class="mw-page-title-main">Ibuprofen</span> Medication treating pain, fever, and inflammation

Ibuprofen is a nonsteroidal anti-inflammatory drug (NSAID) that is used to relieve pain, fever, and inflammation. This includes painful menstrual periods, migraines, and rheumatoid arthritis. It may also be used to close a patent ductus arteriosus in a premature baby. It can be taken orally or intravenously. It typically begins working within an hour.

<span class="mw-page-title-main">Tramadol</span> Opioid pain medication

Tramadol, sold under the brand name Ultram among others, is an opioid pain medication and a serotonin–norepinephrine reuptake inhibitor (SNRI) used to treat moderately severe pain. When taken by mouth in an immediate-release formulation, the onset of pain relief usually begins within an hour. It is also available by injection. It is available in combination with paracetamol (acetaminophen).

<span class="mw-page-title-main">Opioid</span> Psychoactive chemical

Opioids are a class of drugs that derive from, or mimic, natural substances found in the opium poppy plant. Opioids work in the brain to produce a variety of effects, including pain relief. As a class of substances, they act on opioid receptors to produce morphine-like effects.

<span class="mw-page-title-main">Pethidine</span> Opioid analgesic

Pethidine, also known as meperidine and sold under the brand name Demerol among others, is a fully synthetic opioid pain medication of the phenylpiperidine class. Synthesized in 1938 as a potential anticholinergic agent by the German chemist Otto Eisleb, its analgesic properties were first recognized by Otto Schaumann while working for IG Farben, in Germany. Pethidine is the prototype of a large family of analgesics including the pethidine 4-phenylpiperidines, the prodines, bemidones, and others more distant, including diphenoxylate and analogues.

Anti-inflammatory or antiphlogistic 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 opposed to opioids, which affect the central nervous system to block pain signaling to the brain.

<span class="mw-page-title-main">Mefenamic acid</span> Chemical compound

Mefenamic acid is a member of the anthranilic acid derivatives class of nonsteroidal anti-inflammatory drugs (NSAIDs), and is used to treat mild to moderate pain.

<span class="mw-page-title-main">Ketorolac</span> Nonsteroidal anti-inflammatory drug (NSAID; analgesic)

Ketorolac, sold under the brand name Toradol among others, is a nonsteroidal anti-inflammatory drug (NSAID) used to treat pain. Specifically it is recommended for moderate to severe pain. Recommended duration of treatment is less than six days, and in Switzerland not more than seven days. It is used by mouth, by nose, by injection into a vein or muscle, and as eye drops. Effects begin within an hour and last for up to eight hours. Ketorolac also has antipyretic (fever-reducing) properties.

<span class="mw-page-title-main">Phenazone</span> Chemical compound

Phenazone is an analgesic, antipyretic and anti-inflammatory drug. While it predates the term, it is often classified as a nonsteroidal anti-inflammatory drug (NSAID). Phenazone was one of the earliest synthetic medications — when it was patented in 1883, the only synthetic medical chemicals on the market were chloral hydrate, a sedative, trimethylamine, and iodol (tetraiodopyrrol), an early antiseptic. One of the earliest widely used analgesics and antipyretics, phenazone was gradually replaced in common use by other medications including phenacetin, aspirin, paracetamol and modern NSAIDs such as ibuprofen. However, it is still available in several countries either as an over-the-counter or prescribed drug.

<span class="mw-page-title-main">Etodolac</span> Nonsteroidal anti-inflammatory drug

Etodolac is a nonsteroidal anti-inflammatory drug (NSAID).

Propyphenazone/paracetamol/caffeine is an analgesic combination indicated for the management of headache. It contains the analgesics propyphenazone and paracetamol and the stimulant caffeine.

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 analgesics and dyes.

<span class="mw-page-title-main">Piritramide</span> Synthetic opioid

Piritramide(R-3365, trade names Dipidolor, Piridolan, Pirium and others) is a synthetic opioid analgesic that is marketed in certain European countries including: Austria, Belgium, Czech Republic, Slovenia, Germany and the Netherlands. It comes in free form, is about 0.75x times as potent as morphine and is given parenterally for the treatment of severe pain. Nausea, vomiting, respiratory depression and constipation are believed to be less frequent with piritramide than with morphine, and it produces more rapid-onset analgesia when compared to morphine and pethidine. After intravenous administration the onset of analgesia is as little as 1–2 minutes, which may be related to its great lipophilicity. The analgesic and sedative effects of piritramide are believed to be potentiated with phenothiazines and its emetic (nausea/vomiting-inducing) effects are suppressed. The volume of distribution is 0.7-1 L/kg after a single dose, 4.7-6 L/kg after steady-state concentrations are achieved and up to 11.1 L/kg after prolonged dosing.

<span class="mw-page-title-main">Tilidine</span> Synthetic opioid painkiller

Tilidine, sold under the brand name Valoron among others, is a synthetic opioid analgesic, used mainly in Belgium, Bulgaria, Germany, Albania, Luxembourg, South Africa, and Switzerland for the treatment of moderate to severe pain, both acute and chronic. Its onset of pain relief after oral administration is about 10–15 minutes and peak relief from pain occurs about 25–50 minutes after administration.

An equianalgesic chart is a conversion chart that lists equivalent doses of analgesics. Equianalgesic charts are used for calculation of an equivalent dose between different analgesics. Tables of this general type are also available for NSAIDs, benzodiazepines, depressants, stimulants, anticholinergics and others.

<span class="mw-page-title-main">Opiate</span> Substance derived from opium

An opiate is an alkaloid substance derived from opium. It differs from the similar term opioid in that the latter is used to designate all substances, both natural and synthetic, that bind to opioid receptors in the brain. Opiates are alkaloid compounds naturally found in the opium poppy plant Papaver somniferum. The psychoactive compounds found in the opium plant include morphine, codeine, and thebaine. Opiates have long been used for a variety of medical conditions, with evidence of opiate trade and use for pain relief as early as the eighth century AD. Most opiates are considered drugs with moderate to high abuse potential and are listed on various "Substance-Control Schedules" under the Uniform Controlled Substances Act of the United States of America.

References

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  5. ↑ "Notice of Amendment: Addition of Metamizole (Dipyrone) to the Prescription Drug List (PDL)". Government of Canada. 2022-07-18. Archived from the original on 2022-08-30. Retrieved 2023-08-04.
  6. ↑ "Risikoinformationen - Metamizol (Novalgin, Berlosin, Novaminsulfon, etc.): BfArM weist auf richtige Indikationsstellung und Beachtung von Vorsichtsmaßnahmen und Warnhinweisen hin" [Risk information - Metamizol (Novalgin, Berlosin, Novaminsulfon, etc.): BfArM points out the correct indication and compliance with precautionary measures and warnings]. Bundesinstitut für Arzneimittel und Medizinprodukte (Federal Institute for Pharmaceuticals and Medical Products). 2009-05-28. Archived from the original on 2023-05-18. Retrieved 2023-08-04.
  7. ↑ "Recent NZ Gazette Notices Relating to Classification". medsafe.govt.nz. 2020-03-06. Archived from the original on 2023-04-29. Retrieved 2023-08-04.
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  9. 1 2 FDA's Center for Veterinary Medicine (November 26, 2019). "Zimeta (dipyrone injection) - Veterinarians". FDA. Archived from the original on 2022-01-17. Retrieved 2023-08-04.
  10. 1 2 European Medicines Agency (2018-09-17). "Metamizole containing medicinal products - EMA recommends aligning doses of metamizole medicines and their use during pregnancy and breastfeeding". European Medicines Agency. Archived from the original on 2023-02-01. Retrieved 2023-08-04.
  11. 1 2 3 4 5 6 7 Jage J, Laufenberg-Feldmann R, Heid F (April 2008). "[Medikamente zur postoperativen Schmerztherapie: Bewährtes und Neues. Teil 1: Nichtopioide]" [Drugs for postoperative analgesia: routine and new aspects. Part 1: non-opioids]. Der Anaesthesist (in German). 57 (4): 382–390. doi:10.1007/s00101-008-1326-x. PMID   18351305. S2CID   32814418.
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