Pharmacological Characteristics of Metamizole
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Polish Journal of Veterinary Sciences Vol. 17, No. 1 (2014), 207–214 DOI 10.2478/pjvs-2014-0030 Review Pharmacological characteristics of metamizole A. Jasiecka, T. Maślanka, J.J. Jaroszewski Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, University of Warmia and Mazury, Oczapowskiego 13, 10-718 Olsztyn, Poland Abstract Metamizole (dipyrone) is a popular analgetic, non-opioid drug, commonly used in human and veterinary medicine. In some cases, this agent is still incorrectly classified as a non-steroidal anti-inflammatory drug (NSAID). Metamizole is a pro-drug, which spontaneously breaks down after oral administration to structurally related pyrazolone compounds. Apart from its analgesic effect, the medication is an antipyretic and spasmolytic agent. The mechanism responsible for the analgesic effect is a complex one, and most probably rests on the inhibition of a central cyclooxygenase-3 and activation of the opioidergic system and cannabinoid system. Metamizole can block both PG-depend- ent and PG-independent pathways of fever induced by LPS, which suggests that this drug has a profile of antipyretic action distinctly different from that of NSAIDs. The mechanism responsible for the spasmolytic effect of metamizole is associated with the inhibited release of intracellular Ca2+ as a result of the reduced synthesis of inositol phosphate. Metamizole is predominantly applied in the therapy of pain of different etiology, of spastic conditions, especially affecting the digestive tract, and of fever refractory to other treatments. Co-administration of morphine and metamizole produces superadditive, antinociceptive effects. Metamizole is a relatively safe pharmaceutical preparation although it is not completely free from undesirable effects. Among these side-effects, the most serious one that raises most controversy is the myelotoxic effect. It seems that in the past the risk of meta- mizole-induced agranulocytosis was exaggerated. Despite the evidence showing no risk of teratogenic and embryotoxic effects, the drug must not be administered to pregnant women, although it is allowed to be given to pregnant and lactating animals. This paper seeks to describe the characteristics of metamizole in the light of current knowledge. Key words: metamizole, analgesics, non-opioids, NSAIDs, antinociception Introduction present, metamizole is classified as a non-opioid anal- gesic (Vazquez et al. 2005, Chaparro et al. 2012, Es- Metamizole (dipyrone) is a pyrazolone derivative cobar et al. 2012), although for years it was claimed to (Brogden 1986), introduced to pharmacotherapy in belong to non-steroidal anti-inflammatory drugs 1922 (Hinz et al. 2007). This is one of the strongest (NSAIDs) (Batu and Erol 2007, López-Mun˜oz et al. non-opioid analgesic drugs, used in both human and 2008, Smith et al. 2008, Dom´nguez-Ramı ´rezı et al. veterinary medicine (Baumgartner et al. 2009). At 2010). In the light of what we know today, the latter Correspondence to: A. Jasiecka, e-mail: [email protected], tel.: +48 89 523 3758 208 A. Jasiecka et al. classification appears erroneous because, in contrast mizole in a dose of 750 mg, the bioavailability of to NSAIDs, the mechanism through which meta- MAA was 85%, maximum concentration (Cmax) of this mizole acts relies on the inhibition of a central cyc- metabolite was reached in 1.2-2.0 h, and its volume of looxygenase-3 (COX-3) (Chandrasekharan et al. distribution (Vd) was around 1.15 l/kg. The absolute 2002, Mun˜oz et al. 2010). bioavailability after intramuscular and rectal adminis- Chemically, metamizole is sodium N-(2,3- tration was 87% and 54%, respectively (Levy et al. dimethyl-5-oxo-1-phenyl-3-pyrazolin-4-yl)-N-methyl- 1995). MAA is further metabolized with a mean elim- aminomethanesulphonate (Rogosch et al. 2012). In ination half-life (t1/2kel) of 2.6 to 3.25 h to 4-for- Poland, metamizole (as metamizole sodium) is avail- mylaminoantipyrine (FAA), which is an end-meta- able in the form of solutions for injections registered bolite, and to 4-aminoantypyrine (AA) (Levy et al. for human use [Amizolmet (Sanitas, Lithuania), Pyra- 1995). AA is acetylated to 4-acetylaminoantipyrine lgin (Polpharma, Poland] and for such animal species (AAA) (Vlahov et al. 1990, Levy et al. 1995, Rogosch as cattle, sheep, goats, horses, pigs and dogs [mono- et al. 2012). MAA and AA are active metabolites, preparations: Biovetalgin (Biowet Drwalew, Poland), whereas AAA and FAA are compounds which do not Injectio Pyralgini (Biowet Puławy, Poland), Pyralgivet show pharmacological activity (Weithmann and (Vet-Agro, Poland), Vetalgin (Intervet International, Alpermann 1985, Vlahov et al. 1990). Moreover, Poland); a complex preparation containing meta- MAA and AA undergo further transformations to ac- mizole sodium and hyoscine butylbromide: Buscopan tive arachidonoyl amides, whose presence was detec- Compositum Vet (Boehringer Ingelheim Vetmedica, ted in the brain and spinal cord of mice (Rogosch et Germany)]. Metamizole is one of just six non-opioid al. 2012). Arachidonoyl amides are formed with the analgesics (apart from metamizole, these are car- participation of fatty acid amide hydrolase (FAAH), profen, flunixin meglumine, ketoprofen and tol- an enzyme which appears in high concentrations in fenamic acid) present in preparations registered for the brain, hence the suggestion that these compounds use on cattle in Poland. are created in the CNS. However, one must not reject In some countries, metamizole has been with- the possibility that these compounds originate periph- drawn from the market (e.g. Sweden, the USA, Japan, erally because the liver is another organ which shows the UK, Australia and Iran), but in many more coun- high expression of FAAH. Furthermore, it is known tries (some European states, Asia, South America) it that metamizole derivatives (i.e. MAA, AA, FAA, is still broadly used, both in human medicine (as an AAA) can easily permeate through the blood-brain OTC drug) and in veterinary practice (Edwards et al. barrier and their concentration in the cerebrospinal 2001, Wessel et al. 2006, Baumgartner et al. 2009, fluid, though lower than in plasma, is sufficiently high Imagawa et al. 2011). In Canada, metamizole is regis- to induce a therapeutic effect (Cohen et al. 1998). tered for use only on small animals and horses, where- as in the USA it has been prohibited from use on food producing animals (Fajt 2001, Smith et al. 2008). The mechanism of the drug’s activity and pharmacological effects Pharmacokinetics Although metamizole has been successfully used for over 90 years, the mechanism of its effect has not The available literature lacks any data on the been thoroughly elucidated. For a long time, meta- pharmacokinetic properties of metamizole in animals, mizole was considered to be a non-selective COX-1 although we have information about the fate of meta- and COX-2 inhibitor (Hinz et al. 2007, Pierre et al. mizole administered to people. When discussing the 2007, Rogosch et al. 2012). The mechanism involved pharmacokinetic properties of metamizole, we actual- in its analgesic effect is complex (Fig. 1). Most prob- ly mean the characteristics of its metabolites because ably, this effect is achieved through both the action of metamizole is a pro-drug, which in a hydrous environ- COX-3 and the impact on the opioidergic system and ment undergoes spontaneous breakdown to numerous cannabinoid system. metabolic products (Vlahov et al. 1990, Levy et al. The re-interpretation of the mechanisms involved 1995). The parent drug is detectable in blood serum in the action of this medication was encouraged by the for just 15 minutes after intravenous administration, discovery of cyclooxygenase isoforms. According to but when given orally it is detectable neither in plasma the available references, metamizole acts as a pain nor in urine (Vlahov et al. 1990). In the digestive reliever by blocking COX-3 (Chandrasekharan et al. tract, metamizole is hydrolyzed to 4-methylaminoan- 2002, Schug and Manopas 2007, Muńoz et al. 2010). tipyrine (MAA) and absorbed in this form. It has been This mechanism, is for example, implied by the results demonstrated that after oral administration of meta- obtained by Chandrasekharan et al. (2002), who Pharmacological characteristics of metamizole 209 Inhibition of COX-3 Activation Analgesic effect Activation of opioidergic system of metamizole of cannabinoid system Fig. 1. Possible mechanisms responsible for the analgesic effect of metamizole. concluded that metamizole, like acetaminophen, of metamizole induces antinociception in awake rats phenacetin or antipyrine, has an inhibitory effect on and, when carried out repetitively, induces tolerance the activity of COX-3 in a dog’s brain. COX-3 is to metamizole and cross-tolerance to morphine (PAG a splice variant of COX-1, which occurs mainly in the is the main site of opioidergic analgesia). Moreover, CNS (Chandrasekharan et al. 2002). Retardation of these investigators indicate that since the effects of COX-3 leads to a reduction in the synthesis of pros- PAG-microinjected metamizole are diminished by taglandin E2 (PGE2) (Chandrasekharan et al. 2002). a microinjection of naloxone (i.e. an antagonist of As a result of the blocking of the PGE2 synthesis in opioidergic receptors) in the same site, these effects the CNS, the sensitivity of nociceptors (i.e. peripheral must be related to local endogenous opioids. Their pain receptors) to pain mediators decreases, which conclusion is corroborated by other researchers,