Metamizole A Review Profile of A Well Known Forgotten Drug Part II Clinical Profile

Biotechnology & Biotechnological Equipment
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Metamizole: A Review Profile of a Well-Known

“Forgotten” Drug. Part II: Clinical Profile
Irina Nikolova, Valentina Petkova, Jasmina Tencheva, Niko Benbasat, Julian

Voinikov & Nikolai Danchev
To cite this article: Irina Nikolova, Valentina Petkova, Jasmina Tencheva, Niko Benbasat, Julian
Voinikov & Nikolai Danchev (2013) Metamizole: A Review Profile of a Well-Known “Forgotten”
Drug. Part II: Clinical Profile, Biotechnology & Biotechnological Equipment, 27:2, 3605-3619, DOI:
10.5504/BBEQ.2012.0135
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PHARMACEUTICAL BIOTECHNOLOGY
Metamizole: A review profile of A well-known “forgotten”
drug. Part II: clinical profile
Irina Nikolova, Valentina Petkova, Jasmina Tencheva, Niko Benbasat, Julian Voinikov, Nikolai Danchev
Medical University of Sofia, Faculty of Pharmacy, Sofia, Bulgaria
Correspondence to: Irina Nikolova
E-mail: nikolova60@gmail.com
Abstract
Part I of this review provided the pharmaceutical and non-clinical profile of metamizole, a non-narcotic analgesic with excellent
analgesic and antipyretic effects. Metamizole is banned drug in many countries (United States, Japan, Australia, part of the
European Union and nearly 30 other countries) for more than 40 years, where it is completely unknown or forgotten, while it
is still freely available over-the-counter drug in many other countries, including Bulgaria. The drug’s availability in oral and
parenteral preparations has allowed its use in a range of clinical situations as monotherapy or in combination. It is known
with different generic names, like metamizole, dipyrone, noramidopyrine, sulpyrine, novaminsulfon, methylmelubrin, etc. and
marketed under hundreds of brand names worldwide. The objective of Part II of this review is to provide up-to-date scientific
evidence for clinical safety and efficacy of the drug, as well as the place of metamizole in Bulgarian pharmaceutical market.
Biotechnol. & Biotechnol. Eq. 2013, 27(2), 3605-3619 approximately 5 %. Typical signs of agranulocytosis are
Keywords: metamizole, NSAIDs, agranulocytosis, clinical inflammation of the mucosa, sore throat, fever (including
trials, safety, efficacy an unexpected, persistent, or recurrent course), increased
erythrocyte sedimentation without or with only slight lymph node
Overview of safety enlargement, or an unexpected but unspecific deterioration of the
The safety of metamizole has been subject of many general health state. In patients currently receiving antibiotics
contradictory debates provoked by the fact that metamizole symptoms may be minimal. In Europe, the annual incidence of
is a widely used OTC medicine in some countries, while in drug-induced agranulocytosis is between 3.4 and 5.3 cases per
others it is forbidden because of the risk of agranulocytosis. million population, while in the USA the rates range from 2.4
The publication of individual cases of agranulocytosis in the to 15.4 per million per year (6).
medical literature and the lack of a full overview of non-clinical The most serious side effect of metamizole is the negative
and clinical characteristics of the drug provoked our team to effect on the bone marrow. There are various studies from
provide this review. Metamizole sodium possesses the seldom, different countries and populations that have evaluated a
but life-threatening risk of agranulocytosis and anaphylactic possible association between metamizole and blood dyscrasia.
shock. The onset of agranulocytosis is unpredictable, and fatal Some genetic mechanisms might be involved in metamizole-
cases have occurred following short-term or intermittent use related agranulocytosis. Metamizole sodium has to be withdrawn
as well as after long-term administration; a hypersensitivity immediately when signs of agranulocytosis or thrombocytopenia
mechanism is speculated (7, 46, 93). hemolytic anemia occur.
and aplastic anemia have been reported during metamizole
Studies with high incidence. The removal of metamizole
administration. Virtually all adverse reactions to pyrazolones
from the USA market in 1977 was based on two studies that
are non-dose-related (70). Metamizole does not cause
found an incidence of metamizole-induced agranulocytosis in
significant adverse gastrointestinal effects and does not impair
the range of 0.79 %–0.86 %, with a mortality rate of 0.57 %
renal function in otherwise healthy subjects, effects typical for
(28, 44). In Sweden, all metamizole-containing products were
other NSAIDs (79); however, prolonged use may prove to be
first withdrawn in March 1974 due to an estimated incidence
toxic to the kidneys. Furthermore, skin rashes and asthma can
of agranulocytosis of 1 in 3000 patients. After registration
also be caused due to allergy (51).
of metamizole in Sweden, an incidence of 700 per 1 million
Agranulocytosis users was claimed to be found. Therefore, in September 1995,
Agranulocytosis is a rare and serious disease often caused metamizole was re-approved based on the results from the
by drugs. Agranulocytosis is a hematologic syndrome of International Agranulocytosis and Aplastic Anaemia Study
acute onset in which the numbers of circulating neutrophils (IAAAS) (45) and then later, again suspended in April 1999
decrease, often abruptly and to undetectable levels, leading to a based on pharmacy sales data and spontaneous reporting of
markedly increased susceptibility to bacterial infection, serious blood dyscrasias in Sweden. Hedenmalm and Spigset (43)
local infection or sepsis, and a risk of mortality estimated at estimated that the risk of agranulocytosis related to metamizole
Biotechnol. & Biotechnol. Eq. 27/2013/2 3605
appears to be at least 1:1439 prescriptions, a much higher Hamerschlak et al. (42) and Maluf et al. (60) reported overall
figure than previously estimated. Ninety-two percent of the agranulocytosis and AA incidence rate of 0.38 and 1.64 cases
cases of blood dyscrasias occurred during the first 2 months per 1 million inhabitant–years, respectively in the LATIN study.
of treatment. Additional risk factors were identified in 36 % Despite that the authors reported no statistically significant
of the patients. In addition, they reported that agranulocytosis association, metamizole was the drug most commonly inducing
was not the only manifestation of metamizole-induced blood agranulocytosis or AA in this multinational case–control study,
dyscrasias; in some of the cases all three haematopoiesis were designed to identify risk factors for agranulocytosis and AA
affected according to bone marrow sample findings. In these and to estimate the incidence rate in Brazil, Argentina and
cases, the outcome was significantly poorer. In particular, the Mexico.
Swedish study has reignited the question of a genetic diversity In Bulgaria the risk of agranulocytosis is accounted to be
with regard to this adverse effect. Backstrom et al. (10) making
0.037 to 1 million persons (94).
certain assumptions, calculated that the risk of metamizole-
induced agranulocytosis would be approximately 1:31000 In conclusion, the incidence of metamizole-induced
metamizole-treated inpatients and 1:1400 metamizole-treated agranulocytosis has varied geographically and from study to
outpatients. study. In our point of view, it is mostly due to differences in
study methodology, patterns of use, terms of dose, duration
Studies with low incidence. The IAAAS (45) found a reported and concomitant medications; however, some genetic
overall incidence increase by metamizole use of 1 case per predisposition could not be excluded, since metamizole
million users; however, it showed a wide regional variability of appears to be strongly associated with agranulocytosis
the incidence. As a part of this study, data collection from Sofia in certain regions of the world, but for reasons that are not
(population 1142000), Bulgaria, was extended from 1982 until understood, much less so in others. In 1996, a paper published
1987, due to very few cases. During that period 18 cases of by Vlahov et al. (96) revealed significant differences between
agranulocytosis were compared with 106 controls; 9 cases and the agranulocytosis patients and the healthy population in the
27 controls were exposed to metamizole, for a multivariate RR human lymphocyte antigen (HLA) allele frequencies, and
estimate of 1.7 (95 % confidence interval 0-4-7-3). Sales of in the degree and the frequency of chromosome aberrations.
products containing metamizole rose steadily between 1982 Five patients with metamizole-induced agranulocytosis were
and 1987, but the annual incidence of agranulocytosis was
included in the study. A higher frequency of the HLA24 antigen
stable (3–4 per million). Authors concluded that there is no
and a lower frequency of the DQA1*0501 allele were evident
evidence of an increased risk of agranulocytosis related to the
for the ex-agranulocytosis patients as compared to the controls
use of metamizole in Bulgaria and certainly not one as great as
(11 % versus 57 %, respectively). In the patients exposed to
that found in Germany and Spain (95).
metamizol, an A24-B7 haplotype was found with a frequency
In a pharmacovigilance, prospective 12-month study in
higher than that in the non-exposed patients and the reference
Poland involving 24 of 25 haematology centres that provide
group. The HLA-DQwl antigen and metamizol-related
specialist care for the 30 million adults in Poland, revealed
agranulocytosis were evidently associated in all cases (5/5;
21 cases of agranulocytosis, 48 of aplastic anaemia, 15 of
100 %) in contrast to the patients not exposed to metamizol
neutropenia, and 11 of pancytopenia. Of these cases, three
and the controls. The HL-A2 antigen was absent in four of the
(2 agranulocytosis; 1 aplastic anaemia) were judged as being
five metamizol-associated agranulocytosis cases (20 %), while
possibly related to metamizole. Crude estimates of the rate
of agranulocytosis and aplastic anaemia associated with in the control group it was present in 56 % of the patients.
metamizole were 0.16 and 0.08 cases/million person-days The degree of structural rearrangements (0.62 % ± 0.2 %) and
of use, respectively. Ongoing national safety surveillance in the frequency of chromosome breakages (7.75 % ± 0.68 %) in
Poland showed that, despite the possibility of drug-induced agranulocytosis patients were higher than those in the healthy
blood dyscrasias with metamizole, the risk is very low (12). population (0.3 % ± 0.12 %, P < 0.05 and 1.42 % ± 0.27 %). The
Another study from Poland found no case of agranulocytosis abnormalities affected predominantly Chromosomes 1(1p13),
related to metamizole use despite a consumption of over 110 2(2p12) and 5(5p12). No differences were found between
million tablets per year (59). the agranulocytosis patients and the healthy population when
A study performed in Bangkok, indicated that the incidence considering the haemoglobin subtypes, ABO-and RH-blood
of agranulocytosis in the ambulatory population is exceedingly groups, glucose-6-phosphate dehydrogenase activity, and the
low, at 0.7 per million per year (84). rates of slow and rapid acetylators.
In a case control study from Spain, Ibanez et al. (46) There is no doubt that metamizole can induce
calculated a rate of 0.56 cases of metamizole-induced agranulocytosis and other serious blood dyscrasias that
agranulocytosis per 1 million inhabitants per year, with a justifies the ban on the drug in some countries, but in many
lower risk if metamizole was used for a short period of time others, including Bulgaria, enormously high consumption of
and at low doses of 1 g/day to 2 g/day. No association between metamizole-containing products does not correlate with steady
aplastic anemia and the use of metamizole was found. and low incidence of agranulocytosis.
3606 Biotechnol. & Biotechnol. Eq. 27/2013/2
Anaphylaxis The more serious life-threatening cutaneous complication
Anaphylactic shock which has resulted in fatalities has is that of Stevens–Johnson’s syndrome and toxic epidermal
been reported with metamizole (incidence of 1 in 5000 necrolysis (Lyell’s syndrome). Cases have been reported
administrations) (14, 30). Anaphylactic reactions may following the use of pyrazolones. A large population-based
develop immediately following intake/injection or hours later case-control study covering about 120 million inhabitants of
(49). Immediate hypersensitivity reactions are presumably France, Germany, Italy, and Portugal was conducted between
IgE-mediated and clinically characterised by laryngeal and the years 1989 and 1992 to quantify the risks associated with
angioneurotic oedema, generalised urticaria, bronchospasm, the use of specific drugs within the week preceding the first
vasomotor collapse, and death. In a study of a population of manifestation of the disease. Seven of the 245 cases (3 %)
14.5 million in Holland, for two years an incidence of drug and 1 % of the controls used pyrazolones. The association
induced anaphylaxis of 3.7 per million annually was found. The between both pyrazolones as a group and metamizole and
excess mortality estimate associated with metamizole use was these conditions, according to the multivariate relative risk, is
0.22 per 100 million (93). Risk factors for severe metamizole- statistically not significant (77).
induced allergy are: allergies/intolerability to metamizole and
Respiratory effects
other non-opioids and bronchial asthma.
Patients with analgesic intolerance commonly exhibit asthma
Severe anaphylactic reaction without any cutaneous attacks in case of allergic reactions to metamizole. Bronchospasm
symptoms after IV infusion of metamizole has been reported has been described following administration of metamizole
(87, 100). Allergic reaction after previous intake of metamizole (7, 51). Current evidence indicates that COX inhibition
without side effects has also been described (50, 52). and increased production of cysteinyl leukotriene plays an
Cutaneous reactions important part in these obstructive reactions. A cross-reaction
A variety of cutaneous reactions have been attributed to has been shown between NSAIDs, including metamizole, in
metamizole, including nonspecific skin rash, urticaria, the precipitation of asthmatic attacks. The incidence and risk
morbilliform, scarlatiniform, erythematous, bullous, purpuric, estimates of the asthma syndrome induced by pyrazolones are
exudative, fixed drug eruption, and toxic epidermal necrolysis unknown.
(7, 68). Diaphoresis has been reported following oral and In a one-centered, non-randomized, non-comparative,
parenteral metamizole. Brenner et al. (22) reported three cases open-labeled study, 15 normal healthy volunteers and 15
of pemphigus vulgaris believed to be induced or exacerbated COPD patients were treated with metamizole as an oral
by metamizole. All three of these patients had histologic suspension at a dose of 20 mg/kg. All of the normal healthy
evidence of suprabasal acantholysis and intercellular deposits volunteers and COPD patients, except one in the COPD
of IgG. Gonzalo-Garijo et al. (39) reported an acute generalized group, completed the study without any adverse events
exanthematous pustulosis in a 58-year-old man. The patient during the study. An adverse event, characterized by dyspnea,
had been operated 48 h earlier for a ruptured tendon with wheezing and cough, occurred in one COPD patient 45 min
mepivacaine and bupivacaine, and concurrent medications after metamizole intake. The patient recovered totally after
included cefazoline, metamizole, and enoxaparin. He had treatment with bronchodilators. The relation between drug
no known allergies, no history of drug or food reactions, nor exposure and the bronchospasm was estimated as ‘‘possible’’.
contact hypersensitivity. Cefazoline and metamizole were The authors conclude that metamizole can be safely used in
discontinued, and the eruption resolved without sequelae such patients when indicated (41).
after 1 week of treatment with oral dexclorpheniramine and
Gastrointestinal effects
prednisone, with emollients. Three months after the adverse
Metamizole has favorable gastric tolerability (81). nausea,
reaction, only metamizole was positive in patch tests.
vomiting, gastric irritation, and xerostomia have been
In 1973 the Boston Collaborative Drug Surveillance described only with high doses oral and parenteral metamizole
Program noticed that drug rash occurred more frequently administration.
in Israeli than in US patients. At that time 41.6 % of Israeli
patients received metamizole, whereas in the USA metamizole Cardiovascular findings
was not in use. The risk of metamizole rash was estimated to Hypotension has been reported following parenteral and oral
be 2.4 % of the exposed patients. However, it was recognised administration of metamizole (40). This is not necessarily
as being caused by the drug in only one-third of the affected a symptom of drug intolerance, since it is observed as a
cases. In most cases metamizole rash was mild. Rarely, it may procedure-related (not drug-related) side effect.
also be part of a generalised drug reaction. Pyrazolone-induced
urticaria/angio-oedema can also be a manifestation of a Renal findings
pseudoallergic reaction, probably occurring via COX inhibition Deterioration of the renal function (proteinuria, oliguria,
(57). Asero (9) has shown that three out of 34 patients (9 %) anuria) were rarely observed. The occurrence of acute
with a history of pyrazolone-induced urticaria/angio-oedema interstitial nephritis is mostly a consequence of drug abuse
had such reactions after ASA administration. and rare enough to still be subject of single case reports (16).

A summary of adverse events associated with metamizole, amount of baclofen and metamizole. The toxicological analyses
by organ systems, is given in Table 1. According to the revealed high concentration of 4-methyl-aminoantipyrine
Uppsala Monitoring Centre, WHO Collaborating Centre for in blood and urine. Circumstantial evidence suggests the
International Drug Monitoring, the number of adverse effects deceased had probably ingested acetylsalicylic acid, laxatives,
registered in the years 1978–2009 (March) was 14441 for terazosin and about 8 g of defibrotide, too. Therefore, they
metamizol and 67581 for paracetamol (101). were not considered a factor in the cause of death.
In conclusion, life threatening reactions, including Stevens– Sinus tachycardia has been reported in 8 % of metamizole
Johnson’s syndrome, toxic epidermal necrolysis, anaphylaxis, overdoses (70). Ataxia, lethargy, stupor, vertigo, seizures,
and agranulocytosis are extremely rare. Mild allergic reactions agitation, coma, hallucinations, and paresthesias may occur
may deteriorate or generalize and may be associated with with severe overdose. CNS depression is less frequent
urticaria, severe angio-oedema, bronchospasm, arrhythmia, with metamizole overdose. Headaches and weakness were
hypotension, and cardiovascular shock. reported in 7 and 11 patients (n = 39), respectively, following
metamizole overdose ingestions. Toxic gastroenteritis, with
Overdose
nausea, vomiting, and epigastric pain, is common, reported in
The incidence of acute toxicity of metamizole is very low. 45 % of metamizole overdose cases. Gastric ulceration may
Clinical manifestations are not immediately evident and an occur as well.
observation period of 8 h is warranted.
Forrester (35) repoted no death cases in a survey of 81
A retrospective review of prospectively collected poison metamizole exposures reported to poison centers in Texas
center data on acute exposure to metamizole over a three- during a period from 1998 to 2004. Of 81 metamizole
year period was published by Bentur and Cohen (15). A total exposures, 52 (64 %) were isolated and 29 (36 %) were non-
of 243 records (204 asymptomatic and 39 symptomatic) met isolated. Twenty-two percent (11/51) of isolated cases were
the inclusion and exclusion criteria. Median age was 17 y intentional, while 59 % (17/29) of non-isolated cases were
(4 m–83 y), median amount 5 g (250 mg–45 g), and median intentional. Of those cases with a known medical outcome,
time to consultation was 2 h (5 min–48 h). Toxic events the medical outcome was no adverse clinical effect for
(49) occurred in 39 (16 %) patients; 57 % of these were 76 % (16/21) of isolated exposures and 42 % (8/19) of non-
gastrointestinal and all were mild. Suicidal patients (n = 99) isolated exposures. The specific adverse clinical effects
ingested significantly larger amounts, as did patients with reported for isolated exposures were primarily neurological
gastrointestinal symptomatology. No agranulocytosis was (n = 6), gastrointestinal (n = 4), and dermal (n = 3). The most
reported. Metamizole overdose was associated with mild, frequently reported treatment for isolated exposures was some
mainly gastrointestinal toxicity. form of decontamination (n = 11). Although the majority of
Peces and Pedrajas (73) reported a case of non-oliguric isolated and non-isolated metamizole exposures were adults, a
acute renal failure and abortion following the ingestion of an higher proportion of isolated exposures involved children less
overdose of 11.5 g metamizole in an otherwise healthy 14-year- than 6 years of age, while a higher proportion of non-isolated
old girl. The mechanism of abortion in this case is unknown, exposures involved older children. Non-isolated exposures
however due to high dose, part of the drug probably entered were significantly more likely to be intentional, particularly,
the fetal tissues, and might have induced the abortion by direct suspected suicide attempts.
toxic effect. Renal damage probably occurred as a result of toxic Metamizole has been shown to be a very effective
tubular necrosis, since it was not reversible despite volume antipyretic and is capable of causing hypothermia when an
repletion. In addition, she also presented microhaematuria and overdose is given (61).
proteinuria, and renal function was rapidly reversible following
steroid therapy. Therefore, on the basis of the time course of Treatment. Treatment should include symptomatic and
the disease, the authors speculated that the renal damage in supportive measures for respiratory and cardiovascular
this patient might be due to a toxic effect producing a tubular function. Gastrointestinal decontamination (i.e., activated
lesion and interstitial nephritis. Berruti et al. (16) reported a charcoal) can be considered if 5 g or more have been ingested
case of acute renal failure due to acute interstitial nephritis, and if the patient presents within 1 h after exposure. Routine
following the ingestion of a self-prescribed megadose (30 g hematological follow-up does not seem to be warranted (15).
over 2 days) of metamizole in an otherwise healthy 45-year- In 81 reported metamizole exposures in Texas (from 1998 to
old man. Mild gastrointestinal distress was the most commonly 2004) surveyed by Forrester (35), specific adverse clinical
occurring adverse effect (57 %), in a series of 39 patients who effects were recorded for 12 (30.8 %) of the cases. The
were symptomatic following metamizole overdose ingestions, highest proportion of cases had neurological effects, followed
and included vomiting (n = 16), nausea (n = 3), and abdominal by gastrointestinal and dermal effects. The most frequently
pain (n = 9). The median amount of metamizole ingested was reported specific adverse clinical effect was vomiting. No
7.5 g (range of1 g to 25 g) (15). specific treatment was listed for the majority of cases. The most
De Giovanni and d’Aloja (27) reporetd a fatal suicidal frequently reported type of treatment was decontamination,
intoxication in a 56-year-old man after ingestion of an unknown most frequently by administration of charcoal. Treatment other

TABLE 1
Summary of adverse events associated with metamizole, by organ systems
System Adverse effects

Immunological Hypersensitivity, anaphylaxis
Blood Aplastic anemia, agranulocytosis
Nonspecific skin rash, urticaria, morbilliform, scarlatiniform, erythematous, bullous, purpuric, exudative,
Skin
fixed drug eruption, diaphoresis, toxic epidermal necrolysis, Stevens–Johnson’s syndrome
Respiratory Bronchospasm
Gastrointestinal nausea, vomiting, gastric irritation, xerostomia
Cardiovascular Hypotension
Renal Deterioration of the renal function
TABLE 2
Registered metamizole-containing products in Bulgaria (13)
Trade name Status/MAH Strength

Products containing metamizole sodium as an active ingredient as ATC code: N02BB02
Algozone OTC/Ozone Laboratories 500 mg tabl. (adults and children over 15)
Analgin OTC/Sopharma 500 mg tabl. (adults and children over 10)
Analgin Chin OTC/Sopharma 250 mg film coated tabl. (adults and children over 10)
Dialgin OTC/Himax 1000 mg powder for oral solution (adults and children over 16)
Dialgin OTC/Himax 500 mg powder for oral solution (adults and children over 14)
Dialgin Junior OTC/Himax 250 mg powder for oral solution (children over 7)
Hexalgin OTC/Hexal 500 mg/mL oral solution (adults and children over 3 months)
Medphalgin OTC/Sevex 500 mg tabl. (adults and children over 16 kg)
Angetop OTC(Rx)/Inbiotech 500 mg tabl. (OTC – adults and children over 12; Rx – children over 7)
Freshalgin OTC(Rx)/Adipharm 500 mf tabl. (OTC – adults and children over 15; Rx – children over 7)
Proalgin OTC(Rx)/Chaikapharma 500 mg tabl. (OTC – adults and children over 15; Rx – children under 15)
Analgin Rx/Sopharma 500 mg/mL solution for injection (adults and children over 15)
Metamizole
Rx/Vetprom 500 mg/mL solution for injection (adults and children over 15)
sodium-Vetprom
Metamizole combinations
Trade name Status/MAH Active ingredients Strength ATC code
metamizole sodium, caffeine, 500 mg/50 mg/38.75 mg tabl.
Benalgin OTC/Actavis N02BB52
thiamine (adults and children over 12)
metamizole sodium, caffeine, 30 mg/20 mg/300 mg/200 mg tabl.
Paracofdal OTC/Unipharm N02BB52
codeine, paracetamol (adults and children over 14)
metamizole sodium, 500 mg/5 mg/0.1 mg tabl.
Spasmalgon OTC/Actavis A03DA02
pitofenone, fenpiverine (adults and children over 9)
metamizole sodium, 500 mg/2 mg/0.02 mg/mL amp.
Spasmalgon Rx/Actavis A03DA02
pitofenone, fenpiverine (adults and children over 15)
metamizole sodium,
500 mg/20 mg film-coated tabl.
Tempalgin OTC/Sopharma triacetonamine-4- N02BB72
(adults and children over 15)
toluensulfonate
metamizole sodium, 300 mg/15 mg/150 mg/50 mg/10 mg tabl.
Rx/Balkanpharma
Sedalgin-Neo paracetamol, phenobarbital, (contraindicated for children, age not N02BE71
Dupnitza
caffeine, codeine mentioned)

than decontamination was reported in only 5 of the cases. the dose and time of treatment. The clinical data support the
view that during short-term treatment the incidence is low
Fatal cases. The absolute risk of mortality associated with
and even smaller than with other NSAID (32).
metamizole appears to be similar to that for acetaminophen
and substantially lower than the risk associated with other
NSAIDs, like aspirin and diclofenac. The estimated excess
Overview of efficacy
mortality due to agranulocytosis, aplastic anemia, anaphylaxis, Since its introduction in 1922, metamizole has been widely used
and serious upper gastrointestinal complications was 185 per as an effective analgesic and antipyretic drug. The antipyretic
100 million for aspirin, 592 per 100 million for diclofenac, 20 action of metamizole was one of the earliest observations that
per 100 million for acetaminophen, and 25 per 100 million were made with this compound. The claimed efficacy in pain
for metamizole. The estimates were largely influenced by derives from the long-term therapeutic experience.
the excess mortality associated with upper gastrointestinal Therapeutic indications
complications, an adverse effect more commonly associated 1. Pain of different origin: headache, toothache,
with the use of aspirin and diclofenac than with the use of neuralgia, neuritis, myalgia, injuries, burns,
metamizole or acetaminophen. While the absolute values of postoperative pain, “phantom” pain, cancer pain
the excess mortality varied according to patient age and history a. Dysmenorrhea
of peptic ulcer disease, the disparity in estimates between the b. Abdominal colics
agents remained (5, 54). c. Renal colics
Contraindications, precautions and warnings d. Biliary colics
2. Fever – as an antipyretic in the combined treatment of
Metamizole is contraindicated in: acute upper respiratory tract infections, tracheitis,
• Blood dyscrasias; tracheobronchitis, infectious diseases (flu, measles,
• Bone marrow suppression; varicella, etc.).
• Hypersensitivity to metamizole;
• Hypersensitivity (immunologic-based) to aspirin Pain
or other nonsteroidal anti-inflammatory drugs (e.g., Pain is a common complaint of patients and its appropriate
symptomatic response of rhinitis, urticaria, asthma); management is medical precept. Metamizole is indicated
• Acute intermittent hepatic porphyria; in the treatment of pain of various origin and intensity:
• Myeloic function disorders or hemopoietic system toothache, headache, arthralgia, neuralgia, myositis, mild to
diseases; moderate visceral pain, pain after surgery and trauma, pain
• Children below 7 years of age. associated with neoplastic diseases, colic pain etc. Single-
dose metamizole appears to be of similar efficacy to ibuprofen
Precautions: 400 mg and other analgesics, as frequently used in the treatment
• Cardiac conditions, including hypertension, of moderate to severe postoperative pain. In a meta-analysis,
aggravated by fluid retention and oedema; 15 studies were included; 8 used placebo and 7 used an active
• Glucose-6-phosphate dehydrogenase deficiency; control (oral dexketoprofen 12.5 mg or 25 mg, oral ketorolac
• History of gastrointestinal ulceration, bleeding, or 10 mg, intramuscular pethidine 100 mg or ketorolac 30 mg,
perforation; intravenous tramadol 100 mg or rectal suprofen 300 mg). In
• Infection, pre-existing; 5 trials (288 patients) the mean response rate (proportion of
• Liver dysfunction; patients with at least 50 % pain relief) for single dose oral
• Porphyria; metamizole 500 mg was 73 % (range of 54 % to 87 %) and
• Renal dysfunction; with placebo it was 32 % (19 % to 41 %) in moderate to severe
• Pregnancy and lactation. postoperative pain over 4–6 hours. In 2 studies (113 patients)
Long-term safety: the response rate with oral metamizole 1 g was 69 % (61 %
Regarding the clinical experience with respect to the long-term and 77 %) and with placebo it was 20 % (11 % and 25 %). In
safety of metamizole treatment, it has to be considered that the one study (70 patients) the response rate with intramuscular
clinical studies on the efficacy and safety of metamizole exhibit metamizole 2 g was 74 % compared to 46 % in the placebo
substance-specific safety problems of long-term treatment. group. The response rates in the active-controlled trials were
Blood dyscrasias (agranulocytosis, thrombocytopenia, aplastic similar to those reported in the placebo-controlled trials.
anemia) have been reported. As mentioned already, metamizole The commonest adverse effects were somnolence, gastric
has been used for almost 90 years (since 1922) in the treatment discomfort, and nausea (31, 33).
of fever and pain, and is, hence, a product with long-term In a randomised, double-blind multi-center study, 253
marketing experience. Different opinions exist on the adverse patients who had undergone extraction of the lower third molar,
event profile of metamizole. There is no doubt that the life- metamizole 2 g was superior to ibuprofen 600 mg. Metamizole
threatening adverse event of agranulocytosis can be related to 1 g and ibuprofen 600 mg showed similar therapeutic effect.
metamizole. However, the appearance of this event depends on

No serious adverse effects developed and none of the patients component of multi-modal analgesia in countries where it is
had to leave the study for this reason (74). registered and its use widespread (83).
The objective of the study of Tulunay et al. (92) was to Perioperative metamizole, combined with opioids, provides
evaluate the analgesic effectiveness of metamizole, when effective analgesia of improved quality in postoperative
given before removal of nasal packing in patients undergoing pain treatment. In a double-blind, randomised, placebo-
septoplasty (n = 38) in a placebo-controlled, randomised controlled trial the analgesic effect of perioperative high-dose
design. Metamizole 1 g IM was found to be effective in metamizole infusion was examined in 155 patients undergoing
lowering initial pain intensity and in reducing it during the first orthopaedic or trauma surgery. Metamizole 5 g was given
10 min after removal. intravenously within 1 h, starting 30 min before the end of
In a survey of postoperative pain treatment in 348 children surgery. Quality of analgesia was improved with a significant
3–14 years of age, Baños et al. (11) determined that metamizole reduction in the visual analogue scores (VAS) (P < 0.006) and
was the most prescribed drug, followed by propyphenazone, the doses of opioids required (P < 0.0001), with no additional
paracetamol, and codeine. The total daily dose of metamizole side effects. This trial showed a highly significant reduction
ranged between 1.6 g and 3.4 g. of the first pain score after arrival in the recovery room in the
In a prospective, randomized, double-blinded study, metamizole group, with a significant reduction of subsequent
Rawal et al. (76) compared the analgesic efficacy of three requirements for rescue analgesia by opioid injection (21). The
drugs: tramadol 100 mg every 6 h, metamizole 1 g every 6 h, fact that typical toxic effects of NSAIDs such as compromised
and paracetamol 1 g every 6 h in 120 patients scheduled to renal, hepatic and gastrointestinal function do not occur with
undergo ambulatory hand surgery with regional anesthesia. metamizole use and as the risk of agranulocytosis linked to
At discharge, oral analgesic tablets were prescribed. Tramadol its use is extremely low, the substance offers advantages over
was the most effective analgesic. However, the incidence of NSAIDs.
side effects was also increased with tramadol. Metamizole and Cesarean pain. Cesarean section is one of the most common
acetaminophen provided good analgesia in about 70 % and operations. An open prospective study was conducted on
60 % of patients, respectively, with a decreased incidence of women who had a cesarean section with epidural analgesia,
side effects. during two consecutive periods of 3 months each. In the first
Steffen et al. (89) investigated the analgesic combination group of 109 women, an oral solution of 1 g metamizole was
of metamizole and diclofenac after trauma surgery with allowed every 4 h, upon patient request. Patients requesting
respect to the postoperative opioid consumption (via patient- additional analgesia were administered a tablet of 30 mg
controlled analgesia [PCA]) in the first 24 h after surgery, immediate-release morphine sulfate. In the second group
and the reduction of pain in the immediate postoperative of 90 women, the same protocol was used; however, oral
period. In a double-blind randomized placebo controlled morphine was the drug of choice and metamizole was used
study, 48 patients received either metamizole (three for rescue analgesia. The results showed duration of analgesic
doses of 1 g intravenously) and diclofenac (two doses of effect of metamizole – 6.5 h, and the satisfaction score – 90.
100 mg suppository) or placebo, beginning immediately The duration of analgesic effect of oral morphine was 5.05 h
preoperatively and repeated postoperatively. All patients were and the satisfaction score was 83.7. Overall, patients in both
allowed to order levomethadone from a PCA-pump for 24 h groups requested only 25 % of the permissible dosage of
after surgery. The patients receiving verum had significantly analgesia. Oral analgesia following cesarean section provides
less pain at all points in time except for 2 h and ordered a satisfactory pain relief, is easily administered, and is a
significantly lower cumulated dose of levomethadone during substantially less costly alternative to the new pain treatment
the first 24 h postoperatively than placebo-treated subjects technologies currently in use (48).
(opioid-sparing effect after 24 h: −74 %). There were no
Headache and migraine. In 417 patients with moderate episodic
significant differences in the incidence of side effects between
tension-type headache the efficacy and safety of oral single
the two groups. Perioperative application of metamizole and
doses of 0.5 g and 1 g metamizole versus 1 g acetylsalicylic
diclofenac results in better pain relief and significantly lowers
acid (ASA) was assessed in a randomized, double-blind,
opioid requirements in patients after minor trauma surgery.
placebo- and active-controlled, parallel, multicentre trial (62).
Repeated doses of metamizole to 4 g per 24 h were identical Treatment arms were metamizole 0.5 g (n = 102), metamizole
in efficacy to 4 g of IV paracetamol after breast surgery with 1 g (n = 108), ASA 1 g (n = 102), and placebo (n = 105). The
regard to analgesia achieved, opioid-rescue consumption, analgesic efficacy of 0.5 g and 1 g metamizole vs. placebo
and patient satisfaction. Furthermore, it has been shown that was highly statistically significant (a = 0.025; one-sided)
combining an NSAID such a ketoprofen with metamizole for sum of pain intensity differences, maximum pain intensity
increases the analgesic efficacy. Although the utilisation of difference, number of patients with at least 50% pain reduction,
metamizole as a peri-operative analgesic is not as well studied, time to 50% pain reduction, maximum pain relief and total pain
there is a considerable clinical experience with its use as a relief. A trend towards an earlier onset of a more profound pain
relief of 0.5 g and 1 g metamizole over 1 g ASA was noticed.

All medications including placebo were almost equally safe free. At 60 min and 90 min, 2 (13 %) and 5 (33 %) patients
and well tolerated. Twenty-two out of 28 patients assessed from the metamizole group and 11 (73 %) and 13 (86.7 %)
drug-related, mild to moderate adverse events. There were patients from the LC group were pain-free (P < 0.001). At
4 in the 0.5 g metamizole group, 5 in the 1 g metamizol 60 min, significantly more patients from the LC group were
group, 6 in the 1 g ASA group, and 7 in the placebo group. nausea-free (P < 0.001). Regarding photophobia, there were
Dyspepsia was the most frequent drug-related adverse event no differences between the groups at 60 min. Pain and burning
(16 patients). The authors concluded that metamizole showed at the site of the injection was reported by more patients of
slight advantages over ASA with regard to efficacy and safety. the LC group compared to the metamizole group (P < 0.0001).
In 2002, Bigal et al. (17, 18) presented two randomized,
Cancer pain. Poor information is available about the isolated
placebo-controlled and double-blind studies evaluating the
effectiveness of metamizole in the treatment of cancer pain;
efficacy of metamizole in patients that sought emergency
in fact, it is not a usual practice to treat cancer pain with a non-
room assistance with the complaint of acute migraine or
opioid drug alone, but rather to use these drugs in add-on therapy
acute episodic tension-type headache. In the first study, a
in order to achieve a sufficient analgesia where opioids alone
small double-blinded, randomized, placebo-controled trial,
cannot provide satisfactory pain relief. Indeed metamizole is
metamizole successfully aborted pain in episodic tension-type
a widely used add-on therapeutic in cancer patients (99). In a
headache. Sixty patients were randomized to receive placebo)
double-blind, randomised, parallel clinical trial, Rodriguez et
or 1 g metamizole. The patients receiving metamizole
al. (78) concluded that the analgesic effect of metamizole 2 g
(n = 30) showed a statistically significant improvement
every 8 h for the treatment of cancer pain is similar to morphine
(P < 0.05) of pain compared to placebo up to 30 min after drug
10 mg every 4 h. According to clinical experience, metamizole
administration. There were statistically significant reductions
acts complementary to other analgesics such as opioids, like
in the recurrence (metamizole = 25 %, placebo = 50 %) and use
morphine. In a double-blind placebo-controlled randomized
of rescue medication (metamizole = 20 %, placebo = 47.6 %)
crossover study Duarte Souza et al. (29) evaluated whenever
for the metamizole group (17).
morphine was started, if associating metamizole with it would
In the second study, Bigal et al. (18) studied 86 patients improve pain control and if this effect was time dependent.
during an acute migrainous attack, with aura at the moment Thirty-four ambulatory cancer patients experiencing cancer-
of the evaluation. Patients were randomized to receive one related pain for which oral morphine was to be started at the
of the following substances, in a parenteral route: placebo, dose of 10 mg orally (PO) every 4 h, were randomized to take
metamizole, chlorpromazine, and magnesium sulphate. either metamizole 500 mg PO every 6 h or placebo. After
Metamizole and chlorpromazine reduced the duration of 48 h, patients would be switched from metamizole to placebo
the aura, when compared to placebo, 60 min following their and vice versa. At first, 16 patients were randomized to start
administration. with placebo (group 1) and 18 with metamizole (group 2).
In another recent study, Fernandes Filho et al. (34) conducted Pain scores for groups 1 and 2 were at baseline: 7.31 ± 0.29
a pilot randomized study comparing intravenous metamizole vs 6.88 ± 0.28 (P = 0.3), at 48 h: 7.06 ± 0.32 vs 5.5 ± 0.31
to intravenous metoclopramide in 27 patients presenting acute (P = 0.001), and at 96 h: 3.18 ± 0.39 vs 1.94 ± 0.37 (P = 0.03).
crisis of migraine. In men, metoclopramide reduced pain in Both groups had significant improvements in pain scores after
80.0 % compared with 55.0 % from metamizole (P = 0.052). In introducing metamizole (P < 0.001, for both). Main toxicities
women, there was a reduction of 65.0 % with metoclopramide were nausea, vomiting, epigastric pain, and myalgias. Twenty-
and 71.2 % with metamizole (P = 0.748). The small number eight patients chose metamizole, four placebo, and two were
of patients in the study might have influenced these results. indifferent. The authors conclude that metamizole adds
Significant collateral effects were not found. There was no significantly to the analgesic effect of morphine and, when
difference either in the intensity of pain reduction, or in the given at the time of starting morphine, results in better pain
development of collateral effects, comparing metamizole to scores even after metamizole is discontinued.
metoclopramide. To collect data on pain management in paediatric oncology with
A single-blind study for the effect of metamizole in the respect to the WHO ladder approach, eight German tertiary
treatment of severe migraine attacks was published in 2008 care paediatric oncology centres prospectively documented
by Krymchantowski et al. (53). The authors evaluated the all their inpatient pain treatment courses from June 1999
efficacy and tolerability of the intravenous formulations of to December 2000. Two hundred and twenty-four patients
lysine clonixinate (LC) and metamizole. Thirty patients were (median age, 9 years; range 0.2–32.1) were enrolled. Three
randomized into 2 groups when presenting to an emergency hundred and thirty-three pain episodes comprising a total of
department with severe migraine attack. Headache intensity, 2265 treatment days were documented. The most frequently
nausea, photophobia, and side effects were evaluated at 0 min, administered non-opioid analgesics were metamizole and
30 min, 60 min, and 90 min after the drug administration. paracetamol. On WHO step 2, tramadol was almost the only
Rectal indomethacin as rescue medication (RM) was available opioid used. During tramadol monotherapy average daily
after 2 h and its use compared between groups. At 30 min, 0 % pain scores were lower than with a combination of tramadol
of the metamizole group and 13 % of the LC group were pain- and non-opioid analgesics. On WHO step 3, morphine was at
least part of the analgesic regimen on most treatment days. intensity differences (PID) at 20 min, 30 min, and 50 min after
Strong opioids were combined with a non-opioid analgesic on drug administration, and was significantly more effective than
41 % of the treatment days. The mean intravenous morphine butylscopolamine at 30 min and 50 min for the secondary
equivalence dose was 0.034 mg/kg/h. During opioid and efficacy endpoint, pain intensity differences on a categorical
non-opioid combination therapy, adverse effects were more scale. Only 5 patients receiving metamizole needed “rescue”
frequent, and average pain scored higher than on opioid medication as compared with 13 patients given tramadol and
monotherapy. In this patient group, there is no evidence that a 11 patients receiving butylscopolamine. Adverse events were
combination of an opioid with a non-opioid is more effective observed in 4 patients receiving butylscopolamine and in 1
than opioid therapy alone in inpatient paediatric oncology pain patient each given metamizole and tramadol. One patient in the
treatment (99). metamizole group experienced moderate “light-headedness”
lasting for 0.25 h at roughly 15 min after the first injection.
Renal colics. Renal colic is a common disorder, with the main
The same patient complained of nausea 35 min after receiving
complaint of unbearable pain. NSAIDs and opioids have been
the drug and vomited at the end of the evaluation period. The
widely used in the treatment of renal colic and their efficacy
relationship to the study drug was evaluated as “probable”
has been confirmed in many studies.
(88).
A randomized, double-blind, multicentre clinical trial was
designed to compare the analgesic efficacy of i.m. metamizole Fever
1 g and 2 g, IM diclofenac sodium and IM pethidine in acute Fever is a common childhood illness symptom, accounting for
renal colic. The study was carried out in 451 patients in 13 19 % to 30 % of paediatric emergency visits. Antipyretic drugs
Spanish hospitals. The main parameter of drug efficacy was are the main form of treatment. Metamizole should be given
the need for rescue treatment –pethidine 100 mg i.m. 30 min only when other measures to control severe or life-threatening
after the experimental treatment. Rescue treatment was fever have been unsuccessful, or if the patient is intolerant to
required in 93 patients: they represented 24.1 % of the group other antipyretic agents. Metamizole should be administered
given metamizole 1 g; 22.3 % of those on metamizole 2 g; for the shortest period possible. In a recent study, Alves et
16.4 % of those given diclofenac sodium; and 19.5 % of al. (4) performed a randomized clinical trial to evaluate the
those on pethidine. The differences between the groups were effectiveness of tepid sponging in addition to metamizole
not significant. In the remaining 358 patients, no difference to promote fever control in children from six months to five
between treatments was observed. The results suggest that in years of age with axillary temperature greater than 38 °C in the
acute renal colic the use of metamizole 2 g is unjustified as emergency ward between January and July 2006. One hundred
metamizole 1 g is equally effective. Diclofenac sodium is a and twenty children were randomly assigned to receive oral
valid alternative, which shows similar analgesic efficacy (8). metamizole (20 mg/kg) or oral metamizole and tepid sponging
Miralles et al. (64) in a randomized, double-blind clinical for 15 min. The primary outcome was mean temperature
trial including 50 patients, compared the efficacy and tolerance reduction after 15 min, 30 min, 60 min, 90 min, and 120 min.
of single doses of intramuscular diclofenac 75 mg and Secondary outcomes were crying and irritability. One hundred
metamizole 2 g in acute renal colic. Both drugs were equally and six children finished the study. After the first 15 min,
effective, but diclofenac was better in terms of complete relief the fall in axillary temperature was significantly greater in
of pain. the sponged group than in the control group (P < 0.001).
In a double-blind, double-dummy randomized controlled From 30 min to 120 min, better fever control was observed
clinical trial, the onset and duration of the analgesic effect of in the control group. Crying and irritability were observed
metamizole, 1 g or 2 g, and diclofenac sodium, 75 mg, by either respectively in 52 % and 36 % of the sponged children and in
the IM or the IV route were compared in 293 patients with none and only two of the controls. The authors concluded that
acute renal colic. The analgesic response was more marked tepid sponging plus metamizole cooled faster during the first
and prolonged among patients receiving metamizole 2 g IM 15 min, but metamizole alone presented better fever control
or metamizole 2 g IV. There were no significant differences over the two-hour period (4).
between metamizole 1 g and diclofenac sodium 75 mg, by Only a few controlled clinical trials have compared
either the IM or the IV route. All treatment regimens were well metamizole with other analgesics in children. Much of the
tolerated (67). information has been derived from open uncontrolled trials
To investigate the combined analgesic and spasmolytic and, although antipyresis was obtained, the data have not been
effect of metamizole, 104 patients suffering from “severe” or validated. Several single-blind and double-blind studies have
“excruciating” colic pain due to a confirmed calculus in the also evaluated metamizole using different galenic preparations
upper urinary tract were randomized to receive IV either 2.5 g in febrile children (2). In a randomized, single-blind clinical
metamizole, 100 mg tramadol, or 20 mg butylscopolamine in a trial, Prado et al. (75) compared the antipyretic efficacy and
multicentre, observer-blind, parallel-group study conducted in tolerability of a single dose of oral ibuprofen (10 mg/kg),
8 German centres. Metamizole was significantly more effective oral metamizole (15 mg/kg) or IM metamizole (15 mg/kg)
than tramadol in reducing pain for the primary endpoint, pain in febrile children from six months to six years of age.
Antipyretic efficacy and tolerability were similar for oral
ibuprofen, oral metamizole and intramuscular metamizole. Prado et al. (75) performed a randomized, single-blind
There was a significant decrease in fever-associated symptoms clinical trial, including 75 children who were randomly
for all groups. Six patients (four receiving oral metamizole and assigned to receive a single dose of oral ibuprofen (10 mg/kg),
two receiving ibuprofen) were withdrawn because of vomiting oral metamizole (15 mg/kg) or IM metamizole (15 mg/kg).
within 20 min after the first dose of the study medication. There was a significant decrease in fever-associated symptoms
Fever is a common symptom in cancer patients. In a for all groups. Six patients (four receiving oral metamizole and
non-randomized, open-label pilot study, three intravenous two receiving ibuprofen) were withdrawn because of vomiting
antipyretics were tested in five groups of patients: diclofenac within 20 min after the first dose of the study medication.
(75 mg, brief IV infusion) vs. metamizole (2500 mg or 1000 mg, Antipyretic efficacy and tolerability were similar for oral
brief IV infusion) vs. propacetamol (2000 mg or 1000 mg, ibuprofen, oral metamizole, and IM metamizole.
slow IV injection or brief IV infusion). All tested antipyretics In 22 healthy volunteers, the analgesic effect of 1 g
significantly improved the comfort in febrile patients. Overall, metamizole, 1 g paracetamol, and 800 mg ibuprofen was
87 % of patients declared improvement in their comfort after compared in a double-blind crossover study (36). Ibuprofen, but
administration of antipyretics (69). Diclofenac and metamizole not paracetamol, led to a decrease in pain perception similar to
(both 2500 mg and 1000 mg) were tolerated at best. metamizole.
Gozzoli et al. (40) investigated the metabolic, hemodynamic, Acetylsalicylic acid. Metamizole 500 mg orally was considered
and inflammatory responses of pharmacological and physical superior to acetylsalicylic acid 500 mg in the treatment of
therapies aimed at reducing body temperature in febrile postoperative pain in one study (7). In 17 gynaecological
critically ill patients in an open-label, randomized trial in a patients with postoperative pain the analgesic efficacy of
surgical intensive care unit. Thirty patients were randomized IV lysine salicylate 1.8 g (corresponding to acetylsalicylic
to receive either IV metamizole, IV propacetamol, or external acid [ASA] 1.0 g) and metamizole 1.0 g were compared in a
cooling. Body temperature decreased significantly in all double-blind randomized study. In the ASA group, the mean
treatment groups. Metamizole induced a significant decrease pain relief and pain intensity difference scores reached a
in arterial pressure and urine output compared to baseline and maximum 30 min after drug administration and remained at
to the other two groups. this level for the next 90 min. In the metamizole group, these
Comparative efficacy/Evaluation with other therapies scores reached their peak 60 min after drug administration and
seemed to fall off during the next hour. The mean pain relief
Acetaminophen. Metamizole 1.0 g, paracetamol 1.0 g and and intensity difference scores were greater following ASA
placebo were compared in a double-blind parallel-group study than metamizole (19).
in 264 patients with episiotomy pain. Both drugs were more
effective than placebo, and metamizole was significantly more Ketoprofen. Dexketoprofen 50 mg administered as a single
effective than paracetamol, particularly where initial pain was IV bolus was effective for the relief of moderate to severe
severe. The efficacy of metamizole 1.0 g was also compared pain in patients with renal colic, with a good safety profile
with paracetamol 1.0 g in relieving pain after tooth extraction and efficacy similar to i.v. metamizole 2 g. Dexketoprofen
in 90 patients. Metamizole was consistently and significantly produced analgesia that was faster in onset. In this multicenter,
more effective than paracetamol (38). randomized, double-blind, double-dummy, parallel, and
In a double-blind study in patients with typhoid fever, 25 active-controlled study 308 patients were randomized to
patients received 500 mg metamizole and 28 received 500 mg dexketoprofen 25 mg (n = 101), dexketoprofen 50 mg
paracetamol. The onset of antipyretic effect in patients given (n = 104), and metamizole 2 g (n = 103). The study medications
metamizole (30 min) was significantly different from that in were tolerated well (82).
patients given paracetamol (1 h). The area under the time- Comparison to opioids
temperature curves was signicantly greater for patients given Pethidine. In a double-blind parallel-group study metamizole
metamizole. Both treatments were well tolerated (3). 2.5 g IM was compared with pethidine 100 mg intramuscularly
Ibuprofen. In a double-blind, randomized, international study in patients with moderate or severe postoperative pain
that evaluated the effects of metamizole in 628 febrile children following abdominal surgery. Onset of pain relief was rapid
(mean age 6 months to 6 years), metamizole, ibuprofen, and within 30 min – and was maintained for 6 h. At the doses
acetaminophen decreased fever in 555 children (metamizole used, analgesia with metamizole was similar in terms of onset,
in 82 %, ibuprofen in 78 %, while the antipyretic effect of degree and duration to that of pethidine. No side-effects were
acetaminophen was statistically lower – 68 %). The onset attributed to either drug in this study (72).
of antipyretic effect of metamizole was statistically more A randomized, double-blind, multicentre clinical trial was
rapid and the duration longer in comparison to ibuprofen designed to compare the analgesic efficacy of IM metamizole
and acetaminophen (98). All three drugs showed comparable 1 g and 2 g, IM diclofenac sodium and IM pethidine in acute
tolerability profiles. renal colic. The study was carried out in 451 patients in 13
Spanish hospitals. The main parameter of drug efficacy was

the need for rescue treatment –pethidine 100 mg IM 30 min with 4.0 g metamizole and 2.5 mg DHB; and in group 3, only
after the experimental treatment. Rescue treatment was 2.5 mg droperidol. Additionally, a patient-controlled analgesia
required in 93 patients: they represented 24.1 % of the group (PCA) device with morphine was provided to each patient as
given metamizole 1 g; 22.3 % of those on metamizole 2 g; a rescue in the case of insufficient pain relief. After the 24 h
16.4 % of those given diclofenac sodium; and 19.5 % of study period, a significant pain relief was observed in all three
those on pethidine. The differences between the groups were groups. The consumption of morphine via PCA, however,
not significant. In the remaining 358 patients, no difference was significantly lower in group 2 (tramadol/metamizole)
between treatments was observed. The results suggest that in than in the tramadol or the placebo group, and also the
acute renal colic the use of metamizole 2 g is unjustified as patients in group 1 (tramadol) had received significantly less
metamizole 1 g is equally effective (37). morphine than those in the placebo group. These data suggest
Tramadol. Cander et al. (24) examined the relative efficacy a significantly superior analgesic efficacy of a continuous
of analgesics such as tramadol hydrochloride, metamizole infusion of tramadol combined with metamizole compared to
sodium, and diclofenac sodium in 100 patients (12 to 66 years an infusion of tramadol alone or placebo (86).
of age) who presented to the emergency service with traumatic Administration of metamizole 2 g following extended
injuries and fractures of the extremities. Pain became less abdominal or urological surgery, reduced postoperative
severe after 15 min in 92 % of patients who received tramadol morphine requirements from 50 mg to 32 mg in the first 24 h
IV; pain became less severe after 30 min in 72 % of those who postoperatively (58). Following musculoskeletal procedures,
received metamizole IV. In contrast, pain became less severe however, the opioid-sparing effect of metamizole was distinctly
after 45 min in 65 % of patients who received diclofenac IM. lower. This is explained by the minor anti-inflammatory effect
Tramadol was the most effective analgesic and was also more of metamizole; it inhibits peripheral prostaglandin synthesis
effective earlier than the other analgesics tested. only a little and does not accumulate in inflamed tissues,
Opioid sparing effect. Pain is a very frequent problem in gastrointestinal mucosa or the kidney.
patients with cancer, with a prevalence of 90 % in advanced To determine whether metamizole has an opioid-sparing
disease. Additive effects between opioids and NSAIDs, effect in post-operative pain therapy, Tempel et al. (90)
including metamizole have been reported in animals (65). performed a randomized, observer-blind, parallel-group,
Metamizole has opiate-sparing effect in postoperative pain placebo-controlled study. The effect of metamizole was
therapy with morphine and has been used for many years as a compared to that of placebo during patient-controlled morphine
substitute for other opioid analgesics. A prospective double- therapy (PCA). One hundred and six adult patients who were
blind study with intravenous patient-controlled analgesia to undergo abdominal or urological surgery under 90 min
using metamizole, buprenorphine, and morphine, concluded standardized inhalational anaesthesia were entered and 103
that metamizole was the drug of choice (91). were included in the efficacy analysis (53 on metamizole, 50 on
The aim of the prospective clinical study of Lempa placebo). The drugs used were preprogrammed PCA (0.03 mg
and Kohler (56) was to test the feasibility of a metamizole/ morphine/kg per bolus) with either metamizole (initially 2.0 g
tramadol combination for pain therapy after laparoscopic and IV and 1.0 g/2 mL IV at 4 h, 8 h and 16 h) or placebo (saline).
open obesity surgery. Following laparotomy, the combination The total consumption of opiates in the metamizole group
infusion provided effective analgesia. On the first and fourth (median 31.6 mg) was significantly less than in the placebo
postoperative days, the pain scores at rest were 1.5 and 2.3, group. Global assessment of efficacy was good to excellent in
respectively. The pain scores did not increase significantly with more than 90 % of cases in both groups. Adverse events were
movement (2.7 and 2.2, respectively). Following laparoscopic mainly nausea and/or vomiting (metamizole, n = 4; placebo,
gastric banding the pain scores were less than 2.0 at rest and n = l); 1 patient in the placebo group had bradycardia. Authors
with movement on the first postoperative day. On the fourth made a conclusion, that concomitant administration of
postoperative day the pain scores at rest and with movement metamizole with on-demand morphine (PCA) reduces opiate
were 0.2. This feasibility study suggests that a combination consumption while maintaining post-operative pain relief with
of the strong non-opioid metamizole and the atypical opioid a low incidence of side-effects.
tramadol provides good analgesia following laparotomy and The aim of the Ozcakir et al. (71) study was to compare
laparoscopic surgery for morbid obesity not only at rest, but the postoperative analgesic effects of tramadol and tramadol-
also during mobilization. metamizole and tramadol-lornoxicam combinations
In another prospective, randomised and double-blind administered by intravenous PCA in lower abdominal surgery.
clinical study, the analgesic efficacy of a continuous infusion Sixty adult patients undergoing lower abdominal surgery were
of tramadol combined with metamizole was compared included in the study. Patients were randomly allocated into
with tramadol alone or with placebo during the first 24 h one of three groups. The solutions were prepared containing
postoperatively. Ninety patients were allocated into three study 500 mg tramadol in 50 mL saline (10 mg/mL tramadol) for
groups. In group 1, the patients received 600 mg tramadol Group I (n = 20), 250 mg tramadol + 3000 mg metamizole in
with 2.5 mg droperidol; in group 2, 600 mg tramadol together 50 mL saline (5 mg/mL tramadol + 60 mg/mL metamizole) for
Group II (n = 20), and 250 mg tramadol + 20 mg lornoxicam
in 50 mL saline (5 mg/mL tramadol + 0.4 mg/mL lornoxicam) metamizole) was decreased; treatment with liothyronine
for Group III (n = 20). In all groups the loading dose (10 mL) partially corrected this. In the hyperthyroid subjects, plasma
was administered 40 min before the end of operation. PCA metamizole levels were normal and the urinary excretion of
was started at the first complaint of pain. There were no AA was decreased; treatment increased the excretion of AA
significant differences between the groups in terms of first toward normal. These findings suggest that in humans an
analgesic requirement time, peripheral oxygen saturation, absence of thyroid hormone decreases the N-demethylation of
and heart rates. Total tramadol and anti-emetic consumption, metamizole and that excessive endogenous thyroid hormone
postoperative nausea and vomiting were significantly higher in may have a similar effect.
Group I as compared with other groups (P < 0.05). Tramadol–
Effects on ability to drive and use machines. At recommended
metamizole and tramadol–lornoxicam combinations
doses, no impairment of the vigilance is known. Undesirable
administered by intravenous PCA provide efficient analge sia
effects on the ability to drive and use machines have not yet
with less side effects.
been reported after use of metamizole. However, at higher
Use in special groups of patients doses or in case of concomitant alcohol intake, it should be
considered that the ability of driving, operating machines, or
Pregnancy and lactation. Metamizole permeates the placenta.
performing dangerous activities may be reduced.
Three cases of acute renal failure with oligohydramnios have
been described with high dose, overdose and/or prolonged Marketing experience
ingestion of metamizole during pregnancy (73, 80, 97).
Analgesic agents make up well over half of the OTC drug
Metamizole-induced renal failure during pregnancy may
market. The estimated consumption of analgesics is (20–60) g/
be explained by induction of reversible renal ischemia
capita/year in industrialized countries. Metamizole was first
secondary to inhibition of prostaglandin synthesis, and acute
synthesized in 1920 by the German company Hoechst AG(now
tubulointerstitial nephritis. A weak association with Wilms’
part of Sanofi–Aventis), and its mass production started in
tumor in children of women who took metamizole during
1922. It stayed freely available worldwide until the 1970s,
pregnancy has been also proposed (20, 85). Two population-
when the drug was discovered to pose a risk of agranulocytosis.
based case-control studies (1, 26), performed in Hungary
As already mentioned, in Sweden, all metamizole-containing
and Brazil reported no association of metamizole with the
products were first withdrawn in March 1974; the ban was
outcomes of congenital abnormalities, intrauterine death,
lifted in 1995 only to be re-introduced in 1999. Metamizole
preterm birth, or low birth weight.
was banned in the USA in 1977, and since then, in more
After ingestion by the mother, metamizole and its than 30 other countries (including Japan, Australia, Iran,
metabolites appear in breast milk in rather large amounts and several EU member states). In Germany, Hungary, Italy,
(102). It is found in the blood and urine of breastfed infants Portugal and Spain it is a prescription drug. In other parts of
and can cause pharmacological effects in the breastfed infant. the world (including Bulgaria, Mexico, India, Egypt, Brazil,
Despite the fact that metamizole is not recommended during Poland, Russia, Turkey, the Republic of Macedonia, Romania,
breastfeeding, Chaves et al. (25) reported metamizole as the Israel, and some developing countries) metamizole is still
most common self-medication drug used by nursing mothers freely available OTC, and remains one of the most popular
in Brazil (31.5 % used metamizole vs. 17.9 % – paracetamol). analgesics, commonly used in self-medication. Possibly no
Paediatric patients. Metamizole should be given only when other analgesic is subject to as much controversy, especially
other measures to control severe or life-threatening fever the exact level of risk of haematological toxicity associated
have been unsuccessful, or if the patient is intolerant to other with its use. Differences in the methods used in the various
antipyretic agents. pharmacovigilance studies and concurrent drug use probably
account for the widely differing estimates of the risk of blood
Geriatric patients. Clinical studies of metamizole did not dyscrasias associated with metamizole. The polarisation of
include sufficient numbers of subjects aged 65 and over to opinions on metamizole seems never ending (58, 63, 66).
determine whether they respond differently from younger
subjects. Other reported clinical experience has not identified Market place of metamizole in Bulgaria
differences in responses between the elderly and younger Metamizole continues to be traditionally the most used
patients (103). painkiller in Bulgaria and one of the strongest Bulgarian brands.
However, in many countries, among them Bulgaria, the drug
Comorbidity. Brunk et al. (23) studied the metabolism of
is widely used as an OTC product in different pharmaceutical
metamizole in patients with thyroid abnormalities. In 8 normal
forms, as monotherapy or included in combination with other
subjects, no change in metamizole metabolism was detected
drugs, and considered safe (Table 2).
when liothyronine was given. The effect of hypothyroidism
on metamizole metabolism was studied in six patients; and the Systemic analgesics remain the most popular type of OTC
effect of hyperthyroidism, in two patients. In the hypothyroid analgesics on the Bulgarian market, and the most popular
subjects, plasma metamizole levels were elevated and urinary product among them is Analgin® (metamizole sodium), which
excretion of 4-aminoantipyrine (AA, active metabolite of has been a favourite of Bulgarians since its launch in 1954.

TABLE 3
Market share in units for general pain relief drugs for adults for 2008–2011
Units Units Units Units

YEAR 2008 YEAR 2009 YEAR 2010 YEAR 2011
(Absolute) (Absolute) (Absolute) Absolute)
02A1 GENERAL PAIN RELIEF ADULTS 25 056 876 24 379 744 23 436 951 26 244 921
ANALGIN 8 272 174 7 949 625 6 979 943 7 070 527
ACETYSAL 4 608 093 5 069 811 3 878 763 4 057 325
PARACETAMOL 3 713 909 3 725 478 2 697 693 2 444 829
UPSARIN C 1 674 545 1 469 955 1 258 537 1 407 384
BENALGIN 862 122 761 603 1 578 502 1 741 095
NUROFEN 800 160 568 014 608 625 568 465
ASPIRIN C 651 777 790 295 653 295 615 563
PARACETAMAX 0 0 854 002 1 782 073
TABLE 4
Market share in value (EURO) for general pain relief drugs for adults for 2008–2011
EURO Sales EURO Sales EURO Sales EURO Sales

MNF MNF MNF MNF
YEAR 2008 YEAR 2009 YEAR 2010 YEAR 2011
(Absolute) (Absolute) (Absolute) (Absolute)
02A1 GENER PAIN RELIEF ADULTS 15 444 018 16 252 422 17 077 994 20 048 941
ANALGIN 4 115 330 4 156 153 4 046 267 3 986 822
PARACETAMOL 1 859 966 1 975 598 1 428 815 1 286 785
UPSARIN C 1 542 056 1 553 127 1 544 862 1 961 896
NUROFEN 1 272 633 1 043 898 1 145 242 1 092 135
ACETYSAL 1 269 939 1 670 748 1 572 630 1 933 757
ASPIRIN C 927 478 1 322 223 1 506 473 1 549 819
BENALGIN 778 832 831 783 1 138 365 1 230 073
PARACETAMAX 0 0 395 525 824 111
Furthermore, for years it was the only systemic analgesic 20 048 941 Euro for 2011, with an expected CAGR of 15 %
product on the market, and therefore remained popular even between 2010 and 2011.
when competitive products became available. Out of about According to the IMS Health official data (47) about
160 OTC analgesics available on the market, metamizole is the market share of the analgesics on the Bulgarian market,
the number one most used OTC analgesic for the last ten years Analgin® is the leader in:
(2001–2010) (55). • market share in units for 2008, 2009, 2010, 2011 (33 %,
The analgesics category was valued at BGN 88.8 m 32.6 %, 29.8 %, and 26.9 % from the sales in units
($66.4 m) in 2009, representing a Compound Annual Growth for all the general pain relief agents on the Bulgarian
Rate (CAGR) of 11.6 % since 2004. By the end of 2014, the market, respectively) (Table 3);
analgesics category will be worth BGN 125.3 m ($93.7 m), • market share in value for 2008, 2009, 2010, 2011
with an expected CAGR of 7.1 % between 2009 and 2014. (26.6%, 25.6%, 23.7%, and 19.9% from the sales in
Analgin® has been the top-selling item on the Bulgarian value for all the general pain killers on the Bulgarian
market for years. In the period January 2000–August 2010, market, respectively) (Table 4).
approximately 140 million packs of Analgin® were sold.
The Bulgarian pharmaceutical market grew in terms
In 2011 the tendency for the analgesics market – more drugs of value in 2011, but shrank in terms of volume. Bulgaria’s
for more money – was restored. According to the analysis of pharmaceutical market continues to be under pressure owing
IMS Health (47), the general pain relief drugs share was worth to the current economic crisis. The decrease in the Analgin®

shares in value and in units (2008–2011) is due to a weakening 7. Arellano F., Sacristan J.A. (1990) Eur. J. Clin. Pharmacol.,
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(1974) J. Clin. Pharmacol., 14, 271-279.
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Metamizole A Review Profile of A Well Known Forgotten Drug Part II Clinical Profile

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Biotechnology & Biotechnological Equipment

ISSN: 1310-2818 (Print) 1314-3530 (Online) Journal homepage: http://www.tandfonline.com/loi/tbeq20

Metamizole: A Review Profile of a Well-Known

Irina Nikolova, Valentina Petkova, Jasmina Tencheva, Niko Benbasat, Julian

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EURO Sales EURO Sales EURO Sales EURO Sales

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