Discovering interactions in polypharmacy: Impact of metamizole on the metabolism of quetiapine.

AIMS: Metamizole is quite an old drug with analgesic, antipyretic and spasmolytic properties. Recent findings have shown that it may induce several cytochrome P450 (CYP) enzymes, especially CYP3A4 and CYP2B6. The clinical relevance of these properties is uncertain. We aimed to unravel potential pharmacokinetic interactions between metamizole and the CYP3A4 substrate quetiapine. METHODS: Plasma concentrations of quetiapine from a large therapeutic drug monitoring database were analysed. Two groups of 33 patients, either receiving quetiapine as a monotherapy (without CYP modulating comedications) or with concomitantly applied metamizole, were compared addressing a potential impact of metamizole on the metabolism of quetiapine being reflected in differences of plasma concentrations of quetiapine and dose-adjusted plasma concentrations. RESULTS: Patients comedicated with metamizole showed >50% lower plasma concentrations of quetiapine (median 45.2 ng/mL, Q1 = 15.5; Q3 = 90.5 vs. 92.0 ng/mL, Q1 = 52.3; Q3 = 203.8, P = .003). The dose-adjusted plasma concentrations were 69% lower in the comedication group (P = .001). Subgroup analyses did not suggest a dose dependency of the metamizole effect or an influence of quetiapine formulation (immediate vs. extended release). Finally, the comedication group exhibited a significantly higher proportion of patients whose quetiapine concentrations were below the therapeutic reference range (78.8% in the metamizole group vs. 54.4% in the control group, P = .037) indicating therapeutically insufficient drug concentrations. CONCLUSION: The combination of metamizole and quetiapine leads to significantly lower drug concentrations of quetiapine, probably via an induction of CYP3A4. Clinicians must consider the risk of adverse drug reactions, especially treatment failure under quetiapine when adding metamizole.

Risk of agranulocytosis with metamizole in comparison with alternative medications based on health records in Spain.

PURPOSE: We aimed to estimate the absolute (incidence) and relative (hazard ratio; HR) risk of agranulocytosis associated with metamizole in comparison with non-steroidal antiinflammatory drugs (NSAIDs). METHODS: A cohort study of new users of metamizole versus NSAIDs was performed with BIFAP (Pharmacoepidemiologic Research Database in Public Health Systems; Spain). Patients aged ≥ 2 years in 2005-2022 were followed up from the day after their first metamizole or NSAID dispensation till the end of the treatment period to identify patients hospitalized due to idiosyncratic agranulocytosis. Incidence rate (IR) and adjusted HR of agranulocytosis with metamizole versus NSAID were estimated assuming the onset date of agranulocytosis was the date of hospitalization sensitivity analysis or 7 days before (main analysis). In secondary analyses, we used (1) opioids-paracetamol as negative control and (2) any hospitalized neutropenia as outcome (assuming the onset was 7 days before). RESULTS: The cohorts included 444,972 new users of metamizole, 3,814,367 NSAID, and 3,129,221 opioids-paracetamol on continuous treatment during a median of 37-40 days. Overall, 26 hospitalized agranulocytosis occurred, 5 in the first week (and so removed in main analysis) and 21 thereafter. IR of agranulocytosis was 14.20 (N = 5 cases) and 8.52 (N = 3), 1.95 (N = 6) and 1.62 (N = 5), and 4.29 (N = 15) and 3.72 (N = 13)/107 person-weeks of continuous treatment using the date of hospitalization or 7 days before, respectively. Two, 0 and 2 of cases identified in both analyses had neoplasia in every cohort, respectively. HR of agranulocytosis associated with metamizole was 7.20 [95% CI: 1.92-26.99] and 4.40 [0.90-21.57] versus NSAID, and 3.31 [1.17-9.34] and 2.45 [0.68-8.83] versus opioid-paracetamol, respectively. HR of neutropenia with metamizole was 2.98 [1.57-5.65] versus NSAID. CONCLUSIONS: Agranulocytosis was very rare but more common (above 4 times more) with metamizole than other analgesics. The impact of the drug-induced agranulocytosis was less precise with metamizole than the comparators due to its lower use, which precluded to find statistical differences in main analysis. The increased risk of hospitalized neutropenias with metamizole supports the link with its severity although triggers unavailable during the follow-up (ex. cytotoxic medication) can not be discarded.

Effect of the combination of diuretics, renin-angiotensin-aldosterone system inhibitors, and non-steroidal anti-inflammatory drugs or metamizole (triple whammy) on hospitalisation due to acute kidney injury: A nested case-control study.

PURPOSE: Concomitant use of diuretics, renin-angiotensin-aldosterone system (RAAS) inhibitors, and non-steroidal anti-inflammatory drugs (NSAIDs) or metamizole, known as 'triple whammy' (TW), has been associated with an increased risk of acute kidney injury (AKI). Nevertheless, there is still uncertainty on its impact in hospitalisation and mortality. The aim of the study was to analyse the association between exposure to TW and the risk of hospitalisation for AKI, all-cause mortality and the need for renal replacement therapy (RRT). METHODS: A case-control study nested in a cohort of adults exposed to at least one diuretic or RAAS inhibitor between 2009 and 2018 was carried out within the Pharmacoepidemiological Research Database for Public Health Systems (BIFAP). Patients hospitalised for AKI between 2010 and 2018 (cases) were matched with up to 10 patients of the same age, sex and region of Spain who had not been hospitalised for AKI as of the date of hospitalisation for AKI of the matching case (controls). The association between TW exposure versus non-exposure to TW and outcome variables was analysed using logistic regression models. RESULTS: A total of 480 537 participants (44 756 cases and 435 781 controls) were included (mean age: 79 years). The risk of hospitalisation for AKI was significantly higher amongst those exposed to TW [adjusted odds ratio (aOR) 1.36, 95% confidence interval (95%CI) 1.32-1.40], being higher with current (aOR 1.60, 95%CI 1.52-1.69) and prolonged exposure (aOR 1.65, 95%CI 1.55-1.75). No significant association was found with the need of RRT. Unexpectedly, mortality was lower in those exposed to TW (aOR 0.81, 95%CI 0.71-0.93), which may be influenced by other causes. CONCLUSION: Vigilance should be increased when diuretics, RAAS inhibitors, and NSAIDs or metamizole are used concomitantly, especially in patients at risk such as elderly patients.

Additive or synergistic analgesic effect of metamizole on standard pain treatment at home after arthroscopic shoulder surgery: A randomised controlled superiority trial.

BACKGROUND: There is growing evidence that the analgesic effect of metamizole is mediated at least partly by central mechanisms, including the endocannabinoid/endovanilloid system. Consequently, metamizole may have additive or even synergistic analgesic effects with paracetamol and nonsteroidal anti-inflammatory drugs (NSAID). OBJECTIVE: This study aimed to assess if triple therapy with metamizole, ibuprofen and paracetamol (MIP) is superior to double therapy with ibuprofen and paracetamol (i.p.) in treating pain at home after ambulatory arthroscopic shoulder surgery. DESIGN/SETTING/PATIENTS/INTERVENTION: In this double-blind, controlled, high-volume single centre, superiority trial, 110 patients undergoing elective ambulatory arthroscopic shoulder surgery were randomised to receive either MIP ( n  = 55) or i.p. ( n  = 55) orally for 4 days between December 2019 and November 2021. Pain intensity at movement and rest, using a numeric rating scale (NRS), perceived pain relief, use of rescue medication and adverse effects of study medication were recorded at the post-anaesthesia care unit (PACU) and on postoperative day (POD) 1 to 4 and 7. Quality of Recovery (QoR) and satisfaction with study medication were measured at POD 7 with telephone follow-up. MAIN OUTCOME MEASURE: The primary outcome measure was postoperative pain intensity on movement measured by an 11-point NRS (where 0 = no pain and 10 = worst pain imaginable) on POD 1. RESULTS: For the primary outcome, superiority of MIP in reducing postoperative pain at movement on POD 1 was not confirmed: mean difference NRS [95% confidence interval (CI), -0.08 (-1.00 to 0.84)]. For pain on movement and at rest, no significant differences were found between groups in the PACU nor on POD 1 to 4 or day 7. Nausea was reported significantly more frequently in the metamizole group (22.6 vs. 58.5; P  < 0.001). Other adverse effects of study medication, rescue opioid consumption, perceived pain relief, QoR at POD 7, and overall patient satisfaction were similar in both groups. CONCLUSION: Clinically, triple oral treatment with metamizole, paracetamol and ibuprofen is not superior to oral paracetamol and ibuprofen in multimodal pain treatment at home after ambulatory arthroscopic shoulder surgery. TRIAL REGISTRATION: European Union Clinical Trials Register 2019-002801-23 and Clinicaltrials.gov NCT04082728.

Design, synthesis and in vivo evaluation of 1,4-dioxo-2-butenyl aryl amine derivatives as a promising anti-inflammatory drug prototype.

Inflammation is a natural response of the organism to an infection, trauma, or cellular stress. Pain is the first symptom of acute and chronic inflammation. The standard class of medication to treat inflammatory pain is the nonsteroidal anti-inflammatory drug (NSAID). These drugs are associated with severe side effects such as gastric ulcers, gastritis, or internal bleeding. One of NSAIDs, Dipyrone® (metamizole) is largely used in many European and South American countries despite its dubious effectivity and its withdrawal from the market of several countries. Here, aiming to identify a new anti-inflammatory drug prototype based on Dipyrone® structure, a set of 27 molecules were virtually screened, and 4 compounds containing the active metabolite 4-aminoantipyrine and 1,4-dioxo-2-butenyl fragment were selected for docking, synthesis, and biological evaluation. The selection was based on the number of H-bonds and π- π stacking interactions between the inhibitor and the amino acids within the binding site of the enzyme. Carrageenan-induced paw edema, acetic acid-induced writhing, and formalin assays were used to evaluate inflammation and pain response. The selected compounds 1-4 inhibited the involvement of biogenic amines in the formation of paw edema. Compounds 1-4 also reduced pain in the inflammatory response phase. It has to be noted that 4-AA may cause agranulocytosis, which should be borne in mind when developing drug candidates of similar structure. Our new drug prototypes based on 4-aminoantipyrine and 1,4-dioxo-2-butenyl moieties open a gate for developing a prototype of nonsteroidal anti-inflammatory drugs.

NAT2 polymorphisms as a cause of metamizole-induced agranulocytosis.

Metamizole is a widely prescribed NSAID with excellent analgesic and antipyretic properties. Although very effective, it is banned in some countries because of the risk for severe agranulocytosis. We here describe three patients with metamizole-associated agranulocytosis. Patient #1 suffered from agranulocytosis and tonsillitis followed by severe sepsis by Streptococcus pneumoniae and Epstein-Barr virus reactivation. Her dizygotic twin sister (patient #2) also suffered from agranulocytosis after a surgical intervention. Patient #3 initially had a tonsillitis and also developed neutropenia after metamizole intake. For all patients, pharmacogenetic diagnostic for the genes CYP2C9, CYP2C19 and NAT2, which are involved in metamizole metabolism and degradation of toxic metabolites, was initiated. Pharmacogenetic analysis revealed NAT2 slow acetylator phenotype in all three patients. Additionally, patient #2 is an intermediate metabolizer for CYP2C19 and patient #3 is a poor metabolizer for CYP2C9. Impairment of these enzymes causes a reduced degradation of toxic metabolites, for example, 4-methylaminoantipyrine (4-MAA) or 4-aminoantipyrine. The metabolite 4-MAA can complex with hemin, which is an early breakdown product during hemolysis. Hemolysis is often observed during invasive infections or after surgical procedures. It is known that the 4-MAA/hemin complex can induce cytotoxicity in the bone marrow and interrupt granulocyte maturation. In conclusion, metamizole-induced agranulocytosis most likely was a consequence of the underlying genetical predisposition, that is, polymorphisms in the genes NAT2, CYP2C9 and CYP2C19. Hemolysis may have increased the toxicity of metamizole metabolites.

A possible increased risk of metamizole-associated neutropenia among COVID-19 patients.

Metamizole is commonly used as analgesic and antipyretic drug. The use of metamizole is prohibited in several countries due to its rare side effect of neutropenia and even agranulocytosis. Among the many symptoms of COVID-19, fever and diffuse pain predominant and therefore it can be assumed that metamizole may be widely used in the current epidemic period. So far, there have been no reports on the safety of metamizole in COVID-19 patients. We describe a series of 3 patients who developed severe neutropenia under metamizole treatment, raising a concern of a possible increased risk of this side effect among COVID-19 patients.

Assessment of the cytoprotective effect of the homeopathic compound Canova® on African green monkey kidney (VERO) cell line exposed to the drug dipyrone sodium.

Dipyrone or metamizole is one of the most frequently used analgesic worldwide. Despite its widespread use, this drug may exert genotoxic and cytotoxic effects on lymphocytes. Therefore, studies with therapeutic agents that may provide protection against these effects are important. The homeopathic compound Canova® (CA) appears to be a beneficial candidate for preventing DNA damage and cellular lethality, since this compound acts as an immunomodulator associated with cytoprotective actions. Hence, the aim of the present investigation was to determine the potential cytoprotective effects of CA using cell line VERO as a model. VERO cells were incubated with sodium dipyrone and subsequently subject to the comet, apoptosis and immunocytochemistry assays. Data demonstrated that sodium dipyrone induced an increase in DNA damage index (DI) employing the comet assay. However, when VERO cells were co-treated with CA at the three concentrations studied, a significant reduction in DI was observed, indicating an antigenotoxic effect attributed to CA. Further dipyrone induced an elevation in %apoptosis at 24 and 48 hr. However, when dipyrone was co-incubated with CA, a significant reduction in %apoptosis was noted at the three concentrations of CA employed. Results from immunocytochemical analysis showed a rise in the expression of caspase 8 and cytochrome C when cells were exposed to dipyrone. In contrast, co-treatment of dipyrone and CA significantly reduced the effect of dipyrone. Therefore, evidence indicated that CA acted as an anticytotoxic and antigenotoxic agent counteracting damage induced by dipyrone.

[Adequacy of the safety of metamizole and agranulocytosis]. / Adecuación de la seguridad del metamizol y agranulocitosis.

OBJECTIVE: To analyze whether the drug safety update issued by the Spanish Agency of Medicines and Healthcare Products (AEMPS), dated October 30, 2018, on agranulocytosis and metamizole contains accurate and necessary information to protect patients from the presentation of this adverse reaction (AR) and if the official documentation of medicines containing metamizole for doctors, pharmacists and the general population conforms to the guidelines of the AEMPS to reduce this risk. SETTING AND PARTICIPANTS: Drug safety update, bibliographic search, information at the European Medicines Agency on metamizole drugs marketed in Spain, technical datasheets, leaflets, Bot PLUS Health Information Database and Catalog of Pharmaceutical Specialties. Notification of 4cases of agranulocytosis due to metamizole after the drug safety update was issued. MAIN INTERVENTIONS AND MEASUREMENTS: Comparison of the key points of the drug safety update and official documents on metamizole with the bibliography. Description of the 4cases of agranulocytosis due to metamizole and application of the causality and severity algorithm. RESULTS: The drug safety update contains omissions and contradiction in respect to the bibliography and the actual use of metamizole in healthcare practice. The official documents show a lack of updating, unapproved indications and doses higher than those recommended. The drug safety update has not stopped the presentation of cases of agranulocytosis due to metamizole. CONCLUSIONS: The AEMPS drug safety update can be improved and it is necessary to update the official information documents on metamizole for health professionals and patients in order to decrease the risk of agranulocytosis.

Challenges in diagnosis and management of neutropenia upon exposure to immune-checkpoint inhibitors: meta-analysis of a rare immune-related adverse side effect.

BACKGROUND: Cancer immunotherapy via immune-checkpoint inhibition (ICI) by antibodies against cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and cell death protein 1 (PD-1) have significantly improved the outcome of metastasized melanoma and of a rapidly increasing number of other cancer types. The anti-tumor effect is often accompanied by immune-related adverse events (irAE). Hematological irAE, specifically neutropenia, are rarely observed. However, neutropenia is associated with high morbidity and mortality due to infection complications. Thus, early detection and treatment is crucial. METHODS: We present the clinical course of two patients with severe neutropenia after ICI therapy and demonstrate the difficulty of the diagnosis when a comedication of metamizole, a well-known analgesic drug used to treat cancer pain, is present. Further, we provide a comprehensive descriptive and statistical analysis of published data on diagnostics, treatment and infection complication in patients with at least grade 4 neutropenia by a systematic database search. RESULTS: Finally, 34 patients were analyzed, including the two case reports from our cohort. The median onset of neutropenia was 10.5 weeks after first ICI administration (interquartile range: 6 weeks). In 76% (N = 26), a normalization of the neutrophil count was achieved after a median duration of neutropenia of 13 days. In a subsample of 22 patients with detailed data, the infection rate was 13%, proven by positive blood culture in 3 cases, but 68% (N = 15) presented with fever > 38 °C. Treatment regime differed relevantly, but mainly included G-CSF and intravenous corticosteroids. Death was reported in 14 patients (41%), 3 of whom (9%) were associated with hematological irAE but only two directly associated with neutropenia. CONCLUSION: With an increasing number of cancer patients eligible to ICI therapy, the incidence of severe hematological toxicities may rise substantially over the next years. Clinicians working in the field of cancer immune therapies should be aware of neutropenia as irAE to provide immediate treatment.

Metamizole: An underrated agent causing severe idiosyncratic drug-induced liver injury.

AIMS: Drug-induced liver injury (DILI) is a heterogenous entity leading to liver damage. We have analysed the frequency, biochemical and histological patterns and clinical courses of DILI cases due to metamizole at our tertiary care centre in Hamburg, Germany. METHODS: Consecutive patients with DILI who presented to our clinic were analysed retrospectively. Causes of acute hepatitis other than DILI were excluded. RESULTS: In total, 154 DILI cases were admitted to our centre from 2008 to 2017. After phenprocoumon, metamizole was the second most frequent putative agent causing DILI (23 of all 154 DILI cases, 14,9%). The biochemical pattern on admission of metamizole-induced DILI cases was hepatocellular with median levels of alanine transaminase (779 U/L, 64-3532 U/L) by far exceeding median alkaline phosphatase levels (131 U/L, 42-578 U/L). In 17 of the 23 cases (74%) liver biopsy was performed. Moderate to severe inflammatory histological activity and severe centrilobular necrosis (>30%) was present in 76.5 and 35.3%, respectively. Metamizole was involved in 2 DILI cases progressing to acute liver failure, then receiving liver transplantation and still alive at time of assessment. Our data were supported by re-exposure in 4 patients. Furthermore, a database search for metamizole-induced liver injury in the European Medicines Agency's database identified about 300 reports on suspected metamizole-induced DILI in Europe. CONCLUSION: Elevation of liver enzymes or acute liver failure are not mentioned in the German drug label of metamizole as potential side effects. Our study reveals that in Germany and Europe, metamizole is a frequent and underrated agent causing DILI.

[Agranulocytosis after use of metamizole - an underestimated risk?] / Agranulozytose nach Metamizol-Einnahme ­ ein unterschätztes Risiko?

OBJECTIVE: Metamizole was the second most common drug prescribed in Germany in 2018 despite the known risk of agranulocytosis and the strict indication. According to Stammschulte et al. up to 25 % of all prescriptions are off-label use. Although mandatory according to the prescribing information of metamizole, regular blood cell counts are not performed in up to 50 % of the patients with long-term use of this drug. MATERIAL AND METHODS: Retrospective analysis of eight cases metamizole-induced agranulocytosis over a period of five years (2016-2020) in the university ENT department in Erlangen. Five patients were men and three women. Mean age of diagnosis was 52,4 years (±â€Š25,6). RESULTS: Agranulocytosis after use of metamizole is a serious adverse drug reaction that may affect patients of all ages. Frequently, only distinct clinical symptoms such as temperature of unknown origin, dysphagia and tonsillitis in combination with abscesses in the head and neck area result in the detection of a metamizole-induced agranulocytosis. An agranulocytosis provokes partially radical surgery and/ or intensive-care measures and could lead to sepsis with organ failure or even to death. CONCLUSIONS: These patient cases show that agranulocytosis is a dangerous or even deadly adverse drug reaction after use of metamizole. Although the risk of agranulocytosis appears to increase with duration of use, we would recommend patient education as well as documentation of even a single administration of metamizole. This may facilitate early diagnosis of metamizole-induced agranulocytosis and thus prevent the onset of severe complications with possible lethal outcome.

Metamizole (dipyrone)-induced agranulocytosis: Does the risk vary according to ethnicity?

WHAT IS KNOWN AND OBJECTIVE: Based on spontaneous reports from Spain, it is claimed that the British, Irish and Scandinavians are at a greater risk of dipyrone-induced agranulocytosis. This report examines the evidence. COMMENT: Although interethnic differences in drug response are well known, there are no reliable epidemiologic data to support the above claim. Available information on chlorpromazine suggests variable ethnic sensitivities to drug-induced agranulocytosis. Agranulocytosis induced by at least four drugs has been associated with variant HLA alleles. Preliminary evidence also suggests that the presence of specific variant HLA alleles may sensitize individuals to dipyrone-induced agranulocytosis. There are historical reasons to suspect that the three populations referred to may share some key genetic features, including the potentially culprit variant HLA alleles, that predispose them to dipyrone-induced agranulocytosis. WHAT IS NEW AND CONCLUSION: The possibility that the British, Irish and Scandinavians show higher susceptibility than other populations to dipyrone-induced agranulocytosis cannot be ruled out. If this complication is linked to specific HLA allele(s), populations with higher frequency of variant HLA allele(s) may be at a greater risk. If confirmed, screening for the risk allele may be useful in reducing the risk of dipyrone-induced agranulocytosis.

Metamizole vs. ibuprofen at home after day case surgery: A double-blind randomised controlled noninferiority trial.

BACKGROUND: NSAIDs and paracetamol are the cornerstones of pain treatment after day case surgery. However, NSAIDs have numerous contraindications and consequently are not suitable in up to 25% of patients. Metamizole is a non-opioid compound with a favourable gastro-intestinal and cardiovascular profile compared with NSAIDs. OBJECTIVES: The study aimed to assess if a combination of metamizole and paracetamol is noninferior to a combination of ibuprofen and paracetamol in treating pain at home after painful day case surgery. DESIGN: A double-blind randomised controlled trial. SETTING: Single centre. PATIENTS: Two hundred patients undergoing elective ambulatory haemorrhoid surgery, arthroscopic shoulder or knee surgery, or inguinal hernia repair. INTERVENTION: Patients were randomly allocated to receive either metamizole and paracetamol (n = 100) or ibuprofen and paracetamol (n = 100) orally for four days. MAIN OUTCOME MEASURES: Average postoperative pain intensity using a numerical rating scale and use of rescue medication were measured in the postanaesthesia care unit (PACU) and on postoperative days (POD) 1 to 3. A difference in mean numerical rating scale score of 1 point or less was considered noninferior. Adverse effects of study medication and satisfaction with study medication were measured on PODs 1 to 3 by telephone follow-up. RESULTS: In the PACU, the difference in mean ±â€ŠSD pain score between metamizole and paracetamol and ibuprofen and paracetamol was 0.85 ±â€Š0.78. From POD 1 to 3, this difference was lower than 1, resulting in noninferiority. Rescue opioid consumption in the PACU and on PODs 1 and 3 was not significantly different between treatment groups. Rescue opioid consumption on POD2 was significantly higher in the ibuprofen and paracetamol group (P = 0.042). Adverse effects of study medication and overall patient satisfaction were similar in both groups. CONCLUSION: Paracetamol/metamizole and paracetamol/ibuprofen are equally effective in treatment of acute postoperative pain at home after ambulatory surgery with comparable patient satisfaction levels. TRIAL REGISTRATION: European Union Clinical Trials Register 2015-003987-35.

[Recommendations for the perioperative use of dipyrone : Expert recommendation of the working group on acute pain of the German Pain Society, the scientific working group on pain medicine of the German Society for Anesthesiology and Intensive Care Medicine and the surgical working group on acute pain of the German Society for Surgery with participation of representatives of the Drug Commission of the German Medical Association]. / Empfehlungen zur perioperativen Anwendung von Metamizol : Expertenempfehlung des Arbeitskreises Akutschmerz der Deutschen Schmerzgesellschaft, des Wissenschaftlichen Arbeitskreises Schmerzmedizin der Deutschen Gesellschaft für Anästhesiologie und Intensivmedizin und der Chirurgischen Arbeitsgemeinschaft Akutschmerz der Deutschen Gesellschaft für Chirurgie unter Beteiligung von Vertretern der Arzneimittelkommission der deutschen Ärzteschaft.

BACKGROUND: Dipyrone (metamizole) is widely used for perioperative pain management in countries where it is marketed; however, uncertainty exists concerning the safe use of this drug, specifically considering the rare adverse event of an agranulocytosis. METHODS: As evidence from published studies was lacking, an expert panel developed recommendations for the perioperative use of dipyrone. After a formal, structured consensus process, the recommendations were approved by the involved medical societies. RESULTS: The panel agreed that blood cell counts shall not be standard for short-term perioperative use in patients unless they are at risk for neutropenia. The medical staff shall be aware of the symptoms and course of action when agranulocytosis is suspected. Patients shall be informed about the risks and benefits of dipyrone and about potential alternatives. The expert group concluded that dipyrone has a relatively positive risk-benefit ratio compared to other nonopioid analgesics. The group strongly recommended educating patients about the symptoms of agranulocytosis if they have received dipyrone over several days and/or treatment is to be continued after discharge, because agranulocytosis can occur several days after discontinuation of metamizole. Further recommendations refer to the information of the physician taking over the patient's care after discharge and the avoidance of re-exposure in patients having previously suffered from dipyrone-induced agranulocytosis. CONCLUSION: The group's recommendations shall be communicated in order to raise medical staff's and patients' awareness of the appropriate use of dipyrone in the perioperative period.

[Considerations concerning the perioperative use of metamizole]. / Überlegungen zum perioperativen Einsatz von Metamizol.

BACKGROUND: The non-opioid analgesic metamizole (dipyrone) is approved for the treatment of severe pain and is often used in the perioperative period. As it can cause agranulocytosis, a severe adverse event, its perioperative administration is controversially discussed. OBJECTIVE: Is there enough evidence for a high risk of metamizol-induced agranulocytosis (MIA)? What are the consequences of its perioperative use with respect to the risk profiles of alternative analgesics? MATERIAL AND METHODS: Rapid review of the literature on the risk of MIA and adverse effects of non-opioid analgesics. RESULTS: The incidence of MIA is estimated to be one case per million inhabitants per year. The risk seems low compared to other drugs associated with a risk of agranulocytosis, such as antithyroid drugs and ticlopidine. The risk profile of metamizole concerning hepatotoxicity, nephrotoxicity, bleeding and cardiovascular adverse effects is favorable compared to other non-opioid analgesics. None of the non-opioid analgesics are licensed to be administered intraoperatively. CONCLUSION: The perioperative use of metamizole is possible after a thorough evaluation of the indications as it provides good analgesia with a generally favorable side effect profile and is administered intravenously. The risk of agranulocytosis is small but needs to be mentioned during patient informed consent in order to optimize early recognition. Intraoperative administration aims at reducing the expected severe postoperative pain. A documentation and justification for the evaluation of the indications are recommended.

[Recommendations for the perioperative use of dipyrone : Expert recommendation of the working group on acute pain of the German Pain Society, the scientific working group on pain medicine of the German Society for Anesthesiology and Intensive Care Medicine and the surgical working group on acute pain of the German Society for Surgery with participation of representatives of the Drug Commission of the German Medical Association]. / Empfehlungen zur perioperativen Anwendung von Metamizol : Expertenempfehlung des Arbeitskreises Akutschmerz der Deutschen Schmerzgesellschaft, des Wissenschaftlichen Arbeitskreises Schmerzmedizin der Deutschen Gesellschaft für Anästhesiologie und Intensivmedizin und der Chirurgischen Arbeitsgemeinschaft Akutschmerz der Deutschen Gesellschaft für Chirurgie unter Beteiligung von Vertretern der Arzneimittelkommission der deutschen Ärzteschaft.

BACKGROUND: Dipyrone (metamizole) is widely used for perioperative pain management in countries where it is marketed; however, uncertainty exists concerning the safe use of this drug, specifically considering the rare adverse event of an agranulocytosis. METHODS: As evidence from published studies was lacking, an expert panel developed recommendations for the perioperative use of dipyrone. After a formal, structured consensus process, the recommendations were approved by the involved medical societies. RESULTS: The panel agreed that blood cell counts shall not be standard for short-term perioperative use in patients unless they are at risk for neutropenia. The medical staff shall be aware of the symptoms and course of action when agranulocytosis is suspected. Patients shall be informed about the risks and benefits of dipyrone and about potential alternatives. The expert group concluded that dipyrone has a relatively positive risk-benefit ratio compared to other nonopioid analgesics. The group strongly recommended educating patients about the symptoms of agranulocytosis if they have received dipyrone over several days and/or treatment is to be continued after discharge, because agranulocytosis can occur several days after discontinuation of metamizole. Further recommendations refer to the information of the physician taking over the patient's care after discharge and the avoidance of re-exposure in patients having previously suffered from dipyrone-induced agranulocytosis. CONCLUSION: The group's recommendations shall be communicated in order to raise medical staff's and patients' awareness of the appropriate use of dipyrone in the perioperative period.

[ACUTE RENAL FAILURE INDUCED BY METAMIZOLE].

INTRODUCTION: Sodium metamizole (Optalgin) is one of the most prevalent analgesic and anti-pyretic medications used in Israel. We describe a case of acute kidney injury subsequent to the use of metamizole in a healthy young patient. Metamizole may cause kidney injury in a number of different mechanisms and it is vital that this fact will be emphasized due to the widespread use of this medication.

[Case Report - Metamizole-Induced Agranulocytosis]. / Kasuistik: Metamizol-induzierte Agranulozytose.

Metamizole is primarily used for severe perioperative pain, acute injury and colic, and cancer pain. For other acute/chronic forms of pain and high fever, it should only be used if unresponsive to other agents. Metamizole should not be used for middle and low pain. Oral application should be preferred. A contraindication for metamizole is leukopenia. Clinical signs for agranulocytosis are fever, tonsillitis and aphthous stomatitis.