This article is accompanied by the following Invited Commentary:
Rollason V, Desmeules JA. Use of metamizole in children and the risk of agranulocytosis. Is the benefit worth the risk? Eur J Anaesthesiol 2015; 32:837–838.
Metamizole (dipyrone) is a NSAID with analgesic, spasmolytic and antipyretic properties and can be used orally and parenterally to prevent or treat pain related to surgery. It has been in clinical use since 1922 and is now a popular analgesic drug to treat postoperative, colic, cancer or migraine pain in many countries, whereas it is banned in other countries (USA, Japan and Sweden) because of its possible association with agranulocytosis, hypotension and allergy.1,21,2
The analgesic effect of metamizole seems to be partly based on a dual mechanism that includes the inhibition of cyclooxygenase enzyme activity and the stimulation of cannabinoid receptors.1 In addition, the peripheral antinociceptive effect may due to the activation of ATP-sensitive K+ channels.3 In Germany and Austria, metamizole is included in the recommendations for perioperative pain therapy in children, but a debate about its use is ongoing.4,54,5 Proponents cite the potent analgesic effects and the low frequency of significant adverse effects when compared with other NSAIDs, although opponents point out the lack of clinical studies with large sample sizes and case reports of patients with life-threatening agranulocytosis. We, therefore, conducted a prospective, multicentre, observational, postauthorisation safety study (PASS) with a large number of paediatric patients to evaluate the use of metamizole in children undergoing surgery with a particular focus on serious adverse drug reactions (ADRs).
Materials and methods
Following local ethics committee approval (Ethical Committee of Hanover Medical School, Germany, Chairperson Prof. Dr H. D. Troeger, No. 1973- 2013 on 13 September 2013), the study was carried out at six paediatric centres where metamizole was routinely used for perioperative pain therapy. The study enrolled paediatric patients aged up to 6 years [American Society of Anesthesiologists’ (ASA) physical status class I to III] undergoing surgical procedures with the administration of intravenous metamizole for perioperative analgesia in accordance with local guidelines. Patient demographics, main and secondary diagnoses, the surgical procedures performed, metamizole dose and infusion time, haemodynamic data before and after metamizole administration, use of other analgesics, adjuvants and regional blocks, results of pain measurement in the recovery room and ADR incidence (haemodynamic, anaphylactic or respiratory reactions and agranulocytosis) were documented using a standardised case report form from induction of anaesthesia until discharge from the recovery room. For pain measurement, the Children and Infants Postoperative Pain (ChIPPS) scale from 0 to 10 was used.6 As blood counts were not part of routine postoperative monitoring, agranulocytosis was regarded as unlikely in cases without persistent postoperative fever and other possible manifestations of agranulocytosis such as tonsillitis, stomatitis or pneumonia. On the basis of an estimated ADR probability of less than 3/N for N patients [confidence interval of 95% (95% CI)], we planned to observe 1000 patients for this observational study to detect an ADR with an incidence of 0.3%. All recorded data were analysed using a MS Excel (Excel 2010; Microsoft Corporation, Redmond, Washington, USA) and SPSS programme tool (IBM SPSS Statistics 22, Armonk, New York, USA) and are presented as mean ± SD (range) or frequency. Wilcoxon test and linear regression analysis were performed for metric data with a predefined significance level of α equal to 0.05.
A total of 1177 children were investigated at six different paediatric centres in Germany from September 2013 to September 2014. Owing to the high number of study sites and the different modes of recruitment, it was not possible to terminate the study after exactly 1000 children. Thirty-two patients (2.7%) with incomplete data collection were excluded from the analysis except for the presence of ADRs.
Demographic data, details of the surgical procedures, duration of anaesthesia, metamizole dose and infusion time are summarised in Table 1 and Fig. 1. The studied cohorts included 113 patients (9.9%) younger than 1 year of age and 34 patients (3%) younger than 1 month. Allergy was reported in 38 patients (3.3%) and bronchial asthma in 23 patients (2%) as a secondary diagnosis.
Metamizole was administered preoperatively in 28 patients (2.5%), intraoperatively in 1104 patients (96.4%) and postoperatively in 13 patients (1.1%). Additional nonopioids were used in 164 patients (14.3%), opioids in 942 patients (82.3%) and adjuvant analgesics in 340 patients (29.7%). In 335 patients (29.3%), general anaesthesia was combined with local or regional anaesthesia (Fig. 2).
ADRs of pruritus, swelling and exanthema were reported in one patient each (total 0.3%, 95% CI -0.035 to 0.56). No respiratory adverse events directly related to metamizole administration and no clinical courses suggestive of agranulocytosis were observed. Heart rate (HR) and mean arterial pressure (MAP) remained stable within the physiological range during metamizole administration [HR before infusion 103.5 ± 20.4 (56 to 177), after infusion 104.3 ± 20.6 (52 to 175) beats min−1; MAP before infusion 55.7 ± 11.3 (25 to 98), after 56.6 ± 11.3 (25 to 99) mmHg; P < 0.05 for both]. There were no significant correlations between metamizole dose or infusion time and changes in MAP. The distribution of changes in MAP is presented in Fig. 3. The incidence of a decrease in MAP more than 30% was 1.7%.
The pain scale results (CHIPPS) showed 0.2 ± 1 (0 to 9) at admission and 0.4 ± 1 (0 to 8) points at discharge from the recovery room (P < 0.001). A pain score less than 5 was found in 98.2% of the patients when transferred to the children's ward.
The main finding of this study was that the probability of serious ADRs (haemodynamic, anaphylactic or respiratory reactions and agranulocytosis) after a single dose of metamizole for the prevention or treatment of postoperative pain is extremely low in children aged up to 6 years.
Common methods for drug surveillance are national spontaneous reporting systems (pharmacovigilance databases) to detect rare but severe ADRs and retrospective case–control studies or prospective cohort studies to detect more common ADRs.7 On the basis of published epidemiologic evidence, the estimated excess mortality (most frequently caused by upper gastrointestinal complications) associated with the short-term use of nonopioids was 592 per 100 million for diclofenac, 20 per 100 million for acetaminophen and 25 per 100 million for metamizole.8 A rare, but severe, serious ADR associated with metamizole is agranulocytosis. Recent studies have shown that, over the last few years, the number of cases reported annually increased proportionally with metamizole sales figures and the calculated incidence was 0.16 to 1.63 cases per million person-days of use.9–119–119–11 In World Health Organisation (WHO) and Swiss spontaneous safety reports, the lowest numbers were reported for the age group 0 to 9 years, but no data regarding age-specific use of metamizole are available. Therefore, it cannot be concluded that agranulocytosis occurs less frequently in children.9 In case reports, agranulocytosis was described in three children aged 4, 9 and 17 years after multiple metamizole doses for treatment of fever. All of the patients recovered after administration of steroids and haematopoietic growth factor.12–1412–1412–14 Reports of children with agranulocytosis after single-dose metamizole for postoperative analgesia are lacking. In a Cochrane meta-analysis reviewing the use of metamizole for acute postoperative pain in adults, no serious events or adverse event withdrawals were reported.15 In this study, we found no clinical courses suggestive of agranulocytosis, but several limitations of this prospective cohort study are apparent: the sample size was too small to detect agranulocytosis; follow-up was too short; and blood cell counts were not routinely performed.
Other more common ADRs of metamizole are haemodynamic, anaphylactic or respiratory reactions. Surprisingly, HR and MAP remained stable during metamizole infusion in this study and the numbers of patients with MAP increases and decreases were comparable. Linear regression analysis showed no significant correlation between metamizole dose or infusion rate and change in MAP. The haemodynamic changes found, therefore, are probably not caused by the metamizole infusion alone but also by other factors associated with the patient's condition, anaesthesia or surgery. A hospital drug monitoring study from Switzerland included a large cohort of adult patients having a metamizole infusion and found that only 0.34% had a significant fall in SBP.16 Other studies with critically ill adult patients showed a more frequent reduction of arterial blood pressure after treatment of fever using metamizole, paracetamol or dexketoprofen, but it was unclear whether this was a drug reaction or a consequence of the decrease in body temperature.17,1817,18 Even though the current study showed that the haemodynamics of children undergoing elective surgery were remarkably stable during intravenous metamizole administration, a cautious approach should be used. This should include a careful correction of possible fluid deficits before metamizole infusion, the use of slow infusion rates and close blood pressure monitoring as per the recommendations in the product's summary of product characteristics (SPC). Skin reactions were reported in 0.3% of the cases, but intradermal allergy tests were not performed and, therefore, the causality was not proven.19 Respiratory reactions with a close temporal relation to the metamizole administration were not reported, but a study with adult patients showed that bronchospasm after metamizole is more frequent in patients with metamizole intolerance and bronchial asthma.20 Studies with children are lacking and in the small number of children with asthma included in this study, there were no reports of skin reactions or bronchospasm. Nevertheless, it is recommended in the SPC to avoid metamizole in patients with bronchial asthma.
The low pain scores in the recovery room indicate the high efficacy of a multimodal analgesic strategy with metamizole as a nonopioid agent. Metamizole was used most frequently in patients undergoing ear, nose and throat, abdominal and urological surgery. Studies in children and adults showed that the concomitant administration of metamizole reduced the postoperative opioid consumption with a low incidence of adverse effects.21,2221,22 According to a Cochrane meta-analysis reviewing the use of a single dose of metamizole for acute postoperative pain in adults, a 500 mg oral dose of metamizole had similar efficacy as ibuprofen 400 mg and a 2.5 g intravenous metamizole dose was equivalent to 100 mg intravenous tramadol (in terms of providing at least 50% pain relief).15 In a study with children undergoing lower abdominal surgery, rescue analgesia was needed less frequently after metamizole when compared with placebo.23
In recently published recommendations and reviews on perioperative pain management, metamizole was considered as first-line treatment in the perioperative period because of an excellent balance between efficacy and adverse effects and it was suggested, that according to the current state of knowledge, the rare but severe ADR of agranulocytosis does not justify a general rejection of the use of metamizole for short-term perioperative administration in children.5,24,255,24,255,24,25 Other authors stated that metamizole should be prescribed conservatively after weighing the potential risk of myelotoxicity against the adverse effects of possible alternatives.8–108–108–10
In conclusion, single intravenous doses of metamizole used for prevention or treatment of postoperative pain were well tolerated in more than 1000 children aged up to 6 years. The probability of serious ADRs (haemodynamic, anaphylactic or respiratory reactions) is lower than 0.3%. The sample size and follow-up was not sufficient to detect episodes of agranulocytosis.
Acknowledgements related to this article
Assistance with the study: none.
Financial support and sponsorship: none.
Conflicts of interest: none.
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