Postoperative administration of metamizole for one single day

A retrospective cohort study

Editor,

We read the study by Fieler et al.¹ with great interest. Their study addresses an important aspect of postoperative analgesia management. They did not report any cases of agranulocytosis following metamizole administration in more than 1000 children. A single dose of intravenous metamizole for treatment of postoperative pain seems to be well tolerated without adverse events directly related to metamizole administration. We would like to report a retrospective cohort investigation we performed in 2012, on consecutive adult patients, with the aim of investigating whether postoperative intravenous metamizole leads to agranulocytosis. After ethical approval (Medical Ethical Committee of Erasmus University Medical Centre, Rotterdam (Secretary Mrs. W.C.M. Tielemans, BASc, and chairman Prof. Dr H.W. Tilanus) in 2013/2014), we retrospectively included a cohort of 2377 different administrations of metamizole. This study was designed as a hypothesis-generating study for future prospective studies. Our primary outcome was the occurrence of agranulocytosis (defined as a decrease in peripheral granulocytes (neutrophil, eosinophil and basophil) count to less than 0.5 × 10⁹ cells l^–1, in accordance with our laboratory standards, or a decrease in the leukocyte count. For our primary analysis, we only used cases with both pre-administrative and post-administrative leukocyte counts to estimate the difference in the leukocyte counts and the percentage change. Exposure status was defined as dose of metamizole - Consumed Daily Dosage (CDD) in grams. As potential confounders, we included age, sex, nephrectomy, and current bone marrow suppressing therapies such as chemotherapy, radiotherapy, brachytherapy or immunosuppressive therapy. Data on metamizole administrations were obtained from the Patient Data Management System (PDMS) and from Electronic Patient Dossier (EPD – Elpado) of the Erasmus University Medical Centre, The Netherlands. The unadjusted and adjusted (corrected for age, sex and chemotherapy) odds ratios were calculated using logistic regression. As a reference category, we used a CDD of 1 g. Ninety-five percent confidence intervals and significance levels were obtained for all values. All analyses were done with IBM SPSS (Statistics for Windows version 21.0; IBM Corp., Armonk, New York, USA).

In our cohort with 2377 administrations of metamizole, 2049 patients (86%) received metamizole for one single day postoperatively. Data on both pre-administrative and post-administrative leukocyte count were available for 449 patients who received metamizole in one single day. When selecting only those who received metamizole for 1 day, mean age was 54 years (SD 16.80). The majority of these patients, 262 (58.6%), received 1 g in 1 day, 149 (33.2%) received 2 g, 18 (4.0%) received 3 grams, 17 (3.8%) received 4 g and two (0.4%) patients received 5 g. Of the 2377 eligible administrations of metamizole, only one case (0.042%) of possible agranulocytosis occurred. This person had a neutropenia (0.31 × 10⁹ l^–1) and a leukocyte count of 0.8 × 10⁹ l^–1 after using metamizole. Pre-administration, the leukocyte and neutrophil count was 6.00 × 10⁹ l^–1 and 4.9 × 10⁹ l^–1, respectively. This patient received metamizole together with his seventh RCHOP (Rituximab, Vincristine, Doxorubicine, Cyclofosfamide and Prednison) and intrathecal (Methotrexate and Dexamethasone) chemotherapy for a relapsed testicular B-cell lymphoma with liquor metastases. No complications or diagnostic confirmation of agranulocytosis was registered.

Leukopenia (≤3.4 × 10⁹ cells l^–1) occurred in 18 persons (4%) after metamizole. Compared with their pre-administration levels, 236 patients (52.6%) had a drop in their leukocyte count with a mean difference of −0.53 (SD 4.45) × 10⁹ l⁻¹, which represents a −4.73% difference. Patients who received up to 4 g within 1 day had a no significant higher chance of a decreased leukocyte count after administration [adjusted odds ratio (OR) 2.57, 95% confidence interval (95% CI) 0.89 to 7.44, P = 0.083]. For both unadjusted and adjusted analysis, we see a trend of increasing odds for higher dosages, but no significance was reached due to small numbers (see Table 1).

Table 1: Estimates for primary outcomes

Adjusting for age, sex and chemotherapy did not result in a significant drop in leukocyte count when 4 or 5 g of metamizole was administered. Regarding the potential case with agranulocytosis, it is important to note that the patient received concomitantly RCHOP chemotherapy. Unfortunately, no complete blood count or bone marrow examination was performed to evidence the metamizole-related diagnosis of agranulocytosis. Moreover, no other serious complications such as gastrointestinal or allergic complications were reported.

On the basis of the literature and the reported incidences, we should have included a larger number of patients exposed to metamizole to be able to detect cases of agranulocytosis.² In the Netherlands, however, the use of metamizole is still scarce. Although no cases of agranulocytosis were reported in our hospital since the reintroduction of metamizole in 2004, our reported incidence is similar to other studies including one Dutch study.² For reference numbers, in 2012, our hospital administered 8358 ampoules of 1000 mg metamizole. In a recent correspondence, Souki³ also highlighted the safety of 2 g metamizole.

Considering the retrospective design of the current study, we were unable to control for possible confounders such as concomitant drug use, steroid administration, fluid transfusions, American Society of Anesthesiologists physical status classification and a rise in leukocytes in response to surgery. Other reports investigating long-term exposure to metamizole reported incidences ranging from 0.08 to 0.56 per million daily dosages when used as an analgesic.^4,5 Fieler et al.¹ found no agranulocytosis in a smaller cohort of children (n = 1177) aged up to 6 years when a single dose of intravenous metamizole was administered for postoperative pain. Nevertheless, in a recent editorial, Rollason and Desmeules⁶ claimed that there was insufficient evidence to promote metamizole as a well tolerated drug for use postoperatively, particularly given that agranulocytosis is a life-threatening adverse drug reaction. One may wish to put the rare incidence of agranulocytosis into perspective, alongside with the more common complications observed following the administration of nonsteroidal anti-inflammatory drugs, such as haemorrhages, gastrointestinal complications, allergic reactions and kidney failure.⁷ In our opinion, metamizole, as a nonopioid analgesic, deserves a place in postoperative acute pain treatment. Although our report does not provide strong evidence for the safety of metamizole, we also do not have strong evidence of a serious safety risk of giving a single bolus of 1 to 2 g postoperatively and not more than 4 g within the first 24 postoperative hours – as recommended in the Dutch postoperative pain protocol. Exceeding 4 g or administering metamizole for longer periods should be done while monitoring leukocyte and neutrophil counts. Future research should preferably be designed as a nested case–control study to investigate rare events such as agranulocytosis.

Acknowledgements relating to this article

Assistance with the study: none.

Financial support and sponsorship: this study was funded by the Department of Anaesthesiology, Erasmus MC, Rotterdam, The Netherlands. There was no other financial support or sponsorship.

Conflicts of interest: M. Klimek has received a fee for one lecture on metamizole as part of the official Polish protocol for postoperative pain-therapy by Polpharma.