Reply to Ziesenitz, Victoria; Erb Thomas; Trachsel, Daniel; van den Anker, Johannes

Sir
We would like to thank Ziesenitz and colleagues for their additive comments to our review concerning the evidence of analgesic efficacy of dipyrone in children.
Since dipyrone was recently included in the Dutch national guideline for postoperative pain treatment, our first aim was to obtain more insight in the evidence of the analgesic efficacy when used in children: eg, if it is more potent than other analgesics prescribed for mild pain like paracetamol or nonsteroidal anti-inflammatory drugs. For this we found no evidence. On the contrary, in good quality randomized controlled trials, the efficacy of dipyrone or paracetamol appeared similar. In lower quality RCTs, it was similar or even less effective than ketorolac.
About the safety we have given a warning but the pharmaco-epidemiologic calculations are done for the risk on agranulocytosis; results and estimations differ every time in each study.
We share the concerns by Ziesenitz regarding the risk of agranulocytosis with dipyrone; as pediatric studies largely differed in design, we were not able to provide a risk to develop this serious adverse event in children.2 In the studies mentioned by Ziesenitz, mean age of patients who developed agranulocytosis was around 60 years (11-93). Only a small proportion of patients (3.7% and 3.9%) were younger than 18 years. The greatest risk factors mentioned in both articles are: older age, female sex, triple blood line dyscrasia, and concomitant treatment with methotrexate.
We are worried that the risk of developing agranulocytosis is underestimated. First, because of the possibility of underreporting of this serious and sometimes fatal adverse drug reaction and second because the numbers are increasing because of an increase in prescriptions of dipyrone partly due to off label indications. We are aware of the increasing use of opioids in both North America and Europe with associated life-threatening respiratory events, a subject also frequently debated in the Pediatric Pain List.
Therefore, we would certainly advocate the perioperative use of adjuvant analgesics to reduce opioid prescriptions. But based on the available evidence in literature, there is certainly no place for the use of dipyrone. There are enough alternatives available, including intravenous paracetamol, though for some also with limited evidence.