Accepted: 10 September 2017

DOI: 10.1111/pan.13257

SYSTEMATIC REVIEW

The use of dipyrone (metamizol) as an analgesic in children:

What is the evidence? A review

Thomas G. de Leeuw1 | Maaike Dirckx1,2 | Antonia Gonzalez Candel1 |

Gail P. Scoones1 | Frank J. P. M. Huygen2 | Saskia N. de Wildt3,4

1
Department of Anesthesiology, Erasmus
MC—Sophia Children’s Hospital, Summary
Rotterdam, The Netherlands Dipyrone has analgesic, spasmolytic, and antipyretic effects and is used to treat
2
Center for Pain Medicine, Erasmus MC,
pain. Due to a possible risk of agranulocytosis with the use of dipyrone, it has
Rotterdam, The Netherlands
3
Department of Pediatric Intensive Care been banned in a number of countries. The most commonly used data for the
and Pediatric Surgery, Erasmus MC—Sophia use of dipyrone are related to adults. Information relating to the use of dipyrone
Children’s Hospital, Rotterdam, The
Netherlands in children is scarce. Given the potential added value of dipyrone in the treat-
4
Department of Pharmacology and ment of pain, a review of the literature was conducted to obtain more insight
Toxicology, Radboud University, Nijmegen,
into the analgesic efficacy of dipyrone in children as well as the safety of dipy-
The Netherlands
rone in terms of adverse events. A literature search was done for original articles
Correspondence
(in English, German, or Spanish language) which met the following criteria: the
Thomas G. de Leeuw, Erasmus MC—Sophia
Children’s Hospital, Department of use of dipyrone for pain and children up to the age of 17 years old. All titles
Anesthesiology, Rotterdam, The Netherlands.
and abstracts retrieved were reviewed, independently, by two of the authors, for
Email: t.deleeuw@erasmusmc.nl
their suitability for inclusion. The references of the selected articles were also
Section Editor: Mark Thomas
checked for additional relevant papers. The publications were categorized into
case reports, observational studies, or randomized controlled trials. To assess the
methodological quality of the studies, the Jadad score was used. In the limited
available data, the analgesic efficacy of intravenous dipyrone appears similar to
that of intravenous paracetamol. Evidence is lacking to support the claim that
dipyrone is equivalent or even superior to Non-Steroid-Anti-Inflammatory-Drugs
in pediatric pain. While the absolute risk of agranulocytosis with dipyrone in chil-
dren, based on available literature, cannot be determined, case reports suggest
that this risk is not negligible.

KEYWORDS
adverse events, analgesic, children, dipyrone, efficacy, pain

1 | INTRODUCTION 2.1,2 The inhibition of prostaglandin biosynthesis is thought to con-

Dipyrone, also known as metamizol (noramidopyrine-methane-sulfo-
nate), is a member of the phenylpyrazolon group. It has analgesic,
spasmolytic, and antipyretic effects and is used to treat postopera-
tive pain, colic pain, cancer pain, and migraine.
The mechanism of the analgesic effect is not exactly known.
Dipyrone is an inhibitor of cyclooxygenase, both COX-1 and COX-
tribute to the analgesic activity. Dipyrone, believed to be a “pro-
drug,” is hydrolyzed in vivo to 4-methylaminoantipyrine which is
further metabolized to 4-aminoantipyrine and 4-formylacetylami-
noantipyrine. Recently, two unknown metabolites, that is, arachi-
donoyl amides of known metabolites (4-methylaminoantipyrine and
4-aminoantipyrine), were identified. Both appeared to have cannabis
receptor binding properties.2 This is similar to the dual analgesic

Pediatric Anesthesia. 2017;1–9. wileyonlinelibrary.com/journal/pan © 2017 John Wiley & Sons Ltd | 1
2 |
mechanism of paracetamol (acetaminophen). The spasmolytic effect
of dipyrone might be explained through stimulation of the cannabis
receptors.2 There is probably also a peripheral antinociceptive effect
3
due to activation of ATP-sensitive K-channels. The antipyretic
effect is achieved by COX-2 inhibition.4
In the Cochrane review “Single dose dipyrone for acute
postoperative pain,” the analgesic effect of various doses of dipy-
rone, administered either orally or intravenously, was compared
with other analgesics. It was concluded that the analgesic efficacy
of a single 500 mg oral dose of dipyrone appears similar to that
of ibuprofen 400 mg, while a single 2.5 g intravenous dose
5
appears equivalent to 100 mg intravenous tramadol. These results
were recently withdrawn because the same authors concluded
that the data used were insufficient to support former conclusions
and so were unable to compare dipyrone directly with other
6
analgesics.
Dipyrone was first introduced into clinical use in Germany in
1922, where it is still one of the most frequently prescribed anal-
gesics.7 In contrast, its use in many other countries has been
banned due to the possible risk of agranulocytosis, defined as a
neutrophil count of less than 0.5 9 10 L 9 1
(˂500 lL 1
). This risk
of agranulocytosis seems to increase with duration of use, while it
disappears 10 days after the last dose. As a result of the risk of
agranulocytosis, it has not been used in the United States since
the early 1970s when it was removed from the pharmaceutical
market. Many cases of hematologic reactions have been described
with the use of another pyrazolone derivate: aminopyrine, medica-
tion used for the same indications but later replaced by dipyrone
because of claims of less toxicity and higher level of efficacy.
Because a cross-sensitivity exists for dipyrone and aminopyrine, it
has been assumed that the risk of agranulocytosis when using
dipyrone is similar to that of aminopyrine.1,8 Interestingly, in Swe-
den, it was withdrawn in 1974 and re-approved in 1995 after an
International Agranulocytosis and Aplastic Anemia study in which
an incidence of agranulocytosis as low as 1.1 per million users
was suggested.9 In 1999, it was removed again based on a new
study suggesting an incidence of 1 on 1439 prescriptions.10
Finally, the most recent study concluded that the use of dipyrone
is associated with an estimated risk of agranulocytosis of 0.56
(0.4-0.8) cases per million.11
Currently, dipyrone is still used in parts of Europe, Asia, and Cen-
tral and South America, 12,13
see Table 1, for the use worldwide.
Dipyrone has recently been registered in the Netherlands, where its
use is restricted to the intravenous route.
The indication for the use of dipyrone also seems to differ
considerably worldwide. In the Netherlands, the registered indica-
tions for dipyrone are short-term treatment of severe acute pain
or high fever, if other drugs are contraindicated, or in case of
high fever, when other methods have failed. These conditions
apply to both adults and children. These restricted indications are
in contrast to pediatric pain management in some other countries.
In Spain, a survey of postoperative treatment in children showed
that dipyrone was one of the most frequently used analgesics14
DE LEEUW ET AL.
and a German study showed dipyrone and paracetamol as the
most frequently administered nonopioid treatments in pediatric
oncology.7
Information relating to age, dose, and routes of administration of
dipyrone in children is unclear. The summary of product characteris-
tics advises against the use dipyrone for children younger than
6 months. The intramuscular route is recommended in children aged
6-12 months, while this route is strongly discouraged in children, for
reasons of pain and discomfort, if another route of administration,
including intravenous administration, is available. In the Netherlands,
the Dutch National Formulary “Farmacotherapeutisch Kompas”
advises intravenous dipyrone only for children over 3 years of age.
At present, the consensus reached among Dutch pediatricians and
pharmacists is that the risks of dipyrone outweighed any possible
analgesic benefit. This practice is in contrast to the practice in other
countries, where dipyrone is even given to neonates.15
In conclusion, there are many uncertainties about the use of
dipyrone, especially in children. Given the potential added value of
dipyrone in the treatment of acute pain, a balanced risk-benefit anal-
ysis is needed to provide better guidance to physicians.
The aim of this review was to evaluate the analgesic efficacy of
dipyrone in children as well as the safety of dipyrone in terms of
adverse events.
2 | MATERIALS AND METHODS
2.1 | Literature search
The literature search was designed with help from the Biomedical
Information Specialist of the Erasmus MC Medical Library. The dif-
ferent databases were searched from inception up to December
2015. The search was for original articles (in the English, German, or
Spanish language) which met the following criteria: the use of dipy-
rone for pain and children up to the age of 17 years old.
The initial search strategy included ((dipyrone or dipyrone or
novalgin or metamizol) AND (child/exp OR newborn/exp OR ado-
lescent/exp OR adolescence/exp OR “child behavior”/de OR “child
parent relation”/de OR pediatrics/exp OR childhood/exp OR “child
nutrition”/de OR “infant nutrition”/exp OR “child welfare”/de OR
“child abuse”/de OR “child advocacy”/de OR “child development”/
de OR “child growth”/de OR “child health”/de OR “child health
care”/exp OR “child care”/exp OR “childhood disease”/exp OR
“child death”/de OR “child psychiatry”/de OR “child psychology”/de
OR “pediatric ward”/de OR “pediatric hospital”/de OR (adolescen*
OR infan* OR newborn* OR (new NEXT/1 born*) OR baby OR
babies OR neonat* OR child* OR kid OR kids OR toddler* OR
teen* OR boy* OR girl* OR minors OR underag* OR (under
NEXT/1 (age* OR aging)) OR juvenil* OR youth* OR kindergar*
OR puber* OR pubescen* OR prepubescen* OR prepubert* OR
pediatric* OR paediatric* OR school* OR preschool* OR high-
school*):ab,ti)).
All titles and abstracts retrieved were reviewed,
independently, by two of the authors (TdL and MD), for their
DE LEEUW ET AL. | 3

T A B L E 1 Availability and restrictions on use of dipyrone by country worldwide

Prescription only,
Completely Prescription only, extensive limited restrictions Over the counter
banned restrictions on its use on its use with limited restrictions No data available
United States Kuwait Philippines Israel Canada Iran
Australia Italy Belgium Pakistan Panama Afghanistan
Norway Sudan Germany Sri Lanka Nicaragua Mongolia
Denmark Bangladesh Netherlands Colombia El Salvador Japan
Sweden Egypt Switzerland Mexico Guatemala New Zealand
France Spain Peru China Suriname North Korea
Saudi Arabia Thailand Russia Indonesia Ecuador South Korea
United Arab Brazil Paraguay Cambodia
Emirates
Malaysia Chile Vietnam
Ghana Argentina Oman
Nepal Bolivia Jordan
Syria Uruguay New Guinea
Yemen Great Britain Kazakhstan
Zimbabwe Portugal Turkmenistan
Morocco Finland Azerbaijan
Lithuania Estonia Myanmar
Armenia Latvia Lebanon
Bahrain Poland Cuba
Greece Belarus Jamaica
Ireland Ukraine Iceland
Singapore Austria Honduras
Venezuela Hungary Libya
Czech Republic Tunisia
Slovak Republic Algeria
Serbia Sudan
Croatia Congo
Slovenia Ethiopia
Macedonia Kenya
Montenegro Tanzania
Bulgaria Uganda
Albania Mozambique
Romania South- Africa
Turkey
Iraq
All other countries except
mentioned in other columns

suitability for inclusion. The full texts were retrieved if one of the
authors considered the title or abstract suitable. The references of
the selected articles were also checked for additional relevant
papers.
In addition to reviewing the analgesic effect and adverse events
in the full text by two of the three authors (TdL, AGC, and MD), the
following information was also retrieved: setting, type of surgery,
sample size, age, dose and duration of medication, route of
administration, how intensity of pain was measured, and primary
outcome measures.
2.2 | Quality of studies
The publications were categorized into case reports, observational
studies, or randomized controlled trials (RCT). To assess the method-
ological quality of the RCTs, the Jadad score was used.16
4 | DE LEEUW ET AL.

3 | RESULTS

The literature search yielded 1165 abstracts (Table 2).

After assessment of these 1165 abstracts, 19 were suitable for
inclusion in this review. Of these 19 articles, 8 were randomized
controlled trials (RCT), 4 observational studies (OL), and 7 case
reports (CR) (Figure 1 and Table 3).

3.1 | Analgesic effect

3.1.1 | Randomized controlled trials

The 8 RCTs included 604 patients. Using the Jadad score (see
Table 4), only 3 RCTs were of good or excellent quality.17-19 In all
three RCTs, the medication was given for postoperative pain, ie,
day-case lower abdominal surgery,17 tonsillectomy with or without
adenoidectomy18, and elective tonsillectomy.19 Furthermore, in all
three studies, patients were randomized to receive dipyrone or
paracetamol or placebo. In two studies, the dose of dipyrone was
1
15 mg kg intravenously (iv)17,18 and in the third dipyrone was
given intravenously via patient-controlled analgesia (loading dose
1 1 1
of 4.5 mg kg , followed by 0.5 mg kg h basal infusion, 1 mg
1
kg bolus dose, lock out 30 minutes for 24 hours).19 In all stud-
ies, pethidine was used as rescue analgesic. The primary outcome
measures were pain at rest,17 cumulative pethidine requirement18,
or paracetamol being a superior or an acceptable alternative for
dipyrone.19 Pain was measured using the VAS,17,19 Cheops18, or
Pain relief score.18,19 Pain scores were significantly lower with
dipyrone or paracetamol groups compared to placebo. The cumula- FIGURE 1 Flowchart of literature search and selection
tive pethidine requirements were also significantly lower in
patients using paracetamol or dipyrone. They concluded that the iv dipyrone has also been compared with placebo; however, keta-
analgesic properties of both paracetamol and dipyrone were better mine was used simultaneously.24
than placebo, with no significant differences between paracetamol
and dipyrone.
3.1.2 | Observational studies
In the other RCTs, dipyrone was compared with different anal-
gesics or placebo. The combination oral naproxen and paracetamol The 4 observational studies included 1254 patients. The analgesic
provided better analgesia than oral dipyrone alone; however, no pain effect of iv dipyrone was more effective than iv acetaminophen.25
20
scores were mentioned. Use of rectal nimesulide or rectal dipyrone In the study of Izhar et al, the reason for the use of dipyrone was
provided similar pain relief21 in a postoperative setting. In compar- not for the prevention or treatment of postoperative pain, but pain
1
ison with iv ketorolac, iv dipyrone (10 mg kg ) was less effective22 due to various reasons and/or fever.26 The route of administration
1
or, at a dose of 20 mg kg , as effective as ketorolac.23 Preemptive in this study is unknown. In the two other observational studies,
the primary goal was to identify side effects when using
dipyrone for postoperative pain management in preterm infants
T A B L E 2 Literature search (up to December 2015) and term neonates27 or serious adverse drug reactions with the
use of iv dipyrone for prevention or treatment of postoperative
Database Number of refs After deduplication
pain.28
EMBASE (EMBASE 1002 998
and MEDLINE)
MEDLINE (Ovid) 368 127 3.1.3 | Case reports
Cochrane Central 37 6
The 7 case reports related to seven different patients.29-35 In 5 of
Web of Science 126 31
the 7 case reports, a specific disease or syndrome was discussed and
PubMed recent 6 3
dipyrone was used as an analgesic. However, little information relat-
Total 1539 1165
ing to the efficacy of dipyrone was provided.
DE LEEUW ET AL.
3.2 | Safety
3.2.1 | Randomized controlled trials
None of the RCTs mentioned significant adverse events. One study
measured bleeding time and white blood cell count as secondary
outcome measures.23 For the other RCTs, it is unclear whether there
was any active monitoring for the occurrence of (serious) adverse
events.
3.2.2 | Observational studies
As mentioned above, in two of the four studies, the primary goal
27
was to identify side effects or serious adverse drug reactions
28
(ADRs) with the use of dipyrone. Other than pruritus, swelling,
exanthema, and vomiting, no (serious) adverse events were men-
tioned. It was concluded that the probability of serious ADRs (he-
modynamic, anaphylactic, or respiratory reactions) is lower than
0.3%.28 The author commented that the sample size (1177 chil-
dren) and follow-up were not sufficient to detect episodes of
agranulocytosis.
3.2.3 | Case reports
Two case reports discussed serious adverse events (ie, neutropenia
and agranulocytosis) possibly related to the use of dipyrone as an
analgesic.29,30
4 | DISCUSSION
This literature review was conducted to assess the empirical evi-
dence for the analgesic efficacy and safety of dipyrone in children.
Our review shows that limited high-quality data are available.
Using the Jadad score, only 3 studies were classified as being
of a good or excellent quality. These studies showed that intra-
venous dipyrone provided better postoperative analgesia than pla-
cebo therapy and analgesia at best, comparable to intravenous
paracetamol.17-19 The main limitation of these 3 RCTs is that they
are all from the same research group from one hospital and that
the data have not been confirmed in a different setting by other
studies.
In fact, it would be interesting to know whether dipyrone could
be used as an equally effective alternative drug to other Non-Steroid
Anti-Inflammatory Drugs (NSAIDs). In 4 of the 8 RCTs, dipyrone has
20-23
been compared with NSAIDs. However, these studies, when
applying the Jadad score, were classified as poor, making definite
conclusions impossible. A recent literature review in adults suggested
that, although firm evidence is lacking, the use of dipyrone in
patients with an increased risk of gastrointestinal bleeding and/or
renal disease may be safer than other NSAIDs.36
The spasmolytic effects of dipyrone may offer an added anal-
gesic benefit in comparison with other nonnarcotic analgesic
| 5
medication. Unfortunately, no studies were found comparing the
spasmolytic effects of dipyrone to other spasmolytic medication.
Failure to assess the severity of pain is one of the common
concerns in pain management and pain trials in children.37 The
three previously mentioned high-quality RCTs used a pain score
which was validated for the age groups studied (VAS and
CHEOPS).17-19 In two other RCTs, validated pain scores were used,
but it was unclear whether the appropriate score was used for the
different age groups (Oucher, modified McGrath and VAS).22,23
One RCT used a pain score which is not validated for the whole
age group.24 In the other RCTs, pain relief was observed by the
physician without using a validated pain score21 or no pain score
was mentioned at all.20 With regard to the observational studies,
an age-related pain score was used27,28, and in two others, it is
unclear whether the pain score was used appropriately26 or the
age of the patients was unknown.25 No pain scores were men-
tioned in the case reports.
There is a wide variation in the daily dosage of dipyrone. In a
study, in which epidural administration of fentanyl was
compared with morphine for postoperative analgesia, both groups
1
received 40 mg kg of intravenous dipyrone every 6 hours.38 We
did not include this study, because of inability to obtain the full text
of this article and from the abstract it appeared that dipyrone was
only used as comedication. The effective analgesic dose of dipyrone
for analgesia is not known to the best of our knowledge.
With respect to safety, we were only able to find 2 case reports
relating serious adverse events to the use of dipyrone. The first
described the development of neutropenia and serious infection.30
Unfortunately, neither the nature of the pain nor the dosage,
frequency or length of dipyrone use was mentioned. The second
described an agranulocytosis after use of oral dipyrone (750 mg 4
times a day for 3 weeks), as postoperative pain therapy for a patho-
logic femur fracture; however, this patient also used diclofenac,
which may also have caused the agranulocytosis.29
Agranulocytosis is the reason why dipyrone is not available in
some countries, but the question remains whether this fear for the
use of dipyrone is justified.39 Although the time of onset of agranu-
locytosis can be within 2 days after starting dipyrone, the risk seems
to increase with duration of use and disappears 10 days after the
last dose. Recently, reports of fatal drug-related agranulocytosis
cases (not necessarily related to dipyrone) have decreased which
may be due to swift discontinuation of the drug and the administra-
tion of broad-spectrum antibiotics and granulocyte-colony-stimulat-
ing factor.40 In two-thirds of the cases, agranulocytosis was caused
by a limited number of drugs, eg, salicylates, indomethacin, diclofe-
nac, and pyrazolones including dipyrone.9,39,41
A recent study, which especially focused on the probability of
serious ADRs in children, identified the problem of sufficient sample
sizes and follow-up needed to detect agranulocytosis.28 This same
problem was noted in the Cochrane review on the efficacy and
adverse events of a single dose of dipyrone for acute postoperative
pain in adults, in which no serious adverse events were shown.6
Although agranulocytosis is a serious condition, it should be
6 | DE LEEUW ET AL.

TABLE 3 Overview of included studies

Sample
Year Author Ref nr Type Setting Type of surgery/intervention size Age Dose

1986 Morena 25 RCT Respiratory disease – 50 1-12 y 25 mg/kg/day

Mart
ınez
1990 Sch€arli 26 RCT Postoperative pain Inguinal herniorrhaphy 50 4-12 y 300 mg, minimum
interval 6 h

1997 Cuevas 27 RCT Immediate postoperative Ophthalmic surgery 60 Average of 7.4 y 10 mg/kg

1999 Izhar 31 OS Oral temperature 38.5 or more 9 3 mo-12 y 10-15 mk/kg/dose

and/or complaining of pain due 6 to 8 hourly
to various reasons
1999 Lauretti 29 RCT Preemptive analgesia Inguinal herniorrhaphy 24 0-10 y 10 mg/kg

2002 Bonkowsky 33 CR Pain 1 4y

2003 Pe~
nuelas- 28 RCT Preventive analgesia Different surgical procedures 120 3-6 y 20 mg/kg
Acu~
na

2010 Altinel 34 CR Postoperative pain Transumbilical LESS bilateral 1 14 y 1 gram

nephrectomy

2010 Smiljanic 30 OS Orthopedic surgical patients 30 0.1 mL/kg

2011 Pfersdorff 13 CR Analgetic therapy Pathologic fracture of the neck 1 17 y 750 mg

of the femur

2012 van den 35 CR Spondylodiscitis 1 19 mo 250 mg once

Heuvel
2013 Howell 32 OS Post-op at NICU Laparotomy, craniotomy and 70 1dag-3mnd 40 mg/kg per day
ductus ligation

2013 Caliskan 22 RCT Early postoperative period Elective lower abdominal surgery 60 8-15 y 15 mg/kg
under spinal anesthesia

2013 Kocum 23 RCT Day case Tonsillectomy  adenoidectomy 120 3-6 y 15 mg/kg

2013 Maranh~ao 36 CR Postoperative analgesia Resection of posterior 1 1 y and 5 mo 30 mg/kg

mediastinal tumor
2014 Knorr 37 CR Analgesia in vaso-occlusive crisis 1 6y
with sickle cell disease
2015 Sener 24 RCT Postoperative pain Tonsillectomy  adenoidectomy 120 Loading dose:
4.5 mg/kg, followed
by 0.5 mg/kg/u
and 1 mg/kg bolus
with lock out 30 min
2015 Prottengeier 38 CR Postoperative analgesia Tonsillectomy 1 6y 15 mg/kg
2015 Fieler 12 OS Prevention or treatment of Different surgical procedures 1145 Up to 6 y 17.3  2.9 mg/kg
postoperative pain

CR, Case Report; OS, Observational Study; RCT, Randomized Controlled Trial; Iv, Intravenous; Im, Intramuscular.
DE LEEUW ET AL. | 7

Route of
Duration administration Pain Score Primary outcome measures Outcome Adverse events

3 times a Oral Unknown Analgesic and antipyretic Naproxen + paracetamol attains a higher efficacy No undesirable side
day for 5 d efficacy in analgesic and antipyretic effects effects
Maximum Suppository Four-point scale (0, Pharmacokinetic No statistically significant differences between Nausea (one in each
of 6 d absent; 3 severe) investigation and RCT with the analgesic activities of the two treatment group)
Dipyrone as reference drug groups.
Once iv VAS Pain immediate VAS 0-30 K:70% D: 40%—VAS 30-80 K:30% D: None
postoperative 60%
3d Pain on a scale of 0- Clinical Success Rate 100% for pain Vomiting: 4.3%
10

Once before iv VAS Time for first administering Time to first rescue: CG = DG < KG < KDG/ None
tracheal analgesic and number of Consumption: CG > DG = KG = DKG
intubation rescue analgesics in 24 h
Neutropenia or
leukopenia and
serious infection
Once prior iv Observator: Oucher- 40% no pain, 55% minimal-moderate pain in both None
tos surgery scale/3-4 y: groups
McGrath/5-6 y:
VAS
Single dose im

iv VAS and The Faces Evaluate analgesic effects of Sign.larger analgesic effect by metamizol
Pain Scale acetaminophen and
metamizol and then
comparing those analgesic
effects
4 times a Oral Agranulocytosis
day, for
3 wks

11 d? Oral

3 d or until NIPS (neonatal Identify side effects when NIPS reduced None showed negative
pain score infant pain score) using metamizol in side effects
was postoperative pain
negative management

Once ? iv VAS Pain at rest Postoperative pain scores significantly lower in

the active groups in the first and second
postoperative hour
Once iv Pain intensity: Cumulative pethidine Cumulative pethidine requirement sign.less in No sign.adverse events
CHEOPS/Pain requirement paracetamol and dipyrone vs placebo
relief: 5 point
verbal scale

iv

iv VAS and pain relief IV-PCA with paracetamol is VAS sign lower with paracetamol compared to No sign differ among
score superior and an acceptable placebo and dipyrone compared with placebo groups
alternative for dipyrone by
IV-PCA

Single dose iv Children and Infants Serious adverse drug Probability of serious ADRs is extremely low Pruritus, swelling, and
Postoperative Pain reactions exanthema
Scale (ChIPPS)
8 | DE LEEUW ET AL.

T A B L E 4 Jadad Scores (for assessing

Study reference
methodological quality of the studies)
~ uelas-
Pen Morena
Caliskan Kocum Sener Sch€arli Acun~a Lauretti Cuevas Mart
ınez
Item no.
1 1 1 1 1 1 1 0 1
2 1 1 1 1 0 1 0 1
3 1 0 1 0 0 0 0 0
4 1 1 1 0 0 0 0 0
5 1 1 1 0 0 0 0 0
6 0 0 0 1 1 1 0 1
7 0 0 0 0 0 0 0 0
Total 5 4 5 1 0 1 0 1

Score interpretation: 0-2 poor/3-4 good/5+ excellent.

Item no.:
1. Was the study described as randomized (this includes the use of words such as randomly, ran-
dom, and randomization)?
2. Was the study described as double blind?
3. Was there a description of withdrawals and dropouts?
4-7: Either give a score of 1 point for each “yes” or 0 points for each “no”. There are no in-
between marks.
Give 1 additional point if: For question 1, the method to generate the sequence of randomization
was described And it was appropriate (table of random numbers, computer generated, etc.) and/
or: If for question 2, the method of double blinding was described and it was appropriate (identi-
cal placebo, active placebo, dummy, etc.). Deduct 1 point if: For question 1, the method to gener-
ate the sequence of randomization was described and it was inappropriate (patients were
allocated alternately, or according to date of birth, hospital number, etc.) and/or: For question 2,
the study was described as double blind but the method of blinding was inappropriate (eg, com-
parison of tablet vs injection with no double dummy).

considered in comparison with other potentially life-threatening ACKNOWLEDGMENTS

adverse effects of analgesics. A study in adults, in which the serious
The authors want to thank Ir. G.B. de Jonge (Biomedical Information
adverse effects following short-term treatment with aspirin, diclofe-
Specialist) for her assistance with the literature search.
nac, acetaminophen, and dipyrone were investigated, showed that
the estimated excess risk of mortality due to agranulocytosis, aplastic
anemia, anaphylaxis, and serious upper gastrointestinal complications KEY LEARNING POINTS
associated with dipyrone and acetaminophen were similar and sub- • Current literature showed no analgesic benefits of dipyrone in com-
stantially lower than the risk associated with aspirin and diclofe- parison to paracetamol or Non-Steroid-Anti-Inflammatory Drugs.
nac.41 Unfortunately, this has not been investigated in children. To • Indications fort the use of dipyrone are not well defined.
adequately study the incidence of (fatal) agranulocytosis, large epi- • Further well designed research is necessary to identify the indica-
demiological studies are needed. tions for the use of dipyrone in pediatric pain treatment.
In conclusion, using the limited available data, analgesic efficacy
1 17,18 1
of iv dipyrone 15 mg kg or a loading dose of 4.5 mg kg ,
1 1 1 CONFLICT OF INTEREST
followed by 0.5 mg kg h infusion and 1 mg kg boluses with a
lockout time of 30 minutes19, appears similar to that of iv paraceta- The authors report no conflicts of interests.
mol in similar doses. Evidence is lacking to support the claim that
dipyrone is equivalent or even superior to NSAIDs in pediatric pain.
ORCID
While the absolute risk of dipyrone-induced agranulocytosis in chil-
dren, based on the current literature, cannot be determined, case Thomas G. de Leeuw http://orcid.org/0000-0001-9516-3088
reports suggest that this risk is low but not negligible. In view of the
lack of evidence to support the claim that dipyrone is superior to
paracetamol or NSAIDs, the use of dipyrone for pediatric analgesia REFERENCES
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How to cite this article: de Leeuw TG, Dirckx M, Gonzalez
Candel A, Scoones GP, Huygen FJPM, de Wildt SN. The use
of dipyrone (metamizol) as an analgesic in children: What is
the evidence? A review. Pediatr Anesth. 2017;00:1–9.
https://doi.org/10.1111/pan.13257