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\begin{document}

\title{The use of Dipyrone in Pre-emptive and Postoperative Analgesia in
Tonsillectomy in Children: A Systematic Review}



\author[1]{Maira Isis Stangler}%
\author[2]{João Pedro Lubianca}%
\author[2]{Jaqueline Lubianca}%
\author[3]{José   Lubianca Neto}%
\affil[1]{Universidade Federal de Ciências da Saúde de Porto Alegre}%
\affil[2]{Federal University of Rio Grande do Sul}%
\affil[3]{Santa Casa de Misericordia de Porto Alegre}%


\vspace{-1em}



  
  \date{May 15, 2024}


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\selectlanguage{english}
\begin{abstract}
Tonsillectomy is the most common surgery in children. Post-tonsillectomy
pain is universal and associated with considerable morbidity. Dipyrone
is banned in some countries and the analgesic most commonly used in
others. Evidence of the effectiveness of dipyrone in postoperative
analgesia of tonsillectomy are scarce. Serious adverse effects such as
agranulocytosis and anaphylaxis are rare and their incidence varies in
different populations.%
\end{abstract}%



\sloppy


\textbf{The use of Dipyrone in Pre-emptive and Postoperative Analgesia
in Tonsillectomy in Children: A Systematic Review}

\textbf{Introduction:}

Acute postoperative pain is the pain present in surgical patients
following the procedure\textsuperscript{1}. Pre-emptive analgesia
describes the attempt to control pain in the pre-incisional period. It
aims to prevent central hyperexcitability, which tends to amplify in the
postoperative period\textsuperscript{2}. A recent review of systematic
reviews concluded that evidence for the efficacy of various drugs and
strategies for managing postoperative pain in children is still
inconclusive\textsuperscript{3}. Dipyrone, however, was not evaluated in
this review.

Dipyrone is effective in postoperative pain in children. There are 8
clinical trials that have used it alone or in combination with other
medications\textsuperscript{4-11}. It is one of the most widely-used
analgesics in the postoperative period in several
European\textsuperscript{12-13}, African\textsuperscript{14} and Latin
American countries\textsuperscript{15}. However, there is concern about
its potential for associated anaphylaxis and
agranulocytosis\textsuperscript{16}. Its use is banned in more than 20
countries.

The real incidence of these adverse effects, however, is low. In a
multicentre study involving more than 1,177 children treated with
dipyrone in the postoperative period, the incidence of serious adverse
effects was less than 0.3\%, with no case of
agranulocytosis\textsuperscript{17}. Two studies, one involving several
European countries (Germany, Italy and Spain)\textsuperscript{18} and
another only in the city of Berlin\textsuperscript{19}, estimated an
incidence of agranulocytosis of 1.1 per million inhabitants/year and
0.96 cases per million inhabitants/year, respectively. In the city of
Barcelona, the estimate was 0.56 cases per million
inhabitants/year\textsuperscript{20}. The risk of severe complications
and the availability of alternatives continue to contraindicate its use
in the opinion of some\textsuperscript{21}. Despite the ban in several
countries, dipyrone is the most widely used painkiller in the
postoperative period for children in Brazil, perhaps due to its low cost
and the lack of an injectable form of paracetamol, at least until April
2020\textsuperscript{22}. In terms of oral analgesic medication, in
contrast with the preference for paracetamol in different regions of the
world\textsuperscript{23}, in our country it is the most widely-used
self-medication, as it is sold as an over-the-counter
medicine\textsuperscript{24}.

Dipyrone has been used for decades in children in the postoperative
period of tonsillectomy. This surgery is the 2nd most common outpatient
procedure in the USA\textsuperscript{25,26}. Its main complication is
pain that can lead to a reduction in oral intake, dehydration and weight
loss\textsuperscript{27}. The latest North-American Clinical Practice
Guideline on Tonsillectomy contains 2 strong recommendations about
analgesia: 1. to use analgesics in the post-operative period and 2. the
contraindication in the use of opioids, especially in children under
12\textsuperscript{27}. This latter recommendation is based on the FDA's
warning of the risk of respiratory depression and death using
codeine\textsuperscript{28}. In context of tonsillectomy, intravenous
dipyrone could represent an alternative to opioids, where odynophagia
with consequent difficulty in swallowing is almost universal.

The aim of this study was to review the analgesic use of dipyrone in the
postoperative period of tonsillectomy in children.

\textbf{Materials \& Methods:}

This study is a systematic review of the literature, which involved the
work of two researchers independently evaluating the quality of each
article. The formulation of the research question was based on the PICO
strategy\textsuperscript{29}. The following questions guided the
bibliographic search: Is the action of dipyrone indicated for
pre-emptive or postoperative analgesia in tonsillectomy in children? Are
there any positive or negative influences? The search was carried out in
the databases MEDLINE / PubMed, EMBASE and Virtual Health Library (VHL /
Lilacs), using separate and combined terms, with the Boolean operator OR
and, using the following subject descriptors in health sciences from
BIREME (DeCS): dipyrone OR metamizole AND postoperative pain; dipyrone
OR metamizole AND postoperative pain AND children, dipyrone OR
metamizole AND tonsillectomy, dipyrone OR metamizole AND tonsillectomy
AND children, dipyrone AND metamizole AND pre-emptive analgesia,
dipyrone OR metamizole AND pre-emptive analgesia AND children.
Additionally, the references of the selected articles were reviewed in
the search for other relevant publications. The selection of articles
was carried out in the months of June / 20 and July / 2020.

The inclusion criteria were as follows: studies that addressed the
treatment of pain with dipyrone in a pre-emptive way or after the end of
surgery in children. This was then refined for studies with a randomised
clinical trial design and that dealt exclusively with tonsillectomies,
with dipyrone alone or in combination with another drug in one of the
comparison groups. There was no time limit for publications, and we
included all articles available in full in Portuguese, English, Spanish
and German. As exclusion criteria, the following were adopted:
publications corresponding to theses, dissertations, abstracts of
congresses and annals and all articles that exclusively included
evaluation of chronic pain and studies in adults.

The studies were classified according to the level of evidence,
following the Oxford Centre for Evidence Based Medicine
recommendations\textsuperscript{30}. The studies were also described
according to the GRADE\textsuperscript{31} classification, which takes
into account the quality of the evidence (high or level A, moderate or
level B, low or level C and very low or level D) and the degree of
recommendation (strong or weak). Finally, the two included studies were
classified according to the Jadad\textsuperscript{32} scores, which
assess the methodological quality of the study using specific criteria:
poor (scores 0-2), good (3-4) or excellent (score 5 or more). The PRISMA
strategy (Preferred Reporting Items for Systematic Reviews and
Meta-Analysis)\textsuperscript{33} was used in this review in order to
qualify the work when performing a critical analysis of the selected
studies. Figure 1 shows the flowchart of identification, selection and
inclusion of studies based on the PRISMA recommendation.

\textbf{(Figure 1:} PRISMA flowchart\textbf{)}

\textbf{Results:}

The maximum number of 1151 articles were selected using the descriptors
``dipyrone or metamizol and postoperative pain''. The number of articles
found in EMBASE was 1,151, in PUBMED 336 and in VHL 345. When the
descriptor ``children'' was introduced to the previous search, the
corresponding numbers were 120, 49 and 42. When adding ``randomised
clinical trial'', the corresponding numbers were 31, 13 and 19. It was
decided not to use the last search and the abstract, and the materials
and methods of each article obtained from the search with the
descriptors ``dipyrone or metamizole and postoperative pain and
children'' were manually reviewed. Nine randomised clinical trials were
identified evaluating the postoperative analgesic effect of dipyrone in
isolation or associated with one of the groups. When only studies
dealing with tonsillectomy were selected, 3 remained and it was seen
that there was a duplicate of one. The final search result was 2
randomised clinical trials that evaluated the effect of dipyrone against
placebo, one in pre-emptive and the other in the postoperative
analgesia, in children undergoing tonsillectomy, with or without
adenoidectomy or placement of ventilation tubes.

Tables 1, 2 and 3 show information on the 2 articles included. Table 1
shows the study identification, investigational model, follow-up time,
inclusion criteria, age, sex and the sample size.

\textbf{(Table 1:} Characteristics of selected articles.\textbf{)}

The studies had short follow-up times (maximum 24 hours). While the
first study involved only older children, the second study included
children from 3 years old. While in the first study, only cases of
isolated tonsillectomy were evaluated, in study 2, tonsillectomy either
with or without associated adenoidectomy and / or placement of
ventilation tubes was allowed.

Table 2 shows the description of the data referring to the intervention
groups (random number and number who completed the study in each group),
type of analgesia and form of administration of dipyrone. Both studies
had a 100\% completion rate for the randomised sample. While in the
first study analgesia was post-operative, in the 2nd it was applied
pre-emptively, thus, making it difficult to directly compare the two
studies. The first study brought an innovation to the paediatric surgery
postoperative period, in the use of PCA (patient-controlled analgesia).

\textbf{(Table 2:} Description of the intervention groups, type of
analgesia and form of administration of dipyrone.\textbf{)}

Table 3 describes the strengths and weaknesses of each study, the
primary and secondary outcomes, the results, the level of evidence
according to Oxford criteria, the levels of evidence and degrees of
recommendation according to the GRADE classification and the Jadad
scores.

\textbf{(Table 3:} Strengths and weaknesses, primary and secondary
outcomes, main results and Oxford, GRADE and Jadad classifications of
studies.\textbf{)}

It is evident that both studies demonstrated care in their
methodological approach. For this reason, the Jadad classification for
the first paper was excellent (score = 5) and the second was classed as
good (score = 4). The study by Kocum et al. lost a point for not
explicitly describing withdrawals and losses. The other classifications
were equal for both studies. Regarding the analgesic results measured by
validated pain scales in childhood, dipyrone and paracetamol were
superior to placebo and similar to each other in many measured
intervals. The same was observed for the use of rescue pethidine, and
this did not differ between active comparison groups.

\textbf{Discussion:}

\textbf{1) Effectiveness of miscellaneous analgesics with emphasis on
dipyrone in the post-operative period of tonsillectomy in children:}

Dipyrone has an efficacy, measured by the number of patients needed to
treat to achieve a 50\% reduction in postoperative pain in 4 to 6 hours,
that is lower than potassium diclofenac and etoricoxib, but greater than
several NSAIDs (paracetamol, naproxen, ibuprofen, celecoxib, aspirin and
sodium diclofenac). Unfortunately, all these estimates are for adults,
and there are no similar studies in children\textsuperscript{34}. There
is one systematic review specifically evaluating the efficacy of
dipyrone in postoperative pain in children\textsuperscript{35}. Ten
systematic reviews were identified regarding postoperative analgesia in
tonsillectomy performed in children. The first studied the use of
systemic paracetamol, NSAIDs and opioids. However, it did not comment on
dipyrone\textsuperscript{36}. Two analysed the effect of ketamine via
peritonsillar or systemic injection\textsuperscript{37,38}, two studied
the effect of corticosteroids\textsuperscript{39,40}, one focused on the
effect of bupivacaine\textsuperscript{41} and the other on
dexmedetomidine compared to morphine or fentanyl\textsuperscript{42}. A
Cochrane systematic review analysed the form of analgesic prescription
(different analgesics, but never dipyrone), if required or
fixed\textsuperscript{43}. Finally, there was another review that was
restricted to the use of oral rinses and sprays to improve recovery
followed by tonsillectomy\textsuperscript{44}. An overview of all these
systematic reviews was given in the recent work by Boric et al.,
2017\textsuperscript{3}.

As demonstrated in the present review, there are only two randomised
clinical trials that have evaluated the analgesic effect of dipyrone in
the postoperative period of tonsillectomy in
children\textsuperscript{6,7}. Unfortunately, it was not possible to
perform a meta-analysis, as one study included isolated
tonsillectomy\textsuperscript{7} and the other allowed associated
adenoidectomy and / or ventilation tubes\textsuperscript{6}, which can
lead to different levels of pain, due to the greater manipulation of the
patients. In addition, one study evaluated
preemptive\textsuperscript{6}and the other postoperative
analgesia\textsuperscript{7}. Finally, the study of pre-emptive
analgesia gave a single dose of dipyrone or placebo right after
introduction of the anaesthetic\textsuperscript{6}, while the other
study evaluated analgesia initiated in the postoperative period through
the use of PCA\textsuperscript{7}. The limitation is that PCA is not
available in most hospitals and requires the understanding and
collaboration of the patient, thus being ineffective for young children.

Both studies demonstrated adequate methodological care, with sample size
calculations, and with randomisation performed through the website
randomization.com. Moreover, hypotheses were established a priori, with
the use of a placebo with the same characteristics as the active
medication, with adequate blinding of both patients and examiners, and
with effective and validated outcome measures, in addition to a careful
choice of the statistical tests used. Together with another study
dealing with abdominal surgery\textsuperscript{5}, they comprise the 3
clinical trials with the best level of evidence of all studies commented
here, according to the Oxford classification, the GRADE system or the
Jadad scores.

However, the studies have short follow-up times (maximum 24 hours). It
would be preferable to have a longer follow-up time to monitor the
effect of dipyrone, as the pain after tonsillectomy persists for at
least 7 days. Another limitation of the results is that, in addition to
being developed by the same group of researchers and not being able to
be combined for a meta-analysis for the reasons already specified, the
data have never been replicated elsewhere by different researchers,
which can limit the extrapolation of data to populations other than
Turkish patients.

\textbf{2) Agranulocitose:}

Agranulocytosis is defined as an absolute circulating neutrophil count
of less than 500 / \selectlanguage{greek}µ\selectlanguage{english}l\textsuperscript{45}. The most common clinical
course of agranulocytosis is associated with pharyngotonsillitis,
stomatitis and / or pneumonia. The frequency of the disease varies with
age, with only 10\% of cases being reported in children and young
adults, and more than half of the episodes occurring in people over 60
years of age. It is a rare condition and is associated with a fatality
rate of 8 to 10\%. Association rates with drug use vary in the different
studies, but in Brazil, for example, it is around
56\%\textsuperscript{46}.

No randomised clinical trials using dipyrone as a postoperative
analgesic in children have reported the occurrence of agranulocytosis to
date. Studies show that the incidence of agranulocytosis varies between
countries. The LATIN\textsuperscript{46} study was a prospective
case-control study carried out in cities in Brazil, Argentina and
Mexico. The overall incidence rate was estimated at 0.38 per million
inhabitants/year. Methimazole was the only drug significantly associated
with agranulocytosis (p \textless{}0.001), and there was no significant
association with dipyrone. A rare incidence of agranulocytosis
associated with drugs has been reported in a retrospective study in the
city of S\selectlanguage{ngerman}ão Paulo / Brazil (0.44 to 0.82 cases per million inhabitants /
year)\textsuperscript{47} and in the collaborative study of Brazil,
Argentina and Mexico mentioned above, similar to the finding in Thailand
- 0.8:1 million inhabitants/year\textsuperscript{48}. This contrasts
with the higher incidence reported in the United States of America, from
2.4 to 15.4 per million inhabitants / year\textsuperscript{49}, and in
European countries, such as that of the collaborative study in Germany,
Italy, Spain, Hungary, Bulgaria and Sweden, in addition to Israel, which
found 1.1 to 6.2 cases / million / year and a mortality rate of 0.5
cases / million / year. However, this study noted a great regional
variability in the presentation of blood dyscrasias\textsuperscript{50}.
The risk was significantly associated with the use of ticlopidine,
sulphonamides, non-steroidal anti-inflammatory drugs, calcium
dobesilate, antithyroid drugs, spironolactone and dipyrone. There was a
subsequent study, in the city of Barcelona, \selectlanguage{english}\selectlanguage{english}which found an incidence
of agranulocytosis associated with medications in the order of 3.46
cases per million inhabitants / year\textsuperscript{20}. In France, the
corresponding number was 6 cases per million inhabitants /
year\textsuperscript{51}. The specific incidence of agranulocytosis
associated with dipyrone varied from one for every 1,439 prescriptions
in Sweden3\selectlanguage{english}6, to 0.56 cases per million inhabitants / year in
Barcelona\textsuperscript{20}, reaching up to 0.96 cases per million /
year in Berlin\textsuperscript{19}. A cohort of hospitalised patients in
Bogot\selectlanguage{ngerman}á, Colombia, involving 2,743 patients, showed no cases of
agranulocytosis\textsuperscript{52}. In the LATIN
study\textsuperscript{47}, the odds ratio (OR) for drug-associated
agranulocytosis was 2.4 (95\% CI 0.8--6.7). The corresponding figures in
Barcelona were 25.8 (95\% CI 8.8-79.1)\textsuperscript{20}. In a study
published in 2020, the OR for agranulocytosis and drug-induced
neutropenia was 3.03 (95\% CI 2.49 to 3.69). The risk of developing
agranulocytosis and neutropenia after a dipyrone prescription was
1:1,602 (95\% CI 1:1,926 to 1:1,371)\textsuperscript{53}. There are
several possible explanations for the differences found in incidence
between the various studies, ranging from the use of different
methodologies to the genetic heterogeneity of populations, with probable
gene polymorphisms of their own, which have not yet been studied
specifically for dipyrone.

Even though the risk of agranulocytosis with dipyrone is undeniable, its
real incidence in the population is not known, but it is assumed to be
low. For this reason, the German consensus that brought together several
representative entities concluded that dipyrone has a positive
risk-benefit rate compared to other non-opioid analgesics, recommending
its use\textsuperscript{54}.

\textbf{Conclusion:}

Although it appears that dipyrone exhibits a profile suitable for use in
children, more well-designed studies are needed to establish its role in
the postoperative period of tonsillectomy due to the scarcity of
randomised clinical trials evaluating its postoperative analgesic
effect. The argument for the occurrence of agranulocytosis does not seem
strong enough to justify the abandonment of these studies, because its
incidence is very low, mainly in children, at least in Latin America.
Specially in low-income countries, its use is attractive because it has
a low cost and can be used intravenously, an advantageous feature in the
postoperative period of tonsillectomy where odynophagia is universal.

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