[e-drug] Can Paracetamol cause asthma/allergy?

E-DRUG: Can Paracetamol cause asthma/allergy?
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On 2 October 2008 a report has been published in a leading State Newspaper(Rajasthan Patrika) on paracetamol causing asthma and/or allergic reactions. The report without quoting source has claimed this on a study said to have been conducted on about 200,000 children in 31 countries(Iran, Canada, News land, Nigeria, Belgium, Thailand, Portugal, Panama, Barbados, Lithuania, Columbia, Estonia, Brazil, Mexico, Chile, Hungary, Spain, Taiwan, India, etc.). This has caused panic reaction in the medical community is what to prescribe in fever.

Have you come across such findings? Is there any substantial evidence for this alert? I need an urgent answer to this so as to dispel confusion in the prescribing community.

With my best regards

Dr NK Gurbani,
Member Secretary, Rajasthan State Essential Medicines Committee
and Professor & Head of the Pharmacy Department
Public Health Training Institute,
JAIPUR 302 002, Rajasthan (India)
Tel. (O): +91 141 2575705
     (R): +91 141 2634225
     (M): +91 94145 22696

E-DRUG: Can Paracetamol cause asthma/allergy? (2)
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This is based on the following study:

Beasley R, Clayton T, Crane J, von Mutius E, Lai CK, Montefort S,
Stewart A; ISAAC Phase Three Study Group.

Association between paracetamol use in infancy and childhood, and
risk of asthma, rhinoconjunctivitis, and eczema in children aged 6-7
years: analysis from Phase Three of the ISAAC programme. Lancet
2008 Sep 20;372(9643):1039-48.

Collaborators (96)
A<t-Khaled N, Anderson HR, Asher MI, Bj"rkst,n B, Brunekreef B,
Crane J, Ellwood P, Garc¡a-Marcos L, Foliaki S, Keil U, Lai CK,
Mallol J, Robertson CF, Mitchell EA, Odhiambo J, Pearce N, Shah J,
Stewart AW, Strachan D, Weiland SK, Weinmayr G, Williams H,
Wong G, Asher MI, Clayton TO, Ellwood P, Mitchell EA, Howitt ME,
Weyler J, de Freitas Souza L, Rennie D, Amarales L, Aguilar P,
Cepeda AM, Aristiz bal G, Ordo¤ez GA, Riikj,rv MA, Zsigmond G,
Rego S, Suresh Babu PS, Singh V, Jain KC, Sukumaran TU,
Awasthi S, Joshi MK, Pherwani AV, Mantri SN, Salvi S, Sharma SK,
Hanumante NM, Bhave S, Kartasasmita CB, Masjedi MR, Steriu A,
Odajima H, Imanalieva C, Kudzyte J, Teh KH, Quah BS,
Del-R¡o-Navarro BE, Barrag n-Meijueiro M, Garc¡a-Almaraz R,
Baeza-Bacab M, Merida-Palacio JV, Gonz lez-D¡az SN,
Linares-Zapi,n FJ, Romero-Tapia S, Asher MI, Moyes C, Pattemore
P, MacKay R, Onadeko BO, Cukier G, Lis G, Br&#710;borowicz A, C&#402;mara
R, Rosado Pinto JE, Nunes C, Lopes dos Santos JM, Goh DY, Lee
HB, L¢pez-Silvarrey Varela A, Carvajal-Urue¤a I, Busquets RM,
Gonz lez D¡az C, Garc¡a-Marcos L, Garcia-Hern ndez G,
Su rez-Varela MM, Al-Rawas O, Mohammad Y, Huang JL, Kao CC,
Vichyanond P, Trakultivakorn M, Lapides MC, Aldrey O.

Medical Research Institute of New Zealand, Wellington, New
Zealand.

Abstract
BACKGROUND: Exposure to paracetamol during intrauterine life,
childhood, and adult life may increase the risk of developing asthma.
We studied 6-7-year-old children from Phase Three of the
International Study of Asthma and Allergies in Childhood (ISAAC)
programme to investigate the association between paracetamol
consumption and asthma.
METHODS: As part of Phase Three of ISAAC, parents or guardians
of children aged 6-7 years completed written questionnaires about
symptoms of asthma, rhinoconjunctivitis, and eczema, and several
risk factors, including the use of paracetamol for fever in the child's
first year of life and the frequency of paracetamol use in the past 12
months. The primary outcome variable was the odds ratio (OR) of
asthma symptoms in these children associated with the use of
paracetamol for fever in the first year of life, as calculated by logistic
regression.
FINDINGS: 205 487 children aged 6-7 years from 73 centres in 31
countries were included in the analysis. In the multivariate analyses,
use of paracetamol for fever in the first year of life was associated
with an increased risk of asthma symptoms when aged 6-7 years
(OR 1.46 [95% CI 1.36-1.56]). Current use of paracetamol was
associated with a dose-dependent increased risk of asthma
symptoms (1.61 [1.46-1.77] and 3.23 [2.91-3.60] for medium and
high use vs no use, respectively). Use of paracetamol was similarly
associated with the risk of severe asthma symptoms, with
population-attributable risks between 22% and 38%. Paracetamol
use, both in the first year of life and in children aged 6-7 years, was
also associated with an increased risk of symptoms of
rhinoconjunctivitis and eczema.
INTERPRETATION: Use of paracetamol in the first year of life and in
later childhood, is associated with risk of asthma, rhinoconjunctivitis,
and eczema at age 6 to 7 years. We suggest that exposure to
paracetamol might be a risk factor for the development of asthma in
childhood.

This is the accompanying comment [copied as fair use]:

Barr RG. Does paracetamol cause asthma in children? Time to
remove the guesswork

Paracetamol (or acetaminophen) was first synthesised in 1878 (1)
and has been in widespread use since its introduction in the
mid-1950s. 580 million tablets were sold in the UK in 2001-02.(2) In
today's Lancet, Richard Beasley and colleagues (from the ISAAC
Phase Three study) show that most children in samples in Africa, the
eastern Mediterranean, the Indian subcontinent, the Americas,
Europe, and New Zealand were given paracetamol in their first year
of life.(3) Despite this widespread use, a large randomised trial to
test the long-term safety of paracetamol in children has not been
done.

ISAAC Phase Three reveals an association of moderate magnitude
(odds ratio 1ú5, 95% CI 1ú4-1ú6) of reported use of paracetamol in the
first year of life with current wheeze at age 6-7 years in a very large
sample of children from 31 countries. Similar supportive results were
found for symptoms of rhinoconjunctivitis and eczema (1ú5, 1ú4-1ú6;
and 1ú3, 1ú2-1ú4, respectively). The study has many strengths,
including its large size, use of standardised measures and methods,
and generally consistent results across multiple sites and countries
with widely varying prevalences not only of paracetamol use (9-91%)
but also of current wheeze (2ú4-23ú7%), and competing risk-factors
for asthma.

However, I think the ISAAC Phase Three investigators would agree
that a cross-sectional survey with a retrospectively ascertained
primary exposure is not a design on which we prefer to make
therapeutic decisions. Recall bias (parents of children with asthma
might better remember giving paracetamol in the first year of life) and
reporting bias (parents more attuned to their children's maladies
might be more likely to give paracetamol and report the current
wheeze) could account for the findings. Furthermore, although many
important potential confounders were included in multivariate
analyses, confounding by underlying respiratory disease, differences
in hygiene, and use of other antipyretics might also explain the
findings.

In particular, neither aspirin use nor use of other non-steroidal
anti-inflammatory drugs (NSAIDs) were reported. Although aspirin
use was probably rare, other NSAIDs (eg, ibuprofen) are more widely
used in children. Aspirin causes asthma exacerbations in a few
patients with asthma;(4) however, effects of NSAIDs on
cyclo-oxygenase and lipoxygenase pathways are highly variable
between individuals (probably related to genotype(5), (6) and (7) and
NSAIDs cause bronchodilation in some individuals.(8) In a cohort of
adult women in which frequency of paracetamol use predicted a new
diagnosis of asthma by the doctor, frequency of aspirin use was
associated with a lower risk of asthma.(9) This finding is consistent
with Varner's hypothesis that aspirin may protect against the
development of asthma,(10) and has subsequently been confirmed
in post-hoc analyses of large randomised trials of aspirin in men and
women.(11) and (12) Although these findings for adult-onset asthma
may or may not apply to children, they agree with the post-hoc
analysis of the 4-week randomised trial of ibuprofen versus
paracetamol for paediatric febrile illness,(13) which showed that
outpatient visits for asthma were greater in the paracetamol group
than the ibuprofen group.(14) Hence it remains unclear whether, on
average, paracetamol might increase or NSAIDs might decrease
asthma and asthma symptoms.

The report from ISAAC Phase Three is the largest and most
important contribution to date on the growing literature, summarised
well by Beasley and colleagues, on paracetamol use and childhood
asthma. It ends, appropriately, with a question rather than a
conclusion and that question is about causality. The authors, and I,
can offer informed opinion - or educated guesses - on the causal
effects of paracetamol on incident childhood asthma. The studies to
date are suggestive but not definitive enough to recommend a
wholesale change in antipyretic use in children. Paracetamol has
known benefits for paediatric febrile illness as well as known
toxicities. The drug might contribute to asthma incidence and it might
be prudent to minimise casual use of this-and all-drugs in otherwise
healthy children. However, we need to take the guess-work out of
recommending and prescribing antipyretic drugs for children. I agree
with Beasley that a population-based randomised trial of adequate
power and duration to examine childhood asthma incidence, with
paracetamol compared with an active control such as ibuprofen and
placebo, is warranted. In view of the heterogeneous nature of
asthma, the pharmacogenetics of such a study is likely to be
fascinating.

I have been a Generalist Physician Faculty Scholar, funded by the
Robert Wood Johnson Foundation, on a project about
acetaminophen, inflammation, and asthma.

References
1 NM Morse, Ueber eine neue Darstellungsmethode der
Acetylamidophenole, Berichte deutsch chemischen Gesellschaft 11
(1878), pp. 232-233.
2 K Hawton, S Simkin and J Deeks et al., UK legislation on analgesic
packs: before and after study of long term effect on poisonings, BMJ
329 (2004), p. 1076.
3 R Beasley, T Clayton, J Crane et al. and for the ISAAC Phase
Three Study Group, Association between paracetamol use in infancy
and childhood, and risk of asthma, rhinoconjunctivitis, and eczema in
children aged 6-7 years: analysis from Phase Three of the ISAAC
programme, Lancet 372 (2008), pp. 1039-1049.
4 C Jenkins, J Costello and L Hodge, Systematic review of
prevalence of aspirin induced asthma and its implications for clinical
practice, BMJ 328 (2004), p. 434.
5 JS Park, HS Chang and CS Park et al., Association analysis of
cysteinyl-leukotriene receptor 2 (CYSLTR2) polymorphisms with
aspirin intolerance in asthmatics, Pharmacogenet Genomics 15
(2005), pp. 483-492.
6 SH Kim, JH Choi and HS Park et al., Association of thromboxane
A2 receptor gene polymorphism with the phenotype of acetyl salicylic
acid-intolerant asthma, Clin Exp Allergy 35 (2005), pp. 585-590.
7 N Jinnai, T Sakagami and T Sekigawa et al., Polymorphisms in the
prostaglandin E2 receptor subtype 2 gene confer susceptibility to
aspirin-intolerant asthma: a candidate gene approach, Hum Mol
Genet 13 (2004), pp. 3203-3217.
8 D Kordansky, NF Adkinson Jr, PS Norman and RR Rosenthal,
Asthma improved by nonsteroidal anti-inflammatory drugs, Ann
Intern Med 88 (1978), pp. 508-511.
9 RG Barr, CC Wentowski and GC Curhan et al., Prospective study
of acetaminophen use and risk of newly diagnosed asthma among
women, Am J Respir Crit Care Med 169 (2004), pp. 836-841.
10 AE Varner, WW Busse and RFJ Lemanske, Hypothesis:
decreasing use of pediatric aspirin has contributed to the increasing
prevalence of childhood asthma, Ann Allergy Asthma Immunol 81
(1998), pp. 347-351.
11 RG Barr, T Kurth, MJ Stampfer, JE Buring, CH Hennekens and
JM Gaziano, Low dose aspirin and decreased adult-onset asthma:
randomized comparisons from the Physicians' Health Study, Am J
Respir Crit Care Med 175 (2007), pp. 120-125.
12 T Kurth, RG Barr, JM Gaziano and JE Buring, Randomized
aspirin assignment and risk of adult-onset asthma in the Women's
Health Study, Thorax 63 (2008), pp. 514-518.
13 SM Lesko and AA Mitchell, The safety of acetaminophen and
ibuprofen among children younger than two years old, Pediatrics 104
(1999), p. e39.
14 SM Lesko, C Louik, RM Vezina and AA Mitchell, Asthma morbidity
after the short-term use of ibuprofen in children, Pediatrics 109
(2002), p. e20.

So do not panic but as with all medication use, not least in children,
make sure there is an indication for use.

Ms Kirsten Myhr
Head
RELIS Drug Info & Pharmacovigilance Centre
Ulleval University Hospital
OSLO, Norway
kirsten.myhr@relis.ulleval.no

E-DRUG: Can Paracetamol cause asthma/allergy? (3)
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It is interesting how the media create serious doubt in just one study.
After reading Dr. Gurbani question I found an article appearing in the
Lancet, 2008, 372: 1039 - 1048 in which Prof Dr. Richard Beasley of the
Medical Research Institute of New Zealand had written about the results of
the ISAAC Phase 3 study. The methametical analysis, "have established an
association not a cause.." of paracetamol use in the first year of life to
the development of asthma at the age of 6 - 7 yrs. This Lancet article was
quoted Health Editor of The Independant, Mr. Jeremy Laurence in their
publication dated Sept 19th, 2008. In the newspaper article one Prof. Dr.
Glenis Scadding an ENT consultant, added that this study needs to furter
looked into since it is quite possible that this association might have been
due to "recurrent viral cold" What in pharmacoepidemiology might be
considered as confounder. There is yet another publication from the BBC
which came out just after the newspaper article. I hope this will help you
find out the truth of the matter. In fact all these publications highlight
the need of using paracetamol for the right indication, a temp of 38.5 and
above.

Qasim Ahmed Al Riyami
Assistant Dean for Training
College of Pharmacy & Nursing
University of Nizwa
P.O.Box 33 PC 616
Birket Al Mouz, Nizwa
Oman
tel: + 968 2544 6442 (Off)
fax: + 968 2544 6246 (Off)
email: karafuu@gmail.com & qasim@gmail.com