National pholcodine consumption and prevalence of IgE-sensitization: a multicentre study.

Abstract

The aim of this study was to test, on a multinational level, the pholcodine (PHO) hypothesis, i.e. that the consumption of PHO-containing cough mixtures could cause higher prevalence of IgE antibodies to PHO, morphine (MOR) and suxamethonium (SUX). As a consequence the risk of anaphylaxis to neuromuscular blocking agents (NMBA) will be increased.
National PHO consumptions were derived from the United Nations International Narcotics Control Board (INCB) database. IgE and IgE antibodies to PHO, MOR, SUX and P-aminophenyl-phosphoryl choline (PAPPC) were measured in sera from atopic individuals, defined by a positive Phadiatop test (>0.35 kU(A)/l), collected in nine countries representing high and low PHO-consuming nations.
There was a significant positive association between PHO consumption and prevalences of IgE-sensitization to PHO and MOR, but not to SUX and PAPPC, as calculated both by exposure group comparisons and linear regression analysis. The Netherlands and the USA, did not have PHO-containing drugs on the markets, although the former had a considerable PHO consumption. Both countries had high figures of IgE-sensitization.
This international prevalence study lends additional support to the PHO hypothesis and, consequently, that continued use of drugs containing this substance should be seriously questioned. The results also indicate that other, yet unknown, substances may lead to IgE-sensitization towards NMBAs.

Full text

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ORIGINAL ARTICLE
EPIDEMIOLOGY AND GENETICS
National pholcodine consumption and prevalence of
IgE-sensitization: a multicentre study
S. G. O. Johansson1, E. Florvaag2,3, H. O¨man4, L. K. Poulsen5, P. M. Mertes6, N. J. N. Harper7,
L. H. Garvey8, R. Gerth van Wijk9, T. Metso10, A. Irgens11, T. Dybendal12, J. Halsey13,
S. L. Seneviratne14& A. B. Guttormsen15
1Department of Clinical Immunology and Transfusion Medicine, Karolinska University Hospital, Stockholm, Sweden;2Laboratory of Clinical
Biochemistry and Section for Clinical Allergology, Department of Occupational Medicine, Haukeland University Hospital, Bergen, Norway;
3Institute of Internal Medicine, University of Bergen, Norway,4MIAB, Uppsala, Sweden;5Allergy Clinic, National University Hospital, Copen-
hagen, Denmark;6Service d’Anesthe ´sie-Re ´animation Chirurgicale, Ho ˆpital Central, Nancy, France;7Department of Anaesthesia, Manchester
Royal Infirmary, Central Manchester and Manchester Children’s University Hospitals Trust, Manchester, UK;8Danish Anaesthesia Allergy
Centre, Rigshospitalet, Copenhagen, Denmark;9Department of Allergology, Erasmus MC, Rotterdam, The Netherlands;10Helsinki University
Central Hospital, Skin and Allergy Hospital, Helsinki, Finland;11Department of Occupational Medicine, Haukeland University Hospital, Bergen,
Norway;12Kongsvinger Hospital Pharmacy, Kongsvinger, Norway,13IBT Laboratories, Lenexa, KS, USA;14Department of Clinical Immunol-
ogy, St. Mary’s Hospital, Imperial College, London, UK;15Department of Anaesthesia and Intensive Care, Haukeland University Hospital and
Section for Anaesthesiology and Intensive Care, Department of Surgical Sciences, University of Bergen, Bergen, Norway
To cite this article: Johansson SGO, Florvaag E, O¨man H, Poulsen LK, Mertes PM, Harper NJN, Garvey LH, Gerth van Wijk R, Metso T, Irgens A, Dybendal T,
Halsey J, Seneviratne SL, Guttormsen AB. National pholcodine consumption and prevalence of IgE-sensitization: a multicentre study. Allergy 2010; 65: 498–502.
Anaphylactic reactions during general anaesthesia are rare
but dramatic events that have been reported with increasing
frequency during the last decades. Neuromuscular blocking
agents (NMBAs) represent the most frequent causes, with
suxamethonium (SUX) as the prominent culprit drug.
In most cases immunoglobulin E (IgE)-mediated mecha-
nisms are involved. Since up to half of the patients have not
been exposed to NMBAs previously, other drugs or environ-
mental chemicals sharing the quaternary ammonium ion
(QAI) epitope, regarded as the major NMBA allergenic
epitope, are suspected of initiating the IgE-sensitization (1)
which is the prerequisite for the anaphylaxis.
The reported frequency of reactions varies considerably
between countries, starting at about one in 200 000 and
reaching one in 5 000 anaesthetics in high prevalence coun-
tries (2). NMBA-related anaphylaxis seems to be about 10
times more common in Norway than in Sweden, a discrep-
ancy that, at least partly, could be explained by different
Keywords
anaphylaxis; cough mixtures; IgE-
sensitization; international prevalence study;
pholcodine.
Correspondence
S. G. O. Johansson, Department of
Medicine, Clinical Immunology and Allergy
Unit, Karolinska University Hospital L2:04,
S-171 76 Stockholm, Sweden.
Accepted for publication 5 August 2009
DOI:10.1111/j.1398-9995.2009.02193.x
Edited by: Marek Kowalski
Abstract
Background: The aim of this study was to test, on a multinational level, the pholco-
dine (PHO) hypothesis, i.e. that the consumption of PHO-containing cough mix-
tures could cause higher prevalence of IgE antibodies to PHO, morphine (MOR)
and suxamethonium (SUX). As a consequence the risk of anaphylaxis to neuromus-
cular blocking agents (NMBA) will be increased.
Methods: National PHO consumptions were derived from the United Nations
International Narcotics Control Board (INCB) database. IgE and IgE antibodies to
PHO, MOR, SUX and P-aminophenyl-phosphoryl choline (PAPPC) were measured
in sera from atopic individuals, defined by a positive Phadiatop?test (>0.35 kUA/
l), collected in nine countries representing high and low PHO-consuming nations.
Results: There was a significant positive association between PHO consumption and
prevalences of IgE-sensitization to PHO and MOR, but not to SUX and PAPPC,
as calculated both by exposure group comparisons and linear regression analysis.
The Netherlands and the USA, did not have PHO-containing drugs on the markets,
although the former had a considerable PHO consumption. Both countries had high
figures of IgE-sensitization.
Conclusion: This international prevalence
the PHO hypothesis and, consequently, that continued use of drugs containing this
substance should be seriously questioned. The results also indicate that other, yet
unknown, substances may lead to IgE-sensitization towards NMBAs.
studylends additional support to
Allergy
498
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exposure and sensitization to PHO in the two populations
(3).
The effect of possible IgE sensitizers, using morphine
(MOR) as recommended for screening for IgE antibodies to
QAI (4), was studied by testing 84 different chemicals
collected from Norwegian and Swedish homes, of which
several inhibited IgE binding to SUX and/or MOR. How-
ever, no difference in exposure to the above chemicals was
found, except for the use of cough mixtures containing
pholcodine (PHO) (3). These have until recently been
purchased over the counter (OTC) in Norway but are not
available in Sweden.
Further, the prevalence of IgE-sensitization to MOR, SUX
and PHO in Norway and Sweden was investigated. In
Bergen, Norway 0.4% of blood donors, 3.7% of atopic
patients and 38.5% of patients with anaphylaxis to NMBAs
were sensitized to SUX, as were 5.0%, 10.0% and 66.7%,
respectively, to MOR. IgE antibodies to SUX or MOR were
undetectable in blood donors and atopics from Stockholm.
Similar figures for IgE antibodies to PHO were found in
Norwegian samples but, again, in none from Sweden (3).
Additionally, in a pilot study, two Norwegian individuals
IgE-sensitized to PHO, MOR and SUX responded, after
taking one single daily dose of PHO for one week, with a
dramatic increase in total serum IgE and IgE antibodies to
SUX, MOR and PHO reaching 60 and 105 times the levels
prior to exposure (5). A similar increase has, so far, only
been seen after bone marrow transplantation (6). In a recent
follow up exposure study, 11 patients previously diagnosed
with IgE-mediated anaphylaxis to NMBAs and IgE-sensitized
to PHO, were given a 20 mg daily dose of PHO for one
week. IgE and IgE antibodies to PHO, MOR and SUX were
raised highly significantly by 3 weeks after cessation of
exposure (7).
To explain the observed differences between Norway and
Sweden the pholcodine hypothesis was proposed (8), accord-
ing to which the consumption of PHO-containing cough
mixtures could be responsible for both the higher prevalences
of IgE antibodies to PHO, MOR and SUX and also for the
higher frequencies of anaphylaxis to NMBAs. The manufac-
turer of the cough medicine subsequently withdrew the drug
from the Norwegian market in March 2007, which already
after 2 years have led to a dramatic decrease in IgE-sensitiza-
tion and successively tending to reduce the frequency of
anaphylaxis to NMBA (unpublished observation). However,
the question whether PHO exposure and IgE-sensitization
could be of relevance for the different prevalences of peri-
anaesthetic anaphylaxis reported from other countries than
Norway and Sweden remains to be answered (8).
The aim of this international multi centre study was to
take a further step in explaining anaphylaxis to NMBA by
investigating the prevalences of serum IgE antibodies to
PHO, MOR and SUX. Atopic individuals, attending allergy
centres and/or allergy laboratories in nine high or low PHO-
consuming nations, were chosen because they are likely to be
high IgE responders. In addition, IgE antibodies to P-amin-
ophenylphosphoryl-choline, (PAPPC), proposed to detect
IgE-sensitization to QAI, were also measured.
Materials and methods
Samples
Serum was collected at the collaborating centres in Stock-
holm (Sweden), Bergen (Norway), Copenhagen (Denmark),
Helsinki (Finland),Nancy
Rotterdam (The Netherlands), Freiburg (Germany) and
Lenexa, KS (USA). The sera, aiming at 200 samples per cen-
tre, were collected at each site either as superfluous volumes
from routine allergy laboratories, or were drawn from
patients referred for allergological examinations at allergy
centres. The anonymized sera were collected during the years
of 2005–2007 and stored at the respective centres at )20?C
until analysed.Inclusioncriteria
volumes of at least 1.0 ml and, for reason of homogeneity, a
positive Phadiatop?test (Phadia AB, Uppsala, Sweden) as
the definition of atopy. The study was approved by the local
Ethical Committees for medical research at each participating
centre.
(France), Manchester(UK),
wereavailable serum
Immunoglobulin analyses
The serum concentrations of IgE (kU/l) were determined by
ImmunoCAP?Total IgE (Phadia AB). Each serum sample
was tested for IgE antibodies to a mix of common inhalant
allergens, Phadiatop?(Phadia AB), and for IgE antibodies
(kUA/l) to pholcodine (c261), morphine (c260), suxamethoni-
um (c202) and PAPPC (Rc777) by ImmunoCAP?Specific
IgE (Phadia AB) according to the manufacturer’s instruc-
tions.
Pholcodine consumption and exposure
Data on the national PHO consumptions summarized for the
years 2001–2005 were taken from the United Nations Inter-
national Narcotics Control Board (INCB) database (http://
www.incb.org).Arbitrarylevels
(>100 kg per million inhabitants) and low (<40 kg) PHO
consumption. In addition, the number of PHO containing
drugs available in 2005 in the individual national markets
was obtained (source: Drugdex). No information is available
on the number of individuals actually exposed to PHO,
neither in the general populations, nor among the individuals
who donated serum samples.
werechosen forhigh
Statistical evaluations
Based on the results from a previous publication (2), the
present study design and the sampling criteria defined above,
the sample size of approximately 200 sera collected at each of
nine centres representing high and low consumption coun-
tries, respectively, would yield a statistical power sufficient to
test the null hypothesis, i.e. no difference in PHO sensitiza-
tion between high and low PHO consumption countries.
nQuery Advisor?5.0; Statistical Solutions Ltd, Cork, Ireland
was used for the power calculations.
Comparison of number of sera containing IgE antibodies
to PHO in the high and low consumption countries included
Johansson et al.
Pholcodine and IgE-sensitization
Allergy 65 (2010) 498–502 ª 2009 John Wiley & Sons A/S
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both a complete dataset analysis (all countries) and a subset
analysis (NL and USA excluded). Direct group comparisons
were done by Pearson chi-square exact method. Further anal-
ysis of the association between PHO consumption in kg per
million inhabitants and percent sensitized sera was performed
with linear regression analysis.
Results
In the participating countries Sweden (SE), Denmark (DK),
United states of America (USA), Germany (GE), The Neth-
erlands (NL), Finland (FI), Norway (NO), United Kingdom
(UK) and France (FR) the 5 year accumulated consumption
of PHO during the period from 2001 to 2007 varied from 0
to 184.9 kg per million of inhabitants (Table 1). In the
countries with high consumption like the UK and FR, as
many as 14 different PHO-containing drugs were available,
many of them in different commercial presentations, e.g.
special preparations for children. The third highest PHO-con-
suming country, NO, had only one cough mixture, but it had
been on the market since 1966 in different formulations, and
an estimated 40% of the population has been exposed.
The percentages of atopic individuals IgE-sensitized to
PHO, MOR and SUX varied from below 1% in low PHO-
consuming countries (DK, FI, GE, SE) to between 2.4% and
7.0% for high consumption countries (FR, NO, UK)
(Table 2). It is highly noteworthy that the samples from USA
and NL did have a surprisingly high prevalence of IgE anti-
bodies to PHO, 2.0% and 4.9%, respectively, but differed
considerably for SUX, 2.5% and 0%, respectively. However,
no PHO-containing drug is available in these countries
according to the respective National Medicines Agencies.
Examining the associations between PHO consumption and
IgE-sensitization, two sets of statistical analyses were there-
fore performed, one including all countries and another all
except NL and USA, respectively.
The countries were categorized according to PHO con-
sumption (Table 1, Fig. 1) in high consumption countries
(FR, NO, UK) and low consumption countries (DK, FI,
GE, NL, SE, USA). Comparing high consuming countries
with all low consuming countries showed a significant differ-
ence in the number of sera with IgE antibodies to PHO
(P < 0.001) and MOR (P < 0.001), but neither to SUX
(P = 0.13) nor to PAPPC (P = 0.52). Comparing high and
low consuming countries after NL and USA were excluded,
showed a significant difference in number of sera IgE positive
to PHO(P < 0.001), MOR
(P = 0.01), but still no difference was seen for PAPPC
(P = 0.63).
Linear regression analysis including all countries demon-
strated a statistically significant association between PHO
consumption and IgE-sensitization to PHO (P = 0.027), but
not to MOR (P = 0.10), SUX (P = 0.11) and PAPP-C
(P = 0.59) as shown in Fig. 2A. Excluding NL and USA,
a statistically significant association between PHO con-
sumption and IgE-sensitization to PHO (P = 0.010), MOR
(P = 0.004) and SUX (P = 0.032), but not to PAPPC
(P = 0.89) was demonstrated (Fig. 2B).
(P < 0.001)andSUX
Discussion
The aim of this multi-centre, international study was to test
the PHO hypothesis (8) originally suggested as an explanation
for thereporteddifferent
reactions to NMBAs in Sweden and Norway (9). In order to
reduce number of serum samples needed atopics were selected
since in Norway they have twice as high prevalence of IgE
antibodies to PHO as healthy individuals (3). The results, at
least partially, support the hypothesis by showing a statisti-
cally significant association between PHO consumption and
prevalence of IgE-sensitization to PHO and MOR, but not to
SUX when all nine countries were included. However, when
NL and USA were excluded from the analysis, the associa-
tions between consumption
stronger and even the association to SUX reached statistical
significance.
The information from NL is confusing since according to
the United Nations International Narcotics Control Board
frequenciesofanaphylactic
andsensitization became
Table 1 Accumulated PHO consumption in the nine participating
countries and number of PHO-containing drugs on the individual
national markets
Country
PHO
consumption
(kg) during
2001–2005
PHO consumption
(kg) per mill.
inhab. during
2001–2005
No. of PHO-
containing
drugs on
the market
Sweden
Denmark
USA
Germany
The Netherlands
Finland
Norway
UK
France
0
0
0
0
0
0
0.5
10.1
37.5
104.4
108.0
184.9
0
0
0
0
0
1
1*
14
14
45
163
195
470
6478
11095
*Sera from Norway were collected before the drug was taken off
the market in March 2007.
Table 2 Number of sera collected from the participating countries
and the respective percentages of sera with IgE antibody levels of
0.35 kUA/l or higher to PHO, MOR, SUX and PAPPC
CountryCity
No of
sera PHO % SUX % MOR % PAPPC %
Sweden
Denmark
USA
Germany
The
Netherlands
Finland
Norway
UK
France
Stockholm
Copenhagen 179
Lenexa
Freiburg
Rotterdam
213 0
0.6
2.0
0
4.9
0
0
2.5
0.5
0
0.5
1.1
5.0
0.9
6.0
0.9
0.6
2.0
2.4
1.6
200
211
184
Helsinki
Bergen
Manchester 209
Nancy
209
199
1.0
7.0
2.4
6.5
0
1.0
0
3.7
1.0
5.5
2.4
7.5
1.4
0.5
0
1.9 214
Pholcodine and IgE-sensitization
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(INCB) (Table 1) there is a considerable consumption of
PHO but according to Dragex there are no PHO-containing
drugs on the market. In the USA there are, to our knowl-
edge, no PHO consumption and PHO containing drugs on
the market, although IgE-sensitization to PHO is prevalent.
This does not fit with the PHO hypothesis and one explana-
tion could be that other, yet unknown, environmental factors
besides PHO may lead to the production of IgE antibodies to
PHO and SUX. The presence of other, so far unknown,
sensitizers is further supported by the discrepancy between
NL and USA regarding IgE antibodies to SUX; none
detected in NL while USA had the next highest prevalence
figure, 2.5%, and deserves further studies.
IgE-sensitization to PAPPC was unrelated to PHO con-
sumption both when all nine countries were included and
when NL and USA were excluded. In fact in both cases the
relationship showed a slight inverse trend (Figs 1 and 2).
Thus PAPPC does not seem to be a preparation useful for
detection of IgE-sensitization to QAI, although it does
contain the QAI determinant.
The relation between PHO consumption and exposure
must be viewed with caution. The data from the INCB
(Table 1) actually represent amounts of PHO officially
purchased by the individual nations as registered during the
A
B
Figure 1 Total number of sera IgE-sensitized to PHO, SUX, MOR
and PAPPC, (A) in all nine countries divided into high (>100 kg
PHO/million inhabitants, i.e. NO, UK and FR) and low (<40 kg PHO/
million inhabitants, i.e. SE, DK, USA, GE, NL and FI) consumption
groups respectively, and (B) after excluding NL and USA where the
low consumption group is represented by DK, FI, GE and SE.
Regression coefficient
R2
PHO0.030 0.527
_ _ _
MOR0.023 0.339
____
SUX0.011 0.011
…..
PAPPC–0.002 0.044
_ . _
PAPPC –0.001 0.004
_ . _
Regression coefficient
R2
PHO0.037 0.767
_ _ _
MOR 0.035 0.843
____
SUX 0.015 0.633
…..
0
1
2
3
4
5
6
7
8
050100 150 200
Consumption kg per million inhab.
Sensitized (%)
PHO
MOR
SUX
PAPPC
0
1
2
3
4
5
6
7
8
050 100150200
PHO
MOR
SUX
PAPPC
Sensitized (%)
Consumption kg per million inhab.
A
B
Figure 2 Linear regression analysis of the associations between
PHO consumption and IgE-sensitization to PHO, MOR, SUX and
PAPPC in all countries (A), and after excluding NL and USA (B).
Johansson et al.
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stated period. Thus they do not necessarily reflect exposure
of the general population. Furthermore, it is not known how
many of the anonymous allergic serum donors had actually
been exposed to PHO. Another study design, for example,
directly comparing PHO exposed vs nonexposed individuals
would allow to assay the association between exposure and
IgE-sensitization more directly than in this study.
Likewise, it can be questioned whether the number of PHO
containing drugs on the respective markets necessarily give
a reliable indication of PHO exposure. In Norway, for exam-
ple, until recently there was only one drug, a cough mixture,
containing PHO, to which the producer from the sales data
carefully estimated that about 40% of the Norwegian popula-
tion had been exposed. This drug was available in several
formulations of which one was sold OTC for adults and
children down to the age of 5 years. Similar exposure estima-
tions for the other participating nations are not available.
PHO is monovalent for two noncross reacting allergenic
determinants (3) which might explain why allergic reactions
to PHO seem to be very rare. However, one of the allergens
is the QAI epitope and IgE-sensitization to PHO thus could
predispose for an IgE-mediated anaphylaxis to NMBA.
Due to the differences in prevalences of IgE sensitization
to PHO in Norway and Sweden, which related to incidences
of NMBA anaphylaxis, and to the unique effects on IgE syn-
thesis (3, 5, 7), it was taken off the market in Norway by the
producer in March 2007. Studies in progress indicate that
2 years later the prevalence of IgE sensitization has dropped
considerably and the frequency of NMBA anaphylaxis shows
a descending tendency.
The above responses to withdrawing PHO-containing
cough suppressants in Norway will clearly be of interest from
a preventive point of view, not least when taken together
with recent historic exposure response data reported from
Sweden. During the 1970s and 1980s a PHO containing
cough syrup (Tussokon; Pharmacia AB, Uppsala, Sweden)
was available in Sweden. Analyses of allergics’ sera sampled
from 1970 to 2000 revealed that as many as 5–6% had IgE
antibodies to PHO during the years Tussokon was available
(10). However, only 2% of the sera from the 1990s were
positive. Among 300 sera from 2002 (3) and the 213 sera in
the present study no PHO positive sample was found. Varia-
tions in IgE-sensitization to PHO during these years followed
the number of reported cases of anaphylaxis to NMBA.
It wasattempted to obtain
the reported cases of anaphylactic reactions to NMBAs in
the participating countries during the study period. Even
through considerable efforts from the Norwegian Medicines
Agency it was not possible to get complete, homogenous and
reliable data from all participating countries. Thus, unfortu-
nately, we were not allowed the option of investigating the
associations between PHO consumption, IgE-sensitization
and the frequencies of NMBA related anaphylaxis. However,
in a few countries routines for reporting anaphylaxis during
anaesthesia are established and in NO, FR and UK a high
prevalence of IgE-sensitization to PHO was combined with a
high prevalence of anaphylaxis and in DK the opposite was
found (unpublished observation).
In conclusion, this multi-centre, international prevalence
study in part supports the pholcodine hypothesis, but also
supplies evidence for the probability that other, yet unknown,
environmental substances may lead to IgE-sensitization to
PHO and SUX. Further studies should be initiated on national
levels to collect corroborating information allowing the respec-
tive drug agencies to consider withdrawal of PHO containing
drugs. Good indications are now coming up that such inter-
ventions will results in a dramatic decrease of IgE-sensitization
and descending frequencies of NMBA-induced anaphylaxis.
cumulative dataon
Acknowledgments
The authors thank Torkel Harboe, Bergen, Norway and
Mogens Krøigaard, Copenhagen, Denmark for discussions
on the protocol. The following persons are thanked for help-
ing us collect serum samples: Sune Sved, Phadia Europe,
Michael Land, Phadia US Inc., Gerhard Burow and Corinna
Steigert, Phadia, Germany, AW van Toorenenbergen, Eras-
mus Medical Center, Rotterdam, The Netherlands, Dr Rich-
ard Pumphrey, Manchester, UK. Ingegerd A˚gren-Andersson
is acknowledged for performing the ImmunoCAP?analyses.
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