Background: Buprenorphine is a low-molecular-weight, lipophilic, opioid analgesic. The transdermal delivery system (TDS) containing it has skin irritation potential, but at least two cases of contact allergy to the active principal have been described previously

A N Goossens

Ana Gime´nez-Arnau

Claude Jacobs

Dominique Tennstedt

Elisabeth Parera Amer

Kim Vander Hulst

Marie Baeck

Ramo´n M Pujol Vallverdu´2

Virginie Dewulf

CiteSeerX

Contact Dermatitis 2008: 59: 366–369
Printed in Singapore. All rights reserved
# 2008 The Authors
Journal compilation # 2008 Blackwell Munksgaard
CONTACT DERMATITIS
Allergic contact dermatitis from transdermal
buprenorphine
KIM VANDER HULST1, ELISABETH PARERA AMER2, CLAUDE JACOBS3, VIRGINIE DEWULF4, MARIE BAECK4,
RAMÓN M. PUJOL VALLVERDÚ2, ANA GIMÉNEZ-ARNAU2, DOMINIQUE TENNSTEDT4 AND AN GOOSSENS1
1Department of Dermatology, University Hospital, K.U. Leuven, B-3000 Leuven, Belgium, 2Department of
Dermatology, Hospital del Mar, IMAS, Universitat Autònoma, 08003 Barcelona, Spain, 3Private Dermatologist,
1150 Brussels, and 4Department of Dermatology, University Hospital Saint-Luc, Brussels, 1200 Belgium
Background: Buprenorphine is a low-molecular-weight, lipophilic, opioid analgesic. The transdermal
delivery system (TDS) containing it has skin irritation potential, but at least two cases of contact
allergy to the active principal have been described previously.
Objective: To confirm allergic contact dermatitis from transdermal buprenorphine (TDB) in five
older patients suffering from chronic pain and who developed persistent, pruritic erythematous
plaques at the contact sites, with two of them also presenting with a generalized skin eruption.
Methods: Besides the baseline patch test series, all five patients were tested with the TDB, four of
whom were also tested with the placebo transdermal delivery system as provided by the manufac-
turer; one patient was also tested with other preparations containing buprenorphine.
Results: All reacted to the TDB containing the active principal, the placebo being negative in the four
patients tested. The patient tested with the other buprenorphine preparations did react positively to
them as well. Tests with TDB in 28 healthy controls were negative.
Conclusion: We report five cases of delayed hypersensitivity reactions to a TDS containing bupre-
norphine. Such adverse reactions might be under-reported. A fentanyl-containing TDS is a good
alternative in these cases.
Key words: allergic contact dermatitis; alternative; analgesics; buprenorphine; fentanyl; opioids;
pain control; transdermal delivery system. # Blackwell Munksgaard, 2008.
Accepted for publication 26 July 2008
Buprenorphine is a strong opioid analgesic and is
a partial m-opioid receptor agonist and a semi-
synthetic derivate of the morphine alkaloid
thebaine (1, 2). It is available for parenteral, sub-
lingual, and transdermal administration, and since
2001, it has been available in several European
countries in a transdermal delivery system (TDS)
for the treatment of chronic and moderate-
to-severe pain of malignant and non-malignant
origin (3). Transdermal buprenorphine (TDB)
provides a continuous release at 35, 52.5, or
70 mg/hr corresponding to daily doses of 0.84,
1.26, and 1.68 mg/day, respectively (2). Buprenor-
phine is highly lipophilic, has a low molecular
weight, and is highly potent, which makes it an
ideal medication for transdermal delivery (1, 2, 4).
The advantages of a TDS are multiple: it is non-
invasive, it avoids the first-pass metabolism in the
liver, there is a slow and continuous release of the
active compound, which leads to a constant and
predictable serum drug concentration over a pro-
longed period, avoiding adverse effects due to
plasma peaks, and more frequent dosing; the lat-
ter results in better compliance (1, 3, 4).
Patients and Methods
Case 1
A 63-year-old atopic man was referred to the
Contact Allergy Unit in Leuven in August 2007,
because of intolerance to TDB (35 mg/hr, Trans-
tec1; Grünenthal NV, Sint-Stevens-Woluwe,
Belgium). He had suffered from chronic muscle
and joint pain since the age of 26 years and had
been treated with different medications: non-
steroidal anti-inflammatory drugs (acetylsalicylic
acid and paracetamol) and the narcotic analgesic
tramadol, as advised by the pain clinic. Because of
drug adverse events such as headache and gastro-
intestinal symptoms and lactose intolerance, in
September 2004, his physician started treatment
with TDB, which resulted in successful pain con-
trol. One year later, however, the patient devel-
oped pruritic and burning erythema at the
contact sites of TDB, especially when sweating.
Fluticasone propionate (Flixonase Aqua1;
GlaxoSmithkline SA/NV, Genval, Belgium) as
well as triamcinolone acetonide 0.1% in petrola-
tum (pet.) improved the skin lesions but could not
prevent their recurrence. The patient thereupon
tried to stop using the patches and to use alterna-
tive medication, i.e. tilidine combined with nalox-
one, but this was insufficient for pain control. He
further had a history of intolerance to adhesive
plasters.
The patient was tested with the European base-
line series (Trolab1; Hermal, Reinbek, Germany),
TDB and the placebo transdermal delivery
system (PTDS) as provided by the manufacturer,
and additional allergens. Positive reactions were
observed to TDB (þ D2 and þþD4) (Fig. 1) and
Myroxylon pereirae (balsam of Peru) (þ D4), the
latter for which no relevance could be found. Test-
ing with PTDS in this patient and with the TDB in
three controls was negative. As an alternative for
the Transtec1 patch, fentanyl TDS (Durogesic1;
Janssen-Cilag NV, Berchem, Belgium) was started
and the patient has since remained pain and
lesion-free (contacted by telephone).
Case 2
A 79-year-old man with a personal history of pen-
icillin allergy, hypertension, diabetes mellitus, and
multiple vertebral fractures secondary to severe
osteoporosis was investigated in the Dermatology
Department in Hospital del Mar, because of the
development of a pruritic, erythematous reaction
limited to the site of application of TDB (Trans-
tec1; Grünenthal, Madrid, Spain). He had been
applying TDB for several weeks for chronic back
pain before the lesions developed. After TDB
withdrawal and topical high-potency corticoste-
roids, the lesions resolved. Patch tests with TDB
showed a papular erythematous reaction (þþ
D4), suggesting a delayed hypersensitivity reac-
tion. The baseline patch test series (Trolab1;
Almirall, Reinbek, Germany) and the adhesive
part of TDB were negative. No further testing
could be performed because the patient died.
Case 3
A 90-year-old woman with a history of hyperten-
sion, diabetes mellitus, and duodenal ulcer was
referred to the same department as in case 2. Dur-
ing the previous year, she had at least four epi-
sodes of erythema and transient oedema on the
face and eczematous lesions on the eyelids. These
signs persisted for more than 1 day and were con-
sidered to be consistent with a delayed hypersen-
sitivity reaction. She also reported episodes of
bronchospasm. She was using TDB (Transtec1)
because of chronic pain secondary to a degenera-
tive arthropathy as well as several other drugs, i.e.
losartan, furosemide, pentoxifiline, naproxene,
omeprazole, and miglitol. There was also a weak
erythematous and persistent infiltrated plaque at
the application site of the TDB. After withdrawal
of buprenorphine, furosemide, naproxene, and
pentoxifiline, the symptoms disappeared. Patch
tests were performed and positive reactions were
observed to TDB (as is) (þþ D4) and to three
forms of Buprex1 (Schering-Plough, Madrid,
Spain) (þþ D4), i.e. the i.v. solution containing
buprenorphine 0.3% aqueous, the sublingual
tablet Buprex 0.2 mg (in powder as is), and the
same tablet (in powder and moistened with
water) (Fig. 2). In the baseline patch test series,
M. pereirae (balsam of Peru) (þþD4) and neomy-
cin (þþ D4) were positive. PTDS as provided by
Grünenthal, the non-steroidal anti-inflammatory
drug series (Martı́ Tor, Barcelona, Spain) and
losartan (a 12.5-mg tablet in powder and diluted
in a minimum amount of pet.) showed negative
results. All drugs, except buprenorphine, were
successively reintroduced without adverse reac-
tions. The relation between the bronchospasm
Fig. 1. Positive test (þþ D2) to the Transtec1 transdermal
delivery patch (transdermal buprenorphine) (case 1).
Contact Dermatitis 2008: 59: 366–369 TRANSDERMAL BUPRENORPHINE 367
and the TDB was not clear, but the symptoms did
disappear after its withdrawal. The dermatitis was
considered to be both a local and a systemic aller-
gic reaction to buprenorphine. Tests with TDB in
25 healthy controls were negative.
Case 4
A 72-year-old man with a history of chronic urti-
caria and intestinal disease was observed by a der-
matologist (C. J.) inBrussels.Hehadbeenapplying
Transtec1 TDS patches because of skeletal pain
but after a few applications had started to develop
eczematous reactions under the central zone of the
patches. The patient was tested with the baseline
and acrylate series (Chemotechnique, Vellinge,
Sweden), TDB, and PTDS, but he only reacted to
the patch containing the active principal (þþ D2
and þþþ D4). The patient had satisfactory pain
control with systemic tramadol hydrochloride.
Case 5
A 79-year-old woman was admitted to the
Department of Dermatology of the University
hospital Saint-Luc in Brussels in March 2008,
for a recurrent, generalized eczematous eruption
present for 1 year. The first episode had followed
a toxicoderma due to clarithromycin and low-
molecular-weight heparins. The eczematous
eruptions had been treated with potent topical
corticosteroids (betamethasone dipropionate and
clobetasol propionate) and sometimes with sys-
temic corticosteroids. She had known contact all-
ergies: patch tests performed in 1986 and 2007 had
shown positive reactions to potassium dichromate,
nickel sulfate, p-phenylenediamine, fragrance mix
1, and ethylenediamine. She had used fentanyl
TDS (Durogesic1) because of back pain due to
scoliosis, which was stopped because of confusion
problems. Transtec1 TDS patches were applied
from February 2008, but the patient developed
itchy plaques at the contact sites. Patch tests were
performed with the European baseline standard
series and her medication, including Transtec1
TDS and PTDS and Durogesic1 TDS. Positive
patch test reactions were observed to budesonide
(þ D4), ethylenediamine (þþ D4), tixocortol
pivalate (þ D4), and Transtec1 TDS (þ D4).
Durogesic1 TDS and PTDS remained negative.
The patient’s recurrent generalized eczema possi-
bly had different causes: atopic constitution and
contact allergy to corticosteroids, but more prob-
ably a local and systemic allergic reaction to
buprenorphine. Indeed, the patient had not used
any topical corticosteroid before the exacerbation
of the skin eruption, and the lesions considerably
improved after withdrawal of TDB. The patient
was put on systemic tramadol hydrochloride,
which provided satisfactory pain control.
Results
The diagnosis in the five cases, three men and two
women, was a delayed hypersensitivity reaction to
the TDS containing buprenorphine (Transtec1)
used to treat chronic pain. Two patients also pre-
sented with systemic allergic dermatitis. Table 1
gives the patch test results obtained. Tests with
TDB in 28 controls were negative.
Discussion
Allergic contact dermatitis from TDB has not
often been described. We found two case reports
in the literature, both from Spain (5, 6). In the
latter, the authors also reported on another case,
which they considered to be irritant (7). In a post-
marketing surveillance study of TDB in 13 179
patients, Griessinger et al. reported 109 contact
dermatitis cases (0.8%). They did not specify
whether the dermatitis was due to the adhesive
or active compound. In the same study, they also
reported pruritus and an erythematous rash as an
adverse drug reaction in 0.7% and 0.5% of the
patients, respectively (3). During the clinical
development programme of the buprenorphine
TDS, which consisted of three double-blind, par-
allel group, placebo-controlled studies and one
open-label follow-up study, erythema was seen
in 25.4% and pruritus in 22% of all patients. All
local adverse events were considered mild to mod-
erate in intensity (4).
Fig. 2. Positive tests (þþ D4) to the Transtec1 transdermal
buprenorphine and to several Buprex1 preparations (case 3).
368 VANDER HULST ET AL. Contact Dermatitis 2008: 59: 366–369
Besides local reactions at the application site,
a hypersensitivity reaction to buprenorphine may
also become generalized or produce a systemic
reaction, such as in our cases 3 and 5. The trans-
dermal system, being a systemic way of drug deliv-
ery, may be more prone to induce such reactions.
In agreement with the literature (6), if a trans-
dermal system is to be preferred, fentanyl TDS is
a good alternative, as it is also a strong opioid
analgesic. It differs from buprenorphine because
of its full m-opioid receptor agonist character and
its chemical structure, namely it is a member of the
phenyl piperidine class of opioids (1). According to
a small study comparing both TDS systems, it was
found that local adverse events (‘skin irritation’
reactions) were more often seen with transdermal
buprenorphine than with transdermal fentanyl (8).
Other opioids, such as codeine, morphine, and
heroine, have been reported as causes of occupa-
tional contact dermatitis in pharmaceutical work-
ers and health care units (9–11). These drugs may
also be responsible for generalized dermatitis after
systemic administration (9, 12, 13), for which pos-
itive patch tests to the opioids suggested a type
IV immunological mechanism. Moreover, cross-
reactions between structural related opioids have
been described (9, 12).
Conclusion
We report five cases of delayed hypersensitivity
reactions to a TDS containing buprenorphine. All
patients developed pruritic erythematous plaques
at the contact sites and two also suffered from gen-
eralized dermatitis. When a transdermal system is
preferred, the TDS containing fentanyl has shown
to be a good alternative to control severe pain.
Acknowledgement
We are very grateful to Grünenthal NV from Belgium
and Spain for providing us with the placebo Transtec1
TDS for epicutaneous testing.
References
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Address:
An Goossens
Department of Dermatology
University Hospital
K.U. Leuven
B-3000 Leuven, Belgium
Tel: 00 32 16 33 78 60
Fax: 00 32 16 33 70 12
e-mail: an.goossens@uz.kuleuven.ac.be
Table 1. Positive patch test reactions in the five subjects reacting to buprenorphine TDS (Transtec1)
Sex
Age
(years)
Duration of
application
Transtec1
TDS
Placebo
TDS Other positive tests Alternative
Case 1 M 63 1 year þ  Myroxylon pereirae Fentanyl
Case 2 M 79 Several weeks þ NT  Patient died
Case 3 F 90 1 year þ  Buprenorphine
M. pereirae neomycin
Fentanyl
Case 4 M 72 A few applications þ   Tramadol hydrochloride
Case 5 F 79 <2 months þ  Potassium dichromate,
nickel sulfate,
p-phenylenediamine,
ethylenediamine, fragrance mix 1,
budesonide, tixocortol pivalate
Tramadol hydrochloride
F, female; M, male; NT, not tested; TDS, transdermal delivery system.
Contact Dermatitis 2008: 59: 366–369 TRANSDERMAL BUPRENORPHINE 369


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