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The effect of a spot-on formulation containing polyunsaturated fatty
acids and essential oils on dogs with atopic dermatitis
q
M. Blaskovic
a
, W. Rosenkrantz
b
, A. Neuber
c
, C. Sauter-Louis
d
, R.S. Mueller
a,
⇑
a
Clinic of Small Animal Medicine at the Centre for Clinical Veterinary Medicine, Ludwig-Maximilian University, Veterinärstrasse 13, 80539 Munich, Germany
b
Animal Dermatology Clinic, Tustin, CA 92780, USA
c
Derm4Pets Clinic, Chiltern Referral Services, Chalfont St. Giles, Buckinghamshire HP8 4AB, UK
d
Clinics for Ruminants at the Centre for Clinical Veterinary Medicine, Ludwig-Maximilians University, Sonnenstrasse 16, 85764 Oberschleissheim, Germany
article info
Article history:
Accepted 18 October 2013
Keywords:
Atopic dermatitis
Canine
Essential fatty acids
Topical therapy
abstract
Recent studies have shown that immunological aberrations and epidermal barrier defects could be
important in the pathogenesis of canine atopic dermatitis (CAD) and that oral polyunsaturated fatty acids
(PUFAs) might influence the epidermal barrier. The aim of this study was to evaluate the effects of a spot-
on formulation containing PUFAs and essential oils on pruritus and lesions caused by CAD. Forty-eight
privately owned dogs of different breeds, ages and genders diagnosed with atopic dermatitis were
included in a randomized, double-blinded, placebo-controlled, multicentre clinical trial. Dogs were trea-
ted with a spot-on formulation containing PUFAs and essential oils or placebo on the dorsal neck once
weekly for 8 weeks. Before and after the study, CAD extent and severity index-03 (CADESI-03) and pru-
ritus scores were determined by veterinarians and owners, respectively.
There was significantly more improvement in CADESI-03 and pruritus scores in the treatment group
than in the placebo group (P= 0.011 and P= 0.036, respectively). Additionally, more dogs improved by
at least 50% in CADESI-03 and pruritus scores in the treatment group than in the placebo group
(P= 0.008 and P= 0.070, respectively). No adverse reactions were observed. The topical preparation con-
taining PUFAs and essential oils was a safe treatment and beneficial in ameliorating the clinical signs of
CAD.
Ó2013 The Authors. Published by Elsevier Ltd. All rights reserved.
Introduction
Canine atopic dermatitis (CAD) is a commonly presented dis-
ease in veterinary practice (Scott and Paradis, 1990) and is associ-
ated with pruritus (Saridomichelakis et al., 1999; Griffin and
DeBoer, 2001) and skin lesions (Griffin and DeBoer, 2001; Favrot
et al., 2010). It is diagnosed by history, clinical signs and the exclu-
sion of differential diagnoses, and clinical diagnostic criteria have
been recently introduced (Favrot et al., 2010). In CAD, a hypersen-
sitivity response against environmental or food allergens develops
due to a genetic predisposition and could be associated with dis-
turbances in the skin barrier function (Merryman-Simpson et al.,
2008; Sandilands et al., 2009; Wood et al., 2009). Allergens in-
volved in the pathogenesis of non-food-induced CAD include house
dust mites, pollens, moulds and insect antigens (Hill and DeBoer,
2001). Allergens can be inhaled or percutaneously absorbed (Olivry
and Hill, 2001; Marsella et al., 2006).
Symptomatic treatment for CAD includes antihistamines, gluco-
corticoids, cyclosporin, topical therapy, and polyunsaturated fatty
acids (PUFAs), while specific treatment employs allergen-specific
immunotherapy (Olivry et al., 2010). PUFAs cannot be synthesized
de novo and need to be ingested pre-formed in the diet. They contain
one or more double bonds, and are classified as omega-3 and omega-
6 fatty acids, depending on the position of the first double bond rel-
ative to the carboxy end of the chain. Important omega-3 fatty acids
are
a
-linolenic acid (in linseed oil), eicosapentaenoic acid (EPA) and
docosahexaenoic acid (DHA; in fish oils). Omega-6 fatty acids are lin-
oleic acid (in sunflower or safflower oil),
c
-linoleic acid (in evening
primrose oil) and dihomo-
c
-linoleic acid.
In vitro, PUFAs are reported to have anti-inflammatory (Ziboh
and Chapkin, 1988; Ziboh et al., 2000) and immunomodulating
(Stehle et al., 2010) effects. A further possible mechanism of action
is improvement of the epidermal barrier function, presumably by
changing the composition of epidermal lipids. Oral fatty acid sup-
plementation has been reported to change cutaneous lipids in Bea-
gle dogs (Campbell and Dorn, 1992).
In contrast to many other symptomatic therapies for CAD, oral
supplementation with PUFAs rarely causes adverse effects (Olivry
1090-0233/$ - see front matter Ó2013 The Authors. Published by Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tvjl.2013.10.024
q
This is an open-access article distributed under the terms of the Creative
Commons Attribution-NonCommercial-ShareAlike License, which permits non-
commercial use, distribution, and reproduction in any medium, provided the
original author and source are credited.
⇑
Corresponding author. Tel.: +49 8921 802654.
E-mail address: R.Mueller@lmu.de (R.S. Mueller).
The Veterinary Journal 199 (2014) 39–43
Contents lists available at ScienceDirect
The Veterinary Journal
journal homepage: www.elsevier.com/locate/tvjl
et al., 2001; Mueller et al., 2004), although diarrhoea might occur
with oral supplementation (Scott et al., 1992). Adverse effects of
topically administered PUFA therapy have not been reported (Tret-
ter and Mueller, 2011). Concurrent treatment with PUFAs might
permit reduction of the dosage of other anti-inflammatory medica-
tions, such as glucocorticoids, and further improvement in clinical
signs (Scott and Miller, 1993; Bond and Lloyd, 1994; Saevik et al.,
2004).
Studies on the use of oral fatty acid supplementation have been
published (Mueller et al., 2004; Saevik et al., 2004), but reports
about the efficacy of topically applied PUFAs or ceramides are rare
and describe non-blinded and open trials (Piekutowska et al., 2008;
Tretter and Mueller, 2011). The aim of this study was to evaluate
the efficacy of a commercial spot-on containing PUFAs and essen-
tial oils on the clinical signs of CAD in a prospective, placebo-con-
trolled, randomised trial.
Materials and methods
The study was approved by the Ethics Committee of the Centre for Clinical Vet-
erinary Medicine/Ludwig Maximilian University Munich (Approval number 03-
051012). Prior to enrolment, dog owners gave their written consent (Appendix A:
Supplementary material).
Study design and study objects
This was a randomized, double-blinded, placebo-controlled multicentre study.
Three dermatology referral practices in Germany (Centre for Clinical Veterinary
Medicine, Ludwig Maximilian University Munich), the UK (Derm4Pets Clinic, Buck-
inghamshire/Berkshire) and the USA (Animal Dermatology Clinic, Tustin, California)
participated.
Forty-eight privately owned dogs with atopic dermatitis were included, of dif-
ferent genders, ages and breeds. The treatment group consisted of 23 dogs classified
with either moderate to severe CAD (n= 12) or mild CAD (n= 11). There were 25
dogs in the placebo group (16 classified with moderate to severe CAD and nine with
mild CAD).
Randomization
The dogs were stratified into two subgroups with mild disease characterized
prior to treatment by either low lesion scores i.e. a CAD extent and severity in-
dex-03 (CADESI-03) < 60 (n= 20), or moderate to severe disease (CADESI-03 > 60;
n= 28; Olivry et al., 2008). Separate randomization schedules for both groups and
each study centre were created by the study monitor prior to the study according
to a computer-generated randomization list.
1
Medication and identically packaged
placebos were sent to each study centre and each package was specifically marked
and dispensed according to the randomization list.
Inclusion criteria
All dogs had been diagnosed with environmentally-induced atopic dermatitis
based on history, clinical signs and rule-out differential diagnoses by appropriate
means, such as skin cytology, skin scrapings, elimination diets and/or ectoparasite
control measures. Dogs with mild disease were treated exclusively with topical
therapy, either product or placebo. Antihistamines and other topical therapies were
discontinued at least 2 weeks prior to starting the study and glucocorticoids and
cyclosporin were discontinued at least 6 weeks prior to enrolment.
In the group with moderate to severe CAD, exclusive treatment with placebo or
topical fatty acids/essential oils was considered unethical due to the reported lim-
ited improvement seen with oral fatty acid supplementation (Olivry et al., 2001;
Mueller et al., 2004). Concurrent low dose glucocorticoids, antihistamines and top-
ical therapy were permitted if they had been administered at an unchanged dose for
more than 12 weeks prior to inclusion and during the trial. Diet changes were not
permitted within 3 months prior to or during the study. Allergen-specific immuno-
therapy was permitted in dogs that had been receiving it for at least 12 months
prior to inclusion. Dogs with a history or clinical signs of flea bite hypersensitivity
received fipronil spot on (Frontline, Merial) or selamectin spot on (Stronghold, Zoe-
tis) once monthly.
Study protocol
All dogs were treated with a spot-on preparation once weekly for 8 weeks. The
owners applied the product on the dorsal cervical area after being given detailed
instructions on how to spread the hair coat and apply the product directly onto
the skin. Dogs received either a product containing PUFAs (6 mg/mL of
a
-linolenic
and 30 mg/mL of linoleic acid), essential oils (neem oil, rosemary extract, lavender
oil, clove oil, tea tree oil, oregano extract, peppermint extract and cedar bark ex-
tract) and vitamin E (Dermoscent Essential 6 spot-on, LDCA) or a placebo (bio dif-
fusing agents, Dermoscent, LDCA).
Dogs <10 kg received 0.6 mL weekly; dogs weighing 10–20 kg received 1.2 mL
weekly, and dogs of 20–40 kg received 2.4 mL weekly. This protocol was according
to the manufacturer’s recommendations and the same as the protocol used in a pre-
viously published pilot study (Tretter and Mueller, 2011). The commercial product
has a distinct odour that was absent from the placebo. However, the owners of pla-
cebo treated dogs were not aware of this difference. It was previously established
that the odour dissipated within 1 week of application and investigators were un-
able to detect the odour at the time of scoring, thus keeping the integrity of the
blinding intact.
Clinical evaluation
A validated lesion score (CADESI-03; Olivry et al., 2007, 2008) was used to
determine the severity of skin lesions. If the initial CADESI-03 was 660, dogs were
considered to have mild CAD (n= 20). If the CADESI-03 was >60, the disease was
categorized as moderate to severe (n= 28), as previously reported (Olivry et al.,
2008). Dogs with moderate to severe disease commenced the study after their clin-
ical signs had improved with other therapies (see above) and they were considered
stable. Dogs were evaluated at enrolment and after 8 weeks of treatment. The CAD-
ESI-03 score was determined by the clinician at each visit. Similarly, owners com-
pleted a validated pruritus score at each visit, scoring pruritus from 0 to 10 using
a visual analogue scale combined with features of the behaviour and severity-based
scales (Hill et al., 2007;Appendix B).
Statistical analyses
Based on data gathered in a recent pilot study (Tretter and Mueller, 2011), it
was calculated that with at least 20 dogs in each group (treatment and placebo),
a difference of 6 points in CADESI-03 scores and 2 points in pruritus scores could
be determined with a power of 90% and a significance level of P< 0.05. To ensure
similar groups, initial CADESI-03 scores and pruritus scores were compared using
Mann Whitney tests. For the same reason, the age and weight of dogs in both
groups were compared with an unpaired ttest or (if data were normally distrib-
uted) or Mann–Whitney Utests (if data were not normally distributed). Gender dis-
tribution was analyzed using Fisher’s exact tests. Improvements in pruritus and
CADESI-03 scores, respectively, were calculated by subtracting the score at enrol-
ment from the score at the end of the study. This was compared between groups
using an unpaired ttest with Welsh correction (if data were normally distributed),
or a Mann–Whitney Utest (if data were not normally distributed). The number of
dogs improving by at least 50% and the number of dogs deteriorating in the treat-
ment group compared to the placebo group were compared using Fisher’s exact
tests.
A one-sided Pvalue was chosen, as a previously published pilot study had
shown improvement in both pruritus and CADESI-03 scores with this therapy (Tret-
ter and Mueller, 2011) and thus deterioration was not expected in the treatment
group compared to placebo. Significance for all tests was set at P< 0.05. The statis-
tical program used was GraphPad Prism 5.0 (GraphPad). Dogs were excluded from
the per protocol analysis if they exhibited clinical signs of an adverse reaction to the
product, when owner compliance was not satisfactory, or when the clinical signs of
atopic dermatitis deteriorated to the point that additional antipruritic therapy was
needed. An intention to treat analysis, with the last value carried forward, using all
dogs included in the study was performed, as well as a per protocol analysis.
Results
CADESI-03 and pruritus scores
There was no significant difference between treatment and pla-
cebo groups with respect to CADESI-03 scores (P= 0.278) or pruri-
tus (P= 0.909) at enrolment. There was also no difference between
groups in age (P= 0.735), bodyweight (P= 0.782) or gender distri-
bution (P= 0.785). Because two dogs did not complete the study,
per protocol analysis was performed on 46 dogs. As the results of
the intention to treat analysis and that of the per protocol analysis
were similar, only the results of the intention to treat analysis are
reported here.
1
See: http://graphpad.com/quickcalcs/randomN1.cfm (last accessed 15 October
2013).
40 M. Blaskovic et al. / The Veterinary Journal 199 (2014) 39–43
The mean and the confidence intervals of CADESI-03 and pruri-
tus scores pre- and post-therapy are shown in Table 1. Individual
improvements in CADESI-03 scores and pruritus scores in each
dog were significantly higher in the treatment group than in the
placebo group (Mann–Whitney Utest, P= 0.011 and P= 0.036,
respectively). The numbers of dogs improving by at least 50% or
90% are listed in Table 2. More dogs showed an improvement of
P50% in CADESI-03 and pruritus scores in the treatment group
than in the placebo group (Fisher’s exact test, P= 0.008 and
P= 0.07, respectively). Significantly more dogs deteriorated in the
placebo group (15/25) compared to the treatment group (5/23;
Fisher exact test, P= 0.01). Raw data are shown in Appendix B:
Supplementary materials.
Adverse effects and exclusions
All except two dogs completed the study. These had moderate
to severe clinical signs and both deteriorated during the first
4 weeks of the study, requiring their concurrent therapy to be
changed. One of those dogs was in the treatment group and one
was in the placebo group. Adverse effects were not observed in
any of the treated dogs.
Discussion
This study demonstrated that the clinical signs of atopic derma-
titis in dogs with stable CAD that met the study entry criteria sig-
nificantly improved after eight weekly topical treatments of a
commercially available compound containing PUFAs and essential
oils. The degree of improvement was similar to another random-
ized, placebo-controlled study where 29 dogs received oral fatty
acid supplementation for 10 weeks and showed significant
improvement (Mueller et al., 2004). That study used a different
scale to measure outcomes, as it preceded the use of the CADESI-
03 and the visual analogue pruritus scale for use by dog owners
(Mueller et al., 2004).
The results of the present investigation support the findings of a
recent pilot study using the same product (Tretter and Mueller,
2011) and also studies evaluating oral fatty acid supplementation
(Olivry et al., 2010). PUFAs are thought to have lower efficacy than
glucocorticoids and cyclosporin (Olivry et al., 2010), but they are a
safe alternative to other anti-inflammatory therapies. Adverse ef-
fects associated with their use are rare and usually mild (Mueller
et al., 2004; Olivry et al., 2010), which is particularly important in
the long-term treatment of chronic diseases such as CAD. In this
work, no adverse effects were noted with short-term use (8 weeks).
Widespread use of the product over longer periods of time is needed
to make more definitive statements regarding safety.
As this is the first double-blinded, placebo-controlled study
evaluating topical therapy with a commercial product containing
essential oils and PUFAs, the only comparison possible is with oral
PUFA supplementation. There are many studies using oral PUFA
supplementation, but only a few that are placebo-controlled and
double-blinded. In one such study, there was a significant improve-
ment of clinical signs with commercially available EPA and DHA
preparations (Mueller et al., 2004). In another controlled study
based on the measurement of serum arachidonic acid before and
after the trial, dogs with early CAD showed more improvement
than dogs with a longer history of CAD (Abba et al., 2005).
Direct comparison of an oral and topical product is not possible,
but our study provides evidence that the efficacy of topical therapy
with essential oils and PUFAs appears to be comparable to that
reported for studies evaluating oral PUFAs (Mueller et al., 2004;
Saevik et al., 2004). With oral fatty acid supplementation, approx-
imately half of the dogs treated with daily fatty acids improved by
50% or more compared to only 10% in the placebo group in an
earlier study (Mueller et al., 2004). In the current work, the corre-
sponding results were in the same range for CADESI-03 and pruri-
tus scores, suggesting both types of treatment are suitable for the
treatment of CAD, but the success rate for either one is not as high
as that for glucocorticoids or cyclosporin (Steffan et al., 2006;
Olivry et al., 2010).
It was recommended a decade ago that PUFA supplementation
should be administered for at least 12 weeks before assessing the
success of treatment (Olivry et al., 2001). This was based on the
pharmacokinetics of oral PUFAs (Campbell and Dorn, 1992; Camp-
bell et al., 1995). However, other authors observed effects with dai-
ly PUFA supplementation as early as 2 weeks after the initiation of
therapy (Scott et al., 1992, 1997; Olivry et al., 2010). In our study,
an 8-week supplementation period was chosen because the clinical
effects in a pilot study were noted after 8 weeks of administration
(Tretter and Mueller, 2011).
In the present study, a validated pruritus score and a CADESI-03
were used. Pruritus and skin lesions are typically considered the
most relevant parameters in studies evaluating CAD (Olivry et al.,
2010). The scores for lesions and pruritus have been previously val-
idated (Hill et al., 2007; Olivry et al., 2007, 2008). The number of
dogs improving by more than 50% and 90%, respectively, was al-
ways higher in the treatment group than in the placebo group
for both pruritus and CADESI-03 scores (Table 2). However, in
the placebo group more dogs improved in pruritus scores than in
CADESI-03. The improvement in pruritus scores could be perceived
rather than real and might provide evidence for the more subjec-
tive nature of the assessment of pruritus.
PUFAs are considered less efficacious than, for example, gluco-
corticoids (Olivry et al., 2010) or cyclosporin (Steffan et al., 2006)
in the treatment of CAD, but have been shown to be successful
Table 1
Data for CADESI-03 and pruritus scores of dogs with atopic dermatitis treated with either a spot-on formulation containing essential fatty acids/essential oils or placebo.
Treatment
Day 0
Treatment
Day 56
Improvement
a
with
treatment
Placebo Day 0 Placebo Day 56 Improvement
a
with
placebo
Total number of dogs 23 25
Mean CADESI-03 (95% CI) 46 (29–63) 28 (18–39) 18 (4–32) 78 (41–116) 80 (44–115) 1(19 to 13)
Mean pruritus (95% CI) 5.2 (4.2–6.2) 3.9 (2.7–5.2) 1.3 (0.2–2.4) 5.3 (4.3–6.3) 5.0 (4.1–6.0) 0.2 (0.7 to 1.2)
Number of dogs with mild AD 11 9
Mean CADESI-03 (95% CI) 25 (13–36) 15 (9–22) 9 (1 to 20) 22 (11–32) 34 (21–48) 13 (21 to 5)
Mean pruritus (95% CI) 4.8 (2.9–6.6) 4.0 (1.5–6.0) 1 (0.9 to 2.9) 3.8 (2.1–5.5) 4.0 (2.1–5.9) 0.2 (2.6 to 2.2)
Number of dogs with moderate–
severe AD
12 16
Mean CADESI-03 (95% CI) 66 (38–94) 40 (22–58) 24 (1 to 50) 110 (58–163) 105 (53–157) 6 (19 to 30)
Mean pruritus (95% CI) 5.6 (4.4–6.8) 4.1 (2.5–5.7) 1.5 (0–3.0) 6.1 (5.1–7.2) 5.6 (4.5–6.8) 0.5 (0.5 to 1.5)
CADESI-03, canine atopic dermatitis extent and severity index-03; CI, confidence interval.
a
Improvement = Score at the beginning of the trial Score at the end of the trial.
M. Blaskovic et al. / The Veterinary Journal 199 (2014) 39–43 41
as adjunctive therapy (Saevik et al., 2004). For this reason, addi-
tional medications were permitted in dogs with moderate–severe
atopic dermatitis, as outlined above. In addition, it was considered
unethical to treat dogs with more severe disease exclusively with
topical fatty acids/essential oils. Dogs with a CADESI-03 of >60
have been classified as having moderate to severe atopic dermatitis
(Olivry et al., 2008). Since the clinical signs in those dogs were un-
likely to be controlled by sole therapy with PUFAs/essential oils,
the use of concurrent medication was considered ethical and justi-
fied. As the dose of concurrent medications was not changed for
the 12 weeks preceding the study or during the study, those drugs
are unlikely to have influenced the study outcome.
It is not clear how well spot-on preparations containing fatty
acids distribute in the epidermis and how long possible changes
in epidermal ceramide composition last. One study reported a sig-
nificant increase in free ceramides at the application site 3 days
after the last treatment after twice weekly application of a topical
spot-on preparation containing ceramides and free fatty acids for
3 weeks (Popa et al., 2012). The clinical improvement seen in dogs
with multifocal to generalized skin disease treated with such prod-
ucts further supports some effect on the epidermis, but more stud-
ies are needed to provide details regarding the distribution and
mechanism of action of topical essential oils and PUFAs in dogs.
Conclusions
Based on the findings in this study, the application of a spot-on
containing PUFAs and essential oils was beneficial in alleviating the
clinical signs of CAD. As complete remission was not achieved in
the vast majority of dogs, it seems most useful as an adjunctive
therapy in this disease.
Conflict of interest statement
The study was financed by Laboratoire de Dermo-Cosmetique
France, which had no influence on study design, data evaluation
or manuscript preparation. Dr. Blaskovic was financially supported
by LCDA France. None of the authors has any other financial or per-
sonal relationships that could inappropriately influence or bias the
content of the paper.
Acknowledgement
The authors would like to thank Drs. Sonya Bettenay, Tierder-
matologie Deisenhofen and Brett Wildermuth, Tierdermatologie
Dr. Wildermuth for their contributions to protocol design and
manuscript preparation. We are also grateful to Prof. Hywel Wil-
liams for his earlier critical advice on the appropriate analysis
and the owners and dogs for their participation.
Appendix A. Supplementary material
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tvjl.2013.10.024.
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Table 2
Numbers of dogs improving by more than 50% and 90% in CADESI-03 and pruritus scores when treated with a spot-on formulation containing essential fatty acids/essential oils or
placebo.
Treatment improvement Placebo improvement Treatment improvement Placebo improvement
P50% P50% P90% P90%
CADESI-03 (n) 8/23 1/25 1/23 0/25
Pruritus score (n) 9/23 4/25 2/23 1/25
CADESI-03, canine atopic dermatitis extent and severity index-03.
42 M. Blaskovic et al. / The Veterinary Journal 199 (2014) 39–43
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