PhiliPPine Journal of otolaryngology-head and neck Surgery Vol. 27 no. 2 July – december 2012
ORIGINAL ARTICLES
12 PhiliPPine Journal of otolaryngology-head and neck Surgery
ABSTRACT
Objective: Topical cepae extract-heparin sodium-allantoin gel is one of the many non-invasive
scar treatments available to improve the appearance and physical attributes of scars. This paper
aims to compare the effectiveness of topical cepae extract-heparin sodium-allantoin gel versus
placebo based on appearance and physical attributes of hypertrophic thyroidectomy scars.
Methods:
Design: Randomized, double-blinded, split-scar controlled trial
Setting: Out-Patient Department of a tertiary government hospital
Patient: 20 patients with hypertrophic thyroidectomy scars had each side of the scar
randomly assigned treatment with topical extract cepae-heparin sodium-allantoin gel or placebo
(glycerine gel). Each product was applied two times daily for six weeks, and scars were evaluated
prior to initiation of treatment and after six weeks by patients and one observer. Pre- and post-
treatment photo documentation and scar evaluation using a local language translation of the
Patient and Observer Scar Assessment Scale (POSAS) were completed for each side of the scar.
Results: There was no significant difference in effectiveness of topical cepae extract-heparin
sodium-allantoin gel versus placebo for both the patient scale (p = 0.91) and observer scale (p =
0.87) in appearance and physical attributes of a thyroidectomy scar.
Conclusion: Topical cepae extract-heparin sodium-allantoin gel was not proven to be superior
to the placebo as scar therapy in all parameters assessed by the Filipino translation of POSAS. The
small sample size, duration of hypertrophic scar, duration of treatment, and validity and reliability
of the Filipino translation of POSAS may have affected our results; and periodic subjective and
objective assessments with multi-observer evaluation of scars and pre- and post- treatment
photographs may be considered for further studies.
Keywords: Topical Cepae Extract-Heparin Sodium-Allantoin Gel, Glycerine, Patient and Observer
Scar Assessment Scale, thyroidectomy scar, scar
Head and neck surgical scars may be difficult to conceal, and thyroid surgery is a common
head and neck procedure whose scar may create stigma for the patient. The first two months of
scar maturation are especially associated with a tendency for hypertrophic scar development.1
The disfiguring appearance of the linear hypertrophic scar in the neck can produce low self-
Topical Cepae Extract-Heparin Sodium-
Allantoin Gel versus Placebo on Hypertrophic
Thyroidectomy Scars: A Randomized,
Double- Blinded, Split-Scar Controlled Trial
Michael Paolo M. Tapangco, MD1
Waynn Neilsen Destriza, MD1
Bernardo D. Dimacali, MD1, 2
Mildred B. Olveda, MD1
1Department of Otolaryngology
Head and Neck Surgery
Ospital ng Makati
2Department of Otolaryngology
Head and Neck Surgery
Far Eastern University - Nicanor Reyes
Memorial Medical Foundation
Correspondence: Dr. Michael Paolo M. Tapangco
5th floor, Department of ENT-HNS, Ospital ng Makati
Sampaguita St. Pembo Makati City 1208
Philippines
Phone: (632) 882 6316 local 309
Fax: (632) 882 6316 local 309
E-mail: tpx_04@yahoo.com
Reprints will not be available from the author.
The authors declared that this represents original material
that is not being considered for publication or has not been
published or accepted for publication elsewhere, in full or in
part, in print or electronic media; that the manuscript has been
read and approved by all the authors, that the requirements
for authorship have been met by each author, and that each
author believes that the manuscript represents honest work.
Disclosures: The authors signed disclosures that there are no
financial or other (including personal) relationships, intellectual
passion, political or religious beliefs, and institutional affiliations
that might lead to a conflict of interest. Philipp J Otolaryngol Head Neck Surg 2012; 27 (2): 12-16 c Philippine Society of Otolaryngology – Head and Neck Surgery, Inc.
PhiliPPine Journal of otolaryngology-head and neck Surgery Vol. 27 no. 2 July – december 2012
ORIGINAL ARTICLES
PhiliPPine Journal of otolaryngology-head and neck Surgery 13
esteem and social isolation which can significantly interfere with the
psychological well being of the person afflicted.
There are numerous invasive and non-invasive treatment options
to improve scar appearance, including intra-lesional corticosteroids
(triamcinolone), topical silicone gel, compression or pressure therapy
and surgical scar excision or revision, radiotherapy and cryotherapy.1,2,3
Treatment with topical cepae extract-heparin sodium-allantoin gel has
been claimed to have special value in hypertrophic scars due to its anti
inflammatory activity, fibroblast anti-proliferative activity, inhibition of
proteoglycan and collagen formation, loosening of collagen structure
and improvement of scar elasticity.4
However, there is conflicting evidence on the effectiveness of this
preparation in improving scar appearance. Some reported improvement
in the color of scar alone1,2,3,4 while others claim no improvement in
scar appearance.2,3 This study aims to assess the effectiveness of cepae
extract-heparin sodium-allantoin gel versus placebo in the treatment
of thyroidectomy scars using a Filipino translation of the Patient and
Observer Scar Assessment Scale (POSAS).5
METHODS
Study Design and Setting
A randomized, double-blinded, split scar controlled trial was
conducted between January and June 2010 at the Out-Patient
Department of the Ospital ng Makati, a tertiary government hospital in
the Philippines.
Participants
With institutional ethics committee approval, 56 patients with
hypertrophic scars were recruited from the thyroidectomy patients of
the primary investigator. Inclusion criteria were: age between 18-60
years old, total or subtotal thyroidectomy or thyroid lobectomy through
a transcervical incision performed by a single surgeon, benign thyroid
pathology, hypertrophic scar, and at least four weeks healing after
surgery. Excluded were patients under treatment with topical antibiotics
or topical corticosteroids, thyroid malignancy, uncontrolled diabetes,
autoimmune disorders, plans of pregnancy or current pregnancy or
breastfeeding, and patients with known sensitivities to any ingredients
of the test products. With informed consent, 20 patients who were
eligible for the study were randomly assigned patient identification
numbers and frontal-view photographs of the scars were taken.
Procedures
Prior to the start of the study, an independent nurse prepared
10 grams each of cepae extract-heparin sodium-allantoin gel
(Contractubex®, Merz Pharmaceuticals, Frankfurt, Germany) and placebo
(glycerine gel) in paired identical containers. The paired containers had
color-coded red (right) and blue (left) labels. The topical cepae extract-
heparin sodium-allantoin gel was randomly assigned to either right
(red) or left (blue) container. The test drug and placebo shared the same
physical attributes, both being colorless and gel-like. The samples were
kept in identical envelopes and were sealed. Envelopes and sample
containers were also number-coded and were given randomly to the
participants by the independent nurse to ensure that both the patient
and the observer were blinded .
At the start of the study, pre-treatment assesments were separately
performed by each patient and one observer using the Patient and
Observer Scar Assessment Scale Version 1.0 whose validity and
reliability had been previously established (POSAS v1.0, Draaijers et al.,
2004).5 (Appendix A) The patients used a Filipino translation of the scale
which was pre-tested prior to the study and approved by the ethics
commitee. (Appendix B) Pre-treatment photographs were likewise
taken for documentation and comparison. After completing the scales
and photographs, instructions and follow-up schedules with color-
coded containers containing the test drug and placebo in number-
coded envelopes were given each patient by the assistant. Patients
were instructed to divide the scar in the midline by an imaginary line
from the mentum to the sternal notch. Gel was applied in a layer of
1 mm by simple spreading on the skin towards the periphery and
application to each half of the scar was performed twice a day, guided
by the color-labeled containers and instructions in each envelope. To
prevent diffusion of test drug and placebo, patients were instructed
to start the application approximately 1 cm or 1 finger breath away
from the center or the imaginary line drawn from the mentum to the
sternal notch towards left or right side scar. 1mm of gel was rubbed
continuously into each half-scar until it dried up, from the first day after
initial assessment for six weeks. Patients were advised follow-up every
two weeks, to contact the primary investigator in case of untoward side
effects, and to stop treatment immediately if signs of allergy or adverse
drug reactions occured. At the end of the 6-week treatment period,
each patient and the same observer separately accomplished the
Filipino translation of the POSAS for the second time. Post-treatment
photographs were also taken.
Outcome Measures
The primary outcome measures were the subjective observations
of patients and the lone observer with regards to the appearance
and physical attributes of the scar at baseline and after six weeks of
treatment. The normalization or the change in the scar in terms of
pain, pruritus, color, stiffness, thickness, and irregularity were the
specific parameters assessed in the patient scale while the vascularity,
PhiliPPine Journal of otolaryngology-head and neck Surgery Vol. 27 no. 2 July – december 2012
ORIGINAL ARTICLES
14 PhiliPPine Journal of otolaryngology-head and neck Surgery
pigmentation, thickness, relief, and pliability were considered in the
observer scale. Pre and post-tratment photographs were also used to
compare scar appearance.
Data Analysis
After completion of data collection, decoding of the collected data
was performed. Data were recorded and analysed using Statistical
Package for Social Sciences (SPSS) version 17.0 for Windows (IBM,
Armonk, NY, USA). The T-test (p= 0.05) was used to test for any significant
differences of the total POSAS scores pre- and post-treatment.
RESULTS
Of the 56 subjects initially considered, 20 were finally included in
the study, making a total of 40 split-scars. There were 18 women and 2
men, with a mean age of 43.5 years old (range 29 to 60 years old). All of
the patients claimed good compliance with the treatment protocol and
reported no adverse reactions.
Initial visit patient scales yielded a mean score of 5.98 on both sides
while observer scales had mean scores of 5.65 on both sides. At the
end of the 6-week treatment period, the means score for the patient
scales was 3.08 for the placebo and 3.28 for the test drug while on the
observer scale, the mean score for the placebo was 3.71 and for the test
drug was 3.84. Using the t-test, there was no significant difference pre-
treatment and post treatment between test drug and placebo (p= 0.91)
in either the patient scales or observer scale (p=0.87).
DISCUSSION
Hypertrophic scars are among the major concerns of thyroidectomy
patients. The incidence of hypertropic scars following surgery is about
40 to 70%.6,7 In contrast to keloids, which extend beyond the borders of
the original injury, hypertrophic scars remain confined to the borders
of the original wound and most of the time retain their shape.7,8 The
collagen fibers in this type of scar are oriented somewhat parallel to
the long axis of the scar.8 Based on a classification by Mustoe, a linear
hypertrophic (e.g., surgical/traumatic) scar is described as a red, raised,
sometimes itchy scar confined to the border of the original surgical
incision that occurs within weeks after surgery.3
Numerous non-invasive techniques to address scars have been
described. Silicone gel using polyethylene or polyurethane is a safe and
effective management option for hypertrophic scars and keloids.1,6,7
Compression or pressure therapy recommends that pressure be
maintained between 24 and 30 mmHg for 6 to 12 months to be
effective.1 Intralesional corticosteroids using triamcinolone are the
first-line therapy for treatment of keloids and second-line therapy for
treatment of hypertrophic scars if other non-invasive treatment options
have failed.1
Topical cepae extract-heparin sodium-allantoin gel has been
claimed to have special value in hypertrophic scars due to its anti
inflammatory activity, fibroblast anti-proliferative activity, inhibition of
proteoglycan and collagen formation, loosening of collagen structure
and improvement of scar elasticity.4,8 At least three months of continous
use is recommended by the product literature, but one study only used
it for 1 month11 while other studies had application periods ranging
from 3 to 12 months.13 Conflicting results have been reported and no
true consensus has been established. A study by Beuth concluded that
extract cepae gel application proved to be significantly superior to
corticosteroid application in terms of safety and efficacy.4 In another
study, the clinical course of scar development was rated as “very good”
or “good” in more than 90% of treated thoracic surgery patients.8
Extract Cepae was found to be more effective in improving scar color
but statistically ineffective in improving scar height and itching.9, 10
Another study comparing topical cepae extract, heparin, and allantoin
gel preparation with no treatment in thoracic scars concluded that the
rating was “good” and “very good” in 84% of treated cases, compared
to 59% of untreated cases.11 Other studies have contrary findings,
concluding for instance that extract cepae gel did not improve scar
cosmesis or symptomatology when compared with a petrolatum-
based ointment among surgical scars,10 or that topical cepae extract
gel was ineffective in improving scar erythema and pruritus in patients
who underwent Moh’s Surgery.11
Our study showed no significant difference between test drug and
placebo in the comparison of changes in mean scores. This suggests that
topical cepae extract-heparin sodium-allantoin gel was no better than
placebo in improving the appearance of hypertrophic thyroidectomy
scars in our study.
The significant improvement noted in the placebo group may be
attributed to the hydrating effects of glycerine. Glycerine gel is often
used as a lubricant for nasogastric or endotracheal tube insertion.
Like mineral oil, hydrating lotions and petrolatum-based ointments,
glycerine may promote moist healing and rapid epithelialization,
thereby decreasing hypertrophic scar formation.12 Having said that,
the midlines between right and left sides of the scars may have been
affected by various degrees of diffusion from either side, or not at all,
and yet appeared unremarkable. Perhaps neither test drug nor placebo
really made a difference after all?
That this study did not prove cepae extract-heparin sodium-allantoin
gel to be more effective than placebo in improving scar appearance
may also be attributable to the small sample size. The duration of the
PhiliPPine Journal of otolaryngology-head and neck Surgery Vol. 27 no. 2 July – december 2012
ORIGINAL ARTICLES
PhiliPPine Journal of otolaryngology-head and neck Surgery 15
hypertrophic scar at the time of initiation of the study as well as duration
of treatment could also affect results, and a longer period of application
of the test drug in accordance with product recommendations may be
implemented in future studies. The validity and reliability of the Filipino
translation of the POSAS, although pretested, are also limitations to
this study. Periodic subjective and objective assessments aside from
baseline and post-treatment subjective assessments, and multi-
observer evaluation of scars and pre- and post- treatment photographs
can also be included among the parameters to consider for further
studies.
APPENDIx A
Patient Code no: Week number 0 2 4 6
Observer Scar Assessment Scale
RIGHT
1 2 3 4 5 6 7 8 9 10
Vascularization
Pigmentation
Thickness
Relief
Pliability
TOTAL OBSERVER SCALE
Patient Code no: Week number 0 2 4 6
Observer Scar Assessment Scale
LEFT
1 2 3 4 5 6 7 8 9 10
Vascularization
Pigmentation
Thickness
Relief
Pliability
TOTAL OBSERVER SCALE
APPENDIx B
Patient Code no:_____ Week number 2 4 6 8
Patient Scar Assessment Scale
Please answer this scale according to your scar characteristics on the
RIGHT side.
Maaari po bang sagutan ninyo ang mga tanong ukol sa inyong peklat
sa bahaging KANAN
No, No complaints Yes, worst imaginable
Walang reklamo Meron, pinakamatindi
1 2 3 4 5 6 7 8 9 10
Is the scar painful?
Masakit ba ang peklat?
Is the scar itching?
Kumakati ba ang peklat?
No, as to normal skin Yes, very different
Wala kung ikukumpara Oo, malaki pagkakaiba
sa normal na balat
Is the color of the scar
different?
Nagkaiba ba ang kulay
ng peklat?
Is the scar more stiff?
Mas matigas ba ang
peklat?
Is the thickness of the
scar different?
Nagkaiba ba ang
kapal ng peklat?
Is the scar irregular?
Pantay-pantay ba ang
peklat?
TOTAL PATIENT SCALE
PhiliPPine Journal of otolaryngology-head and neck Surgery Vol. 27 no. 2 July – december 2012
ORIGINAL ARTICLES
16 PhiliPPine Journal of otolaryngology-head and neck Surgery
ACKNOWLEDGEMENTS
The authors would like to thank the following: Dr. Alberto F. Calderon and Dr. Howard Enriquez,
who critically reviewed the study proposal; Ms. May Legaspi, for acting as the independent nurse
for blinding of both subjects and investigators; Drs. Angel Cruz-Daylo, Carina Glorioso, Ardie Dizon,
Lorelyn Dino, and Elaine Lagura, for providing and caring for the study participants, and the patients
who actively participated as subjects for this trial.
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Patient Code no:_____ Week number 2 4 6 8
Patient Scar Assessment Scale
Please answer this scale according to your scar characteristics on the
LEFT side.
Maaari po bang sagutan ninyo ang mga tanong ukol sa inyong peklat
sa bahaging KALIWA
No, No complaints Yes, worst imaginable
Walang reklamo Meron, pinakamatindi
1 2 3 4 5 6 7 8 9 10
Is the scar painful?
Masakit ba ang peklat?
Is the scar itching?
Kumakati ba ang peklat?
No, as to normal skin Yes, very different
Wala kung ikukumpara Oo, malaki pagkakaiba
sa normal na balat
Is the color of the scar
different?
Nagkaiba ba ang kulay
ng peklat?
Is the scar more stiff?
Mas matigas ba ang
peklat?
Is the thickness of the
scar different?
Nagkaiba ba ang
kapal ng peklat?
Is the scar irregular?
Pantay-pantay ba ang
peklat?
TOTAL PATIENT SCALE