ORIGINAL ARTICLE

Effects of chlorhexidine/
benzydamine mouth spray on pain
and quality of iife in acute virai
piiaryngitis: A prospective,
randomized, doubie-blind, piacebo
controiied, muiticenter study
Cemal Cingi, MD; Murat Songu, MD; Ahmet Ural, MD; Muzeyyen Yildirim, MD;
Nagehan Erdogmus, MD; Cengiz Bal, MD
Abstract
We eondueted a prospeetive, randomized, double-blind,
plaeebo-eontrolled, multieenterstudy to assess the effieaey
ofehlorhexidineglueonate/benzydamine HCl mouth spray
for redueingpain and improving quality of life in patients
with aeute viral pharyngitis. Prior to treatment, patients
rated the intensity of their pain on a visual analog seale and
evaluated their quality of life on the 36-Item Short-Form
Health Survey. Patients were then randomized to reeeive
either paraeetamol (aeetaminophen) plus ehlorhexidine/
benzydamine or paracetamol plus plaeebo for 7 days. On
days 3 and 7 of treatment, the partieipants again rated
the intensity of their pain, and on day 7, they again rated
their quality of life. A total ofl 64 patients were valuable
at study's end80 in the ehlorhexidine/benzydamine
group and 84 in the eontrol group. A eomparison of
self-evaluations revealed that the aetive treatment group
reported less pain on both day 3 (p < 0.001) and day 7
(p = 0.002). Likewise, the ehlorhexidine/benzydamine
group reported a signifieantly better quality of life on day 7
(p < 0.001). ehlorhexidine/benzydamine was well toler-
ated, and no serious adverse events were observed.
From the Department of Otorhinolaryngology (Dr. Cingi and Dr. Er-
dogmus) and the Department of Biostatistics (Dr. Bal), Osmangazi
University Medical Faculty, Eskisehir, Turkey; the Department of
Otorhinolaryngology, Dr. Behcet Uz Children's Hospital, Izmir,
Turkey (Dr. Songu); the Department of Otorhinolaryngology, Ka-
radeniz Technical University Medical Faculty, Trabzon, Turkey (Dr.
Ural); and the Department of Otorhinolaryngology, Dicle University
Medical Faculty, Diyarbakir, Turkey (Dr. Yildirim).
Corresponding author: Murat Songu, MD, Department of Otorhinolar-
yngology, Dr. Behcet Uz Children's Hospital, 35210, Izmir, Turkey.
E-mail; songumurat@yahoo.com
Introduction
Acute pharyngitis is characterized by an inflamma- i
tion of the oropharyngeal cavity and the surrounding
lymphoid tissue.' Inflammation manifests as pain of
varying intensity. Viruses are the most common cause
of acute pharyngitis, being implicated in 40 to 60% of
cases.^'^ Various reports put the incidence of bacterial
etiology between 5 and 40% of cases.^' In cases of bacte-
rial infection, the most common pathogen is group A
beta-hemolytic Streptoeoeeus (GABHS).^'
Treatment of the cause of viral infections of the
oropharyngeal cavity is not possible, but symptomatic
treatment may reduce the intensity of pain to a great
extent. Numerous pharmaceutical agents that contain
disinfectants, anti-inflammatory agents, and/or topical
anesthetics have been approved for the local treatment
of acute pharyngitis. However, to the best of our knowl-
edge, their effect on improving quality of life has not
been demonstrated in double blind, placebo-controlled
studies.^'''
We conducted a study to evaluate the effect of an in-
vestigational mouth spray that contains chlorhexidine
gluconate and benzydamine HCl in terms of reducing
the intensity of pain and improving quality of life in
patients with acute viral pharyngitis.
Patients and methods
Study design. The trial was designed as a prospee-
tive, randomized, double-blind, placebo-controlled,
parallel-group, muiticenter clinical study to test the
safety and efficacy of combined chlorhexidine gluconate
546 www.entjournal.com
ENT-Ear, Nose & Throat Journal November 2010
EFFECTS OF CHLORHEXIDINE/BENZYDAMINE MOUTH SPRAY ON PAIN AND OUALITY OF LIFE IN ACUTE VIRAL PHARYNGITIS:
A PROSPECTIVE, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, MULTICENTER STUDY
and benzydamine HCl in relieving symptoms of acute
viral pharyngitis in patients who were also taking oral
paracetamol (acetaminophen). Between May 1 and Oct.
31, 2009, we recruited 188 patients at four hospitals
who had presented with complaints of sore throat and/
or odynophagia. Because we wished to concentrate on
viral pharyngitis, we used the Centor criteria to exclude
patients with GABHS pharyngitis. Together, the Centor
criteria represent the most reliable clinical indicator of
GABHS pharyngitis. The four criteria are a history of
fever, the presence of tonsillar exudates, tenderness of
the anterior cervical lymph nodes, and an absence of
cough.^ The positive predictive value of the Centor system
when all four criteria are met is 40 to 60%; when only
one criterion is met, the system has a negative predictive
value of 80%.' Compared with throat culture results,
both the sensitivity and specificity of the Centor criteria
are 75%.' (Complete inclusion and exclusion criteria are
listed in the table.)
Patients were randomized in a double-blind fashion
to one of two parallel treatment groupsparacetamol
plus chlorhexidine/benzydamine and paracetamol plus
placebo. The randomization was generated by the study
coordinator and senior author (CC). Numbered boxes
that contained either the active drug or placebo were
sent to clinical investigators at the four institutions. The
randomly generated number determined whether each
patient received active drug or placebo. Details con-
cerning the contents of each box were unknown to the
investigators. The randomization code for each patient
was stored in two sealed envelopes. One set of envelopes
was kept by the study coordinator and the other set was
sent to the respective study center to be opened in case of
an emergency in the event that knowledge of the actual
treatment became medically necessary. Breaking the
code for one patient would not automatically break the
code for the other patients. All investigators and patients
were blinded to treatment assignment throughout the
course of the study.
Self-ratings. All patients self-rated the intensity of
their pain on a visual analogue scale (VAS) and their
quality of life on the 36-Item Short-Form (SF-36) Health
Survey*'^ prior to treatment. The VAS ratings were made
again on the third day of treatment and on the last day
of treatment (7 days from baseline), while the repeat
SF-36 ratings were made only on day 7. The VAS was
graded on a scale of 0 (no pain) to 10 (the worst pain
imaginable).* For assessing quality of life, the SF-36 is a
well-documented, simple, standardized, and validated
system.*'^ The range of SF-36 scores runs from 0 to 100,
Table. Inclusion and exclusion criteria
Inciusion
Age >16 years
History of sore throat S3 days
<1 Centor criterion
Ability to understand and provide written informed
consent and to report adverse events and concomitant
medication use for the duration of the study
Exclusion
History of sore throat ^8 days
Use of any medication, including herbs or dietary supple
ments, taken for relief of sore throat prior to study initiation
Current use of any analgesic or anti-inflammatory agents,
including steroidal and nonsteroidal drugs
Symptoms of sore throat caused by local irritation of mu'-
oous membranes as a result of gastroesophageal reflux
Pregnancy or a lack of contraception in women of child
bearing potential
Presence of a comorbid condition, uncontrolled metabolic
condition, or psychiatric condition that might make drug
tolerance or evaluation difficult
with higher scores indicating a better quality of life.
Treatment. The scheduled treatment period was
7 days. Patients were allowed to continue treatment
beyond that point if symptoms persisted, but the extra
dosing was not factored into our results. Doses were
self-administered as a mouth spray 4 times per day.
Paracetamol was taken at 500 mg 4 times daily. Patients
were instructed to avoid taking any other medication
for the relief of sore throat. I
Side effects. Patients were asked to note any side ef-
fects of treatment on days 3 and 7 on a custom-designed
questionnaire. Local side effects that have been reported
include taste disturbances, oral mucosal numbness,
burning sensation in the mouth, xerostomia or thirst,
and coloring of the teeth; systemic side effects include
nausea, vomiting, stomach ache, vertigo, and headache.'
Patients evaluated the degree of side effects on a 4-point
Likert scale, with 0 points representing no side effects
and 1, 2, and 3 points denoting mild, moderate, and
severe side effects, respectively. Thus the possible scores
ranged from 0 to 30, with higher scores indicating worse
side effects.
Statistical analysis. Data were analyzed with the Sta-
tistical Package for the Social Sciences software (version
17.0 for Windows; SPSS; Chicago). The Shapiro-WJilk
test was used to test the normality assumption. The
Student test was used for paired samples, and repeated
measures were evaluated with the one-way analysis of
variance (ANOVA). Values were expressed as means
Volume 89, Number 11
www.entjournal.com 547
CINGI, SONGU, URAL, YILDIRIM, ERDOGMUS, BAL
10
8-
< 6 -
i
c 4 -
2-
Q Active drug
m Placebo
Pretreatment Day 3 Day 7
Figure 1. Chart shows the mean pre-, peri-, and post-treatment VAS scores for pain
intensity in the two groups. Subsequent to the initiation of treatment, the differences
between the two groups were statistically significant (p < 0.001 on day 3 and p =
0.002 on day 7).
100 -
90 -
o 70 -
^ 60-
.? 50-
"2 40-
S 30-
20 -
10 -
0 -
D Active drug
H Placebo
Pretreatment Day 7
Figure 2. Chart shows the mean pre- and post-treatment SF-36 scores for quality of life
in the two groups. The difference on day 7 was statistically significant (p < 0.001).
(SD). Statistical significance was accepted for p values
of<0.05.
The study protocol was approved by the Ethics Com-
mittee of Osmangazi University Medical Faculty, and a
consent form was signed by each study patient.
Resuits
Of the 188 patients who met our inclusion criteria,
24 did not complete the trial. Five dropouts said they
could not get time off work to attend the initiation and
follow-up sessions, another 5 felt that treatment was of
no benefit (3 in the active treatment group and 2 in the
control group), 3 said they were too ill to continue with
the trial, and 2 moved to a different area. The rest cited
various other reasons.
The final study population consisted of 164 patients
94 males, aged 17 to 81 years (mean: 37.43 15.94) and
70 females, aged 17 to 71 years (mean: 38.31 16.16).
Of these patients, 80 had been randomized to the active
treatment group and 84 to the control
group. There were no significant dif-
ferences between the two groups in
the distribution of sex (p = 0.413) and
age (p = 0.935).
All patients took their medications as
directed, and none took any additional
medication.
Intensity of pain. Prior to treatment,
the mean VAS score for pain intensity
was 7.41 ( 1.49) in the active treatment
group and 7.76 (1.51) in the control
groupnot a statistically significant
difference (p = 0.938). At day 3 of
treatment, the corresponding seores
were 4.15 (+1.20) and 6.31 (+1.06),
whieh did represent a statistieally
signifieant differenee (p < 0.001). On
day 7, the trend eontinued, as the re-
speetive seores were 2.83 (1.09) and
5.01 (0.99), whieh also represented a
signifieant differenee in favor of aetive
treatment (p = 0.002) (figure 1).
QuaJyo/i/c. At baseline, there was
no signifieant differenee in mean SF-36
seores between the aetive treatment
group and the eontrol group56.24
(18.44) and 48.50 (16.80), respee-
tively (p = 0.79). By day 7, however, the
differenee between the two groups was
statistieally signifieant in favor of the
aetive treatment71.34 (11.10) and 54.37 (12.10),
respeetively (p < 0.001) (figure 2). In faet, a signifieant
improvement in quality of life over time oeeurred in
both the aetive treatment and eontrol groups (p < 0.001 )
eompared with baseline.
Side effects. Analysis revealed no signifieant differenee
between the two groups in side effeet scores on either
day 3 (p = 0.403) or day 7 (p ^ 0.938) (figure 3). The
degree of side effects was minor, and overall, the active
drug was well tolerated.
Discussion
Acute pharyngitis is one ofthe more common conditions
encountered in oflice practice, accounting for 2% of all
ambulatory visits in the United States.^'" Overtreatment
of acute pharyngitis represents one ofthe major causes
of antibiotic abuse, and the Centers for Disease Control
and Prevention have launched a campaign to dissuade
clinicians from routinely prescribing antibiotics for
548 www.entiournal.com
ENT-Ear, Nose & Throat Journal November 2010
EFFECTS OF CHLORHEXIDINE/BENZYDAMINE MOUTH SPRAY ON PAIN AND OUALITY OF LIFE IN ACUTE VIRAL PHARYNGITIS-
A PROSPECTIVE, RANDOMIZED, DOUBLE-BUND, PLACEBO-CONTROLLED, MULTICENTER STUDY
20 -,
16
S
(A
I
12 -
8 -
4 -
pharyngitis." For patients with acute
pharyngitis, the goals of supportive
treatment are to reduce inammation
and the intensity of pain while attempt-
ing to maintain oral intake in order
to avoid dehydration and subsequent
hospitalization.^ Such a strategy would
be expected to improve a patient's
quality of life.
At the moment, numerous phar-
maceutical products that contain dis-
infectants, anti-inflammatory agents,
and/or topical anesthetics are being
prescribed for the local treatment
of acute pharyngitis.^'^ In our study,
we used a mouth spray that contains
chlorhexidine and benzydamine." Ghlorhexidine is an
antimicrobial agent that is frequently used for its topi-
cal antiseptie efeets, and benzydamine is an effeetive
anti-inflammatory and analgsie. The effieaey of ehlo-
rhexidine against gingivitis and reeurrent uleers in the
oral mueosa has been demonstrated in the literature.'^"
Moreover, Bernstein et al eonfirmed the antiviral effi-
eaey of ehlorhexidine against influenza, parainfluenza,
eytomegalovirus, and herpes simplex virus infeetions.'"*
Also, Park and Park showed the signifieant antiviral
effect of ehlorhexidine in vitro."
In our study, we found that ehlorhexidine/benzy-
damine mouth spray signifieantly redueed the intensity
of pain and signifieantly improved the quality of life over
time. The eombination exerted these benefieial effeets
without causing any serious side effects. Some patients
in the treatment group who did report side effects
cited some taste disturbances, oral mucosal numbness,
and discoloration of the teeth for a few days following
treatment. But overall, side effects were mild, and there
was no significant difference between the two groups
in side effect scores. This combination product was well
tolerated at the prescribed dosage.
In conclusion, topical treatment modalities are
becoming more popular in view of their low rates of
systemic side effeets. We believe that ehlorhexidine/
benzydamine mouth spray may prove to beeome a good
addition to the standard treatment armamentarium for
aeute pharyngitis if our findings are borne out in further
researeh. We also believe that it would be worthwhile to
assess the effieaey of this treatment in GABHS tonsil-
lopharyngitis in larger sample sizes and with different
eontrol protoeols.
Volume 89, Number 11
Active drug
D Placebo
Day 3 Day 7
Figure 3. Chart shows the mean Likert scale scores for side effects in the two groups.
The differences were not statistically significant on either day 3 (p = 0.403) or day
(p = 0.938).
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