Current Medical Research and Opinion

ISSN: 0300-7995 (Print) 1473-4877 (Online) Journal homepage: http://www.tandfonline.com/loi/icmo20

Efficacy of flurbiprofen 8.75 mg lozenge in patients

with a swollen and inflamed sore throat

Sue Aspley, Adrian Shephard, Emily Schachtel, Kathleen Sanner, Laurie

Savino & Bernard Schachtel

To cite this article: Sue Aspley, Adrian Shephard, Emily Schachtel, Kathleen Sanner, Laurie
Savino & Bernard Schachtel (2016): Efficacy of flurbiprofen 8.75 mg lozenge in patients
with a swollen and inflamed sore throat, Current Medical Research and Opinion, DOI:
10.1080/03007995.2016.1187119

To link to this article: http://dx.doi.org/10.1080/03007995.2016.1187119

Accepted author version posted online: 05

May 2016.

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Download by: [University of California Santa Barbara] Date: 09 May 2016, At: 01:38
 ORIGINAL ARTICLE

Efficacy of flurbiprofen 8.75 mg lozenge in patients with a swollen and inflamed sore throat

Sue Aspley,1 Adrian Shephard,1 Emily Schachtel,2 Kathleen Sanner,2 Laurie Savino,2 Bernard

Schachtel2,3

1
Reckitt Benckiser Healthcare International Ltd, Slough, Berkshire, UK; 2Schachtel Research

Company, Jupiter, FL, USA; 3Department of Epidemiology & Public Health, Yale University

School of Medicine, New Haven, CT, USA

Address for Correspondence: Adrian Shephard, Senior Global Professional Relations

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Manager, Reckitt Benckiser, Turner House, 103–105 Bath Road, Slough, Berkshire, SL1
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3UH, UK. Phone: +44 (0)1753 446748; adrian.shephard@rb.com

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[Short title: Flurbiprofen lozenge for swollen and inflamed sore throat]
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Key words: Pharyngitis, sore throat, inflammation, swollen, non-steroidal anti-inflammatory drug,

flurbiprofen, acute pain

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 Abstract

Objective

Sore throat is often over-treated with antibiotics, therefore there is a need for non-antibiotic

treatments that provide effective relief. From the patient’s point of view, symptoms of pharyngeal

inflammation such as a “swollen” and “inflamed” throat are often considered the most bothersome;

so, a non-steroidal anti-inflammatory drug could be an appropriate treatment. We investigated the

efficacy and safety of flurbiprofen 8.75 mg lozenge in adults with a swollen and inflamed throat.

Research design and methods

We enrolled adults with moderate-to-severe sore throat and evidence of tonsillo-pharyngitis into a

randomised, double-blind study. Patients received flurbiprofen 8.75 mg or placebo lozenges every

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3–6 hours as needed (up to five lozenges in 24 hours) and rated their symptoms (sore throat pain,
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difficulty swallowing and the sensation of a swollen throat) on standard linear scales regularly over

24 hours. Efficacy of flurbiprofen lozenge was determined in patients reporting a swollen and
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inflamed throat at baseline.

Clinical trial registration

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ClinicalTrials.gov NCT01049334
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Main outcome measures

The main outcome measures were the time-weighted summed differences in patient-reported sore
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throat pain, difficulty swallowing and swollen throat over 24 hours.

Results
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124 of 204 patients (60.8%) described their throats as swollen and inflamed. Flurbiprofen lozenges

provided greater relief than placebo over 24 hours: 79.8%, 99.6% and 69.3% (for sore throat pain,

difficulty swallowing and swollen throat, respectively, all P≤0.01). These outcomes were more

substantial in patients with relatively severe symptoms. No serious or unexpected adverse events

occurred.
 Conclusions

Flurbiprofen 8.75 mg lozenge appears to provide effective, well-tolerated relief of sore throat,

difficulty swallowing and swollen throat in adults with a swollen and inflamed throat. A limitation

of these findings is that, while predetermined, these are secondary outcomes derived from a targeted

sub-group of patients, not the entire study population.

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 Introduction

Sore throat is a symptom of inflammation in the pharynx and/or tonsils1,2, and is one of the most

common reasons for patient visits to healthcare providers3. Viral upper respiratory tract infections

(URTIs) such as the common cold are responsible for most cases (in 85–95% of adults)4,5. For this

reason (and because non-infectious factors can also trigger a sore throat6,7), antibiotic treatment

should be reserved for patients in whom infection by group A β-haemolytic streptococcus is strongly

suspected or confirmed by culture8,9, or for patients who are severely unwell or at high risk of

complications10.

The association between inflammation and sore throat has been demonstrated in studies

where nasal or oropharyngeal challenge with inflammatory mediators (bradykinin and

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prostaglandins) resulted in symptoms of sore throat11–13. Furthermore, research has shown a positive
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correlation between objective indicators of pharyngeal inflammation on the Tonsillo-Pharyngitis

Score (TPS; a 4-point categorical pain intensity scale) (oral temperature, oropharyngeal colour,
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cervical adenopathy and cervical adenitis) and the intensity of sore throat pain (r=0.63; P<0.001)1.

The TPS has since been expanded to include an additional sign of inflammation, tonsillar
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enlargement, and is referred to as the Tonsillo-Pharyngitis Assessment (TPA). This index has been
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used in a number of clinical studies to confirm the inflammatory findings and diagnosis of

pharyngitis in patients with acute sore throat14–16, and some of the indicators in the TPA have been
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shown to correlate more with likelihood of streptococcal infection and physician perceptions of

streptococcal infection17,18.
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The pain and discomfort of a sore throat can have a significant impact on normal daily

activities. In an online survey conducted in the UK, France, Poland and Malaysia, 55% of

respondents reported not being able to function as normal, a lack of energy or reduced ability to

concentrate during episodes of throat discomfort19. In the USA, the common cold is estimated to

cause 70 million lost working days annually due to employees being ill (with an additional 126

million working days lost by parents caring at home for ill children with colds) with significant
 annual economic impact20. Since sore throat is a major symptom of the common cold and a reason

for professional healthcare consultation for advice and reassurance21, it should not be considered a

trivial ailment.

There are different qualities of discomfort that patients with sore throat experience and

complain of, including the sensation of a swollen throat and difficulty swallowing1,22. Relief of these

symptoms is a driver of patients’ consultations with healthcare providers and, of note, their

antibiotic-seeking behaviour21,23. Indeed, a recent study reports that patients with more severe or

painful throat symptoms are more likely to visit their doctor and more likely to take antibiotics23.

Because inflammation is the underlying cause of pharyngitis, treatment of sore throat with lozenges

that contain a non-steroidal anti-inflammatory drug (NSAID) such as flurbiprofen, which inhibits

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prostaglandin synthesis, should offer therapeutic advantages for patients with sore throat, including
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those with relatively severe symptoms24,25.

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The 8.75 mg dose of flurbiprofen has been shown to be a safe, effective, low dose for the
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relief of sore throat14,25,26, thus adhering to the principle of utilising the lowest possible dose of

medication to achieve an optimal efficacy/safety profile27. In randomised, double-blind, placebo-

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controlled trials, flurbiprofen 8.75 mg lozenge has demonstrated effectiveness at reducing throat pain
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and soreness25,26,28–30, difficulty swallowing28–30 and the sensation of a swollen throat26,29,30 with an

immediate onset of activity29 in patients with painful pharyngitis, including those with or without
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streptococcal infection31.

To our knowledge, there is little published evidence on the efficacy of any treatment in
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patients who experience relatively severe sore throat symptoms and are more likely to seek care from

a healthcare provider32. Among these patients, the symptoms of a “swollen” and “inflamed” sore

throat rank high as most bothersome and worrisome (perhaps because of the severity of these

symptoms or patients’ anxiety about the consequences of these symptoms)22,23. Here we present an

evaluation of the efficacy and safety of flurbiprofen 8.75 mg lozenges in such patients, who describe

their throat as swollen and inflamed. We examined efficacy in terms of the reduction of sore throat
 pain, difficulty swallowing and swollen throat on validated instruments that measure these patient-

reported outcomes33,34. To further characterise the pharmacological profile of flurbiprofen 8.75 mg

lozenge in these patients, we also analysed these patient-reported outcomes in patients with

relatively severe symptoms.

Patients and methods

Study design

This was a sub-group analysis of a randomised, double-blind, placebo-controlled, multiple-

dose, single-centre, parallel group study of the efficacy of flurbiprofen 8.75 mg lozenges compared

with placebo lozenges in adult patients with acute sore throat29,31,35.

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This study was conducted from 2 November 2009 to 3 March 2011 at the student health unit
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of a US university in accordance with the International Conference on Harmonisation Good Clinical

Practice guidelines and the ethical principles contained within the Declaration of Helsinki (South
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Africa, 1996). The study also complied with the Code of Federal Regulations of the United States

Food and Drug Administration. Ethical approval was obtained from the university’s institutional
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review board.
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Study population

After informed consent was obtained from all potential subjects ≥18 years of age with
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recent-onset (≤4 days) sore throat29,35, patients who described their throat as swollen and inflamed

(in response to the question “How would you describe your sore throat?”), and who rated their
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throat pain as moderate or severe on the TPS, had at least one symptom of URTI on the URTI

Questionnaire36, and three symptoms commonly associated with sore throat using 100-mm visual

analogue scales: sore throat pain (≥66 mm on the Sore Throat Pain Intensity Scale [STPIS]),

difficulty swallowing (≥50 mm on the Difficulty Swallowing Scale [DSS]) and the sensation of a

swollen throat (≥33 mm on the Swollen Throat Scale [SwoTS])33,34. Evidence of pharyngeal

inflammation was also required, as documented by the practitioner’s physical findings on the
 TPA14, consisting of objective signs of tonsillo-pharyngitis (Table 1), and his/her assessment of the

presence and extent of pharyngeal inflammation on the Practitioner’s Assessment of Pharyngeal

Inflammation (PAIN; a four-category scale: none, mild, moderate, severe).

Exclusion criteria included known allergy and/or hypersensitivity to NSAIDs (including

aspirin) or acetaminophen, use of any throat lozenge, throat spray, cough drop or menthol-

containing product within 1 hour preceding the initial dose of study medication, use of any cold and

flu medications (e.g., decongestants, expectorants) or use of any immediate-release

analgesic/antipyretic within 4 hours (or any sustained-release analgesic/antipyretic within 12 hours)

preceding the initial dose of study medication, evidence of mouth-breathing due to nasal congestion

or coughing that caused throat discomfort, or any active physical disease (such as

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bronchopneumonia) which could compromise respiratory function.
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Study medications
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Patients were randomly assigned to treatment with sugar-based, flavoured,
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flurbiprofen 8.75 mg lozenges or sugar-based, identically flavoured matching vehicle

(placebo) lozenges according to a computer-generated randomisation list that was

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maintained by a statistician. All patients and study site personnel were blinded to treatment
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assignment.

The study nurse instructed patients to suck one lozenge (flurbiprofen 8.75 mg or
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placebo, as randomised). After the full dose was dissolved, the patient was not permitted to

have anything by mouth for the next 2 hours. Patients were then discharged from the clinic
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and supplied with the same assigned study lozenges for use every 3−6 hours as needed, up

to a total of five lozenges in 24 hours. Patients could use the assigned lozenges as needed for

up to 7 days. Rescue medication in the form of acetaminophen 650 mg every 4–6 hours, if

needed for sore throat pain, was permitted up to five times in 24 hours.

Study assessments
 After a medical history was obtained, patients underwent several evaluations at

baseline, including an assessment of vital signs, and the investigator performed a physical

examination, including, in particular, the TPA and a clinical assessment of the extent of

pharyngeal inflammation on the PAIN.

Patients reported throat symptoms on the STPIS, DSS and SwoTS at baseline and at

regular intervals over 24 hours. STPIS scores were reported every 2 minutes during the first

hour, every 10 minutes in the second hour, every 30 minutes from 2–6 hours, and every hour

(if awake) from 6–24 hours; DSS scores were reported every 10 minutes during the first 2

hours, every 30 minutes from 2 to 6 hours, and every hour (if awake) from 6–24 hours;

SwoTS scores were reported at 1 hour, every 10 minutes in the second hour, every 30

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minutes from 2–6 hours, and every hour (if awake) from 6–24 hours.
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All treatment-emergent adverse events (AEs) were recorded using Medical Dictionary for

Regulatory Activities (MedDRA) version 14.0 terminology.

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Statistical analyses

Efficacy was assessed in patients with swollen and inflamed throat by the time-weighted
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summed difference in STPIS, DSS and SwoTS over 24 hours after the initial dose of study
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medication. Patients with swollen and inflamed throat as well as relatively severe symptoms

(>median baseline STPIS/DSS/SwoTS score) were also analysed for each respective endpoint over
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24 hours.

To assess the effects of a single dose of study medication, the percentage changes from
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baseline in STPIS, DSS and SwoTS scores in patients with swollen and inflamed throat, as well as

those with relatively severe symptoms (>median baseline STPIS/DSS/SwoTS score) were

calculated over the first 6 hours after the initial dose. For patients who used additional flurbiprofen

8.75 mg or placebo lozenges in that period, all subsequent changes in STPIS/DSS/SwoTS values

over the 6 hours were set to zero according to the baseline observation carried forward (BOCF)

convention. If a patient used additional pain medication (acetaminophen), all subsequent

 STPIS/DSS/SwoTS scores in the 24-hour interval were assigned the BOCF. Missing scores were

imputed using linear interpolation assuming the time of the missing assessment to be the nominal

time since the initial dose. Efficacy was calculated using least square (LS) means and analysis of

variance (ANOVA) was used to compare the flurbiprofen 8.75 mg and placebo treatment groups,

with the relevant baseline included as a covariate with Bonferroni correction applied for multiple

comparisons. A two-group t-test analysis with a 0.050 two-sided significance level was used, which

provided 78% power to detect the difference between the flurbiprofen and placebo groups. Two-

sided statistical tests were performed with significance determined by reference to the 5%

significance level. All statistical analyses were performed using SAS version 9.2.

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Results
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Patient population
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Of 204 randomised patients, 124 (60.8%) described their throat as swollen and inflamed at
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baseline (Figure 1). Treatment groups (flurbiprofen 8.75 mg lozenge n=59, placebo lozenge n=65)

were generally balanced in terms of demographic and clinical characteristics, although the
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flurbiprofen group had fewer female patients (flurbiprofen 8.75 mg lozenge 42.4%, placebo lozenge
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64.6%) (Table 2). All patients with swollen, inflamed throat reported either moderate or severe

throat pain (on the TPS) and had evidence of tonsillo-pharyngitis (on the TPA). Most (70.9%)
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patients had evidence of moderate or severe pharyngeal inflammation (on the PAIN) and 65.3% had

moderately or much enlarged tonsils (on the TPA).

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Efficacy

Patients with swollen and inflamed throat had greater (79.8%) reduction of sore throat pain

after treatment with flurbiprofen 8.75 mg lozenges than with placebo (P<0.01) (Figure 2a) over 24

hours. In patients that also had relatively severe sore throat pain (baseline STPIS score >80.5 mm),

flurbiprofen 8.75 mg lozenges also provided greater (135.7%) reduction of sore throat pain than

placebo-treated patients (P<0.01) (Figure 2b) over 24 hours.

 For all patients with swollen and inflamed throat, there was 99.6% greater reduction of

difficulty swallowing with flurbiprofen 8.75 mg lozenges compared with placebo (P<0.01) (Figure

3a) over 24 hours. For patients who also had relatively severe difficulty swallowing (baseline DSS

score >77.5 mm), flurbiprofen 8.75 mg lozenges provided 105.4% greater improvement in

swallowing than placebo (P<0.01) (Figure 3b) over 24 hours.

The sensation of a swollen throat was also reduced (69.3%) by treatment with flurbiprofen

8.75 mg lozenges compared with placebo (P<0.05) (Figure 4a) over 24 hours in patients with

swollen and inflamed throat. For patients who also had a relatively severely swollen throat (baseline

SwoTS score >81.5 mm), flurbiprofen 8.75 mg lozenges provided 148.6% greater reduction in

throat swelling than placebo (P<0.001) (Figure 4b) over 24 hours.

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Patients experienced reduction of sore throat pain after the initial single flurbiprofen 8.75
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mg lozenge compared with placebo lozenge from 22–210 minutes (P<0.05) (Figure 5a). Similarly,

reduction of difficulty swallowing beginning at the first measurement time, 10 minutes, through 210
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minutes was also observed (P<0.05) (Figure 5b). For the sensation of a swollen throat, flurbiprofen

8.75 mg lozenge provided greater relief than placebo, beginning at the first assessment of swollen
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throat (at 60 minutes) through 180 minutes (P<0.05) (Figure 5c). Improvement of sore throat pain
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and swallowing after a single dose of study medication was similar for patients with relatively

severe symptoms, with onset differentiated between flurbiprofen 8.75 mg and placebo beginning at
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approximately 30–40 minutes through 180 minutes (P<0.05) (Figures 6a–c).

Use of additional pain medication

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Acetaminophen 650 mg was taken by 14 patients (23.7%) in the flurbiprofen (n=59) group

and 17 patients (26.2%) in the placebo group (n=65) during the first 24 hours. In each group a total

of 25 doses of acetaminophen 650 mg were taken with a minimum of one dose per subject up to a

maximum of four doses per subject.

 Safety

The number of patients who reported any AE during the initial 24 hours was similar for both

treatment groups: 15 (25.4%) in the flurbiprofen 8.75 mg group and 18 (27.7%) in the placebo

group (P=0.775). The most common AEs were headache, nausea and upper abdominal pain (Table

3), with no difference in the number of patients with any gastrointestinal disorder: 8 (13.6%) in the

flurbiprofen 8.75 mg treatment group, 6 (9.2%) in the placebo group (P=0.447). No serious or

unexpected AEs occurred during the study.

Discussion

In our placebo-controlled trial on patients with a swollen and inflamed sore throat,

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flurbiprofen 8.75 mg lozenges provided effective and well-tolerated relief of sore throat pain,
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difficulty swallowing and the sensation of a swollen throat, with onset from the first assessment

(due to the demulcency of the lozenge), reaching statistical significance at 10 minutes.

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These effects of flurbiprofen 8.75 mg lozenge were also observed in patients with relatively

severe symptoms (i.e., those with baseline symptom scores greater than the median score for each
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symptom). Although these more severe symptoms are more resilient to pharmacological effects
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(especially with this low dose of flurbiprofen), the beneficial effects of flurbiprofen 8.75 mg were

pronounced compared with placebo. For the symptom of sore throat pain, for example, patients with
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relatively severe swollen and inflamed throat reported 135.7% greater efficacy after treatment with

flurbiprofen 8.75 mg than placebo (P<0.01). Evidence of efficacy was also noted in patients with
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relatively severe difficulty swallowing and swollen throat (both P<0.01). Additional pain

medication was used with the same frequency in both treatment groups, thus not influencing the

efficacy analyses.

Safety outcomes were similar between flurbiprofen 8.75 mg and placebo lozenges, in accord

with findings from previous studies25,26,28–30. Although oral NSAIDs administered in prescription-

strength dosages for extended periods of time may be associated with gastrointestinal side effects,
 the gastrointestinal tolerability of this low dose (8.75 mg) of flurbiprofen delivered in a topical

(lozenge) format seems to be comparable to that of placebo lozenge containing vehicle ingredients.

In this study (on patients with sore throat which they describe as swollen and inflamed),

flurbiprofen 8.75 mg lozenge appears to be an effective and well-tolerated treatment.

Of further clinical and practical significance, flurbiprofen 8.75 mg lozenges may be a

preferable treatment option to antibiotics for these patients who complain of more bothersome

symptoms. They tend to be the patients who consult their family physician in the hope and intention

of receiving an antibiotic prescription21,23 and, as identified in some guidelines, the patients who are

more likely to receive antibiotics37. However, given the dangers of antibiotic resistance, the

potential side effects of antibiotics, and the fact that only a small percentage of adults with sore

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throat (approximately 10%) have group A β-haemolytic streptococcal infection5,8,9, it may be more
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prudent (and safer) for healthcare providers to recommend flurbiprofen 8.75 mg lozenge as a first-

line treatment for patients presenting with a painful, swollen/inflamed sore throat, which can be
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combined later with antibiotics if/when required28. Furthermore, there is evidence to show that

antibiotic treatment does not provide additional symptomatic relief for sore
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throat beyond that provided by flurbiprofen 8.75 mg lozenges31,38.

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One potential limitation of this study is that the age of the study population comprised only

young adults. However, sore throat occurs more frequently in younger people8. This frequency
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decreases with age as people eventually develop immunity through exposure to viral causes earlier

in life8. Furthermore, conducting the study in young adults could be advantageous as they may have
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fewer co-morbidities which may have influenced the study results. Another limitation of this study

is that it was not designed to investigate the efficacy of flurbiprofen 8.75 mg lozenge for the relief

of sore throat symptoms only in patients with inflamed, swollen sore throat. These patients

comprised only a part (60%) of the entire study sample, and thus this report presents an analysis in a

sub-group of patients. However, because patients who describe the throat as swollen and inflamed
 are those most likely to seek medical intervention, the importance of these findings to practitioners

is clear.

Conclusion

This study indicates that flurbiprofen 8.75 mg lozenges are well tolerated and provide

effective relief of sore throat, difficulty swallowing and swollen throat in patients reporting a

swollen and inflamed throat. Since these are the patients who are most likely to be seeking advice

(and antibiotic treatment), healthcare providers can recommend flurbiprofen 8.75 mg lozenges as a

treatment option for these patients to provide relief, including those with relatively severe

symptoms, specifically for the first few days when symptoms are worst39, thus helping reduce

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unnecessary antibiotic prescribing.
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Transparency

Declaration of funding
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This study was sponsored by Reckitt Benckiser Healthcare International Ltd, UK.

Declaration of financial/other relationships

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SA and AS are employees of Reckitt Benckiser Healthcare International Ltd. BS and ES received
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an investigational grant from Reckitt Benckiser Healthcare International Ltd to design and conduct

this study with KS and LS. KS and LS declare no conflicts of interest. CMRO Peer Reviewers on
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this manuscript have no relevant financial relationships to disclose.

Acknowledgments
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Medical writing assistance was provided by Papia Das (Elements Communications Ltd, UK) and

funded by Reckitt Benckiser Healthcare International Ltd. The authors would like to thank Gary

Smith for his role in the initial analysis and interpretation of the data, and for his help in drafting the

original submitted version of the manuscript. The authors would also like to thank Antonio

Cagnazzo for his further analysis and interpretation of the data.

 Previous presentation:

Some of the data have been previously published as an abstract (and presented as a poster) at the

14th World Congress on Pain, 27–31 August 2012, Milan, Italy: Schachtel B, et al. Efficacy of

flurbiprofen 8.75mg lozenges in patients with swollen/inflamed sore throat.

References

1. Schachtel BP, Fillingim J M, Beiter DJ, et al. Subjective and objective features of sore throat.

Arch Internal Med 1984;144:497–500

2. Bathala S, Eccles R. A review on the mechanism of sore throat in tonsillitis. J Laryngol Otol

2013;127:227–32

D
3. Kenealy T. Sore throat. BMJ Clin Evid 2014;3:1509
Current Medical Research and Opinion

TE
4. Eccles R. Mechanisms of symptoms of the common cold and influenza. Br J Hosp Med (Lond)

2007;68:71–5
EP
5. Worrall GJ. Acute sore throat. Can Fam Physician 2007;53:1961–2

6. Renner B, Mueller CA, Shephard A. Environmental and non-infectious factors in the aetiology
C

of pharyngitis (sore throat). Inflamm Res 2012;61:1041–52

AC

7. Renner B, Ahne G, Grosan E, et al. Tonic stimulation of the pharyngeal mucosa causes pain and

a reversible increase of inflammatory mediators. Inflamm Res 2013;62:1045–51

ST

8. ESCMID Sore Throat Guideline Group, Pelucchi C, Grigoryan L, et al. Guideline for the

management of acute sore throat. Clin Microbiol Infect 2012;18(Suppl. 1):1–28

JU

9. Shulman ST, Bisno AL, Clegg HW, et al. Clinical practice guideline for the diagnosis and

management of group A streptococcal pharyngitis: 2012 update by the Infectious Diseases

Society of America. Clin Infect Dis 2012;55:1279–82

10. Essack S, Pignatari AC. A framework for the non-antibiotic management of upper respiratory

tract infections: towards a global change in antibiotic resistance. Int J Clin Pract 2013;67(Suppl.

180):4–9
 11. Proud D, Reynolds CJ, Lacapra S, et al. Nasal provocation with bradykinin induces symptoms

of rhinitis and a sore throat. Am Rev Respir Dis 1988;137:613–6

12. Doyle WJ, Boehm S, Skoner DP. Physiologic responses to intranasal dose-response challenges

with histamine, methacholine, bradykinin, and prostaglandin in adult volunteers with and

without nasal allergy. J Allergy Clin Immunol 1990;86:924–35

13. Rees GL, Eccles R. Sore throat following nasal and oropharyngeal bradykinin challenge. Acta

Otolaryngol 1994;114:311–4

14. Schachtel BP, Homan HD, Gibb IA, et al. Demonstration of dose response of flurbiprofen

lozenges with the sore throat pain model. Clin Pharmacol Ther 2002;71:375–80

15. Schachtel BP, Pan S, Kohles JD, et al. Utility and sensitivity of the sore throat pain model:

D
results of a randomized controlled trial on the COX-2 selective inhibitor valdecoxib. J Clin
Current Medical Research and Opinion

Pharmacol 2007;47:860–70
TE
16. Wade G, Morris C, Shephard A, et al. A multicentre, randomised, double-blind, single-dose
EP
study assessing the efficacy of AMC/DCBA Warm lozenge or AMC/DCBA Cool lozenge in the

relief of acute sore throat. BMC Fam Pract 2011;12:6

C

17. Schachtel B, Shephard A, Smith G, et al. Subjective and objective indicators of group A
AC

streptococcal sore throat. Abstract presented at the 19th World Organization of National

Colleges, Academies and Academic Associations of General Practitioners/Family Physicians

ST

(WONCA) Europe Conference, 2–5 July 2014, Lisbon, Portugal

JU

18. Shephard A, Schachtel B, Smith G, et al. Clinical Features of Group A Streptococcal Throat

Infection: Findings from Randomised Controlled Trials. Malays Fam Physician

2014;9(Supplement 1):83

19. Addey D, Shephard A. Incidence, causes, severity and treatment of throat discomfort: a four-

region online questionnaire survey. BMC Ear Nose Throat Disord 2012;12:9
 20. Fendrick AM, Monto AS, Nightengale B, et al. The economic burden of non-influenza-related

viral respiratory tract infection in the United States. Arch Intern Med 2003;163:487–94

21. van Driel ML, De Sutter A, Deveugele M, et al. Are sore throat patients who hope for

antibiotics actually asking for pain relief? Ann Fam Med 2006;4:494–9

22. Schachtel BP, Aspley S, Berry P, et al. Chief complaint: the therapeutogenic stimulus as the

primary, individualized endpoint in clinical trials. J Pain 2012;13(Suppl.):S6

23. Shephard A. A questionnaire-based study in 12 countries to investigate the drivers of antibiotic-

seeking behavior for sore throat. J Fam Med Comm Health 2014;1:1014

24. Sefia E, Mann A, Lambkin R, et al. Flurbiprofen lozenges rapidly reduce levels of the

inflammatory mediator prostaglandin E in human respiratory cells in vitro. Abstract presented at

D
the Annual Scientific Meeting of the British Pain Society, Glasgow, Scotland, April 2007
Current Medical Research and Opinion

TE
25. Watson N, Nimmo WS, Christian J, et al. Relief of sore throat with the anti-inflammatory throat

lozenge flurbiprofen 8.75 mg: a randomised, double-blind, placebo-controlled study of efficacy

EP
and safety. Int J Clin Pract 2000;54:490–6

26. Benrimoj SI, Langford JH, Christian J, et al. Efficacy and tolerability of the anti-inflammatory
C

throat lozenge flurbiprofen 8.75mg in the treatment of sore throat: a randomized, double-blind,
AC

placebo-controlled study. Clin Drug Investig 2001;21:183–93

27. National Prescribing Centre. Cardiovascular and gastrointestinal safety of NSAIDs. MeReC
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Extra Issue No. 30. November 2007

28. Blagden M, Christian J, Miller K, et al. Multidose flurbiprofen 8.75 mg lozenges in the
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treatment of sore throat: a randomised, double-blind, placebo-controlled study in UK general

practice centres. Int J Clin Pract 2002;56:95–100

29. Schachtel BP, Aspley S, Shephard A, et al. Onset of action of a lozenge containing flurbiprofen

8.75mg: a randomized, double-blind, placebo-controlled trial with a new method for measuring

onset of analgesic activity. Pain 2014;155:422–8

 30. Schachtel BP, Aspley S, Shephard A, et al. Utility of the sore throat pain model in a multiple-

dose assessment of the acute analgesic flurbiprofen: a randomized controlled study. Trials

2014;15:263

31. Shephard A, Smith G, Aspley S, et al. Randomised, double-blind, placebo-controlled studies on

flurbiprofen 8.75 mg lozenges in patients with/without group A or C streptococcal throat

infection, with an assessment of clinicians' prediction of 'strep throat'. Int J Clin Pract

2015;69:59–71

32. Uztüre N, Menda F, Bilgen S, et al. The Effect of Flurbiprofen on Postoperative Sore Throat

and Hoarseness After LMA-ProSeal Insertion: A Randomised, Clinical Trial. Turk J Anaesth

Reanim 2014;42:123–7

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33. Schachtel BP, Fillingim JM, Beiter DJ, et al. Rating scales for analgesics in sore throat. Clin
Current Medical Research and Opinion

Pharmacol Ther 1984;36:151–6

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34. Schachtel BP, Fillingim JM, Thoden WR, et al. Sore throat pain in the evaluation of mild
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analgesics. Clin Pharmacol Ther 1988;44:704–11

35. Aspley S, Schachtel BP, Berry P, et al. Treatment of odynophagia and dysphagia by
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flurbiprofen 8.75 mg lozenges. Pain Res Manage 2012;17:203

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36. Schachtel BP, Fillingim JM, Klausner MA, Minor MG. A placebo-controlled model for

assessing the symptomatic relief of nasal congestion. Clin Pharmacol Ther 1990;47:152
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37. Chiappini E, Regoli M, Bonsignori F, et al. Analysis of different recommendations from

international guidelines for the management of acute pharyngitis in adults and children. Clin
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Ther 2011;33:48–58

38. Shephard A, Smith G, Aspley S, Schachtel B. Symptomatic relief in streptococcal and non-

streptococcal sore throat patients: pooled analysis of two randomised, placebo-controlled

studies. Abstract presented at the European Congress of Clinical Microbiology and Infectious

Diseases (ECCMID), 27–30 April 2013, Berlin, Germany.

 39. Spinks A, Glasziou PP, Del Mar CB. Antibiotics for sore throat. Cochrane Database Syst Rev

2013;11:CD000023.

Figure 1. Patient flow through the study

Figure 2. ANOVA comparing time-weighted summed reduction over 24 hours in STPIS in

patients with a) a swollen and inflamed throat and b) a swollen and inflamed throat and

baseline STPIS >80.5 mm

ANOVA, analysis of variance; CI, confidence interval; LS, least square; STPIS, Sore Throat Pain

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Intensity Scale.
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Figure 3. ANOVA comparing time-weighted summed reduction over 24 hours in DSS in patients

with a) a swollen and inflamed throat and b) a swollen and inflamed throat and baseline DSS
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>77.5 mm
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ANOVA, analysis of variance; CI, confidence interval; DSS, Difficulty Swallowing Scale; LS, least
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square.
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 Figure 4. ANOVA comparing time-weighted summed reduction over 24 hours in SwoTS in

patients with a) a swollen and inflamed throat and b) a swollen and inflamed throat and baseline

SwoTS >81.5 mm

ANOVA, analysis of variance; CI, confidence interval; LS, least square; SwoTS, Swollen Throat

Scale.

Figure 5. ANOVA comparing percentage reduction from baseline in a) STPIS, b) DSS and c)

SwoTS, following a single dose of study medication in patients with a swollen and inflamed

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throat
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a) Reductions in STPIS were greater (P<0.05) with flurbiprofen 8.75 mg compared with placebo
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from 22–210 minutes.

b) Reductions in DSS were greater (P<0.05) with flurbiprofen 8.75 mg compared with placebo
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from 10–210 minutes.

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c) Reductions in SwoTS were greater (P<0.05) with flurbiprofen 8.75 mg compared with placebo

from 60–180 minutes.

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ANOVA, analysis of variance; DSS, Difficulty Swallowing Scale; LS, least square; STPIS, Sore

Throat Pain Intensity Scale; SwoTS, Swollen Throat Scale.

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 Figure 6. ANOVA comparing percentage reduction from baseline in a) STPIS, b) DSS and c)

SwoTS, following a single dose of study medication in patients with a swollen and inflamed

throat and baseline scores >median

a) Reductions in STPIS were greater (P<0.05) with flurbiprofen 8.75 mg compared with placebo

from 24–26 minutes and from 32–180 minutes.

b) Reductions in DSS were greater (P<0.05) with flurbiprofen 8.75 mg compared with placebo

from 40–180 minutes.

c) Reductions in SwoTS were greater (P<0.05) with flurbiprofen 8.75 mg compared with placebo

from 60–180 minutes.

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ANOVA, analysis of variance; DSS, Difficulty Swallowing Scale; LS, least square; STPIS, Sore
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Throat Pain Intensity Scale; SwoTS, Swollen Throat Scale.

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 Table 1. Tonsillo-Pharyngitis Assessment

Table 2. Baseline demographics and characteristics

DSS, Difficulty Swallowing Scale; PAIN, Practitioner’s Assessment of Pharyngeal Inflammation;

SD, standard deviation; STPIS, Sore Throat Pain Intensity Scale; SwoTS, Swollen Throat Scale;

TPA, Tonsillo-Pharyngitis Assessment; TPS, Throat Pain Scale.

Table 3. Adverse events reported by ≥2% of patients in either treatment group over 24 hours

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Data show number (and percentage) of patients with the adverse event.
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 Table 1. Tonsillo-Pharyngitis Assessment

Item 0 points 1 point 2 points 3 points

Oral temperature ≤98.6°F 98.7–98.9°F 99.0–99.9°F ≥100.0°F

Oropharyngeal colour Normal/pink Slightly red Red Beefy red

Size of tonsils Normal/absent Slightly enlarged Moderately Much enlarged

enlarged

Number of None Few Several Many

oropharyngeal

enanthems (vesicles,

petechiae or exudates)

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Number of anterior Normal Slightly Moderately Greatly
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cervical lymph nodes

Largest size of anterior Normal

increased

Slightly enlarged
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Moderately
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Much enlarged
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cervical lymph nodes enlarged

Maximum tenderness Not tender Slightly tender Moderately Very tender

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of anterior cervical tender

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lymph nodes
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 Table 2. Baseline demographics and characteristics

Baseline characteristic Flurbiprofen Placebo Overall

8.75 mg
(n=65) (n=124)

(n=59)

Age, years

Mean ± SD 19.8 ± 1.71 19.6 ± 1.43 19.7 ± 1.57

Median (range) 19.0 (18.0–26.0) 20.0 (18.0–24.0) 19.0 (18.0–26.0)

Female, % 42.4 64.6 54.0

Throat pain (TPS), %

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Moderate 52.5 56.9 54.8
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Severe 47.5
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Pharyngeal inflammation (PAIN), %

Mild inflammation 27.1 30.8 29.0

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Moderate inflammation 54.2 55.4 54.8

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Severe inflammation 18.6 13.8 16.1

Size of tonsils, %
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Normal 5.1 9.2 7.3

Slightly enlarged 28.8 26.2 27.4

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Moderately enlarged 40.7 38.5 39.5

Much enlarged 25.4 26.2 25.8

TPA overall score

Mean ± SD 10.2 ± 2.66 10.4 ± 2.85 10.3 ± 2.75

 Median (range) 10.0 (6.0–17.0) 10.0 (5.0–17.0) 10.0 (5.0–17.0)

STPIS, mm

Mean ± SD 79.7 ± 9.12 80.3 ± 7.86 80.0 ± 8.45

Median (range) 80.0 (64.0–100.0) 81.0 (66.0–95.0) 80.5 (64.0–100.0)

DSS, mm

Mean ± SD 77.9 ± 12.29 76.0 ± 11.59 76.9 ± 11.92

Median (range) 80.0 (45.0–98.0) 76.0 (46.0–100.0 77.5 (45.0–100.0)

SwoTS, mm

Mean ± SD 80.3 ± 11.5 80.8 ± 11.38 80.6 ± 11.39

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Median (range) 81.0 (42.0–97.0) 82.0 (46.0–100.0) 81.5 (42.0–100.0)

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DSS, Difficulty Swallowing Scale; PAIN, Practitioner’s Assessment of Pharyngeal Inflammation; SD, standard
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deviation; STPIS, Sore Throat Pain Intensity Scale; SwoTS, Swollen Throat Scale; TPA, Tonsillo-Pharyngitis

Assessment; TPS, Throat Pain Scale.

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 Table 3. Adverse events reported by ≥2% of patients in either treatment group over

24 hours

Adverse event Flurbiprofen 8.75 Placebo Overall

mg
(n=65) (n=124)

(n=59)

Headache 1 (1.7) 5 (7.7) 6 (4.8)

Nausea 2 (3.4) 3 (4.6) 5 (4.0)

Upper abdominal pain 3 (5.1) 0 (0.0) 3 (2.4)

Paraesthesia 2 (3.4) 0 (0.0) 2 (1.6)

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Paraesthesia, oral 2 (3.4) 0 (0.0) 2 (1.6)
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Pyrexia 0 (0.0)
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2 (3.1)

Data show number (and percentage) of patients with the adverse event.
2 (1.6)
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