Int J Clin Pract. 2015 Jan;69(1):59-71. doi: 10.1111/ijcp.12536.

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’.

A Shephard,1 G Smith,1 S Aspley,1 BP Schachtel2

1Reckitt Benckiser Healthcare International Ltd, Slough, Berkshire, UK; 2Schachtel Research Company, Jupiter, FL, USA

 

Abstract

BACKGROUND: Diagnosing group A streptococcus (Strep A) throat infection by clinical examination is difficult, and misdiagnosis may lead to inappropriate antibiotic use. Most patients with sore throat seek symptom relief rather than antibiotics, therefore, therapies that relieve symptoms should be recommended to patients. We report two clinical trials on the efficacy and safety of flurbiprofen 8.75 mg lozenge in patients with and without streptococcal sore throat.

METHODS: The studies enrolled adults with moderate-to-severe throat symptoms (sore throat pain, difficulty swallowing and swollen throat) and a diagnosis of pharyngitis. The practitioner assessed the likelihood of Strep A infection based on historical and clinical findings. Patients were randomised to flurbiprofen 8.75 mg or placebo lozenges under double-blind conditions and reported the three throat symptoms at baseline and at regular intervals over 24 h.

RESULTS: A total of 402 patients received study medication (n = 203 flurbiprofen, n = 199 placebo). Throat culture identified Strep A in 10.0% of patients and group C streptococcus (Strep C) in a further 14.0%. The practitioners’ assessments correctly diagnosed Strep A in 11/40 cases (sensitivity 27.5%, and specificity 79.7%). A single flurbiprofen lozenge provided significantly greater relief than placebo for all three throat symptoms, lasting 3-4 h for patients with and without Strep A/C. Multiple doses of flurbiprofen lozenges over 24 h also led to symptom relief, although not statistically significant in the Strep A/C group. There were no serious adverse events.

CONCLUSIONS: The results highlight the challenge of identifying Strep A based on clinical features. With the growing problem of antibiotic resistance, non-antibiotic treatments should be considered. As demonstrated here, flurbiprofen 8.75 mg lozenges are an effective therapeutic option, providing immediate and long-lasting symptom relief in patients with and without Strep A/C infection.

PMID: 25296661

 

Supplements:

Upper Respiratory Tract Infections (URTIs) are one of the most common reasons for General Practitioner consultations,1-3 with sore throat (pharyngitis) being a frequent complaint of URTI.4 The majority of sore throats (85–95% in adults) are caused by viral infection, although some do result from bacterial infection.4-6 Diagnosis of the aetiology of sore throat is difficult and misdiagnosis often leads to inappropriate prescribing of antibiotics.7

Group A beta-haemolytic streptococcus (Strep A) is responsible for approximately 5–15% of sore throats in adults.4,5 Other streptococci (group C and G) have also been associated with the aetiology of sore throat in approximately 3–9% of cases,8-10 however, these are not known to be associated with complications that warrant antibiotics.6 Whether the cause is viral or bacterial, most sore throats resolve spontaneously within 3–7 days,11 with only a small proportion of patients requiring antibiotics. However, antibiotics are still inappropriately prescribed for sore throat around the world. This can lead to patients unnecessarily experiencing the side effects of antibiotics12,13 as well as contributing to the problem of antibiotic resistance.14 In fact, antibiotics have only modest effects on the treatment of sore throat, reducing symptom duration by an average of only 16 hours.11 Despite this, incorrect prescribing of antibiotics remains high, due to diagnostic uncertainty,15 direct pressure from the patient to prescribe antibiotics as well as the physician’s perception of patient pressure.16

Accurate identification of Strep A infection based on clinical features remains a challenge for clinicians as there is much overlap in the signs and symptoms of bacterial and viral pharyngitis.4 Many guidelines recommend a clinical examination with the use of a scoring system to make a diagnosis of pharyngitis caused by Strep A.6 Other guidelines recommend microbiological testing to determine the presence of an infection, however this can take up to 48 hours to produce a result.4,17

In order to refrain from contributing to the problem of antibiotic resistance, physicians should encourage patients to self-manage their sore throat.18 Previous clinical studies have demonstrated the effectiveness of flurbiprofen 8.75 mg lozenge for the relief of sore throat pain, difficulty swallowing and the sensation of a swollen throat in patients with sore throat.19-21 The aim of this research was to determine the safety and efficacy of flurbiprofen lozenge in patients with and without streptococcal infection. At the same time, the sensitivity and specificity of the clinical examination undertaken to diagnose Strep A pharyngitis were also assessed.

Because of the low incidence of streptococcal throat infection in adults, an analysis was performed based on results from two randomised, double-blind, placebo-controlled trials conducted in different practice settings.22-24 Both studies enrolled adults (≥ 18 years) with recent onset (≤ 4 days) sore throat, who had confirmed pharyngitis indicated by a score ≥ 5 on the Tonsillo-Pharyngitis Assessment.25 Inclusion criteria included moderate or severe pain on the Throat Pain Scale and three symptoms commonly associated with sore throat; sore throat pain, difficulty swallowing and the sensation of a swollen throat.26 A total of 402 patients were randomised to receive flurbiprofen 8.75 mg lozenges (n = 203) or identically flavoured placebo lozenges (n = 199). Patients were instructed to suck one dose of their assigned lozenge, and, if needed, they could suck another lozenge every 3–6 hours for up to 7 days. Strep A infection was evaluated clinically by the different practitioners using a Clinical Assessment of Strep Throat (CAST), a categorical scale used to assess globally the likelihood of Strep A infection (unlikely, uncertain, likely, very likely) based on historical, physical and symptomatic findings. Throat cultures were obtained to make a definitive diagnosis of Strep A, C or G infection. Sore throat pain, difficulty swallowing and sensation of a swollen throat were measured at intervals over 24 hours on three different 100-mm visual analogue scales: the Sore Throat Pain Intensity Scale (STPIS),27,28 Difficulty Swallowing Scale (DSS)28 and the Swollen Throat Scale (SwoTS),28 respectively.

Throat culture results showed that 40/401 (10%) patients were positive for Strep A and 56/401 (14%) were positive for Strep C. Upon receipt of the throat culture results, antibiotics were prescribed to all patients diagnosed with Strep A and to 11/56 (19.6%) patients diagnosed with Strep C who were still symptomatic.

The first dose of flurbiprofen 8.75 mg lozenge caused significant pain reduction compared with placebo at 1, 2, 3 and 4 hours for the entire population and for patients without Strep A or C (all p ˂ 0.05) (Figure 1). Pain reduction was also seen at 2 and 3 hours for patients with Strep A or C (p ˂ 0.05).

Difficulty swallowing was reduced after one flurbiprofen lozenge at 1, 2, 3 and 4 hours for the entire population and for patients without Strep A or C (all p < 0.05), and at 3 hours for patients with Strep A or C (p ˂ 0.05). A reduced sensation of swollen throat after one flurbiprofen dose was reported at 1, 2, 3 and 4 hours for the entire population and for patients without Strep A or C (all p ˂ 0.05), as well as at 1, 2 and 3 hours for patients with Strep A or C (p ˂ 0.05).

Reduction in sore throat pain over 24 hours (as determined by time-weighted summed differences on the STPIS over 24 hours) was 52% greater for the flurbiprofen treatment group than the placebo group in the entire population (p ˂ 0.001), 54% greater in patients without Strep A or C (p ˂ 0.001) and 33% greater in patients with Strep A or C (p = 0.10). Flurbiprofen lozenges also provided greater relief of difficulty swallowing and swollen throat in the entire population and in patients without Strep A or C (all p ˂ 0.05) over 24 hours.

Adverse events (AEs) were similar between the flurbiprofen and placebo groups, with the most common AEs being headache, throat irritation, nausea, paraesthesia and gastrointestinal complaints.

This analysis also highlights the difficulty in diagnosing Strep A infections of the throat. In fact, practitioners were uncertain of the diagnosis in 183/401 (45.6%) patients. Based on the CAST, practitioners considered Strep A infection likely or very likely in 85/401 patients (21.2%). Of these 85 patients, 84 had a throat culture and 11/84 (13.1%) were found to be positive for Strep A. This outcome means that by using the CAST, 73/84 patients would have received antibiotics unnecessarily if diagnosis was based only on clinical features (i.e., a false positive rate of 86.9%). Additionally, out of the 316 patients whose Strep A diagnosis the practitioners were uncertain of or considered unlikely, 29 patients (9.2%) with culture-proven Strep A would not have been prescribed antibiotics. Overall, the CAST had a sensitivity of 27.5% and a specificity of 79.7%, confirming the low predictive accuracy and limitations of clinically diagnosing a ‘Strep throat.’

Given that it is difficult to diagnose clinically the cause of a sore throat, it is important to consider non-antibiotic treatments that provide symptomatic relief during the natural course of sore throat. Education is key to helping healthcare professionals promote patients’ self-management with symptomatic treatments (and thus reduce inappropriate prescriptions of antibiotics for sore throat). The Global Respiratory Infection Partnership (GRIP), for example, is one of several healthcare initiatives that provide educational resources and recommendations for the management of URTIs.29 Based on the results of this study of patients with and without streptococcal sore throat, self-management with flurbiprofen 8.75 mg lozenge is a reasonable consideration as a first-line therapeutic option for the symptomatic relief of sore throat. Treatment with antibiotics should be reserved for patients with sore throat who are seriously ill or at increased risk of complications.

 

 JT fig1

Figure 1 Change in sore throat pain following a single dose of study medication. *p ˂ 0.05, **p ˂ 0.01 and ***p ˂ 0.001 for flurbiprofen 8.75 mg compared with placebo. Analysis of variance was used to compare flurbiprofen 8.75 mg and placebo groups for the effects of a single dose on absolute mean change in STPIS score over 6 hours for (A) all patients, (B) patients with group A or C streptococcus and (C) patients without group A or C streptococcus. CI, confidence interval; LS, least square; STPIS, Sore Throat Pain Intensity Scale.

Reproduced from Shephard A, Smith G, Aspley S, Schachtel BP. 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’. The International Journal of Clinical Practice 2015:69(1);59–71, with permission from Wiley.

 

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