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Effects of chlorhexidine/ benzydamine mouth spray on pain and quality of life in acute viral pharyngitis: a prospective, randomized, double-blind, placebo-controlled, multicenter study.

Abstract

We conducted a prospective, randomized, double-blind, placebo-controlled, multicenter study to assess the efficacy of chlorhexidine gluconate/benzydamine HCl mouth spray for reducing pain and improving quality of life in patients with acute viral pharyngitis. Prior to treatment, patients rated the intensity of their pain on a visual analog scale and evaluated their quality of life on the 36-Item Short-Form Health Survey. Patients were then randomized to receive either paracetamol (acetaminophen) plus chlorhexidine/ benzydamine or paracetamol plus placebo for 7 days. On days 3 and 7 of treatment, the participants again rated the intensity of their pain, and on day 7, they again rated their quality of life. A total of 164 patients were evaluable at study's end--80 in the chlorhexidine/benzydamine group and 84 in the control group. A comparison of self-evaluations revealed that the active treatment group reported less pain on both day 3 (p < 0.001) and day 7 (p = 0.002). Likewise, the chlorhexidine/benzydamine group reported a significantly better quality of life on day 7 (p < 0.001). Chlorhexidine/benzydamine was well tolerated, and no serious adverse events were observed.

Introduction

Acute pharyngitis is characterized by an inflammation 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. (2,3) Various reports put the incidence of bacterial etiology between 5 and 40% of cases. (2,3) In cases of bacterial infection, the most common pathogen is group A beta-hemolytic Streptococcus (GABHS). (2,3)

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 knowledge, their effect on improving quality of life has not been demonstrated in double blind, placebo-controlled studies. (3,4)

We conducted a study to evaluate the effect of an investigational 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 prospective, randomized, double-blind, placebo-controlled, parallel-group, multicenter clinical study to test the safety and efficacy of combined chlorhexidine gluconate 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%. (5) Compared with throat culture results, both the sensitivity and specificity of the Centor criteria are 75%. (5) (Complete inclusion and exclusion criteria are listed in the table.)

Patients were randomized in a double-blind fashion to one of two parallel treatment groups--paracetamol 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 concerning 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(6,7) 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. (6,7) The range of SF-36 scores runs from 0 to 100, 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.

Side effects. Patients were asked to note any side effects 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 Statistical Package for the Social Sciences software (version 17.0 for Windows; SPSS; Chicago). The Shapiro-Wilk test was used to test the normality assumption. The Student t test was used for paired samples, and repeated measures were evaluated with the one-way analysis of variance (ANOVA). Values were expressed as means ([+ or -] SD). Statistical significance was accepted for p values of <0.05.

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The study protocol was approved by the Ethics Committee of Osmangazi University Medical Faculty, and a consent form was signed by each study patient.

Results

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 [+ or -] 15.94) and 70 females, aged 17 to 71 years (mean: 38.31 [+ or -] 16.16). Of these patients, 80 had been randomized to the active treatment group and 84 to the control group. There were no significant differences 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 ([+ or -] 1.49) in the active treatment group and 7.76 ([+ or -] 1.51) in the control group--not a statistically significant difference (p = 0.938). At day 3 of treatment, the corresponding scores were 4.15 ([+ or -] 1.20) and 6.31 ([+ or -] 1.06), which did represent a statistically significant difference (p < 0.001). On day 7, the trend continued, as the respective scores were 2.83 ([+ or -] 1.09) and 5.01 ([+ or -] 0.99), which also represented a significant difference in favor of active treatment (p = 0.002) (figure 1).

Quality of life. At baseline, there was no significant difference in mean SF-36 scores between the active treatment group and the control group--56.24 ([+ or -] 18.44) and 48.50 ([+ or -] 16.80), respectively (p = 0.79). By day 7, however, the difference between the two groups was statistically significant in favor of the active treatment--71.34 ([+ or -] 11.10) and 54.37 ([+ or -] 12.10), respectively (p < 0.001) (figure 2). In fact, a significant improvement in quality of life over time occurred in both the active treatment and control groups (p < 0.001) compared with baseline.

Side effects. Analysis revealed no significant difference between the two groups in side effect 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 of the more common conditions encountered in office practice, accounting for 2% of all ambulatoryvisits in the United States. (4,10) Overtreatment of acute pharyngitis represents one of the 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 pharyngitis. (4) For patients with acute pharyngitis, the goals of supportive treatment are to reduce inflammation and the intensity of pain while attempting to maintain oral intake in order to avoid dehydration and subsequent hospitalization. (2) Such a strategy would be expected to improve a patient's quality of life.

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At the moment, numerous pharmaceutical products that contain disinfectants, anti-inflammatory agents, and/or topical anesthetics are being prescribed for the local treatment of acute pharyngitis. (3,4) In our study, we used a mouth spray that contains chlorhexidine and benzydamine. (11) Chlorhexidine is an antimicrobial agent that is frequently used for its topical antiseptic effects, and benzydamine is an effective anti-inflammatory and analgesic. The efficacy of chlorhexidine against gingivitis and recurrent ulcers in the oral mucosa has been demonstrated in the literature. 12,13 Moreover, Bernstein et al confirmed the antiviral efficacy of chlorhexidine against influenza, parainfluenza, cytomegalovirus, and herpes simplex virus infections. (14) Also, Park and Park showed the significant antiviral effect of chlorhexidine in vitro. (15)

In our study, we found that chlorhexidine/benzydamine mouth spray significantly reduced the intensity of pain and significantly improved the quality of life over time. The combination exerted these beneficial effects 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 effects. We believe that chlorhexidine/ benzydamine mouth spray may prove to become a good addition to the standard treatment armamentarium for acute pharyngitis if our findings are borne out in further research. We also believe that it would be worthwhile to assess the efficacy of this treatment in GABHS tonsillopharyngitis in larger sample sizes and with different control protocols.

References

(1.) Melio FR, Holmes DK. Upper respiratory tract infections. In: Rosen P, Barkin RM, eds. Emergency Medicine. Concepts and Clinical Practice. 4th ed. St. Louis: Mosby; 1998:1529-53.

(2.) Wei JL, Kasperbauer JL, Weaver AL, Boggust AJ. Efficacy of single-dose dexamethasone as adjuvant therapy for acute pharyngitis. Laryngoscope 2002;112(1):87-93.

(3.) Shores CG. Infections and disorders of the neck and upper airway. In: Tintinalli JE, Kelen GD, Stapczynski JS, eds. Emergency Medicine. A Comprehensive Study Guide. 6th ed. New York: McGraw-Hill; 2004:1494-1501.

(4.) Cooper RJ, Hoffman JR, Bartlett JG, et al. Principles of appropriate antibiotic use for acute pharyngitis in adults: Background. Ann Intern Med 2001;134(6):509-17.

(5.) Centor RM, Witherspoon JM, Dalton HP, et al. The diagnosis of strep throat in adults in the emergency room. Med Decis Making 1981;1(3):239-46.

(6.) Diaz-Buxo JA, Lowrie EG, Lew NL, et al. Quality-of-life evaluation using Short Form 36: Comparison in hemodialysis and peritoneal dialysis patients. Am J Kidney Dis 2000;35(2):293-300.

(7.) McHorney CA, Ware JE Jr., Raczek AE. The MOS 36-Item Short-Form Health Survey (SF-36): II. Psychometric and clinical tests of validity in measuring physical and mental health constructs. Med Care 1993;31(3):247-63.

(8.) Wewers ME, Lowe NK. A critical review of visual analogue scales in the measurement of clinical phenomena. Res Nurs Health 1990;13 (4):227-36.

(9.) Field EA, Allan RB. Review article: Oral ulceration--aetiopathogenesis, clinical diagnosis and management in the gastrointestinal clinic. Aliment Pharmacol Ther 2003;18(10):949-62.

(10.) Snow V, Mottur-Pilson C, Cooper RJ, Hoffman JR; American Academy of Family Physicians; American College of Physicians-American Society of Internal Medicine; Centers for Disease Control. Principles of appropriate antibiotic use for acute pharyngitis in adults. Ann Intern Med 2001;134(6):506-8.

(11.) Matthijs S, Adriaens PA. Chlorhexidine varnishes: A review. J Clin Periodontol 2002;29(1):1-8.

(12.) Killoy WJ. The use of locally delivered chlorhexidine in the treatment of periodontitis. Clinical results. J Clin Periodontol 1998;25(11 Pt 2):953-8; discussion 978-9.

(13.) Burgess JA, Johnson BD, Sommers E. Pharmacological management of recurrent oral mucosal ulceration. Drugs 1990;39(1):54-65.

(14.) Bernstein D, Schiff G, Echler G, et al. In vitro virucidal effectiveness of a 0.12%-chlorhexidine gluconate mouthrinse. J Dent Res 1990;69(3):874-6.

(15.) Park JB, Park NH. Effect of chlorhexidine on the in vitro and in vivo herpes simplex virus infection. Oral Surg Oral Med Oral Pathol 1989;67(2):149-53.

Cemal Cingi, MD; Murat Songu, MD; Ahmet Ural, MD; Muzeyyen Yildirim, MD; Nagehan Erdogmus, MD; Cengiz Bal, MD

From the Department of Otorhinolaryngology (Dr. Cingi and Dr. Erdogmus) 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, Karadeniz 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 Otorhinolaryngology, Dr. Behcet Uz Children's Hospital, 35210, Izmir, Turkey. E-mail: songumurat@yahoo.com
Table. Inclusion and exclusion criteria

Inclusion

* Age [greater than or equal to] 16 years

* History of sore throat [greater than or equal to] 3 days

* [less than or equal to] 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 supplements,
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 mucous
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
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Title Annotation:ORIGINAL ARTICLE
Author:Cingi, Cemal; Songu, Murat; Ural, Ahmet; Yildirim, Muzeyyen; Erdogmus, Nagehan; Bal, Cengiz
Publication:Ear, Nose and Throat Journal
Article Type:Clinical report
Geographic Code:7TURK
Date:Nov 1, 2010
Words:2594
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