Acetylsalicylic acid (ASA) was first synthesized RESEARCH PAPERS

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1 PAIN MEDICINE Volume 4 Number RESEARCH PAPERS Effects of Acetylsalicylic Acid on Sore Throat Pain and Other Pain Symptoms Associated With Acute Upper Respiratory Tract Infection Ron Eccles, DSc,* Irene Loose, MD, Martez Jawad, MD,* and Lars Nyman, MD *Common Cold Centre, Cardiff University, UK; BG Consumer Care, Bayer, Leverkusen, Germany; Quintiles AB, Quintiles, Uppsala, Sweden ABSTRACT Objective. Acetylsalicylic acid (ASA) has been widely used for over a century to treat pain and fever associated with acute upper respiratory tract infection (URTI), but there is a lack of clinical data to support the efficacy of ASA in this disease state. The objective of this study was to investigate the efficacy and safety of ASA for the treatment of sore throat pain associated with URTI. Design. A double-blinded, placebo-controlled, parallel group design. Two hundred seventy-two patients (mean age: 25 years) with sore throat pain associated with URTI were recruited at two centers. Pain scores were made during a 2-hour laboratory phase and continued for secondary objectives during a 4-hour home phase. Patients were treated with either two effervescent tablets of ASA 400 mg in water or matched placebo tablets. Patients took medication as required over a 3-day home phase. Results. ASA was found to be superior to placebo for: The primary efficacy parameter predefined in the protocol, reduction in sore throat pain intensity over 2 hours (P < 0.001), and for secondary efficacy parameters, reduction in sore throat pain intensity over 4 and 6 hours, relief of sore throat pain over 2, 4, and 6 hours, reduction in intensity of pain associated with headache, and reduction in muscle aches and pains over a 2-hour time period (P < 0.01). No safety problems were encountered. Conclusions. Treatment with ASA was shown to provide relief from sore throat pain, headache, and muscle aches and pains associated with URTI. Key Words. Acetylsalicylic Acid; Common Cold; Sore Throat; Pain Introduction Acetylsalicylic acid (ASA) was first synthesized in 1897 by Felix Hoffman and was introduced to medical use in 1899 [1]. ASA has been widely Reprint requests to: Ron Eccles, DSc, Common Cold Centre, Cardiff School of Biosciences, Cardiff University, Cardiff CF10 3 US, United Kingdom. Tel: ; Fax: ; eccles@cardiff.ac.uk. used for over a century for the treatment of pain and fever associated with acute upper respiratory tract viral infections (URTIs) and, during the pandemic influenza of 1918, was the only effective medicine available to provide relief from pain and fever. ASA is the most commonly consumed drug in the world. In 1980 in the United States alone, annual ASA consumption was around 70 million kg [2]. Despite its present-day widespread use and the long medical history of the use of ASA in relieving pain associated with acute URTIs, such as the American Academy of Pain Medicine /03/$15.00/

2 ASA for Sore Throat Pain With URTI 119 common cold, there is a lack of clinical data to support the efficacy of ASA in this disease state. Clinical studies by Schachtel and colleagues [3,4] reported that ASA was superior to placebo for the treatment of sore throat pain, but there are no other published studies to support the efficacy of ASA for the treatment of pain associated with URTIs. In a recent review of the efficacy of a single dose of ASA for the treatment of acute postoperative pain, the authors concluded that there were few clinical trials of adequate size on ASA and that this made it difficult to assess the analgesic efficacy of ASA, especially when attempting to combine studies in a meta-analysis [5]. Sore throat pain has been accepted by European regulatory authorities as a suitable pain model for acute, mild-tomoderate pain and, therefore, the results of this study are applicable to other forms of acute pain [6]. The aim of the present study was to investigate the efficacy of a single 800-mg dose of ASA for the treatment of sore throat pain associated with URTI in order to provide some sound clinical data for the use of ASA in this disease state. Materials and Methods Study Design The clinical trial was designed as a doubleblinded, single-center, randomized, prospective, parallel group, placebo-controlled study. The study compared the efficacy and safety of 800mg ASA with matched placebo for the treatment of sore throat pain associated with URTI. Approximately 270 patients with sore throat pain associated with URTI were to be recruited by poster advertisement and advertisement in local newspapers. In order to ensure adequate recruitment, a second recruitment center was employed after protocol amendment. The study consisted of two phases, a 2-hour laboratory phase and a 3-day home phase; efficacy was assessed during the 2-hour laboratory phase and for the first 4 hours of the home phase. Safety was assessed over both the laboratory and home phases. Patient Population Adults between 18 and 60 years of age with a history of symptoms of URTI for hours were recruited. Patients were asked to identify the presence or absence of URTI symptoms occurring in the previous 24 hours from a list of 33 items. In order to enter the study, patients had to have at least four symptoms from the following 16 of the 33 symptoms in the previous 24 hours: Sore throat, runny nose, stuffy nose, sneezing, wet cough, dry cough, earache, ear fullness, sinus pain, sinus pressure, muscle aches and pains, feverish discomfort, chills, hoarseness, scratchy throat, headache. The patients also had to score 6 on an 11-point ordinal scale for sore throat pain severity and score 5 on a tonsillopharyngitis assessment. The tonsillopharyngitis score consisted of assessments of oral temperature, oropharyngeal color, size of tonsils, number of oropharyngeal enanthems, largest size of anterior cervical lymph nodes, number of anterior cervical lymph nodes, tenderness of anterior cervical lymph nodes, and presence/amount of phlegm in posterior oropharynx. As a refinement of the original tonsillopharyngitis score [3], the clinical assessment was made for each sign of tonsillopharyngitis on a 0 3 ordinal rating scale that is more familiar to physicians when grading physical findings. Patients were excluded from the study if they were pregnant or lactating females, had a clinical history that would contraindicate taking ASA (e.g., history or existing state of peptic ulceration), had taken any medication that could interfere with the course of the study by influencing sore throat pain (e.g., analgesics within previous 12 hours, NSAIDs within previous 24 hours, or menthol-containing products within previous 4 hours), were unable to breathe through their nose or had a history of mouth breathing, had severe difficulty in breathing or swallowing or a history of any disease or current disease that in the opinion of the investigator required medical attention (e.g., streptococcal infection), or had previously participated in this study or any clinical trial within the past 30 days. Throat swabs were not taken, as the aim of the study was to investigate the effects of ASA on sore throat pain associated with acute URTI and, in most cases, the condition would have resolved by the time the results of any microbiology were available. Treatments In the laboratory phase, each patient received a single dose of either two effervescent ASA tablets (400 mg) or two matched effervescent placebo tablets, dissolved in approximately 6 ounces of water. In the 3-day home phase, patients were instructed to take 1 2 effervescent tablets dissolved in water every 4 6 hours on demand, with a maximum of six tablets per day. The medication could be administered at any time during the study, and no special instructions were given in regard to food intake, in order to reflect the situation in real life.

3 120 Eccles et al. Randomization and Blinding A randomization code was generated and held by the Department of Biometry, Clinical Research Centre, Bayer AG, Wuppertal, Germany with a block size of four. Each study center was supplied with packs of medication numbered sequentially and a sealed copy of the randomization code. Each patient was assigned to the next sequentially numbered medication in ascending number, at the time of enrolment. The center staff and patients were blinded to the randomization code used to allocate the treatment numbers. To ensure blinding, the effervescent tablets were physically identical and produced solutions that were identical in appearance, taste, and degree of effervescence. Any bitter taste of ASA was masked by the effervescence of the product and citric acid in the formulation. The study staff prepared the solution of medication by emptying the two effervescent tablets into a glass with approximately 6 ounces of water. The patient swallowed the entire solution under the supervision of the study staff. Subsequent optional doses of the same assigned medication were prepared and administered by the patient at home. Concomitant Medication During the 6-hour postdosing evaluation period, patients were prohibited from taking any other medication, sucking on lozenges or candy, chewing gum, smoking, snuffing, and using any menthol-containing product (such as mentholated tissues or throat/cough drops) and eating or drinking were prohibited during the initial 2 hours. Patients were discouraged from taking any other medication so that they could rate the effects of the study medication alone. After the initial 2- hour laboratory assessment period, patients were allowed to take rescue medication if required, and this was documented. Efficacy and Safety Measurements The primary efficacy instrument was an 11-point ordinal scale. Patients were instructed at baseline and at each following assessment to swallow and circle the number that shows how much your throat hurts. This vertical 0 10 ordinal scale was marked by integers, with NOT AT ALL below the 0 rating at the bottom of the scale and VERY MUCH above the 10 at the top of the scale. Patients rated sore throat pain at baseline, at 15, 30, 60, 90, and 120 minutes, and at 3, 4, 5, and 6 hours. A sore throat relief scale was used as a secondary efficacy instrument. After each rating of sore throat after baseline, patients were instructed to circle the phrase that best describes the relief of your sore throat. The scale was a seven-category ordinal scale (no relief, slight relief, mild relief, moderate relief, considerable relief, almost complete relief, and complete relief ). An 11-point ordinal scale similar to that used to assess sore throat was used to assess the severity of common cold symptoms (headache, muscle aches and pains, feverish discomfort, and sinus pressure pain) at baseline and at 2 hours following completion of both sore throat scales. All side effects observed by the investigator or noted by the patients during the course of the two phases of the study were recorded as safety assessments. Statistical Analysis The primary efficacy variable was defined in the protocol as the sum of pain intensity difference (SPID) during the 2-hour laboratory phase. SPID was obtained as the sum of each PID (baseline pain intensity score minus pain intensity score during treatment) weighted by time interval for the first 2 hours after treatment. Weighting by time gives a similar result to area-under-the-curve analyses. Secondary efficacy variables included: 4-hour SPID; 6-hour SPID; pain relief, defined as the sum of pain relief scores weighted by time intervals (TOTPAR) over 2, 4, and 6 hours; percentage change in common cold symptoms (headache, muscle aches and pains, feverish discomfort, and sinus pressure pain) 2-hour evaluation minus baseline divided by baseline. The main analyses included all patients valid according to the protocol and all those patients who received medication, the intention-to-treat (ITT) population. A student s two-sided Wilcoxon test was used at a 5% significance level in order to assess statistical significance. Due to the addition of another recruiting center, an analysis of variance with treatment group and center as main effects was performed in order to account for the effect of center. The sample size estimate was based on the primary efficacy variable SPID up to 2 hours. In order to detect a difference of at least one unit between ASA and placebo, assuming a standard deviation of 2.5 units and normally distributed data at a significance level of 5% (two-sided) and a power of 90%, 133 valid patients per treatment group were required.

4 ASA for Sore Throat Pain With URTI 121 Table 1 Demographics and baseline characteristics of the protocol valid patients (n = 272). The sex and race details give the actual numbers whereas the other characteristics are given as the mean values. The table also lists the numbers of patients recruited at the two recruiting centres ASA Placebo p value Test Male CMH Female Caucasian Black CMH Asian 2 7 Age years F(ANOVA) Height cm F(ANOVA) Weight Kg F(ANOVA) BMI F(ANOVA) Systolic BP mmhg F(ANOVA) Diastolic BP mmhg F(ANOVA) Heart rate/minute F(ANOVA) Temperature C F(ANOVA) UK Centre Sweden Centre (CMH) Cochran-Mantel-Haenszel test was used for nominal data and the F-test (ANOVA) for metric data. Both tests were two tailed with alpha =10%. Results Demographics Two hundred seventy-nine patients were recruited to the study and received treatment. Of these, 272 were protocol valid cases for efficacy analysis (109 males and 163 females, mean age: 25 years, range: years). One hundred thirty-nine patients were treated with ASA and 133 were treated with placebo. The two treatment groups were similar, as there were no significant differences in demographics (sex, race, age, height, weight, and body mass index (BMI)). The vital signs for the treatment groups were also similar, with no significant differences found for arterial blood pressures, heart rate, and body temperature. One hundred sixty-one valid patients were recruited at Center 1 (United Kingdom) and 111 valid patients were recruited at Center 2 (Sweden). Symptoms of URTI All patients included in the study were suffering from the symptom of sore throat pain. Patients were also asked to indicate if they were suffering from any of a list of 32 other symptoms associated with URTI in the previous 24 hours, and the percentages of patients suffering from each of those symptoms is illustrated in Figure 1. As an entry criterion, patients had to indicate that they were suffering from at least four symptoms from 16 of the 32 symptoms (including sore throat pain), indicated by asterisks in Figure 1. This entry criterion was made in order to confirm the diagnosis of URTI. The six symptoms with the highest incidence in this population of patients with URTI were runny nose (68%), sneezing (64%), tiredness (61%), headache (60%), stuffy nose (53%), and dry cough (50%). Sore Throat Pain Sore throat pain intensity declined in both the ASA and placebo groups following treatment, and differences in pain intensity from baseline are illustrated in Figure 2. At all time points after treatment, the ASA treatment group had a greater PID than the placebo group, with the maximum separation between the treatment groups occurring between 100 and 200 minutes after treatment. Sums of pain intensity differences (SPIDs) for 2, 4, and 6 hours after treatment are illustrated in Figure 3. There was a significant difference between ASA and placebo for the primary efficacy variable of SPID 0 2 hours. The SPID 0 2 hours was 2.41 (±2.3 SD, 95% confidence interval (CI): ) for placebo and 3.81 (±2.8 SD, 95% CI: ) for ASA (P = , n = 139 and 133). Similarly significant differences were also found for the secondary efficacy parameters SPID 0 4 hours (P = , n = 138, 132) and SPID 0 6 hours (P = , n = 138, 132). Sums of pain relief scores for sore throat (TOTPAR) for 2, 4, and 6 hours after treatment are illustrated in Figure 4. There was a significant difference between ASA and placebo at all time periods: 0 2 hours (P = , n = 139 and 133), 0 4 hours (P = , n = 138, 132), and 0 6 hours (P = , n = 138, 132). Other Pain Associated With URTIs Headache was reduced by 38% following treatment with ASA and 16% after placebo (P = ,

5 122 Eccles et al. *runny nose *sneezing tiredness *headache *stuffy nose *dry cough *scratchy throat *muscle aches and pains *wet cough head heaviness *hoarsness *feverish discomfort *chills *ear fullness up at night sweating head fullness *earache postnasal drip lack of appetite swollen glands *sinus pressure watery eyes heavy eyes burning eyes *sinus pain chest congestion tightness in chest nausea chest pain stomach ache upset stomach Percentage of patients with symptom Figure 1 Symptoms of the common cold. Patients were asked to identify the presence or absence of URTI symptoms occurring in the previous 24 hours from a list of 33 items. In order to enter the study, patients had to have at least four symptoms from the 15 symptoms listed with an asterisk. Sore throat was a mandatory symptom for entry into the study, and 100% of patients had this symptom P = Sore throat PID SPID P < P = Time (minutes) Figure 2 Mean course of PID for sore throat pain with standard deviations. Baseline score minus score at each time point yields positive values for decrease in pain and improvement. N = 139 for ASA, closed symbols; N = 133 for placebo, open symbols Time (hours) Figure 3 Sums of sore throat pain intensity differences, expressed as means with standard deviations. ASA, filled bars; placebo, open bars. P values are for comparisons between treatment groups for each time period.

6 ASA for Sore Throat Pain With URTI P = period in which the efficacy of the treatments was assessed. TOTPAR P < P = Compliance All patients took the first dose of medication, as this was closely supervised by the investigators during the laboratory phase of the study. Patients were allowed to take additional medication on demand following the 6-hour efficacy period over a period of 3 days, and patients were supplied with 20 tablets for home use. Four hundred two tablets were taken by the ASA treatment group and 246 were taken by the placebo treatment group Time (hours) Figure 4 Sums of pain relief scores for sore throat (TOTPAR) for 2, 4, and 6 hours after treatment. ASA, filled bars; placebo, open bars. P values are for comparisons between treatment groups for each time period. n = 106, 106). Muscle aches and pains were reduced by 38% following treatment with ASA and 25% after placebo (P = , n = 103, 95). Sinus pain was reduced by 24% following treatment with ASA and 28% after placebo (P = , n = 82, 84). Feverish discomfort was reduced by 28% following treatment with ASA and 30% after placebo (P = , n = 100, 96). Safety Assessments No serious adverse events were reported. Fifty adverse events were reported in 34 patients, and the most commonly reported events were headache (5 ASA, 5 placebo), abdominal pain (3 ASA, 2 placebo), nausea (2 ASA, 1 placebo), and epistaxis (2 ASA, 1 placebo). Overall, adverse events occurred in 17 patients in each treatment group. There was no change in the frequency and severity of adverse events for repeated doses of the study medications. Concomitant Medication Various oral contraceptive medications were taken by female patients on an ongoing basis. Use of concomitant medication relevant to sore throat pain was rare during the laboratory and home phase. Only one patient in the ASA treatment group and one in the placebo treatment group used additional analgesics during the 6-hour Discussion Patients recruited for this study had to satisfy entry criteria for recent history of URTI symptoms, have a score 6 on an 11-point ordinal scale for sore throat pain severity, and score 5 on a tonsillopharyngitis assessment. In this respect, there was selection of a population of patients with sore throat pain. However, the patient population suffered from multiple symptoms of URTI as well as sore throat pain (Figure 1), with runny nose, sneezing, tiredness, headache, stuffy nose, and cough present in more than 50% of patients. This indicates that sore throat pain is commonly found as one of multiple symptoms associated with the common cold syndrome. Symptoms remote from the upper respiratory tract, such as upset stomach, stomach ache, and nausea, were the least common symptoms. However, the symptom of tiredness, which could also be considered as a symptom not directly related to the upper respiratory tract, was one of the most common symptoms, present in 61% of patients. Symptoms remote from the upper airway may be caused by the release of cytokines from leukocytes in the inflamed upper airway, whereas symptoms localized to the airway, such as sore throat pain, may be caused by the generation of inflammatory mediators such as bradykinin and prostaglandins [7]. ASA has been used for over 100 years for the treatment of pain associated with symptoms of URTI, but clinical evidence of its efficacy in this condition is very limited. The results of the present study demonstrate that a single 800-mg dose of ASA was an effective treatment for sore throat pain associated with URTI for up to 6 hours after treatment. The efficacy of ASA for treatment of sore throat pain was demonstrated by the superiority over placebo treatment for SPIDs and TOTPAR scores over 2, 4, and 6 hours after treat-

7 124 Eccles et al. ment, as these measures of pain are well established for the assessment of efficacy of analgesics [3 5]. The results are robust, and the changes in pain intensity are matched by supporting changes in TOTPAR that act as a kind of internal validation for the study. It was interesting that during the home phase of the study, the ASA treatment group administered 402 tablets, whereas the placebo treatment group administered only 264 tablets. One explanation for this difference in tablet use may be that the ASA group received more benefit from the treatment than the placebo group and, therefore, continued using what they perceived to be an effective medicine for the treatment of their URTI pain-related symptoms. The results support the use of a single dose of ASA for the treatment of acute pain, since the sore throat pain model is accepted by European regulatory authorities as a model to support an acute pain indication for an analgesic medication [6]. In the present study, the effects of treatment on other pain symptoms associated with URTIs, such as headache, muscle aches, sinus pain, and feverish discomfort, were also investigated. The results indicate that a single 800-mg dose of ASA was an effective treatment for headache and muscle aches, as there was an approximately 40% reduction in the severity of these symptoms after treatment with ASA that was significantly different from the 15 20% reduction in pain after treatment with placebo. However, the percent changes in sinus pain and feverish discomfort were not significantly different from the reduction in pain severity associated with placebo treatment. The lack of effect of ASA in treating sinus pain and feverish discomfort may be explained by the low incidence of these symptoms in the study population. Sinus pain was only present in 13% of the population and feverish discomfort in 32%, whereas headache was present in 60% and muscle aches in 43%. Acute URTI is not a single disease entity but is a syndrome of multiple symptoms that vary widely in severity and incidence according to the infectious agent and the patient population. In the present study, the patient population was selected so that all were suffering from sore throat pain, and this means that other symptoms, such as sinus pain and feverish discomfort, were not present in many of the patients. Although the population of this study was relatively small, the safety analysis does not provide any cause for concern and does support the safety of single and multiple doses of ASA over a 3-day period. The incidence of adverse events was low and evenly distributed between the ASA and placebo treatment groups. The management of sore throat pain in clinical practice is controversial, as most patients are suffering from a viral infection yet antibiotics are often prescribed. Treatment with oral analgesics alone is favored by some clinicians, but one needs to balance the risk of nonsuppurative complications of betastreptococcal infections with the rare, but sometimes serious, side effects of analgesic medications. In conclusion, the results of this study indicate that a single 800-mg dose of ASA is a safe and effective treatment for sore throat pain associated with URTI. References 1 Vane J, Botting R. The history of aspirin. In: Vane J, Botting R, editors. Aspirin and other salicylates. London: Chapman and Hall; p Rainsford KD. History and development of the salicylates. In: Rainsford KD, editor. Aspirin and the salicylates. London: Butterworth and Co.; p Schachtel BP, Fillingim JM, Beiter DJ, et al. Rating scales for analgesics in sore throat. Clin Pharmacol Ther 1984;36: Schachtel BP, Fillingim JM, Lane AC, et al. Caffeine as an analgesic adjuvant. A double-blind study comparing aspirin with caffeine to aspirin and placebo in patients with sore throat. Arch Intern Med 1991;151: Edwards JE, Oldman A, Smith L, et al. Single dose of oral aspirin for acute pain (Cochrane Review). In: The Cochrane Library. Issue 2. Oxford: Update Software; Committee for Proprietary Medicinal Products (CPMP) of the European Agency for the Evaluation of Medicinal Products (EMEA). Note for guidance on clinical investigation of medicinal products for treatment of nociceptive pain. Document CPMP/ EWP/612/00. London: EMEA; Eccles R. Pathophysiology of nasal symptoms. Am J Rhinol 2000;14:335 8.