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PHARMACODYNAMICS |
From the Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, Connecticut (Dr Schachtel); Schachtel Research Company, Jupiter, Florida (Dr Schachtel, Ms Sanner, Ms Schachtel, Ms Bey); and Pfizer Global Pharmaceuticals, New York (Dr Pan, Dr Kohles).
Address for correspondence: Bernard P. Schachtel, Schachtel Research Company, 4300 South US Highway One, Suite 203, Jupiter, FL 33477; e-mail: bschachtel.src{at}gate.net.
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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50% of maximum total pain relief over 6 hours). These findings indicate that sore throat is a sensitive model to assess analgesic efficacy.
Key Words: Sore throat • acute pain model • pharyngitis • assay sensitivity • placebo • individual responder rate • valdecoxib • COX-2 selective inhibitor
To date, most of the published studies using the sore throat pain model have been evaluations of non-prescription-strength analgesics. In the present study, we tested the utility and sensitivity of sore throat as a general pain model in evaluating the efficacy of the prescription analgesic, valdecoxib.25-27 Under double-blind, placebo-controlled conditions, we studied a 20-mg formulation, administered twice a day over 24 hours, and a 40-mg formulation, administered once over 24 hours. Valdecoxib, a cyclooxygenase-2 (COX-2) selective inhibitor, had been shown to be effective for the pain and inflammation associated with osteoarthritis,28,29 rheumatoid arthritis,30 and the pain associated with dysmenorrhea31 but was removed from the market in 2004 (after the present trial was completed) because of postmarketing reports of increased incidence of cardiovascular events and potentially severe cutaneous adverse reactions. As this is the first report of testing the analgesic efficacy of a COX-2 selective inhibitor over 24 hours using the sore throat pain model, we attempted to simplify the use of and improve the model itself.
First, we incorporated a new index to specify the diagnosis of tonsillo-pharyngitis (distinct from laryngitis, for example) to ensure that all patients had the same underlying pathophysiology. We had previously used the Tonsillo-Pharyngitis Score (TPS) in our development of the sore throat pain model to provide de minimis evidence of pharyngitis as the cause for throat pain.4,32 In the present trial, we also used an expanded index, the Tonsillo-Pharyngitis Assessment (TPA),14,18 to provide more descriptions and gradations of the clinical signs of tonsillo-pharyngitis and to validate the more refined TPA for future use.
Second, we added a different rating scale to the study design. To measure how sore the throat is (an evaluative word commonly used by patients to describe the symptom of pharyngitis,32 different from pain), we used a numeric rating scale (NRS) based on Lasagna's vertical pain thermometer (Figure 1).8,14,33 Termed the Lasagna Pain Scale after its original designer, this measurement instrument was included in the study to determine its sensitivity to drug and placebo effects, to observe its ability to discriminate between these effects, and—by comparing its results with those measured on conventional visual analog pain intensity and categorical pain relief scales—to validate the Lasagna Pain Scale for use as an indicator of therapeutic response.
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35% reduction in PI and with 50% reduction in PI, respectively, and we calculated the percentage of patients with at least moderate relief and the percentage of patients with at least 50% of the maximum total pain relief (TOTPAR) possible.41-43 Given that number-needed-to-treat (NNT) determinations35 have been reported only for other pain models, this last type of responder analysis enabled us to calculate the NNT41,42 for each dose of valdecoxib in the sore throat pain model. We also report the percentage of the theoretical maximum TOTPAR (%TMT) achieved by patients in the placebo treatment group over 6 hours to compare the sensitivity of the sore throat pain model with other pain models.44 |
METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Patients
Patients aged 18 years who presented to the student health clinic with sore throat of onset 
6 days were eligible if they were experiencing relatively severe throat pain, defined as the upper tertile (ie, 66 mm) on a throat PI scale, a 100-mm visual analog scale (VAS; 0 = no pain, 100 = severe pain).5 In addition, patients were required to have objective evidence of the condition causing sore throat, tonsillo-pharyngitis, which was quantified using a physician-administered rating system during the physical examination, the TPS.4-6,32 This index includes ratings of 0 to 2 for each of 5 clinical features of pharyngitis: oral temperature, oropharyngeal color, presence of oropharyngeal enanthems, anterior cervical adenopathy, and anterior cervical adenitis. Patients were eligible for inclusion if they had at least minimal evidence of pharyngitis, with a total TPS 4. The physician was also asked to specify the objective features for the diagnosis of tonsillo-pharyngitis using the TPA.14,18,45 The TPA is the sum of ratings, on a scale from 0 to 3+, for each of 7 signs of tonsillo-pharyngitis: oral temperature, oropharyngeal color, number of oropharyngeal enanthems, number of anterior cervical lymph nodes, maximum size and tenderness of anterior cervical lymph nodes, and tonsillar size. After the physical examination, the throat was swabbed for microbiologic culture.
Patients were not eligible for inclusion if they were experiencing coughing that caused throat discomfort or if they were mouth breathing, which could worsen throat pain. Patients who were allergic or hypersensitive to valdecoxib, aspirin, or other nonsteroidal anti-inflammatory drugs, COX-2 selective inhibitors, acetaminophen, or sulfonamides were not eligible for the study. Patients were also ineligible if they had taken any of the following: throat lozenges, throat spray, cough drops, or menthol-containing products within 2 hours prior to the study; any cold medication (decongestants, antihistamines, expectorants, antitussives) within 8 hours; aspirin or acetaminophen within 6 hours; ibuprofen within 8 hours; or naproxen within 12 hours.
Study Design
Patients were randomized in a 1:1:1 ratio to receive valdecoxib 20 mg bid, valdecoxib 40 mg qd, or placebo over a 24-hour treatment period under double-blind conditions. Randomization was based on a schedule generated and maintained by the study sponsor. After the first dose of study medication was administered by the study nurse, patients completed assessments every 15 minutes and at 1, 1.5, and 2 hours in the study center; they completed the remaining assessments (at 4, 6, 8, 10, 12, and 24 hours) and the second dosing (at 12 hours) on an ambulatory basis. Rescue analgesic medication (acetaminophen 1000 mg) was permitted at any time.
During the study, patients measured throat PI on the VAS and relief of pain on a 7-category sore throat relief rating scale (0 = no relief, 6 = complete relief).12 Patients also evaluated throat soreness using a vertical 11-point ordinal scale (Figure 1), an NRS where 0 = not sore and 10 = very sore.14,18,33
For the determinations of time to perceptible pain relief and time to meaningful pain relief during the initial 2 hours after dosing, the study nurse started 2 stopwatches when the patient swallowed the first dose of study medication. Patients stopped the first stopwatch when they experienced perceptible pain relief (ie, when they began to feel "any pain-relieving effect" from the study medication) and stopped the second stopwatch when they experienced pain relief that was "meaningful" to them. Time to onset of analgesia was defined as the time recorded by the first stopwatch in patients who experienced meaningful pain relief.
At 12 and 24 hours after dosing, patients provided a global evaluation of the study medication on a 4-point scale (1 = poor, 4 = excellent) and rated their satisfaction with treatment on a 7-point scale (1 = very satisfied, 7 = very dissatisfied).22 All patients randomized to treatment were included in the efficacy and safety analyses.
Efficacy and Safety Endpoints
The primary efficacy endpoint was the sum of PI differences over the 2-hour period post-first dose (SPID-2), measured on the VAS. Secondary endpoints included PI difference (PID) at individual time points and summed over 6-, 12-, and 24-hour time intervals; throat soreness difference (TSD) and sore throat relief ratings at individual time points and summed over 2-, 6-, 12-, and 24-hour time intervals; onset of analgesia; patient's satisfaction with treatment and global evaluation of study medication at 12 and 24 hours; percentages of patients taking rescue analgesic (treatment failures); percentages of patients with 35% reduction in PI (much improvement), percentages of patients with 50% reduction in PI (pain half-gone), and percentages of patients with at least moderate relief at 2, 6, 12, and 24 hours; percentages of patients with 50% of TOTPAR possible over 2, 6, 12, and 24 hours; and the NNT for each dose of valdecoxib.
Time-specific PID and TSD scores were derived by subtracting the throat PI or throat soreness score measured at each posttreatment time point from the respective baseline score. SPID, the sum of TSD scores, and TOTPAR over each time period (2, 6, 12, and 24 hours) were calculated from the area under each relevant curve using the trapezoidal rule.
Adverse events reported over the study period and at the follow-up visit were recorded.
Statistical Analyses
The sample size calculation was based on the primary efficacy variable. Assuming that the common standard deviation in SPID-2 is 48 mm,4,19 58 patients per treatment group were needed to detect a 28-mm difference between valdecoxib and placebo, with a significance level of .025 (adjusted for 2 primary comparisons) and at least 80% power using a 2-sided test.
SPID-2 was analyzed using analysis of covariance (ANCOVA), with treatment as a factor and baseline PI as a covariate. Primary comparisons were for valdecoxib 20 mg bid compared with placebo and for valdecoxib 40 mg qd compared with placebo. The comparisons between each valdecoxib treatment group and placebo were interpreted using the Hochberg's step-up procedure46 for the primary efficacy variables. Time-specific PID and TSD were analyzed using ANCOVA, with treatment as a factor and corresponding baseline measurement as a covariate. Time-specific ratings of relief and satisfaction with treatment were analyzed using analysis of variance (ANOVA), with treatment as a factor.
Time to perceptible pain relief, time to meaningful pain relief, and time to onset of analgesia were analyzed using survival analysis methods. The median time to event for each treatment group was calculated using the Kaplan-Meier product limit estimator. Log-rank tests were used to determine the statistical significance of treatment group differences in the distribution of time to event. Patients' satisfaction and global evaluations of study medication were analyzed using the chi-square test.
Patients provided efficacy assessments just prior to taking rescue analgesia or just prior to withdrawal from the study due to other reasons; all subsequently missing VAS, NRS, and relief scores were extrapolated using the last observation carried forward approach. For missing satisfaction and global evaluation scores, the data collected before withdrawal were carried forward to the 12-hour time point in patients who withdrew before 12 hours and to the 24-hour time point in patients who withdrew between 12 and 24 hours.
At 2, 6, 12, and 24 hours, the percentages of patients with 35% reduction in PI, 50% reduction in PI, and at least moderate pain relief were analyzed using Fisher's exact test. The percentages of patients with 50% of the maximum TOTPAR possible over 2, 6, 12, and 24 hours were analyzed using Fisher's exact test. The NNT for each dose of valdecoxib was calculated from the percentages of patients with 50% of the maximum TOTPAR over 6 hours.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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.001).
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The mean baseline VAS score was 76 to 77 mm across treatment groups, and mean baseline throat soreness scores ranged from 7.7 to 7.8 on the NRS across treatment groups. Baseline and posttreatment changes in VAS and NRS scores correlated highly (r = 0.792-0.973, all P .001).
Among the 197 patients who entered the trial, 14 (7%) had group A beta-hemolytic Streptococcus grown from throat cultures; of these, 4 received valdecoxib 20 mg bid, 7 received valdecoxib 40 mg qd, and 3 received placebo. During the trial, these 14 patients responded to test medication similar to other patients in their respective treatment groups. After completion of the study and within the 48 hours required for culture growth, patients with streptococcal pharyngitis began treatment with an appropriate antibiotic and completed treatment without clinical sequelae. A total of 187 patients (95%) completed the study. Of the 10 patients who discontinued the study, 1 taking valdecoxib 20 mg, 4 taking valdecoxib 40 mg, and 4 taking placebo withdrew owing to insufficient clinical response; 1 patient taking placebo was withdrawn because of protocol violation. All 10 patients received alternative treatment for sore throat.
Efficacy
On all efficacy measures, valdecoxib 20 mg bid and 40 mg qd was shown to provide statistically significant relief of sore throat compared with placebo. There were no statistically significant differences between the 2 dose regimens. Pain reduction measured over the initial 2-hour period (SPID-2) was significantly greater in patients taking valdecoxib 20 mg (30.2 ± 2.76) and valdecoxib 40 mg (25.4 ± 2.74) compared with those taking placebo (12.1 ± 2.74; P < .001); similarly, SPID scores over all time intervals demonstrated the efficacy of both doses of valdecoxib compared with placebo (all P < .05). Mean PID scores at individual time points were significantly improved compared with placebo over the entire 24-hour observation period, starting at 45 minutes in the valdecoxib 20-mg group and at 1 hour in the valdecoxib 40-mg group (P < .05) (Figure 2).
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Both valdecoxib 20 mg and 40 mg provided significantly greater relief of sore throat compared with placebo beginning at the same time points (P < .05) and throughout 24 hours (Figure 4). TOTPAR scores were significantly different for both valdecoxib groups compared with placebo for all time intervals over 24 hours (all P < .05).
The median time to onset of analgesia by the 2-stopwatch technique was significantly shorter following treatment with valdecoxib 20 mg (45 minutes) and valdecoxib 40 mg (84 minutes) than placebo (>2 hours, P < .05). Significantly higher percentages of patients experienced meaningful pain relief within 2 hours after the first dose of valdecoxib 20 mg (66%) and valdecoxib 40 mg (52%) than with placebo (24%) (P < .05).
There were 10 treatment failures: 1 (1.5%) in the valdecoxib 20-mg bid group, 4 (6.1%) in the valdecoxib 40-mg qd group, and 5 (7.6%) in the placebo group. There was no significant difference between treatment groups.
At 12 hours after treatment, both doses of valdecoxib provided significantly more satisfaction than placebo (P < .001), and significantly more patients who received valdecoxib 20 mg bid (59%) or valdecoxib 40 mg qd (51%) rated their study medication as good or excellent compared with placebo (12%) (all P < .001). Similar results were observed at the 24-hour time point.
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.001). Results were similar at the 6-, 12-, and 24-hour time points. According to the criterion of 50% reduction in PI (pain half-gone), significantly more patients treated with valdecoxib 20 mg (37%) and valdecoxib 40 mg (27%) were responders at 2 hours compared with 6% treated with placebo (P .05) (Figure 5), with similar results at 6, 12, and 24 hours. At the 2-hour time point, 59% of patients treated with valdecoxib 20 mg and 42% of patients treated with valdecoxib 40 mg reported at least moderate relief compared with 12% treated with placebo (P < .001). Similar results were observed at 6, 12, and 24 hours (Figure 6).
Over the conventional 6-hour time interval, 31% of patients who received valdecoxib 20 mg and 33% of patients who received valdecoxib 40 mg achieved 50% maximum TOTPAR, compared with <5% of patients who received placebo (P < .001). Results over the 12- and 24-hour time intervals were similar (Figure 7). The NNT was 3.8 for valdecoxib 20 mg and 3.5 for valdecoxib 40 mg.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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To conduct as precise a pharmacologic assay as possible, the basic features of the sore throat pain model4-6 were specifically retained, with 2 changes in the study design and with additional types of analysis. We found that refinements of the description of each objective feature of tonsillo-pharyngitis, as well as the inclusion of "size of tonsils" in the index, made the TPA more representative of all signs of tonsillo-pharyngitis. Expanding the index from a 0 to 2 ordinal ranking of each finding (in the original TPS) to a 0 to 3 ranking (in the TPA) also allowed gradations of the severity of each feature that are familiar to clinicians and readily implemented. Also, both indexes were highly correlated (r = 0.807, P .001). Consequently, the TPA ensured a homogeneous baseline status of patients, one diagnosis as the cause for pain. Because the TPA is more comprehensive, is easy to use, and is now validated, in future trials, we recommend sole use of the TPA to confirm the objective status of patients with the symptom of sore throat.
We also found that the Lasagna Pain Scale (a 0-10 thermometer-like NRS) (Figure 1) is a sensitive instrument for measuring throat soreness both in terms of baseline status and in terms of change in status over time. Posttreatment scores on this NRS also correlated highly with those scores on the VAS measuring PI (r = 0.792-0.973, P .001) and with scores on the sore throat relief rating scale (r = 0.901-0.971, P .001), differentiating each dose of active drug from placebo. (In trials on other agents, the Lasagna Pain Scale may be more sensitive to between-dose and between-drug effects.) Because it is based on the common 0 to 10 rating system, patients found the Lasagna Pain Scale easy to use, too. As a result of these observations, as well as the ability to measure the actual quality of pain32 that patients use to describe a sore throat, we recommend use of this now-validated instrument to other investigators studying patients with sore throat due to pharyngitis. The Lasagna Pain Scale also has utility in evaluating other kinds of throat pain (eg, patients with oral mucositis) and, with modifications, in evaluating other symptoms (eg, gastrointestinal, respiratory, rhino-sinusitis complaints).
As a consequence of incorporating these components of the study design into the core architecture of the sore throat pain model,6 patients' ratings of PI and relief were able to consistently detect the onset, peak, and duration of action of valdecoxib, pharmacodynamic curves that were distinctly different from the placebo time-effect curve (Figures 2, 3 and 4). For example, for the primary endpoint, we observed a 2- to 2.5-fold greater reduction in PI following valdecoxib treatment compared with placebo during the initial 2-hour posttreatment period (P < .001). Even though this was not designed as an onset-of-action study,13 we were able to detect significant activity of valdecoxib 20 mg (and 40 mg) compared with placebo at 45 minutes (and 1 hour) by the timed response ratings and at 45 minutes (and 84 minutes) by the 2-stopwatch technique. Comparisons of each dose regimen with placebo for area under the curve analyses over 6, 12, and 24 hours also demonstrated significant treatment effects. There were no statistically significant pharmacodynamic differences between the 20-mg bid and 40-mg qd dose regimens. Efficacy of each valdecoxib regimen was still evident at 24 hours despite the natural improvement of pharyngitis after several days: many patients entered the trial with 4-day sore throats that were resolving after 24 hours in the clinical trial, a natural course particularly noted among patients in the placebo treatment group (Figures 2, 3, 4, 5, 6 and 7). Importantly, responses on the different measurement instruments were highly correlated with one another. Patients' measurements on the standard PI and relief rating scales were also confirmed by their determinations of "meaningful relief" by the 2-stopwatch method, by their global evaluations of the study medication, and by their assessments of satisfaction with treatment. This consistency of results provides internal validation of the efficacy of valdecoxib for acute pain.4,39,47-49
We also observed a low placebo response,50,51 which is characteristic of the model. (It has been theorized that the explanation for this low placebo response derives from the involuntary act of swallowing: patients with sore throat are continuously reminded of throat discomfort.) Patients who received placebo treatment registered a maximal mean PID response of 10.8 mm on the 100-mm VAS at any 1 time point over 12 hours, and as indicated by the low standard errors (maximally ±2.62 mm), there was low variability among the patients' timed responses to placebo.
To further characterize this low placebo response, we also examined the percentage of the theoretical maximum TOTPAR (%TMT) over 6 hours among patients who received placebo treatment.44 This metric relates the actual TOTPAR achieved by a patient to the maximum TOTPAR possible over 6 hours. A reliable indicator of assay sensitivity, %TMT by placebo-treated patients is inversely related to a pain model's assay sensitivity, with <25% TMT indicating greater ability to demonstrate a difference between drug and placebo.44 We observed 6% TMT by patients with sore throat who were treated with placebo, a rate that is lower than the %TMT in placebo-treated patients with other painful conditions.44,52,53 Because this placebo response rate lies in the same low range of %TMT that has been observed in other studies using the sore throat pain model, it serves as an indicator of the reliability of this implementation of the pain model. (In contrast, a high placebo response rate in a sore throat pain study is a clue to aberrant design and/or conduct.) The low placebo response rate also serves as an indicator of the validity of the study findings.
To examine and confirm the sensitivity of this pain model, analyses based on individual response rates were also conducted to measure the efficacy of valdecoxib compared with placebo. These different types of analysis were consistent with the findings based on conventional analyses of mean treatment group responses. For example, when we applied the criterion of Cepeda et al38 to identify patients with acute pain who had experienced 35% reduction in PI after treatment (corresponding to at least "much improvement"), we found that 54% of patients treated with valdecoxib 20 mg and 44% of patients treated with valdecoxib 40 mg experienced this level of response at 2 hours, significantly different from 17% of patients treated with placebo (P < .001). (These results confirm those for the primary endpoint, SPID over 2 hours, with no difference between the active drugs.) Both doses were also distinguished from placebo by this metric over the commonly used 6-hour period (P < .001). Moreover, when we applied the classic, more stringent "pain half-gone" criterion for drug effect (Figure 5),7,34 we found that significantly more patients treated with valdecoxib 20 mg or 40 mg reported 50% reduction in PI at 2 and 6 hours than patients treated with placebo (P < .001).
For individual responses measured in terms of pain relief, we used the method of Moore et al,41 who reported the percentage of patients achieving a definitive level of relief, such as at least moderate relief (the level, in fact, that most patients with sore throat select as the level of "meaningful relief"54). When we examined the responses of patients at 6 hours, we observed that 51% of patients treated with valdecoxib 20 mg and 53% of patients treated with valdecoxib 40 mg achieved at least moderate relief compared with 14% taking placebo (P < .001) (Figure 6). This observation agrees with the finding that more than twice as many patients reported meaningful relief on the 2-stopwatch method after either dosage of valdecoxib than after placebo. We observed the same significant differentiation of active drug from placebo at 2, 12, and 24 hours by this indicator of efficacy.
Applying another recognized criterion of response,42 we found that both dosages of valdecoxib provided 50% maximum TOTPAR over 12 (and 24) hours to 32% (and 38%) of patients, compared with 8% (and 11%) of patients who received placebo (P < .001) (Figure 7). Over the 6-hour time period commonly used to evaluate analgesic drug response, we found that 6 times as many patients treated with either dose of valdecoxib (31%) experienced this substantive level of pain relief as patients who received placebo (P < .001). Accordingly, the NNT derived for each dosage of valdecoxib was low, indicating reliably good analgesia.35,55
As ways to improve the utility of the report of a clinical trial,41 these different types of analysis present another validation of the study findings and support the observation of good assay sensitivity from conventional analyses. We conclude, therefore, that the sore throat pain model is a sensitive and reliable assay of pharmacologic activity. Incorporating a comprehensive, now-validated diagnostic index of TPA, this use of the model demonstrated significant differentiation of valdecoxib 20 mg bid and valdecoxib 40 mg qd from placebo over 24 hours. There was internal consistency of the patients' responses when measured on different rating scales, including the Lasagna Pain Scale, which was employed here to measure changes in throat soreness, not just baseline status, and was validated as a sensitive rating scale. As observed in other uses of this pain model, there was a low placebo response rate (a corollary of assay sensitivity), indicating reliable implementation of the model and providing confidence in the study results. Finally, there was strong agreement between standard analyses and responder analyses, confirming evidence of analgesic activity and robustness of the model.
In summary, the sore throat pain model augments clinical investigators' armamentarium in the evaluation of acute analgesic drugs.
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ACKNOWLEDGEMENTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Financial disclosure: This study was sponsored by Pfizer, Inc. Editorial support was provided by K. Ayling-Rouse, MSc, of PAREXEL and was funded by Pfizer, Inc.
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REFERENCES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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