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A Prospective, Randomized, Double-Blind, Parallel-Group Single-Dose Study Comparing the Efficacy and Safety of Extra Strength

A Prospective, Randomized, Double-Blind, Parallel Group, Placebo-Controlled, Single-Dose Study Comparing the Efficacy and Safety of Extra Strength Bayer Aspirin, Tylenol with Codeine #3, and Placebo in Subjects with Dental Pain

 

Laureen MacEacherna

James Frickeb

James Sorrentinoc

John Quiringd

Stephen Garreffaa

Diana Plazaa

Randy Kosloa

 

aBayer Corporation, Consumer Care Division, Morristown, NJ 07962

bPPD Pharmaco Inc., Dental Center, Austin TX 78705

cHealthcare Products Development, Inc., Norwalk, CT 06851

dQST Consultations, Allendale, MI 49401

 

 

ABSTRACT

The efficacy and safety of a single dose of two Extra Strength Bayer Aspirin Caplets (each containing aspirin 500 mg) was compared with one Tylenol with Codeine #3 Tablet (containing acetaminophen 300 mg plus codeine phosphate 30 mg) or placebo in the treatment of subjects with acute postsurgical dental pain. One hundred twenty subjects who dosed with Extra Strength Bayer Aspirin and 121 subjects who dosed with Tylenol with Codeine were compared with 61 subjects who dosed with placebo in this double-blind, randomized, parallel group, placebo-controlled, single-dose clinical trial. Qualified subjects who experienced moderate to severe pain following surgical extraction of two or more third molars were randomly allocated to receive two Extra Strength Bayer Aspirin Caplets, one Tylenol with Codeine #3 Tablet, or placebo. At 30 minutes, 1, 2, 3, 4, 5, and 6 hours postdosing, subjects rated their pain intensity, pain relief, and whether the pain relief was meaningful compared to baseline. A significant treatment effect was observed favoring Extra Strength Bayer Aspirin over Tylenol with Codeine for pain intensity difference (PID), peak PID, summed pain intensity difference (SPID), pain relief, total pain relief (TOTPAR), time to taking backup medication, and time to meaningful relief. Extra Strength Bayer Aspirin (1000 mg) was superior to one Tylenol with Codeine #3 in treating moderate to severe dental pain. Both medications were well tolerated.

 

KEY WORDS: dental pain model, acute pain, aspirin, analgesics, surgical extraction

 

INTRODUCTION

In this prospective, randomized, double-blind, parallel, placebo-controlled study, the efficacy and safety of a single dose of two Extra Strength Bayer Aspirin Caplets (each containing aspirin 500 mg) was compared with one Tylenol with Codeine #3 Tablet (containing acetaminophen 300 mg plus codeine phosphate 30 mg) or placebo in the treatment of subjects with acute postsurgical dental pain.

The dose of Extra Strength Bayer Aspirin (1000 mg) used in this study is a common dose included in the approved labeling for nonprescription analgesic medicines.1 The Tylenol with Codeine #3 dose (acetaminophen 300 mg plus codeine phosphate 30 mg) selected in this study is the dose recommended in more than 70% of the prescriptions for acute surgical pain.2

Single-dose analgesic studies reported in the literature support the choice of the dental pain model selected for this study (ie, pain resulting from the surgical extraction of impacted third molars).3-6 This acute pain model can discriminate the effect of a standard analgesic (aspirin 650 mg or acetaminophen 650 mg) from a placebo (downside assay sensitivity) and can separate the test comparator medication from a more potent analgesic medication (upside sensitivity).3-5

 

METHODS

Subject Population and Investigational Products

Subjects were solicited to participate in the study when making appointments for surgery or during a preoperative consultation visit. Those who were scheduled for surgical extraction of two or more third molars, at least one of which was a partial or complete bony impacted mandibular third molar, were randomly assigned to one of three treatment groups on the basis of a predetermined, computer-generated randomization list. A total of 120 subjects received two Extra Strength Bayer Aspirin Caplets (aspirin 1000 mg) plus 1 placebo capsule, 121 subjects received one encapsulated Tylenol with Codeine #3 Tablet (acetaminophen 300 mg plus codeine phosphate 30 mg) plus 2 placebo caplets, and 61 subjects received 2 placebo caplets plus 1 placebo capsule.

 

Study Design

On the day of surgery, prior to the actual performance of the extractions, the following information was elicited from the subject: the subjects date of birth, gender, race, height, weight, method of birth control (if the subject was female), prior and present medications, and medical history. If the subject was female, a urine pregnancy test was done. A common uniform list of inclusion and exclusion criteria was also used to determine the subjects eligibility for the study.

Upon completion of the surgery, subjects were escorted to a recovery room where they were monitored by designated study staff. The designated study staff explained the study procedures and instructed the subject on how to complete the subject site diary.

When the local anesthesia dissipated (all numbness in lower lip had subsided) and the subjects pain was of moderate to severe intensity, the appropriate rating was recorded in the subject site diary as the baseline (0‑Hour) pain intensity assessment.

Provided that he or she had pain of moderate to severe intensity and needed medication to relieve his or her pain, the subject was then administered the study medication with approximately 6 fluid ounces of water. The subject recorded the date and time the medication was taken in the subject site diary. At 30 minutes, 1, 2, 3, 4, 5, and 6 hours after taking the study medication, the subject rated his or her pain intensity on a 4-point scale (0 = none, 3 = severe), pain relief on a 5-point scale (0 = no relief, 4 = complete relief), and whether the pain relief was meaningful compared with the baseline pain. The subject made these ratings interactively with designated study staff, who recorded these ratings in the subject site diary.

All subjects who took the study medication were required to complete all seven timed assessments in the clinic. In the event that the subject took a backup medication during the 6-hour period after taking the study medication, the subject continued to make the hourly assessments throughout the remainder of the 6-hour study period. After completing the 6-hour assessment, the subject was discharged from the clinic.

Prior to discharge of the subject, the following were done:

a. The designated study staff reviewed the subjects pain and relief evaluations for accuracy, completeness, and legibility.

b.      An appointment was made for the subject to return to the clinic for a postsurgical follow-up visit.

c. The subject was supplied with a prescription or a suitable analgesic to be used by the subject after leaving the site, if necessary.

d. Transportation home was provided to any subject who was impaired.

All study subjects were instructed to return to the clinic approximately 1 week following surgery. At this visit, they were asked if they experienced any side effects, and their postsurgical dental procedure was completed. In the event that a subject did not return for the postsurgery visit, he or she was contacted by phone, and any adverse events were recorded in the appropriate Case Report Forms.

 

RESULTS

Demographic and Other Baseline Characteristics

There were 302 subjects enrolled in the study. None of these subjects were excluded from the safety/intent-to-treat analyses, while two were excluded from the primary efficacy analyses.

Variables such as age, weight, and height were considered to be continuous and were analyzed with a one-way analysis of variance with a factor of treatment. Two-tailed, least-significant-difference tests were performed for pairwise comparisons on those variables that had a significant main treatment F-test P value. For categorical variables such as gender and race, a likelihood ratio chi-squared test was used to analyze the differences among the treatment groups. The Cochran-Mantel-Haenszel test (CMH) was used to evaluate the comparability of treatment groups regarding the categorical baseline dental pain intensity score. Pairwise tests were also performed for those variables that resulted in significant overall main treatment P values for the categorical variables using the corresponding statistical test restricted to pairs of treatment data.

Table 1 summarizes the demographic data and subject characteristics of the 302 intent-to-treat subjects. The subjects ages ranged from 15.1 to 50.1 (mean: 23.15) years. One hundred sixteen (38%) subjects were male while 186 (62%) were female. Two hundred one (67%) subjects were Caucasian. Subjects weight ranged from 90.0 to 327.0 (mean: 156.21) pounds. Height ranged from 58.0 to 80.0 (mean: 66.95) inches. Eighty-two percent of subjects reported a baseline pain intensity of moderate, and 18% reported severe pain. There were no significant differences among treatment groups in any of the subject demographic or baseline characteristics (P .235). Two of the intent-to-treat subjects were not analyzed for efficacy. One subject vomited 10 minutes after dosing, and the other was treated for a postoperative bleeding episode 20 minutes after dosing.

 

Analysis of Efficacy

The efficacy variables PID, peak PID, SPID, pain relief, peak relief, and TOTPAR were analyzed using a one-way analysis of covariance with a factor of treatment with baseline pain intensity as a covariant. Two-tailed, least-significant-difference tests were performed for pairwise comparisons for those variables that had a significant main treatment F-test P value. The Cochran-Mantel-Haenszel (CMH) test was used to compare treatment group differences in the cumulative percentage of subjects at each time point for subjects who medicated with backup medication and subjects with meaningful relief. Pairwise tests were conducted with the CMH test by restricting the analyzed data sets to pairs of treatments.

The Extra Strength Bayer Aspirin and the Tylenol with Codeine #3 treatments were significantly different from placebo at all timed PID evaluations, peak PID, and 4- and 6-Hour SPID evaluations (P .003). Additionally, the Extra Strength Bayer Aspirin treatment was statistically superior to the Tylenol with Codeine #3 treatment at the 1-hour PID (P = .014) and 2-hour PID (P = .004) as well as peak PID (P = .028) and 4‑hour SPID (P = .028). The graphic representation of the 6-hour analgesic time-effect curves for pain intensity differences can be seen in Figure 1.

Both Extra Strength Bayer Aspirin and Tylenol with Codeine #3 were statistically superior to placebo (P .043) for all pain relief evaluations, including peak relief and TOTPAR at 4 and 6 hours. The Extra Strength Bayer Aspirin provided significantly higher relief of pain than did Tylenol with Codeine #3 at the 2-hour (P = .005) and 3-hour (P = .016) evaluations (Table 2). In addition, there was a significant difference in pain relief favoring Extra Strength Bayer Aspirin over Tylenol with Codeine #3 for the 4-hour and 6‑hour TOTPARs (P = .020 and P = .049, respectively). The pain relief time effect data are shown graphically in Figure 2.

As shown in Figures 1 and 2, the Extra Strength Bayer Aspirin and Tylenol with Codeine #3 pain intensity differences and pain relief scores are noticeably higher than placebo at 30 minutes. At approximately 1 hour after treatment, Extra Strength Bayer Aspirin and Tylenol with Codeine #3 both reach their peak, while placebo begins to decline. After the first hour after treatment, pain and relief scores for Extra Strength Bayer Aspirin and Tylenol with Codeine #3 begin to decline while placebo scores are essentially at baseline and remain relatively flat throughout the study. The Extra Strength Bayer Aspirin time effect curves clearly demonstrate greater pain intensity change and pain relief when compared with those for Tylenol with Codeine #3 throughout the 6 hours. The ordered treatment effects are Extra Strength Bayer Aspirin greater than Tylenol with Codeine #3 greater than placebo.

The times at which the subjects took a backup medication over the 6-hour treatment period are shown in Figure 3. Both active treatments were significantly different from placebo (P .006) after the 30-minute evaluation. The median time to taking a backup was 3.1 hours for the Extra Strength Bayer Aspirin subjects compared with 2.0 hours for the Tylenol with Codeine #3 subjects. This time difference was significant (P = .006). Figure 3 also shows that there were significantly fewer subjects in the Extra Strength Bayer Aspirin group who took backup medication than in the Tylenol with Codeine #3 group at 2 hours (P = .004) and 3 hours (P < .001), and the difference approached significance at 4 hours (P = .06).

Figure 4 is a graphic representation of the subjects evaluations of meaningful relief delivered by the different treatments over the 6-hour treatment period. Both test medications were significantly favored over placebo at all time points throughout the 6-hour treatment period (P = .007). The figure also shows that significantly more subjects in the Extra Strength Bayer Aspirin group experienced meaningful relief compared with the Tylenol with Codeine #3 group at 2, 3, 4, 5, and 6 hours (P < .04).

 

Analysis of Safety

The Fishers Exact Test was used to compare the proportion of subjects in each treatment group recording a particular adverse event. There were no statistically significant differences in the proportion of subjects reporting adverse events between treatment groups or the proportion of subjects reporting any event. Twenty-four of the 61 (39%) placebo subjects reported a total of 31 events. Thirty-four of the 120 (28%) who dosed with Extra Strength Bayer Aspirin reported a total of 46 events. Thirty-eight of the 121 (31%) subjects who dosed with Tylenol with Codeine #3 reported 54 events.

 

DISCUSSION

This study evaluated the efficacy of treating acute postoperative dental pain with one tablet of Tylenol with Codeine #3 compared with two caplets of Extra Strength Bayer Aspirin and with placebo. In over 70% of the prescriptions written for the treatment of acute painful conditions, such as dental pain or headache, the dose is one tablet of Tylenol with Codeine #3.2 Aspirin users commonly use a dose of two extra strength aspirin tablets (1000 mg) to treat these conditions.1 A possible reason why physicians prescribe only one Tylenol with Codeine #3, which contains 30 mg codeine phosphate, is that this dose avoids any potential adverse effects of codeine at higher doses.7

As documented in the results of the current study, both active medications were significantly different from placebo, and the placebo response was low, as expected. The Extra Strength Bayer Aspirin treatment was significantly better overall than Tylenol with Codeine #3 treatment for almost all of the variables measured (PIDs for the first 3 hours, peak PID, and SPIDs through 4 hours). The aspirin treatment was similarly superior for early pain relief as well as for 4-hour and 6-hour total pain relief. In addition, the aspirin treatment subjects had a significant advantage in the time to taking backup (ie, these subjects were able to wait significantly longer before taking a backup medication). More aspirin subjects experienced meaningful significant relief throughout the test period.

The results of this single-dose comparison of Extra Strength Bayer Aspirin with Tylenol with Codeine #3 and placebo in subjects with dental pain support the robust nature of the impacted third molar dental pain model. As noted in the literature, surgical removal of impacted third molars results in a wide range of pain response from mild to severe. Thus, the dental pain model is a good model to use in the evaluation of analgesics for treating acute pain, and the results can be generalized to other types of acute pain.6,8 Factors that also enhance the analgesic assay sensitivity of this pain model are the inflammation associated with third molar dental pain and the unbiased naivete of the domiciled subjects. Extraction of third molars is usually accompanied by acute inflammation, in which prostaglandins play a major role. The nonsteroidal antiprostaglandin activity of aspirin may be more efficient than Tylenol with Codeine #3 in providing pain relief for acute postsurgical dental pain.9,10 The study population consisted mainly of young healthy subjects who were nave to previous pain from surgery for impacted third molars, and consequently were unbiased to the pain experience.

 

CONCLUSION

A single dose of two Extra Strength Bayer Aspirin Caplets was a superior analgesic treatment compared with a prescription dose of one Tylenol with Codeine #3 tablet in reducing dental pain due to surgery for extraction of impacted third molars. Significantly more Extra Strength Bayer Aspirin subjects reported having attained meaningful pain relief at 2, 3, 4, 5, and 6 hours compared with the Tylenol with Codeine #3 subjects. The Extra Strength Bayer Aspirin subjects waited significantly longer before taking backup medication than did the Tylenol with Codeine #3 subjects. There were no significant differences in the number and type of adverse events reported between the treatment groups.

 

References

 

1. PDR for Nonprescription Drugs and Dietary Supplements, ed 20. Montvale, NJ, Medical Economics Company, 1999, p 611.

2. National Drug and Therapeutic Index, 4Q96-3Q97. Westport, CT, IMS Health Incorporated.

3. Cooper SA, et al: Analgesic efficacy of an ibuprofen-codeine combination. Pharmacotherapy 2:162-174, 1982.

4. Beaver, et al: A method for the 12-hour evaluation of analgesic efficacy in outpatients with postoperative oral surgery pain. Pharmacotherapy 3:235-375, 1983.

5. Forbes JA, et al: Evaluation of ketoralac, ibuprofen, and acetaminophen-codeine combination in postoperative oral surgery. Pharmacotherapy 10(Suppl):945-1055, 1990.

6. Desjardins PJ: Advances in the measurement of acute pain, in Holtz A (ed): International Congress and Symposium Series, no. 218. London, Royal Society of Medicine Press, Ltd., 1996, pp 73-92.

7. Dionne RA, et al: Analgesic efficacy of flurbiprofen in comparison with acetaminophen, acetaminophen plus codeine, and placebo after impacted third molar removal. J Oral Maxilofacial Surg 52:919-924, 1994.

8. Sagne S, et al: Analgesic efficacy and side-effect profile of paracetamol/codeine and paracetamol/dextro-propoxyphene after surgical removal of a lower wisdom tooth. J Int Med Res 15:83-85, 1987.

9. Cooper SA, Beaver WT: A model to evaluate mild analgesics in oral surgery outpatients. Clin Pharmacol Therap 20:241-250, 1976.

10. Seymour RA, et al: Postoperative dental pain and analgesic efficacy, Part II. Br J Oral Surg 21:298-303, 1983.

 


Table 1. Demographic and Subject Characteristics

(Intent-to-Treat Subjects)

 

Variable Placebo Bayer Tylenol Total P values

 

Number of Subjects 61 120 121 302

 

Age (yrs)

Mean 23.39 23.09 23.10 23.15 .948a

SD 7.52 6.45 5.70 6.38

Range 15.1-50.1 15.1-42.1 15.4-47.8 15.1-50.1

 

Sex

Male 26 (43%) 42 (35%) 48 (40%) 116 (38%) .568b

Female 35 (57%) 78 ( 65%) 73 ( 60%) 186 (62%)

 

Race

Caucasian 40 (66%) 82 ( 68%) 79 ( 65%) 201 ( 67%) .867b

Black 5 ( 8%) 5 ( 4%) 9 ( 7%) 19 ( 6%)

Hispanic 11 ( 18%) 26 ( 22%) 28 ( 23%) 65 ( 22%)

Asian 1 ( 2%) 6 ( 5%) 0 ( 0%) 7 ( 2%)

Other 4 ( 7%) 1 ( 1%) 5 ( 4%) 10 ( 3%)

 

Weight (lbs)

Mean 153.61 152.48 161.22 156.21 .235a

SD 34.43 45.29 41.90 42.01

Range 100.0-280.0 90.0-327.0 100.0-290.0 90.0-327.0

 

Height (inches)

Mean 67.46 66.52 67.12 66.95 .328a

SD 4.31 4.15 4.47 4.31

Range 60.0-76.0 58.0-75.0 59.0-80.0 58.0-80.0

 

Baseline Pain Intensity

Moderate 48 ( 79%) 101 ( 84%) 100 ( 83%) 249 ( 82%) .657c

Severe 13 ( 21%) 19 ( 16%) 21 ( 17%) 53 ( 18%)

 

aP values for treatment comparisons from a one-way analysis of variance with a factor of treatment.

bP values from likelihood ratio chi-squared test. For the variable race, the P value was calculated after combining the following categories: Black, Hispanic, Asian, and Other.

cP values from Cochran-Mantel-Haenszel test for row mean scores.


Table 2. PID, Relief, Peak PID, Peak Relief, SPID and TOTPAR Results

 

 

Placebo* Bayer* Tylenol*

Variable LSMean n LSMean n LSMean n P value

Number of Subjects 61 120 119

 

Pain Intensity Difference (PID)

30-Minute -0.12 61 0.23 118 0.20 119 .750

1-Hour -0.38 61 0.66 120 0.40 119 .014

2-Hour -0.38 10 0.53 85 0.20 68 .004

3-Hour -0.39 7 0.28 70 0.08 42 .053

4-Hour -0.46 4 0.13 44 0.02 30 .234

5-Hour -0.46 2 0.10 34 -0.03 24 .155

6-Hour -0.46 2 0.02 27 -0.01 21 .734

 

Relief

30-Minute 0.31 61 0.90 118 0.80 119 .426

1-Hour 0.31 61 1.56 120 1.28 119 .059

2-Hour 0.27 10 1.47 85 0.98 68 .005

3-Hour 0.20 7 1.08 70 0.70 42 .016

4-Hour 0.12 4 0.77 44 0.60 30 .232

5-Hour 0.12 2 0.65 34 0.46 24 .181

6-Hour 0.12 2 0.56 27 0.49 21 .629

 

Variable Mean Mean Mean P value

 

Peak PID -0.00 0.85 0.61 .028

Peak Relief 0.52 1.93 1.63 .080

 

Summed Pain Intensity Difference (SPID)

4-Hour -1.48 1.39 0.61 .028

6-Hour -2.39 1.51 0.56 .069

 

Total Pain Relief (TOTPAR)

4-Hour 0.90 4.55 3.32 .020

6-Hour 1.14 5.76 4.26 .049

 

*Both active medications were statistically superior to placebo (P < .05).

Sample sizes at each time point are the number of subjects with nonextrapolated data.

P value for the difference between Bayer and Tylenol.


Figure 1. Mean Pain Intensity Difference (PID) Scores with Standard Error Bars.

 

 

Note: Both active medications were statistically superior to placebo (P < .01) at all evaluations.


Figure 2. Mean Relief Scores with Standard Error Bars.

 

Note: Both active medications were statistically superior to placebo (P < .01) at all evaluations.


Figure 3. Time to Taking Backup Medication.

 

 

 

Note: Both active medications were statistically superior to placebo (P < .01) after hour.

 

Median times to taking backup medication:

Extra Strength Bayer = 3.1 hours

Tylenol with Codeine = 2.0 hours


Figure 4. Time to Meaningful Relief.

 

 

Note: Both active medications were statistically superior to placebo (P .007) at all evaluations.

 

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