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Pain Relief With Aspirin Is Comparable to Acetaminophen With Codeine
DIAGNOSIS/TREATMENT/PROGNOSIS
ARTICLE ANALYSIS & EVALUATION ARTICLE TITLE AND BIBLIOGRAPHIC INFORMATION Assessment of the efficacy and safety profiles of aspirin and acetaminophen with codeine: results from 2 randomized, controlled trials in individuals with tension-type headache and postoperative dental pain. Gatoulis SC, Voelker M, Fisher M. Clin Ther 2012;34(1)138-48.
Pain Relief With Aspirin Is Comparable to Acetaminophen With Codeine SUMMARY Subjects Three hundred two patients were enrolled in the dental pain study measuring postoperative pain from 0 to 6 h after third molar extractions; 676 patients enrolled in the headache study measuring pain in patients who experienced 2 to 10 tension-type headaches per month. For the dental study, patients had to be age 15 years or older and have had surgical extraction of 2 or more third molars, at least one of which was a partial or complete bony impaction.
REVIEWER Elliot Abt, DDS, MS, MSc
PURPOSE/QUESTION How does aspirin compare to acetaminophen with codeine and placebo in pain relief from headache or dental pain?
SOURCE OF FUNDING Bayer HealthCare
Key Exposure/Study Factor Patients received a single dose of either aspirin (1000 mg), acetaminophen (300 mg) with codeine (30 mg), or placebo only if they experienced moderate to severe pain.
Main Outcome Measure The 2 main outcome measures were the sum of pain intensity differences from baseline over 6 h and the sum of pain relief scores at 30 min, 1, 2, 3, 4, 5, and 6 h after taking medication. Pain intensity was measured on a 4-point ordinal scale (0 = none; 1 = mild; 2 = moderate; 3 = severe). Pain relief was measured on a 5-point ordinal scale (0 = no relief; 1 = dental pain less than half gone; 2 = dental pain half gone; 3 = dental pain more than half gone; 4 = complete relief).
TYPE OF STUDY/DESIGN
Main Results
Randomized controlled study
For the dental study, aspirin and acetaminophen with codeine showed a statistically significant benefit when compared to placebo at all time points. While aspirin provided a statistically significant benefit when compared with acetaminophen and codeine in pain differences at baseline from 0 to 4 h (P = 0.028), this benefit was non-significant at the 0 to 6-h time period (P = 0.069). In the tension-type headache study, both aspirin and acetaminophen with codeine were significantly better than placebo at all time points but were insignificantly different from each another. No differences in adverse events were reported in either study.
LEVEL OF EVIDENCE Level 2: Limited-quality, patient-oriented evidence
STRENGTH OF RECOMMENDATION GRADE Grade B: Inconsistent or limitedquality patient-oriented evidence
Conclusions Aspirin provides a statistically significant benefit for relief of dental pain and tension-type headaches compared to placebo, and similar pain relief when compared to acetaminophen and codeine.
COMMENTARY AND ANALYSIS J Evid Base Dent Pract 2012;12:220-221 1532-3382/$36.00 Ó 2012 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jebdp.2012.09.001
Practitioners would likely welcome research studies demonstrating the effectiveness of aspirin as compared with acetaminophen with codeine. However, there were several problems with the internal and external validity of these investigations. Although the article stated that groups were selected randomly, there was no mention of either sequence generation
JOURNAL OF EVIDENCE-BASED DENTAL PRACTICE
or allocation concealment. Similarly, while the term double-blind was used, there were no details as to the blinding of participants, investigators, or particularly those assessing outcomes. Selection and detection bias are among the major dimensions of quality in trials, and failure to disclose details on randomization and blinding can alter, and oftentimes exaggerate, study results. The primary statistical test employed was analysis of covariance (ANCOVA), or analysis of covariates that essentially combines the features of analysis of variance (ANOVA) and regression analysis. One of the assumptions of ANCOVA is that the (quantitative) data be normally distributed. Yet, the primary outcome data was ordinal in nature, using a 0 to 4-point pain scale. Data were analyzed using means (SD), which is technically incorrect for ordinal data. Data should have been analyzed using medians and inter-quartile range, and a non-parametric test should have been employed for statistical analysis. Additionally, confidence intervals were not provided, nor were any correction factor for the multiple outcomes tested, which inflates the chance for a type I error, or falsely rejecting the null hypothesis. Many results were described as being statistically significant, yet without confidence intervals any measure of clinical relevance is difficult to establish. There were additional issues with this paper. Placebo controls are commonly used when there is uncertainty with any benefit with the experimental group(s). In this
Volume 12, Number 4
case, the benefits of both aspirin and acetaminophen with codeine have been well established, and the benefit of placebos, while unclear for pain studies,1 raises an ethical question: were the study participants who were randomized to the control group denied an obvious therapeutic benefit? Additionally, the use of one-time dosing appears to be inconsistent with the common clinical practice of multiple dosing, raising external validity issues. Furthermore, all 3 listed study authors are either working for, or have relationships with, the sponsoring (aspirin) company. Given the potential for conflict of interest issues, and the number of methodological and statistical limitations described, caution should be used when interpreting study results.
REFERENCE 1. Hr objartsson A, Gøtzsche PC. Placebo interventions for all clinical conditions. Cochrane Database Sys Rev 2010 Jan 20;(1):CD003974 [Review].
REVIEWER Elliot Abt, DDS, MS, MSc Department of Dentistry, Advocate Illinois Masonic Medical Center, Chicago, IL, USA Phone: þ 847 677 2404 [email protected]
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ARTICLE ANALYSIS & EVALUATION ARTICLE TITLE AND BIBLIOGRAPHIC INFORMATION Assessment of the efficacy and safety profiles of aspirin and acetaminophen with codeine: results from 2 randomized, controlled trials in individuals with tension-type headache and postoperative dental pain. Gatoulis SC, Voelker M, Fisher M. Clin Ther 2012;34(1)138-48.
Pain Relief With Aspirin Is Comparable to Acetaminophen With Codeine SUMMARY Subjects Three hundred two patients were enrolled in the dental pain study measuring postoperative pain from 0 to 6 h after third molar extractions; 676 patients enrolled in the headache study measuring pain in patients who experienced 2 to 10 tension-type headaches per month. For the dental study, patients had to be age 15 years or older and have had surgical extraction of 2 or more third molars, at least one of which was a partial or complete bony impaction.
REVIEWER Elliot Abt, DDS, MS, MSc
PURPOSE/QUESTION How does aspirin compare to acetaminophen with codeine and placebo in pain relief from headache or dental pain?
SOURCE OF FUNDING Bayer HealthCare
Key Exposure/Study Factor Patients received a single dose of either aspirin (1000 mg), acetaminophen (300 mg) with codeine (30 mg), or placebo only if they experienced moderate to severe pain.
Main Outcome Measure The 2 main outcome measures were the sum of pain intensity differences from baseline over 6 h and the sum of pain relief scores at 30 min, 1, 2, 3, 4, 5, and 6 h after taking medication. Pain intensity was measured on a 4-point ordinal scale (0 = none; 1 = mild; 2 = moderate; 3 = severe). Pain relief was measured on a 5-point ordinal scale (0 = no relief; 1 = dental pain less than half gone; 2 = dental pain half gone; 3 = dental pain more than half gone; 4 = complete relief).
TYPE OF STUDY/DESIGN
Main Results
Randomized controlled study
For the dental study, aspirin and acetaminophen with codeine showed a statistically significant benefit when compared to placebo at all time points. While aspirin provided a statistically significant benefit when compared with acetaminophen and codeine in pain differences at baseline from 0 to 4 h (P = 0.028), this benefit was non-significant at the 0 to 6-h time period (P = 0.069). In the tension-type headache study, both aspirin and acetaminophen with codeine were significantly better than placebo at all time points but were insignificantly different from each another. No differences in adverse events were reported in either study.
LEVEL OF EVIDENCE Level 2: Limited-quality, patient-oriented evidence
STRENGTH OF RECOMMENDATION GRADE Grade B: Inconsistent or limitedquality patient-oriented evidence
Conclusions Aspirin provides a statistically significant benefit for relief of dental pain and tension-type headaches compared to placebo, and similar pain relief when compared to acetaminophen and codeine.
COMMENTARY AND ANALYSIS J Evid Base Dent Pract 2012;12:220-221 1532-3382/$36.00 Ó 2012 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jebdp.2012.09.001
Practitioners would likely welcome research studies demonstrating the effectiveness of aspirin as compared with acetaminophen with codeine. However, there were several problems with the internal and external validity of these investigations. Although the article stated that groups were selected randomly, there was no mention of either sequence generation
JOURNAL OF EVIDENCE-BASED DENTAL PRACTICE
or allocation concealment. Similarly, while the term double-blind was used, there were no details as to the blinding of participants, investigators, or particularly those assessing outcomes. Selection and detection bias are among the major dimensions of quality in trials, and failure to disclose details on randomization and blinding can alter, and oftentimes exaggerate, study results. The primary statistical test employed was analysis of covariance (ANCOVA), or analysis of covariates that essentially combines the features of analysis of variance (ANOVA) and regression analysis. One of the assumptions of ANCOVA is that the (quantitative) data be normally distributed. Yet, the primary outcome data was ordinal in nature, using a 0 to 4-point pain scale. Data were analyzed using means (SD), which is technically incorrect for ordinal data. Data should have been analyzed using medians and inter-quartile range, and a non-parametric test should have been employed for statistical analysis. Additionally, confidence intervals were not provided, nor were any correction factor for the multiple outcomes tested, which inflates the chance for a type I error, or falsely rejecting the null hypothesis. Many results were described as being statistically significant, yet without confidence intervals any measure of clinical relevance is difficult to establish. There were additional issues with this paper. Placebo controls are commonly used when there is uncertainty with any benefit with the experimental group(s). In this
Volume 12, Number 4
case, the benefits of both aspirin and acetaminophen with codeine have been well established, and the benefit of placebos, while unclear for pain studies,1 raises an ethical question: were the study participants who were randomized to the control group denied an obvious therapeutic benefit? Additionally, the use of one-time dosing appears to be inconsistent with the common clinical practice of multiple dosing, raising external validity issues. Furthermore, all 3 listed study authors are either working for, or have relationships with, the sponsoring (aspirin) company. Given the potential for conflict of interest issues, and the number of methodological and statistical limitations described, caution should be used when interpreting study results.
REFERENCE 1. Hr objartsson A, Gøtzsche PC. Placebo interventions for all clinical conditions. Cochrane Database Sys Rev 2010 Jan 20;(1):CD003974 [Review].
REVIEWER Elliot Abt, DDS, MS, MSc Department of Dentistry, Advocate Illinois Masonic Medical Center, Chicago, IL, USA Phone: þ 847 677 2404 [email protected]
221