SCIENTIFIC REPORT The Efficacy of Nonopioid Analgesics for Postoperative Dental Pain: A Meta-analysis

Nafisa Ahmad,* Helen A. Grad, MScPhm,* Daniel A. Haas, DDS, PhD,* Kristan J. Aronson, PhD,t AlexandraJokovic, BDS, MHSc,* and David Locker, BDS, PhD* *Faculty of Dentistry, University of Toronto, Toronto, Ontario, Canada, and tDepartment of Community Health and Epidemiology, Queen's University, Kingston, Ontario, Canada

The evidence for the efficacy of nonopioid analgesics in the dental pain model was examined by conducting a meta-analysis. Studies were obtained by searching the literature from August 1996 back to 1975 using the terms pain, analgesics, and dentistry. This led to the review of 294 articles, of which 33 studies met the inclusion criteria. Pain scale results were transformed into a common percent scale and con- verted to N-weighted means with differences in efficacy considered significant using a 95% confidence interval. Collectively, therapeutic doses of the nonsteroidal anti- inflammatory drugs (NSAIDs) commonly used in dentistry were significantly more efficacious than the combination of acetaminophen (600 or 650 mg) with codeine (60 mg). Similarly, specific doses of each of diflunisal, flurbiprofen, ibuprofen, and ketorolac were significantly more efficacious than the commonly used acetamino- phen-codeine combination. These quantitative results show that particular NSAIDs may be more efficacious than the acetaminophen-codeine combination for relief of postoperative dental pain. Key Words: Meta-analysis; Analgesics; NSAIDs; Pain; Dentistry.

M anagement of postoperative pain in dentistry is an tent procedure confined to one area of the body, and inherent part of clinical practice. It has been es- consistent postoperative pain ranging from moderate to timated that in the United States alone, dentists write severe intensity.3 approximately 16 million analgesic prescriptions per In 1976, Cooper and Beaver introduced a protocol year for pain of dental origin.' The most commonly pre- for determining efficacy that has become a standard scribed analgesic in dentistry is acetaminophen and co- method for evaluating analgesics.2 Efficacy can be de- deine in combination, even though many clinical trials termined by using a categorical or graded pain scale to have provided evidence that nonsteroidal anti-inflam- measure pain intensity and relief. There is now a body matory drugs (NSAIDs) are efficacious.' Therefore, clin- of literature that has used the pain model of impacted ical practice does not appear to reflect the findings from third molar surgery and standard pain scales. This has clinical trials. led to recommendations to rely increasingly on NSAIDs The studies that have investigated pharmacologic in place of opioid analgesics for the management of management of postoperative dental pain have used the pain in dentistry.'46 The objective of our study was to dental pain model of the extraction of impacted third determine whether or not this recommendation is based molars.2 This postsurgical pain model has several ad- soundly on the available evidence regarding the efficacy vantages, including the use of healthy ambulatory pa- of nonopioids in the management of postoperative den- tients, an elective surgical procedure, a relatively consis- tal pain. In particular, the efficacy of nonopioids was compared with the efficacy of the commonly prescribed Received June 23, 1997; accepted for publication September 8, acetaminophen-codeine combination. This was accom- 1997. Address correspondence to Dr. Daniel A. Haas, Faculty of Dentistry, plished using a meta-analysis and represents, to our University of Toronto, 124 Edward St., Toronto, Ontario, M5G 1G6, knowledge, the first meta-analysis of analgesics used for Canada; [email protected]. postoperative dental pain. Anesth Prog 44:119-126 1997 ISSN 0003-3006/97/$9.50 © 1997 by the American Dental Society of Anesthesiology SSDI 0003-3006(97) 119 120 Meta-analysis of Nonopioid Analaesics Anesth Prog 44:119-126 1997

METHODS It is recorded at each time unit, such as every hour. The total PAR (TOTPAR) is the weighted sum. The peak The methods used for this meta-analysis are based on PAR (PPAR) is the maximum PAR difference. Increasing those described previously.7 '4 A literature search was PAR, TOTPAR, or PPAR values indicate more pain re- conducted using computerized databases on Health and lief and therefore better analgesic efficacy. SPID, PPID, MEDLINE from the years 1975 to August 1996 using TOTPAR, and PPAR were chosen for analysis because three search terms: pain, analgesics, and dentistry, lim- these were the most common measures reported. ited to English-language articles and studies of humans. Therefore, using these measures allowed more compar- Further searches for articles were conducted by check- isons between studies. Other measures, such as the pa- ing all references describing analgesic studies in dentist- tient's overall satisfaction with the drug, SHLFGN (sum ry that were listed in these articles and individual author of observations with pain half gone), and TREMED (time searches for those who have published at least two stud- to remedication), were not used because these measures ies on analgesics used for dental pain. Two hundred were not commonly reported. The 6-hr postoperative ninety-four articles were reviewed and 32 articles re- period was the most commonly reported and is clinically porting on 33 studies met the following inclusion crite- important, and therefore was chosen for analysis. ria: placebo controlled, randomized, double-blind trial with parallel study design, use of the third molar extrac- tion pain model, use of categorical pain scales similar Statistical Analysis to that described by Cooper and Beaver2 with at least Although most articles reported the categorical pain one of the efficacy measures (SPID [summed pain inten- scale described by Cooper and Beaver,2 a few studies sity difference], PPID [peak pain intensity difference], modified this pain scale. We converted all data to a com- TOTPAR [total pain reliefl, or PPAR [peak pain reliefl) mon percentage scale using the formulas described by used, at least one nonopioid (acetaminophen or NSAID) Eisenberg et al14 (Appendix). Higher percentage values administered orally only, postoperative use of at least indicate more effective analgesia. one nonopioid only, no steroid administration, no slow- The N-weighted mean effect was used as the outcome or controlled-release administration, single-dose data, measure when these studies were combined. This al- moderate or severe baseline pain, results reported for lowed calculation of the mean effect of a treatment from at least 6 hr postoperatively and in numerical format, several studies and weighed each study according to its and side effects reported. sample size. The N-weighted mean was calculated sep- The 33 studies included in the analysis are listed in arately for each drug regimen according to the following Table 1. formula, which uses SPID as an example: X (number of patients in particular study x SPID)/total Data Extraction number of patients in all studies. Data were extracted from the published articles and en- The random effects model recommended by Der- tered onto customized forms. In terms of the outcome Simmonian and Laird12 was used to determine differ- measure, analgesic efficacy instruments measuring pain ences in efficacy. The percent relative difference is the intensity and pain relief were recorded. As described by outcome measure of each meta-analysis, presented with Cooper and Beaver,2 the scores and verbal descriptors 95% confidence intervals. A specific test for homoge- for pain intensity consist of 0 = none, 1 = slight, 2 = neity was not conducted because we felt that the inclu- moderate, and 3 = severe. The scores and verbal de- sion criteria were so specific as to greatly minimize any scriptors for pain relief consist of 0 = none, 1 = a little, variations in study design characteristics.7 2 = some, 3 = a lot, and 4 = complete. This paper describes 15 comparisons of drug groups The pain intensity difference (PID) measure is the dif- or individual drug regimens. Within each of these com- ference between the postmedication and premedication parisons the four pain measurements of PPID, SPID, pain intensity, determined by calculating the baseline PPAR, and TOTPAR are considered. pain score minus the pain intensity score at each time point. The weighted sum of each PID is then calculated (SPID). The peak PID (PPID) is the maximum PID dif- RESULTS ference found. Increasing PID, SPID, or PPID values in- dicate decreasing pain intensity and therefore better an- In total, 5171 patients undergoing third molar extrac- algesia. tions were studied in our meta-analyses with treatments The pain relief (PAR) measure is the amount the pain using 12 NSAID regimens, acetaminophen alone, or has decreased compared to the initial or baseline pain. acetaminophen in combination with codeine (60 mg). Anesth Prog 44:119-126 1997 Ahmad et al 121

Table 1. List of Articles Used in These Meta-analyses Number First Author of Drug Studied (dose in milligrams), and Year Patients in Addition to Placebo Cooper 199115 226 Acetaminophen (650), acetaminophen (650)-codeine (60), zomepirac (100), flurbiprofen (50, 100) Forbes 199016 128 Ketorolac (10), aspirin (650), acetaminophen (600)-codeine (60) Forbes 199017 206 Ketorolac (10, 20), ibuprofen (400), acetaminophen (600), acetaminophen (600)-codeine (60) Rowe 198518 167 Meclofenamate (200, 100), aspirin-buffered (600) Markowitz 198519 205 Meclofenamate (200, 100), aspirin-buffered (600) Cooper 198920 184 Ibuprofen (400), acetaminophen (600) Mardirossian 198521 164 Aspirin (650), flurbiprofen (25, 50) Cooper 198322 176 Aspirin (650), suprofen (200, 400) Forbes 198423 109 Fendosal (200), ibuprofen (400), aspirin (650) Giglio 199024 196 Meclofenamate (100), meclofenamate (100)-codeine (60), meclofenamate (50)-codeine (30), codeine (60) Cooper 198825 143 Acetaminophen (600), acetaminophen (600)-codeine (60), meclofenamate (100) Kiersch 199326 203 Naproxen (220), ibuprofen (200) Desjardins 198427 159 Codeine (60), propiram (50), aspirin (650) Forbes 198328 199 Diflunisal (500, 1000), zomepirac (100), aspirin (650) Forbes 198629 198 Naproxen (500), codeine (60), naproxen (550)-codeine (60), aspirin (650) Forbes 198930 88 Flurbiprofen (100), acetaminophen (600), acetaminophen (600)-codeine (60) Sunshine 198631 182 Acetaminophen (650), acetaminophen (650)-codeine (60), zomepirac (100), flurbiprofen (50, 100) Forbes 199032 350 Aspirin (650), caffeine (65), aspirin (650),-caffeine (65), aspirin (1000) Mehlisch 198433 162 Acetaminophen (1000), aspirin (650) Cooper 198634 212 Codeine (60), propoxyphene (65), suprofen (200) Cooper 198634 204 Aspirin (650), aspirin (650)-codeine (60), suprofen (200, 400) Cooper 198035 148 Zomepirac (100, 50), aspirin-phenacetin-caffeine-codeine (60), aspirin-phenacetin-caffeine Nelson 199436 180 Ibuprofen-lysine (200), aspirin (500) Kiersch 199437 226 Naproxen (440), acetaminophen (1000) Moore 198738 130 Codeine (60), suprofen (200), suprofen (200)-codeine (60) Hutton 198339 168 Aspirin (650), etodolac (100, 200) Jain 198640 227 Ibuprofen (100, 200, 400), aspirin (650) Gaston 198641 189 Aspirin (650), etodolac (50, 100, 200) Gaston 198442 161 Aspirin (650), etodolac (50, 200) Nelson 198543 201 Aspirin (650), etodolac (50, 100, 200) Cooper 198644 99 Acetaminophen (1000), acetaminophen (1000)-codeine (30)-caffeine (16) Forbes 199445 232 Acetaminophen (300)-codeine (30), acetaminophen (500)-hydrocodone (7.5) Mehlisch 199546 239 Acetaminophen (1000), ibuprofen-lysine (400)

The 33 clinical trials collectively enrolled a total of 6920 between nonopioids and a placebo on all four pain patients, and after excluding drop-outs, data are avail- scales were statistically significant. Likewise, the next able for 6061. Of these, 890 subjects who were taking comparison in the table shows that NSAIDs are signifi- drugs not considered to be the focus of our investigation candly more efficacious than a placebo on all scales. (meclofenamate-codeine, naproxen-codeine, caffeine, When the commonly used acetaminophen-codeine propoxyphene, codeine, aspirin-phenacetin-caffeine, combination, which consists of either 600 or 650 mg aspirin-phenacetin-caffeine-codeine, acetaminophen- acetaminophen with 60 mg codeine (Acet-Cod-60), is codeine-caffeine, acetaminophen-hydrocodone, aspi- compared with a placebo, Acet-Cod-60 is significantly rin-caffeine, suprofen-codeine, and acetaminophen- more efficacious. Further, when all NSAIDs as a group codeine [30 mg]) were excluded from our analysis. were compared with Acet-Cod-60, there was no statis- Results of the first set of meta-analyses are seen in tical difference between the two groups. However, if we Table 2. First, analgesics were compared with a place- analyze only therapeutic doses of those NSAIDs com- bo. Single doses of a placebo produced a -1 to 30% monly recommended for dentistry,6 namely diflunisal, rate of analgesia, whereas nonopioids produced a 16 to flurbiprofen, ibuprofen, ketorolac, and naproxen, there 63% rate of analgesia. Better pain relief was obtained is significantly superior pain relief compared with Acet- from nonopioids (acetaminophen and NSAIDs) com- Cod-60 on the PPAR and TOTPAR scales; the final pared with a placebo on all four pain scales. Differences comparison appears in Table 2. On the PPID and SPID 122 Meta-analysis of Nonopioid Analgesics Anesth Prog 44:119-126 1997

Table 2. Comparisons of Nonopioids, Acetaminophen and 60 mg of Codeine (Acet-Cod-60), and a Placebo 95% CI" Number of Patients Percentage Effect Upper Lower Scale Analgesic Placebo Analgesic Placebo RD limit limit Difference in efficacyb Nonopioids with Placebol546 PPID 2540 1009 23 13 10 7 13 Nonopioid > placebo SPID 3502 1328 16 -1 17 17 19 Nonopioid > placebo PPAR 2575 1039 63 30 33 30 37 Nonopioid > placebo TOTPAR 3418 1316 39 17 22 20 25 Nonopioid > placebo NSAIDs with Placebo'546 PPID 2161 1009 40 13 27 25 31 NSAIDs > placebo SPID 2996 1306 17 -1 18 17 20 NSAIDs > placebo PPAR 2196 1039 65 30 35 32 39 NSAIDs > placebo TOTPAR 2912 1294 41 17 24 22 28 NSAIDs > placebo Placebo with Acet-Cod-60151725,30,31 PPID 152 173 40 16 24 14 34 Acet-Cod-60 > placebo SPID 183 203 21 5 16 10 24 Acet-Cod-60 > placebo PPAR 152 173 59 31 28 16 39 Acet-Cod-60 > placebo TOTPAR 183 203 37 17 20 11 29 Acet-Cod-60 > placebo Number of Patients Percentage Effect 95% CI Acet-Cod- Acet-Cod- Upper Lower Scale NSAIDs 60 NSAIDs 60 RD limit limit Difference in efficacy All NSAIDs with Acet-Cod-601546 PPID 2161 152 40 40 0 -9 8 Not significant SPID 2996 183 17 21 -4 -2 10 Not significant PPAR 2196 152 65 59 6 -15 2 Not significant TOTPAR 2912 183 41 37 4 -11 4 Not significant Diflunisal (500 and 1000 mg), Flurbiprofen (100 mg), Ibuprofen (400 mg), Ketorolac (10 and 20 mg), Naproxen (440 and 550 mg), (as a group) with Acet-Cod-601'17,20,23,2528-31,3740 Number of Patients Percentage Effect 95% CI Acet-Cod- Acet-Cod- Upper Lower Scale NSAIDs 60 NSAIDs 60 RD limit limit Difference in efficacy PPID 488 152 45 40 5 -14 4 Not significant SSID 578 183 28 21 7 -14 1 Not significant PPAR 488 152 71 59 12 -21 -3 NSAIDs > Acet-Cod-60 TOTPAR 578 183 49 37 12 -20 -3 NSAIDs > Acet-Cod-60 Abbreviations: RD, relative difference in the percentage effect; CI, confidence interval; PPID, peak pain intensity difference; SPID, summed pain intensity difference; PPAR, peak pain relief; TOTPAR, total pain relief; NSAIDS, nonsteroidal anti-inflam- matory drugs. a Any range that includes zero is not statistically significant. b Only statistically significant differences in efficacy are provided. The first drug listed is more efficacious. scales, there was a trend favoring the NSAIDs that did were found with all scores. However, superior pain relief not reach statistical significance. was found with 400 mg of ibuprofen when the PPAR The efficacy of the individual NSAIDs compared with and TOTPAR scales were used, again suggesting a dose- Acet-Cod-60 is seen in Table 3. Diflunisal was more ef- dependent effect. ficacious than Acet-Cod-60, with statistically significant Ketorolac at doses of 10 or 20 mg was more effica- differences for SPID, PPAR, and TOTPAR and with a cious than Acet-Cod-60, with statistically significant dif- nonsignificant difference for PPID. ferences for the PPAR and TOTPAR scores, but not for Flurbiprofen in a dose of 100 mg was more effica- the others. Analysis of the analgesia provided by na- cious than Acet-Cod-60, whereas 50 mg of flurbiprofen proxen at doses of 440 or 550 mg did not demonstrate was not significantly different, suggesting that the effi- significant differences from those provided by Acet-Cod- cacy is dose dependent. When 200 mg of ibuprofen was 60. Although not currently recommended for use in compared to Acet-Cod-60, nonsignificant differences dentistry, ibuprofen-lysine at 200 and 400 mg was sig- Anesth Prog 44:119-126 1997 Ahmad et al 123

Table 3. Comparisons of Individual Nonopioids with Acetaminophen and 60 mg of Codeine (Acet-Cod-60) Number of Percentage Patients Effect 95% CI- Non- Acet- Non- Acet- Upper Lower Scale opioid Cod-60 opioidCod-60 RD limit limit Difference in efficacyb Diflunisal (500 and 1000 mg) with Acet-Cod-6015-1725,28,30,31 PPID 79 152 50 40 10 -24 5 Not significant SPID 79 183 35 21 14 -27 -1 Diflunisal > Acet-Cod 60 PPAR 79 152 75 59 16 -29 -3 Diflunisal > Acet-Cod 60 TOTPAR 79 183 56 37 19 -33 -5 Diflunisal > Acet-Cod 60 Flurbiprofen (50 mg) with Acet-Cod-605'71721,25,30,31 PPID 85 152 37 40 -3 -11 16 Not significant SPID 116 183 25 21 4 -15 7 Not significant PPAR 85 152 61 59 2 -16 12 Not significant TOTPAR 116 183 46 37 9 -21 4 Not significant Flurbiprofen (100 mg) with Acet-Cod-6015-1725,30,31 PPID 67 152 49 40 9 -24 7 Not significant SPID 96 183 31 21 10 -22 2 Not significant PPAR 67 152 70 59 11 -26 4 Not significant TOTPAR 96 183 51 37 14 -27 -1 Flurbiprofen > Acet-Cod-60 Ibuprofen (200 mg) with Acet-Cod-601--1725,26,30,31,40 PPID 128 152 31 40 -9 -3 20 Not significant SPID 128 183 12 21 -9 0 17 Not significant PPAR 128 152 64 59 5 -17 7 Not significant TOTPAR 128 183 37 37 0 -11 12 Not significant Ibuprofen (400 mg) with Acet-Cod-6015-172023,25,30,31,40 PPID 109 152 43 40 3 -10 16 Not significant SPID 170 183 26 21 5 -4 15 Not significant PPAR 109 152 76 59 17 6 30 Ibuprofen 400 > Acet-Cod-60 TOTPAR 170 183 51 37 14 3 25 Ibuprofen 400 > Acet-Cod-60 Ketorolac (10 and 20 mg) with Acet-Cod-60'517'25'303 PPID 103 152 49 40 9 -22 4 Not significant SPID 103 183 32 21 11 -22 1 Not significant PPAR 103 152 72 59 13 -26 -1 Ketorolac > Acet-Cod-60 TOTPAR 103 183 51 37 14 -26 - 1 Ketorolac > Acet-Cod-60 Naproxen (440 and 550 mg) with Acet-Cod-601-'-725,29-3137 PPID 130 152 37 40 -3 -10 14 Not significant SPID 130 183 20 21 -1 -9 10 Not significant PPAR 130 152 63 59 4 -17 7 Not significant TOTPAR 130 183 36 37 -1 -10 13 Not significant Ibuprofen-lysine (200 and 400 mg) with Acet-Cod-6015-17,25830,31,36,46 PPID 173 152 52 40 12 -23 - 1 Ibuprofen-lysine > Acet-Cod-60 SPID 173 183 20 21 -1 -8 10 Not significant PPAR 173 152 80 59 21 -32 -11 Ibuprofen-lysine > Acet-Cod-60 TOTPAR 173 183 34 37 -3 -7 14 Not significant Acetaminophen (650 and 600 mg) with Acet-Cod-6015-1725,30,31 PPID 131 152 30 40 -10 -2 21 Not significant SPID 161 183 14 21 -7 -2 16 Not significant PPAR 131 152 45 59 -14 1 26 Acet-Cod-60 > Acetaminophen TOTPAR 161 183 27 37 -10 0 21 Not significant Acetaminophen (1000 mg) with Acet-Cod-6015-1720,25,303137"46 PPID 248 152 31 40 -9 -2 19 Not significant SPID 345 183 12 21 -9 2 17 Acet-Cod-60 > Acetaminophen PPAR 248 152 55 59 -4 -7 14 Not significant TOTPAR 345 183 26 37 -11 2 20 Acet-Cod-60 > Acetaminophen Abbreviations: RD, relative difference in percentage effect; CI, confidence interval; PPID, peak pain intensity difference; SPID, summed pain intensity difference; PPAR, peak pain relief; TOTPAR, total pain relief. a Any range that includes zero is not statistically significant. b Only statistically significant differences in efficacy are provided. The first drug listed is more efficacious. 124 Meta-analysis of Nonopioid Analgesics Anesth Prog 44:119-126 1997 nificantly more efficacious than Acet-Cod-60 on the reach statistical significance (Tables 2 and 3). These PPID and PPAR scales. quantitative results are consistent with published narra- Better pain relief was obtained from Acet-Cod-60 tive literature reviews on the use of analgesics in den- compared with 600 and 1000 mg of acetaminophen. tistry,l46 and these results support the validity of the Depending on the dose used, the results were statisti- recommendations advocating the use of NSAIDs. cally significant for at least one of PPAR, SPID, and The. review of these articles in this meta-analysis has TOTPAR, and the results showed a slight trend favoring revealed a number of characteristics of the reports that Acet-Cod-60 for the other scores. These results show impeded more extensive analyses. Based on our review, that the addition of 60 mg of codeine enhances anal- we have provided the following recommendations to gesia in the Acet-Cod-60 formulation. make future studies more amenable to assessing the ev- The other NSAIDs reported in the 33 studies are idence regarding the efficacy of analgesics. First, stan- those not usually recommended for use in dentistry or dard deviations should routinely be reported for incor- are no longer available. Those still available did not poration into meta-analytic techniques. Second, results show significant differences compared with Acet-Cod- should be reported according to gender and age group 60, and therefore details of these analyses are not so that a meta-analysis can show whether or not there shown. are gender and age group differences.

DISCUSSION ACKNOWLEDGMENT Meta-analysis utilizes results from a group of studies with common study characteristics to provide a quantitative An abstract of this work was presented at the Interna- basis for conclusions about therapeutic effectiveness. It tional Association for Dental Research Meeting in is emerging as a powerful quantitative review technique, 1997. Dr. Aronson is supported in part through a Re- complementary to the conventional narrative literature search Scholar Award (Health Canada). review, and this technique has been used to determine the efficacy of analgesics in other pain models.13"14,47-51 Meta-analysis is especially useful when several studies REFERENCES disagree in the magnitude or direction of effect, when sample sizes are too small to detect an effect as statis- 1. Dionne RA, Gordon SM: Nonsteroidal anti-inflamma- tically significant, or when one large clinical trial is too tory drugs for acute pain control. Dent Clin North Am 1994; costly and time consuming to perform.7 38:645-667. This meta-analysis shows that, in the dental pain 2. Cooper SA, Beaver WT: A model to evaluate mild an- model, the NSAIDs recommended for use in dentistry algesics in oral surgery outpatients. Clin Pharmacol Ther when they are prescribed at appropriate doses may be 1976;20:241-250. more than 3. Cooper SA: Models for clinical assessment of oral an- efficacious Acet-Cod-60. This conclusion is algesics. Am J Med 1983 (suppl);24-29. based on the finding that statistically significant differ- 4. Troullos ES, Freeman RD, Dionne RA: The scientific ences were found in two of the measures, with a trend basis for analgesic use in dentistry. Anesth Prog 1986;33: favoring the NSAIDs in the other two measures. Differ- 123-138. ences in efficacy may have been found if the inclusion 5. Dionne RA: New approaches to preventing and treat- criteria were altered to look only at severe pain as the ing postoperative pain. J Am Dent Assoc 1992;123:27-34. baseline, as opposed to moderate or severe. It is also 6. Haas DA: Current concepts in the use of analgesics in possible that the summary measures, TOTPAR and dentistry. Oral Health 1993;83(2):7-11. SPID, may be higher in drugs with long duration and 7. L'Abbe KA, Detsky AS, O'Rourke K: Meta-analysis in rapid onset. This latter possibility could affect differ- clinical research. Ann Intern Med 1987;107:224-233. ences in efficacy between drugs of dissimilar pharma- 8. Cohen PA: Meta-analysis: application to clinical den- cokinetics. tistry and dental education. J Dent Educ 1992;56:172-175. In particular, we have demonstrated that specific dos- 9. Proskin HM, Volpe AR: Meta-analysis in dental re- search: a paradigm for performance and interpretation. J Clin es of the NSAIDs diflunisal, flurbiprofen, ibuprofen, and Dent 1994;5:19-26. ketorolac are more effective for relieving pain than the 10. Thacker SB: Meta-analysis: a quantitative approach to commonly prescribed Acet-Cod-60. With the exception research integration. JAMA 1988;259: 1685-1689. of ibuprofen-lysine, where statistical significance was 11. Sacks HS, Berrier J, Reitman D, Ancona-Berk VA, gained in at least one of the pain scores, the same trend Chalmers TC: Meta-analysis of randomized controlled trials. occurred in the other pain scores even if they did not New Engl J Med 1987;316:450-455. Anesth Prog 44:119-126 1997 Ahmad et al 125

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44. Cooper SA, Erlichman MC, Mardirossian G: Double- 51. Porzio E: Meta-analysis of two double-blind compara- blind comparison of an acetaminophen-codeine-caffeine tive studies with the sustained-release form of etodolac in rheu- combination in oral surgery pain. Anesth Prog 1986;33:139- matoid arthritis. Rheumatol Int 1993;13:S25-S30. 142. 45. Forbes JA, Bates JA, Edquist IA, et al: Evaluation of two opioid-acetaminophen combinations and placebo in post- operative oral surgery pain. Pharmacotherapy 1994;14:139- APPENDIX 146. 46. Mehlisch DR, Jasper RD, Brown P, et al: Compara- The following is a description of the calculations used tive study of ibuprofen lysine and acetaminophen in patients to transform the data to a common percent scale, as with postoperative dental pain. Clin Ther 1995;17:852- described by Eisenberg et al.14 For PPID and PPAR, the 860. data were transformed to a common percent scale as 47. Onghena P, Van Houdenhove B: Antidepressant-in- follows: (presented value [PPID or PPAR])/(maximal duced analgesia in chronic non-malignant pain: a meta-anal- - x ysis of 39 placebo-controlled studies. Pain 1992;49:205-219. value minimum value on scale) 100 = value in 48. Turner JA, Denny MC: Do antidepressant medications percent. For example, a PPID of 2 on a scale of 0 to 5 relieve chronic low back pain? J Fam Pract 1993;37:545- was transformed to 40%. For TOTPAR and SPID, the 553. value recorded depends on the number of 49. Zhang WY, Po AL: The effectiveness of topically ap- measurements taken (#) within the 6-hr observation plied capsaicin: a meta-analysis. Eur J Clin Pharmacol 1994; period, which differed from one study to another. 46:517-522. Therefore, the transformation was carried out as 50. Porzio E: Meta-analysis of three double-blind compar- follows: (presented value [SPID or TOTPAR])/([maximal ative trials with sustained-release etodolac in the treatment of value - minimum value on scale] x #) x 100 = value osteoarthritis of the knee. Rheumatol Int 1993;13:S19-S24. in percent.