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 Alexandra Jokovic, 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 converted to N-weighted means with differences in efficacy considered significant using a 95% confidence interval. Collectively, therapeutic doses of the nonsteroidal antiinflammatory 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 acetaminophen-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 inherent part of clinical practice. It has been estimated that in the United States alone, dentists write approximately 16 million analgesic prescriptions per year for pain of dental origin.' The most commonly prescribed analgesic in dentistry is acetaminophen and codeine in combination, even though many clinical trials have provided evidence that nonsteroidal anti-inflammatory drugs (NSAIDs) are efficacious.' Therefore, clinical practice does not appear to reflect the findings from clinical trials. The studies that have investigated pharmacologic management of postoperative dental pain have used the dental pain model of the extraction of impacted third molars.2 This postsurgical pain model has several advantages, including the use of healthy ambulatory patients, an elective surgical procedure, a relatively consisReceived June 23, 1997; accepted for publication September 8, 1997. Address correspondence to Dr. Daniel A. Haas, Faculty of Dentistry, University of Toronto, 124 Edward St., Toronto, Ontario, M5G 1G6, Canada; dhaas@dental.utoronto.ca. Anesth Prog 44:119-126 1997 1997 by the American Dental Society of Anesthesiology

tent procedure confined to one area of the body, and consistent postoperative pain ranging from moderate to severe intensity.3 In 1976, Cooper and Beaver introduced a protocol for determining efficacy that has become a standard method for evaluating analgesics.2 Efficacy can be determined by using a categorical or graded pain scale to measure pain intensity and relief. There is now a body of literature that has used the pain model of impacted third molar surgery and standard pain scales. This has led to recommendations to rely increasingly on NSAIDs in place of opioid analgesics for the management of pain in dentistry.' 46 The objective of our study was to determine whether or not this recommendation is based soundly on the available evidence regarding the efficacy of nonopioids in the management of postoperative dental pain. In particular, the efficacy of nonopioids was compared with the efficacy of the commonly prescribed acetaminophen-codeine combination. This was accomplished using a meta-analysis and represents, to our knowledge, the first meta-analysis of analgesics used for postoperative dental pain.
ISSN 0003-3006/97/$9.50 SSDI 0003-3006(97)

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METHODS
The methods used for this meta-analysis are based on those described previously.7 '4 A literature search was conducted using computerized databases on Health and MEDLINE from the years 1975 to August 1996 using three search terms: pain, analgesics, and dentistry, limited to English-language articles and studies of humans. Further searches for articles were conducted by checking all references describing analgesic studies in dentistry that were listed in these articles and individual author searches for those who have published at least two studies on analgesics used for dental pain. Two hundred ninety-four articles were reviewed and 32 articles reporting on 33 studies met the following inclusion criteria: placebo controlled, randomized, double-blind trial with parallel study design, use of the third molar extraction pain model, use of categorical pain scales similar to that described by Cooper and Beaver2 with at least one of the efficacy measures (SPID [summed pain intensity difference], PPID [peak pain intensity difference], TOTPAR [total pain reliefl, or PPAR [peak pain reliefl) used, at least one nonopioid (acetaminophen or NSAID) administered orally only, postoperative use of at least one nonopioid only, no steroid administration, no slowor controlled-release administration, single-dose data, moderate or severe baseline pain, results reported for at least 6 hr postoperatively and in numerical format, and side effects reported. The 33 studies included in the analysis are listed in Table 1.

It is recorded at each time unit, such as every hour. The total PAR (TOTPAR) is the weighted sum. The peak PAR (PPAR) is the maximum PAR difference. Increasing PAR, TOTPAR, or PPAR values indicate more pain relief and therefore better analgesic efficacy. SPID, PPID, TOTPAR, and PPAR were chosen for analysis because these were the most common measures reported. Therefore, using these measures allowed more comparisons between studies. Other measures, such as the patient's overall satisfaction with the drug, SHLFGN (sum of observations with pain half gone), and TREMED (time to remedication), were not used because these measures were not commonly reported. The 6-hr postoperative period was the most commonly reported and is clinically important, and therefore was chosen for analysis.

Data Extraction Data were extracted from the published articles and entered onto customized forms. In terms of the outcome measure, analgesic efficacy instruments measuring pain intensity and pain relief were recorded. As described by Cooper and Beaver,2 the scores and verbal descriptors for pain intensity consist of 0 = none, 1 = slight, 2 = moderate, and 3 = severe. The scores and verbal descriptors for pain relief consist of 0 = none, 1 = a little, 2 = some, 3 = a lot, and 4 = complete. The pain intensity difference (PID) measure is the difference between the postmedication and premedication pain intensity, determined by calculating the baseline 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 difference found. Increasing PID, SPID, or PPID values indicate decreasing pain intensity and therefore better analgesia. The pain relief (PAR) measure is the amount the pain has decreased compared to the initial or baseline pain.

Statistical Analysis Although most articles reported the categorical pain scale described by Cooper and Beaver,2 a few studies modified this pain scale. We converted all data to a common percentage scale using the formulas described by Eisenberg et al14 (Appendix). Higher percentage values indicate more effective analgesia. The N-weighted mean effect was used as the outcome measure when these studies were combined. This allowed calculation of the mean effect of a treatment from several studies and weighed each study according to its sample size. The N-weighted mean was calculated separately for each drug regimen according to the following formula, which uses SPID as an example: X (number of patients in particular study x SPID)/total number of patients in all studies. The random effects model recommended by DerSimmonian and Laird12 was used to determine differences in efficacy. The percent relative difference is the outcome measure of each meta-analysis, presented with 95% confidence intervals. A specific test for homogeneity was not conducted because we felt that the inclusion criteria were so specific as to greatly minimize any variations in study design characteristics.7 This paper describes 15 comparisons of drug groups or individual drug regimens. Within each of these comparisons the four pain measurements of PPID, SPID, PPAR, and TOTPAR are considered. RESULTS
In total, 5171 patients undergoing third molar extractions were studied in our meta-analyses with treatments using 12 NSAID regimens, acetaminophen alone, or acetaminophen in combination with codeine (60 mg).

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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) 184 Ibuprofen (400), acetaminophen (600) Cooper 198920 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) 143 Acetaminophen (600), acetaminophen (600)-codeine (60), meclofenamate (100) Cooper 198825 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) 212 Codeine (60), propoxyphene (65), suprofen (200) Cooper 198634 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) 99 Acetaminophen (1000), acetaminophen (1000)-codeine (30)-caffeine (16) Cooper 198644 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 patients, and after excluding drop-outs, data are available for 6061. Of these, 890 subjects who were taking drugs not considered to be the focus of our investigation (meclofenamate-codeine, naproxen-codeine, caffeine, propoxyphene, codeine, aspirin-phenacetin-caffeine,

aspirin-phenacetin-caffeine-codeine, acetaminophencodeine-caffeine, acetaminophen-hydrocodone, aspirin-caffeine, suprofen-codeine, and acetaminophencodeine [30 mg]) were excluded from our analysis. Results of the first set of meta-analyses are seen in Table 2. First, analgesics were compared with a placebo. Single doses of a placebo produced a -1 to 30% rate of analgesia, whereas nonopioids produced a 16 to 63% rate of analgesia. Better pain relief was obtained from nonopioids (acetaminophen and NSAIDs) compared with a placebo on all four pain scales. Differences

between nonopioids and a placebo on all four pain scales were statistically significant. Likewise, the next comparison in the table shows that NSAIDs are significandly more efficacious than a placebo on all scales. When the commonly used acetaminophen-codeine combination, which consists of either 600 or 650 mg acetaminophen with 60 mg codeine (Acet-Cod-60), is compared with a placebo, Acet-Cod-60 is significantly more efficacious. Further, when all NSAIDs as a group were compared with Acet-Cod-60, there was no statistical difference between the two groups. However, if we analyze only therapeutic doses of those NSAIDs commonly recommended for dentistry,6 namely diflunisal, flurbiprofen, ibuprofen, ketorolac, and naproxen, there is significantly superior pain relief compared with AcetCod-60 on the PPAR and TOTPAR scales; the final comparison appears in Table 2. On the PPID and SPID

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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 limit Analgesic Placebo Analgesic Placebo RD 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 22 17 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 24 17 22 28 NSAIDs > placebo Placebo with Acet-Cod-60151725,30,31 PPID 152 173 40 24 16 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-CodAcet-CodUpper Lower Scale NSAIDs 60 NSAIDs 60 RD limit limit Difference in efficacy All NSAIDs with Acet-Cod-601546 PPID 2161 152 40 40 0 Not significant 8 -9 SPID 2996 183 17 -4 21 -2 10 Not significant PPAR 2196 152 65 59 -15 6 2 Not significant TOTPAR 2912 183 41 4 37 -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-CodAcet-CodUpper 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-inflammatory 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 not reach statistical significance. The efficacy of the individual NSAIDs compared with Acet-Cod-60 is seen in Table 3. Diflunisal was more efficacious than Acet-Cod-60, with statistically significant differences for SPID, PPAR, and TOTPAR and with a nonsignificant difference for PPID. Flurbiprofen in a dose of 100 mg was more efficacious than Acet-Cod-60, whereas 50 mg of flurbiprofen was not significantly different, suggesting that the efficacy is dose dependent. When 200 mg of ibuprofen was compared to Acet-Cod-60, nonsignificant differences

were found with all scores. However, superior pain relief was found with 400 mg of ibuprofen when the PPAR and TOTPAR scales were used, again suggesting a dose-

dependent effect. Ketorolac at doses of 10 or 20 mg was more efficacious than Acet-Cod-60, with statistically significant differences for the PPAR and TOTPAR scores, but not for the others. Analysis of the analgesia provided by naproxen at doses of 440 or 550 mg did not demonstrate significant differences from those provided by Acet-Cod60. Although not currently recommended for use in dentistry, ibuprofen-lysine at 200 and 400 mg was sig-

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Table 3. Comparisons of Individual Nonopioids with Acetaminophen and 60 mg of Codeine (Acet-Cod-60) Number of Percentage Patients 95% CIEffect Non- Acet- Non- AcetUpper Lower limit Scale limit opioid Cod-60 opioidCod-60 RD Difference in efficacyb
Diflunisal (500 and 1000 mg) with Acet-Cod-6015-1725,28,30,31 PPID 152 50 40 10 79 SPID 79 183 35 21 14 PPAR 79 152 75 59 16 TOTPAR 183 19 79 56 37 Flurbiprofen (50 mg) with Acet-Cod-605'71721,25,30,31 PPID 85 152 37 40 -3 SPID 116 183 25 21 4 PPAR 85 152 61 59 2

-24 -27 -29 -33 -11 -15 -16 -21 -24 -22 -26 -27

5 -1 -3 -5
16 7 12 4

Not significant Diflunisal > Acet-Cod 60 Diflunisal > Acet-Cod 60 Diflunisal > Acet-Cod 60
Not significant Not significant Not significant Not significant

TOTPAR PPID SPID PPAR TOTPAR

116
with

183 152 183 152 183

46 49 31 70 51

37 40 21 59 37

9
9 10 11 14

Flurbiprofen (100 mg)

Acet-Cod-6015-1725,30,31

67 96 67 96

7 2 4 -1

Not significant Not significant Not significant Flurbiprofen > Acet-Cod-60

Ibuprofen (200 mg) with Acet-Cod-601--1725,26,30,31,40

PPID 128 152 31 -9 40 -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 21 26 5 -4 15 Not significant PPAR 109 152 76 59 17 6 30 Ibuprofen 400 > Acet-Cod-60 TOTPAR 51 170 183 14 37 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 -1 -26 Ketorolac > Acet-Cod-60 Naproxen (440 and 550 mg) with Acet-Cod-601-'-725,29-3137 PPID 130 152 37 40 -3 14 -10 Not significant SPID 130 183 20 21 -1 -9 10 Not significant PPAR 130 152 4 63 59 -17 7 Not significant TOTPAR 130 183 36 -1 37 -10 13 Not significant Ibuprofen-lysine (200 and 400 mg) with Acet-Cod-6015-17,25830,31,36,46 PPID 173 152 52 12 -1 40 -23 Ibuprofen-lysine > Acet-Cod-60 SPID 173 183 21 -1 20 -8 10 Not significant PPAR 173 152 80 21 59 -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 -2 -10 21 Not significant SPID 161 183 14 21 -2 -7 16 Not significant PPAR 131 152 1 45 59 -14 26 Acet-Cod-60 > Acetaminophen TOTPAR 161 0 183 27 37 -10 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.

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nificantly more efficacious than Acet-Cod-60 on the PPID and PPAR scales. Better pain relief was obtained from Acet-Cod-60 compared with 600 and 1000 mg of acetaminophen. Depending on the dose used, the results were statistically significant for at least one of PPAR, SPID, and TOTPAR, and the results showed a slight trend favoring Acet-Cod-60 for the other scores. These results show that the addition of 60 mg of codeine enhances analgesia in the Acet-Cod-60 formulation. The other NSAIDs reported in the 33 studies are those not usually recommended for use in dentistry or are no longer available. Those still available did not show significant differences compared with Acet-Cod60, and therefore details of these analyses are not shown.
DISCUSSION

reach statistical significance (Tables 2 and 3). These quantitative results are consistent with published narrative literature reviews on the use of analgesics in dentistry,l46 and these results support the validity of the recommendations advocating the use of NSAIDs. The. review of these articles in this meta-analysis has revealed a number of characteristics of the reports that impeded more extensive analyses. Based on our review, we have provided the following recommendations to make future studies more amenable to assessing the evidence regarding the efficacy of analgesics. First, standard deviations should routinely be reported for incorporation into meta-analytic techniques. Second, results should be reported according to gender and age group so that a meta-analysis can show whether or not there are gender and age group differences.

ACKNOWLEDGMENT
An abstract of this work was presented at the International Association for Dental Research Meeting in 1997. Dr. Aronson is supported in part through a Research Scholar Award (Health Canada).

Meta-analysis utilizes results from a group of studies with common study characteristics to provide a quantitative basis for conclusions about therapeutic effectiveness. It is emerging as a powerful quantitative review technique, complementary to the conventional narrative literature 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 disagree in the magnitude or direction of effect, when sample sizes are too small to detect an effect as statistically significant, or when one large clinical trial is too costly and time consuming to perform.7 This meta-analysis shows that, in the dental pain model, the NSAIDs recommended for use in dentistry when they are prescribed at appropriate doses may be more efficacious than Acet-Cod-60. This conclusion is based on the finding that statistically significant differences were found in two of the measures, with a trend favoring the NSAIDs in the other two measures. Differences in efficacy may have been found if the inclusion criteria were altered to look only at severe pain as the baseline, as opposed to moderate or severe. It is also possible that the summary measures, TOTPAR and SPID, may be higher in drugs with long duration and rapid onset. This latter possibility could affect differences in efficacy between drugs of dissimilar pharmacokinetics. In particular, we have demonstrated that specific doses of the NSAIDs diflunisal, flurbiprofen, ibuprofen, and ketorolac are more effective for relieving pain than the commonly prescribed Acet-Cod-60. With the exception of ibuprofen-lysine, where statistical significance was gained in at least one of the pain scores, the same trend occurred in the other pain scores even if they did not

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APPENDIX
The following is a description of the calculations used to transform the data to a common percent scale, as described by Eisenberg et al.14 For PPID and PPAR, the data were transformed to a common percent scale as follows: (presented value [PPID or PPAR])/(maximal value - minimum value on scale) x 100 = value in percent. For example, a PPID of 2 on a scale of 0 to 5 was transformed to 40%. For TOTPAR and SPID, the value recorded depends on the number of measurements taken (#) within the 6-hr observation period, which differed from one study to another. Therefore, the transformation was carried out as follows: (presented value [SPID or TOTPAR])/([maximal value - minimum value on scale] x #) x 100 = value in percent.