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A double-blind, placebo-controlled trial comparing the analgesic efficacy of two formulations of diclofenac in postoperative dental pain
CURRENT THERAPEUTIC RESEARCH VOL. 52, NO. 3, SEPTEMBER1992
A DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL COMPARING THE ANALGESIC EFFICACY OF TWO FORMULATIONS OF DICLOFENAC IN POSTOPERATIVE DENTAL PAIN R. BAKSHI, 1 L. D. JACOBS, 1 S. LEHNERT, 2 B. PICHA, 3 AND J. REUTHER 4
1Medical Department, Ciba-Geigy Limited, Basel, Switzerland, 2Univ.-Klinik fiir Zahn-, Mund- und Kieferkrankheiten, Bonn, Germany, 3G. H. Besselaar Associates, Munich, Germany, and ~Univ.-Klinik fi~r Zahn-, Mund- und Kieferkrankheiten, Wiirzburg, Germany
ABSTRACT A double-blind, randomized, parallel-group, placebo-controlled study was conducted to compare the analgesic effect of single doses (50 mg) of enteric-coated diclofenac sodium with a new sugar-coated formulation, diclofenac potassium, in 151 adults suffering from moderate to severe pain after extraction of an impacted third molar. Efficacy was assessed over an observation period of 6 hours using verbal rating scales for pain intensity and pain relief. Both diclofenac potassium and diclofenac sodium led to significant reductions from baseline in the mean pain intensity scores starting at 15 minutes and 2 hours, respectively, after dosing; a similar trend was also seen for the mean pain relief scores. Derived indices from the pain intensity/pain relief scores indicated a faster onset and better analgesic effect of diclofenac potassium compared with t h a t achieved with diclofenac sodium with both active medications being superior to placebo. The number of patients reporting drug-related adverse experiences was one with diclofenac sodium and three each with diclofenac potassium and placebo. We conclude t h a t both diclofenac formulations are effective in relieving postoperative dental pain; however, diclofenac potassium may be more suitable for the treatment of acute painful disorders in which a quick onset of analgesic effect is both expected and desirable. INTRODUCTION
Diclofenac, a potent nonsteroidal anti-inflammatory drug (NSAID), has also been shown to exert a pronounced analgesic effect when used to treat various acute painful conditions. 1 The most commonly used formulation of diclofenac is the enteric-coated tablet containing 50 mg of diclofenac sodium.* Diclofenac potassiumt is a new salt of this NSAID formulated as a sugar-coated tablet. Comparative pharmacokinetic studies between enAddress correspondence and reprint requests to: Dr. R. Bakshi, M.D., D.M., Central Medical Adviser, Ciba-Geigy AG, Klybeckstrasse, CH-4002, Basel, Switzerland. Received for publication on June 22, 1992. Printed in the U.S.A. Reproduction in whole or part is not permitted. * Trademark: Voltaren ® (Ciba-Geigy Limited, Basel, Switzerland). t Trademark: Cataflam® (Ciba-Geigy Limited, Basel, Switzerland).
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EFFICACY OF DICLOFENAC IN POSTOPERATIVE DENTAL PAIN
teric-coated diclofenac sodium and sugar-coated diclofenac potassium indicate a similar bioavailability; however, the mean time to reach maximal plasma levels is shorter with diclofenac potassium, approximately 45 minutes, as compared with approximately 2 hours for diclofenac sodium. 2 This is in all likelihood accounted for by the inherent delay in the onset of absorption from diclofenac sodium because of the presence of enteric coating, which prevents dissolution of the tablets in the stomach. To investigate whether this pharmacokinetic difference between the two formulations translates into a faster onset of analgesic effect with diclofenac potassium, a comparative single-dose study in a standardized acute pain model (postextraction dental pain 3) was performed. PATIENTS
AND METHODS
Cooperative and consenting outpatients of either sex complaining of moderate to severe pain secondary to surgical extraction of an impacted third molar tooth and requiring analgesic medication were eligible for inclusion into the study. The trial, conducted at two centers, was designed as a double-blind, randomized, placebo-controlled, comparative investigation of single doses (50 mg) of diclofenac sodium (DS) and diclofenac potassium (DP) over an observation period of 6 hours. Rescue medication was permitted in case of insufficient analgesic effect b u t only if at least 1 hour had elapsed since intake of the test drug. Patients were excluded from the study if their past history suggested any of the following conditions: hypersensitivity to NSAIDs or clinically significant asthma; peptic ulceration/gastrointestinal bleeding or serious intestinal diseases; severe renal, cardiac, hepatic, neurologic, or hematologic disorders; and drug dependency including alcohol abuse. Pregnant or lactating women were also excluded. Intake of analgesics, NSAIDs, anesthetics, or mood-altering drugs was not permitted within the 4 hours preceding the start of the study; however, short-acting anesthetics were allowed during the operative procedure. Patients were asked to evaluate the intensity of their pain postoperatively according to a verbal four-point scale (0 = none, 1 = mild, 2 = moderate, 3 = severe) just before taking the drug and .25, .5, 1, 2, 3, 4, 5, and 6 hours after dosing. They were also asked to assess the degree of pain relief compared with baseline at the above-mentioned time points after drug intake according to the following scale: 0 = none, 1 = a little, 2 = a lot, 3 = complete. Adverse reactions, if any, were to be noted by the patient and global evaluation of efficacy made at the end of the 6-hour observation period or at the time of remedication using a verbal scale: 0 = poor, 1 = fair, 2 = good, 3 = excellent. In the event a patient took rescue analgesic at or a f t e r t h e 1-hour time point, his or h e r p a r t i c i p a t i o n in t h e 436
R. BAKSHI ET AL.
study was terminated and the following values attributed to the remaining hourly assessments: for pain intensity, baseline value or higher if at the time of remedication; for pain relief, zero. Several derived efficacy variables were calculated from the pain intensity/pain relief scores: pain intensity difference (PID) from baseline at each time point, sum of pain intensity differences (SPID) for the entire treatment period weighted by the time between observations, total pain relief (TOTPAR) weighted by the time between assessments, maximum pain intensity difference (MAXPID), maximum pain relief (MAXPAR), and time to MAXPID/MAXPAR. For age, body weight, and height, two-way analysis of variance was performed to determine comparability of the three treatment groups. Comparisons among treatment groups for sex and pain intensity at baseline were made using the Mantel-Haenszel chi-square test. Analysis of variance (ANOVA) based on rank-transformed data was used to evaluate differences among the treatment groups for SPID, TOTPAR, MAXPID, MAXPAR, time to MAXPID, time to MAXPAR, hourly PID, hourly pain relief scores, time to remedication with an alternative analgesic, and global evaluation of efficacy. The Fisher's least significant difference (LSD) procedure computed on ranks was used to compare all three possible pairs of treatments. Since a significant difference was found in baseline pain intensity between the treatment groups, a linear model, including baseline pain intensity as an additional effect, was assumed for all the derived indices. The P values reported are two-tailed for all analyses. RESULTS
Of a total of 180 patients entering the study, 151 were found to be evaluable for efficacy and safety analyses; in 26 cases intake of analgesic medication was not considered necessary while another three patients were lost to follow-up. The number of eligible patients in each treatment group and their demographic characteristics are outlined in Table I. The only significant difference between treatment groups was related to baseline pain intensity with fewer patients on placebo having severe pain as opposed to those receiving DS or DP (P = 0.023). The mean pain intensity and pain relief scores over the 6-hour observation period are listed in Tables II and III, respectively, and plotted in Figures 1 and 2. Compared with placebo, DP produced fast pain relief (within the first hour after drug intake) with its analgesic effect reaching a peak at 2 hours and persisting throughout the evaluation period. The analgesia achieved with DS was slower in onset and somewhat less pronounced than that with DP. For the derived efficacy variable PID, DP was statistically signifi437
EFFICACY OF DICLOFENAC IN POSTOPERATIVE DENTAL PAIN
Table I. Demographic characteristics.
Diclofenac Potassium (DP)
Diclofenac Sodium (DS)
Placebo
P Value
51 25.4 ± 1.2 64.0 _ 1.5 170.8 ± 1.3
54 25.2 ± 0.8 67.7 ± 1.8 172,4 ± 1.1
46 26.4 _ 1.3 66.0 +__1.8 172.8 __ 1,3
0,767* 0.263* 0.479*
22 29
29 25
19 27
0.399**
22 29
26 28
32 14
0,023"*
No. of patients Mean (±SE) age (yrs) Mean (±SE) weight (kg) Mean (±SE) height (cm) Sex Male Female Baseline pain intensity Moderate Severe
* Two-way analysis of variance. ** ManteI-Haenszel chi-square test.
cantly superior to placebo starting from one-quarter hour (P = 0.039) through to the end of the study (P < 0.01). Similarly, DP was marginally superior to placebo at one-half hour (P = 0.056) and significantly superior to placebo thereafter throughout the remainder of the study for pain relief (P < 0.01). Pairwise comparison of DS and placebo for the measure PID showed the former to be significantly superior to placebo at 2 hours and during the remainder of the study (P < 0.05). For pain relief, DS was significantly worse than placebo at one-half hour (P < 0.05), but significantly superior to placebo at 4 hours and 6 hours after dosing (P < 0.05). DP was significantly superior to DS for PID and pain relief for the first 2 hours after dosing (P < 0.05), except for PID at one-quarter hour, but was not significantly different thereafter. The mean SPID value was the highest for DP, 7.8 as compared with 5.3 for DS and 2.6 for placebo (Table IV). For TOTPAR, the mean figures showed a similar trend: 10 for DP, 7.3 for DS, and 5.2 for placebo (Table
Table II, Mean pain intensity scores. (Values are expressed as mean + SE.)
Time Point Baseline 1/4 hr 1/2 hr 1 hr 2 hr 3 hr 4 hr 5 hr 6 hr
Diclofenac Potassium (DP) (n = 51) 2.6 2.4 1.9 1.3 1.0 1.1 1.2 1.3 1.3
Diclofenac Sodium (DS) (n = 54)
_+ 0.07 _+ 0.08 _+ 0.11 _+ 0.14 _+ 0.15 ± 0.16 ± 0.17 ± 0.17 ± 0.17
2.5 2.4 2.3 2.1 1.6 1.4 1.4 1.5 1.6
0 = no pain; 1 = mild pain; 2 = moderate pain; 3 = severe pain. 438
+ 0.07 +_ 0.08 -!-_0.11 _ 0.13 ± 0.16 ± 0.17 ± 0.17 +_ 0.17 -- 0.17
Placebo (n = 46) 2.3 2.3 2.1 2.0 1.8 1.8 1.8 1.8 1.9
-+ 0.07 -+ 0.08 ± 0.11 -+ 0.13 -+ 0.13 ± 0.15 ± 0.16 ± 0.16 ± 0.17
R. BAKSHI E T AL.
Table III. Mean pain relief scores. (Values are expressed as mean - SE.)
Time Point
Diclofenac Potassium (DP) (n = 51)
1/4 hr 1/2 hr 1 hr 2 hr 3 hr 4 hr 5 hr 6 hr
0.3 0.9 1.6 1.9 1.9 1.8 1.6 1.6
Diclofenac Sodium (DS) (n = 54)
+ 0.07 -+ 0.11 _+ 0.15 -+ 0.15 -+ 0.17 -+ 0.18 --+-0.18 -- 0.18
0.1 0.4 0.7 1.3 1.5 1.4 1.4 1.3
-+ -+ -+ -+ -+ -+ -+
Placebo (n = 46)
0.06 0.10 0.13 0.16 0.17 0.18 0.18 0.18
0.2 0.6 0.8 0.9 1.0 0.9 0.9 0.8
-+ 0.07 -- 0.10 -- 0.13 - 0.14 -+ 0.16 -+ 0.18 -+ 0.18 -+ 0.17
Pain relief from initial severity: 0 = no relief; 1 = a little relief; 2 = a lot of relief; 3 = complete relief.
IV). Diclofenac potassium was significantly better t h a n placebo (P < 0.001) for SPID, TOTPAR, MAXPID, and MAXPAR as well as significantly better t h a n DS for SPID (P = 0.009), TOTPAR (P = 0.01), MAXPID (P = 0.045), and marginally better for MAXPAR (P = 0.058). Diclofenac sodium was significantly better t h a n placebo for SPID (P = 0.023) and MAXPID (P = 0.018), but had a significantly longer time to MAXPID (P = 0.035). Fifty-three percent of patients receiving DP rated overall efficacy as good or excellent as compared with 37% on DS and 17% in the placebo mean score 3
2.5
2
1.5
0.5
0
0
1/4 1/2
R
I
1
2
_
_
1
__
3
I
4
_
_
L
J
5
6
hours DP O-no pain 1-mild pain
(n=51)
I
DS
(n=54)
2=moderate pain 3-severe pain
Figure 1. Pain i n t e n s i t y - - t i m e curve. 439
~< P l a c e b o
(n=46)
EFFICACY OF DICLOFENAC IN POSTOPERATIVE DENTAL PAIN
mean score
1.5
0.5
0 0 1/41/2
I
I
I
I
I
1
2
3
4
5
6
hours D P (n=51)
I
DS (n=54)
- •
Placebo
(n=46)
0 = no relief 1 = a little relief 2 = a lot of relief 3 = c o m p l e t e relief
Figure 2. Pain r e l i e f - - t i m e curve.
group. On this global assessment, DP was statistically significantly better than placebo (P < 0.001) and DS (P = 0.034); DS was also significantly better than placebo (P = 0.015). The proportion of patients needing remedication within 6 hours with an alternative analgesic was 33%, 41%, and 59% in the DP, DS, and placebo groups, respectively. The time to remedication was significantly longer with DP as compared with placebo (P = 0.015). The main statistical analyses were repeated after stratifying according to baseline pain intensity separating patients with moderate baseline Table IV. Means for the derived efficacy indices. (Values are expressed as mean -+ SE.)
Derived Efficacy Index SPID TOTPAR MAXPID MAXPAR Time to MAXPID (hr) Time to MAXPAR (hr)
Diclofenac Potassium (DP) (n = 51) 7.8 10.0 1.8 2.2 1.5 1.6
_+ 0.80 _ 0.85 +- 0.14 __ 0.15 -+ 0.17 -+ 0.18
Diclofenac Sodium (DS) (n = 54) 5.3 7.3 1.3 1.7 1.7 1.7
+_ 0.73 +_ 0.87 +_ 0.15 _+ 0.18 +_ 0.20 -+ 0.19
Placebo (n = 46) 2.6 5.2 0.9 1.4 1.3 1.5
_+ 0.83 +_ 0.84 -+ 0.15 _+ 0.16 -+ 0.22 +- 0.21
SPID = sum of pain intensity differences; TOTPAR = total pain relief; MAXPID = maximum pain intensity difference; MAXPAR = maximum paLn relief.
440
R. BAKSHI ET AL.
pain from those with severe baseline pain. The results, in general, did not differ greatly from those obtained without stratification; however, the analgesic effects of the two diclofenac formulations were more pronounced in the subgroup of patients with moderate initial pain intensity. Three patients (6%) in the DP group, 1 patient (2%) receiving DS, and 3 patients (7%) on placebo reported adverse effects that were assessed as possibly or probably related to the trial medication. Details of adverse effects, all mild to moderate in severity, are provided in Table V. DISCUSSION
The conventional enteric-coated formulation of diclofenac sodium, although primarily recommended for the long-term management of chronic rheumatic disorders, has also been shown to be effective for the treatment of nonrheumatic painful conditions including postextraction dental pain. a-s In order to hasten the onset of absorption and thereby therapeutic effect, a formulation without enteric coating (eg, sugar-coated diclofenac potassium) may be more appropriate for such indications. The standardized dental surgery pain model was chosen to evaluate whether the observed pharmacokinetic difference between enteric-coated diclofenac sodium and sugar-coated diclofenac potassium in terms of time to maximal plasma concentration results in a clinically meaningful outcome vis-h-vis analgesic efficacy. In the present study, both formulations of diclofenac have been demonstrated to be significantly better than placebo on most of the efficacy parameters. Nevertheless, it must be noted that diclofenac potassium led to an earlier onset of pain relief coupled with other trends of greater analgesic effect in comparison with diclofenac sodium, for example, higher values for SPID and TOTPAR, lower frequency of rescue analgesic con-
Table V. Adverse effects (possibly or probably related to trial medication).
Diclofenac Potassium ( D P )
DiclofenacSodium (DS)
Placebo
(n = 51)
(n = 54)
(n = 46)
No.
No.
No.
Adverse Effect Abdominal pain Nausea Vomiting Dizziness Vertigo Palpitations Chills Patients with one or more adverse effects
1 1 1 1 1 0 0
0 0 0 0 0 1 0
2 0 0 0 0 0 1
3 (6%)
1 (2%)
3 (7%)
441
EFFICACYOFDICLOFENACIN POSTOPERATIVEDENTALPAIN
sumption, and better overall efficacy ratings. The results of this trial confirm the observations in other studies with diclofenac potassium for postextraction dental pain 9'1° in which clear superiority of this formulation over placebo has been shown; similarly, a relative delay in the onset of analgesic effect has also been noted with enteric-coated diclofenac sodium in the same pain model. 11 The incidence of adverse effects related to the test medication was expectedly low in this single-dose study and practically similar for the three treatment groups. In conclusion, both enteric-coated diclofenac sodium and diclofenac potassium are effective analgesics for the treatment of postsurgical pain after extraction of an impacted third molar, but the latter formulation may be more suited for the initial/short-term treatment of acute painful nonrheumatic conditions because of its quicker onset of analgesic effect. References:
1. Kantor TG. Use of diclofenac in analgesia. A m J Med 1986; 80(Suppl. 4B):64-69. 2. Data on File, Ciba-Geigy Limited, Basel, Switzerland, 1989. 3. Cooper SA. Models for clinical assessment of oral analgesics. A m J Med 1983; 75(Suppl. 5A):24-29. 4. Henrikson P-A, Thilander H, Wahlander LA. Absorption and effect of diclofenac sodium after surgical removal of a lower wisdom tooth. Curr Ther Res 1982; 31(1):20-26. 5. Henrikson P-A, Thilander H, Wahlander LA. Voltaren as an analgesic after surgical removal of a lower wisdom tooth. Int J Oral Surg 1985; 14:333-338. 6. Frame JW, Rout PGJ. A comparison of the analgesic efficacy of flurbiprofen, diclofenac, dihydrocodeine/paracetamol and placebo following oral surgery. B r J Clin Pract 1986; 40(11):463-467. 7. Waiter SL, Cooper SA, Finizio TA, et al. Analgesic efficacy of 50 and 100 mg diclofenac sodium compared to aspirin 650 mg in dental pain. (Abstract) Clin Pharmacol Ther 1987; 41(2):230. 8. Adair SF, Mehlisch DR, Brandes S, et al. Diclofenac sodium (Voltaren) shows analgesic efficacy in dental pain model. (Abstract) J Clin Pharmacol 1988; 28(10):915. 9. Adair SF, Mehlisch DR, Brandes S, et al. Analgesic efficacy of diclofenac potassium in dental pain trial. (Abstract) Clin Pharmacol Ther 1989; 45(2):176. 10. Adair SF, Nelson SL, Brahim JS, et al. Dose-ranging study measuring the analgesic efficacy of diclofenac potassium. (Abstract) Clin Pharmacol Ther 1990; 47(2):163. 11. Mehlisch D, Kiersch T, Brown P, et al. Pain relief following dental impaction surgery using naproxen, diclofenac sodium (enteric-coated), or placebo. (Abstract) J Clin Pharmacol 1991; 31(9):856.
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A DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL COMPARING THE ANALGESIC EFFICACY OF TWO FORMULATIONS OF DICLOFENAC IN POSTOPERATIVE DENTAL PAIN R. BAKSHI, 1 L. D. JACOBS, 1 S. LEHNERT, 2 B. PICHA, 3 AND J. REUTHER 4
1Medical Department, Ciba-Geigy Limited, Basel, Switzerland, 2Univ.-Klinik fiir Zahn-, Mund- und Kieferkrankheiten, Bonn, Germany, 3G. H. Besselaar Associates, Munich, Germany, and ~Univ.-Klinik fi~r Zahn-, Mund- und Kieferkrankheiten, Wiirzburg, Germany
ABSTRACT A double-blind, randomized, parallel-group, placebo-controlled study was conducted to compare the analgesic effect of single doses (50 mg) of enteric-coated diclofenac sodium with a new sugar-coated formulation, diclofenac potassium, in 151 adults suffering from moderate to severe pain after extraction of an impacted third molar. Efficacy was assessed over an observation period of 6 hours using verbal rating scales for pain intensity and pain relief. Both diclofenac potassium and diclofenac sodium led to significant reductions from baseline in the mean pain intensity scores starting at 15 minutes and 2 hours, respectively, after dosing; a similar trend was also seen for the mean pain relief scores. Derived indices from the pain intensity/pain relief scores indicated a faster onset and better analgesic effect of diclofenac potassium compared with t h a t achieved with diclofenac sodium with both active medications being superior to placebo. The number of patients reporting drug-related adverse experiences was one with diclofenac sodium and three each with diclofenac potassium and placebo. We conclude t h a t both diclofenac formulations are effective in relieving postoperative dental pain; however, diclofenac potassium may be more suitable for the treatment of acute painful disorders in which a quick onset of analgesic effect is both expected and desirable. INTRODUCTION
Diclofenac, a potent nonsteroidal anti-inflammatory drug (NSAID), has also been shown to exert a pronounced analgesic effect when used to treat various acute painful conditions. 1 The most commonly used formulation of diclofenac is the enteric-coated tablet containing 50 mg of diclofenac sodium.* Diclofenac potassiumt is a new salt of this NSAID formulated as a sugar-coated tablet. Comparative pharmacokinetic studies between enAddress correspondence and reprint requests to: Dr. R. Bakshi, M.D., D.M., Central Medical Adviser, Ciba-Geigy AG, Klybeckstrasse, CH-4002, Basel, Switzerland. Received for publication on June 22, 1992. Printed in the U.S.A. Reproduction in whole or part is not permitted. * Trademark: Voltaren ® (Ciba-Geigy Limited, Basel, Switzerland). t Trademark: Cataflam® (Ciba-Geigy Limited, Basel, Switzerland).
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EFFICACY OF DICLOFENAC IN POSTOPERATIVE DENTAL PAIN
teric-coated diclofenac sodium and sugar-coated diclofenac potassium indicate a similar bioavailability; however, the mean time to reach maximal plasma levels is shorter with diclofenac potassium, approximately 45 minutes, as compared with approximately 2 hours for diclofenac sodium. 2 This is in all likelihood accounted for by the inherent delay in the onset of absorption from diclofenac sodium because of the presence of enteric coating, which prevents dissolution of the tablets in the stomach. To investigate whether this pharmacokinetic difference between the two formulations translates into a faster onset of analgesic effect with diclofenac potassium, a comparative single-dose study in a standardized acute pain model (postextraction dental pain 3) was performed. PATIENTS
AND METHODS
Cooperative and consenting outpatients of either sex complaining of moderate to severe pain secondary to surgical extraction of an impacted third molar tooth and requiring analgesic medication were eligible for inclusion into the study. The trial, conducted at two centers, was designed as a double-blind, randomized, placebo-controlled, comparative investigation of single doses (50 mg) of diclofenac sodium (DS) and diclofenac potassium (DP) over an observation period of 6 hours. Rescue medication was permitted in case of insufficient analgesic effect b u t only if at least 1 hour had elapsed since intake of the test drug. Patients were excluded from the study if their past history suggested any of the following conditions: hypersensitivity to NSAIDs or clinically significant asthma; peptic ulceration/gastrointestinal bleeding or serious intestinal diseases; severe renal, cardiac, hepatic, neurologic, or hematologic disorders; and drug dependency including alcohol abuse. Pregnant or lactating women were also excluded. Intake of analgesics, NSAIDs, anesthetics, or mood-altering drugs was not permitted within the 4 hours preceding the start of the study; however, short-acting anesthetics were allowed during the operative procedure. Patients were asked to evaluate the intensity of their pain postoperatively according to a verbal four-point scale (0 = none, 1 = mild, 2 = moderate, 3 = severe) just before taking the drug and .25, .5, 1, 2, 3, 4, 5, and 6 hours after dosing. They were also asked to assess the degree of pain relief compared with baseline at the above-mentioned time points after drug intake according to the following scale: 0 = none, 1 = a little, 2 = a lot, 3 = complete. Adverse reactions, if any, were to be noted by the patient and global evaluation of efficacy made at the end of the 6-hour observation period or at the time of remedication using a verbal scale: 0 = poor, 1 = fair, 2 = good, 3 = excellent. In the event a patient took rescue analgesic at or a f t e r t h e 1-hour time point, his or h e r p a r t i c i p a t i o n in t h e 436
R. BAKSHI ET AL.
study was terminated and the following values attributed to the remaining hourly assessments: for pain intensity, baseline value or higher if at the time of remedication; for pain relief, zero. Several derived efficacy variables were calculated from the pain intensity/pain relief scores: pain intensity difference (PID) from baseline at each time point, sum of pain intensity differences (SPID) for the entire treatment period weighted by the time between observations, total pain relief (TOTPAR) weighted by the time between assessments, maximum pain intensity difference (MAXPID), maximum pain relief (MAXPAR), and time to MAXPID/MAXPAR. For age, body weight, and height, two-way analysis of variance was performed to determine comparability of the three treatment groups. Comparisons among treatment groups for sex and pain intensity at baseline were made using the Mantel-Haenszel chi-square test. Analysis of variance (ANOVA) based on rank-transformed data was used to evaluate differences among the treatment groups for SPID, TOTPAR, MAXPID, MAXPAR, time to MAXPID, time to MAXPAR, hourly PID, hourly pain relief scores, time to remedication with an alternative analgesic, and global evaluation of efficacy. The Fisher's least significant difference (LSD) procedure computed on ranks was used to compare all three possible pairs of treatments. Since a significant difference was found in baseline pain intensity between the treatment groups, a linear model, including baseline pain intensity as an additional effect, was assumed for all the derived indices. The P values reported are two-tailed for all analyses. RESULTS
Of a total of 180 patients entering the study, 151 were found to be evaluable for efficacy and safety analyses; in 26 cases intake of analgesic medication was not considered necessary while another three patients were lost to follow-up. The number of eligible patients in each treatment group and their demographic characteristics are outlined in Table I. The only significant difference between treatment groups was related to baseline pain intensity with fewer patients on placebo having severe pain as opposed to those receiving DS or DP (P = 0.023). The mean pain intensity and pain relief scores over the 6-hour observation period are listed in Tables II and III, respectively, and plotted in Figures 1 and 2. Compared with placebo, DP produced fast pain relief (within the first hour after drug intake) with its analgesic effect reaching a peak at 2 hours and persisting throughout the evaluation period. The analgesia achieved with DS was slower in onset and somewhat less pronounced than that with DP. For the derived efficacy variable PID, DP was statistically signifi437
EFFICACY OF DICLOFENAC IN POSTOPERATIVE DENTAL PAIN
Table I. Demographic characteristics.
Diclofenac Potassium (DP)
Diclofenac Sodium (DS)
Placebo
P Value
51 25.4 ± 1.2 64.0 _ 1.5 170.8 ± 1.3
54 25.2 ± 0.8 67.7 ± 1.8 172,4 ± 1.1
46 26.4 _ 1.3 66.0 +__1.8 172.8 __ 1,3
0,767* 0.263* 0.479*
22 29
29 25
19 27
0.399**
22 29
26 28
32 14
0,023"*
No. of patients Mean (±SE) age (yrs) Mean (±SE) weight (kg) Mean (±SE) height (cm) Sex Male Female Baseline pain intensity Moderate Severe
* Two-way analysis of variance. ** ManteI-Haenszel chi-square test.
cantly superior to placebo starting from one-quarter hour (P = 0.039) through to the end of the study (P < 0.01). Similarly, DP was marginally superior to placebo at one-half hour (P = 0.056) and significantly superior to placebo thereafter throughout the remainder of the study for pain relief (P < 0.01). Pairwise comparison of DS and placebo for the measure PID showed the former to be significantly superior to placebo at 2 hours and during the remainder of the study (P < 0.05). For pain relief, DS was significantly worse than placebo at one-half hour (P < 0.05), but significantly superior to placebo at 4 hours and 6 hours after dosing (P < 0.05). DP was significantly superior to DS for PID and pain relief for the first 2 hours after dosing (P < 0.05), except for PID at one-quarter hour, but was not significantly different thereafter. The mean SPID value was the highest for DP, 7.8 as compared with 5.3 for DS and 2.6 for placebo (Table IV). For TOTPAR, the mean figures showed a similar trend: 10 for DP, 7.3 for DS, and 5.2 for placebo (Table
Table II, Mean pain intensity scores. (Values are expressed as mean + SE.)
Time Point Baseline 1/4 hr 1/2 hr 1 hr 2 hr 3 hr 4 hr 5 hr 6 hr
Diclofenac Potassium (DP) (n = 51) 2.6 2.4 1.9 1.3 1.0 1.1 1.2 1.3 1.3
Diclofenac Sodium (DS) (n = 54)
_+ 0.07 _+ 0.08 _+ 0.11 _+ 0.14 _+ 0.15 ± 0.16 ± 0.17 ± 0.17 ± 0.17
2.5 2.4 2.3 2.1 1.6 1.4 1.4 1.5 1.6
0 = no pain; 1 = mild pain; 2 = moderate pain; 3 = severe pain. 438
+ 0.07 +_ 0.08 -!-_0.11 _ 0.13 ± 0.16 ± 0.17 ± 0.17 +_ 0.17 -- 0.17
Placebo (n = 46) 2.3 2.3 2.1 2.0 1.8 1.8 1.8 1.8 1.9
-+ 0.07 -+ 0.08 ± 0.11 -+ 0.13 -+ 0.13 ± 0.15 ± 0.16 ± 0.16 ± 0.17
R. BAKSHI E T AL.
Table III. Mean pain relief scores. (Values are expressed as mean - SE.)
Time Point
Diclofenac Potassium (DP) (n = 51)
1/4 hr 1/2 hr 1 hr 2 hr 3 hr 4 hr 5 hr 6 hr
0.3 0.9 1.6 1.9 1.9 1.8 1.6 1.6
Diclofenac Sodium (DS) (n = 54)
+ 0.07 -+ 0.11 _+ 0.15 -+ 0.15 -+ 0.17 -+ 0.18 --+-0.18 -- 0.18
0.1 0.4 0.7 1.3 1.5 1.4 1.4 1.3
-+ -+ -+ -+ -+ -+ -+
Placebo (n = 46)
0.06 0.10 0.13 0.16 0.17 0.18 0.18 0.18
0.2 0.6 0.8 0.9 1.0 0.9 0.9 0.8
-+ 0.07 -- 0.10 -- 0.13 - 0.14 -+ 0.16 -+ 0.18 -+ 0.18 -+ 0.17
Pain relief from initial severity: 0 = no relief; 1 = a little relief; 2 = a lot of relief; 3 = complete relief.
IV). Diclofenac potassium was significantly better t h a n placebo (P < 0.001) for SPID, TOTPAR, MAXPID, and MAXPAR as well as significantly better t h a n DS for SPID (P = 0.009), TOTPAR (P = 0.01), MAXPID (P = 0.045), and marginally better for MAXPAR (P = 0.058). Diclofenac sodium was significantly better t h a n placebo for SPID (P = 0.023) and MAXPID (P = 0.018), but had a significantly longer time to MAXPID (P = 0.035). Fifty-three percent of patients receiving DP rated overall efficacy as good or excellent as compared with 37% on DS and 17% in the placebo mean score 3
2.5
2
1.5
0.5
0
0
1/4 1/2
R
I
1
2
_
_
1
__
3
I
4
_
_
L
J
5
6
hours DP O-no pain 1-mild pain
(n=51)
I
DS
(n=54)
2=moderate pain 3-severe pain
Figure 1. Pain i n t e n s i t y - - t i m e curve. 439
~< P l a c e b o
(n=46)
EFFICACY OF DICLOFENAC IN POSTOPERATIVE DENTAL PAIN
mean score
1.5
0.5
0 0 1/41/2
I
I
I
I
I
1
2
3
4
5
6
hours D P (n=51)
I
DS (n=54)
- •
Placebo
(n=46)
0 = no relief 1 = a little relief 2 = a lot of relief 3 = c o m p l e t e relief
Figure 2. Pain r e l i e f - - t i m e curve.
group. On this global assessment, DP was statistically significantly better than placebo (P < 0.001) and DS (P = 0.034); DS was also significantly better than placebo (P = 0.015). The proportion of patients needing remedication within 6 hours with an alternative analgesic was 33%, 41%, and 59% in the DP, DS, and placebo groups, respectively. The time to remedication was significantly longer with DP as compared with placebo (P = 0.015). The main statistical analyses were repeated after stratifying according to baseline pain intensity separating patients with moderate baseline Table IV. Means for the derived efficacy indices. (Values are expressed as mean -+ SE.)
Derived Efficacy Index SPID TOTPAR MAXPID MAXPAR Time to MAXPID (hr) Time to MAXPAR (hr)
Diclofenac Potassium (DP) (n = 51) 7.8 10.0 1.8 2.2 1.5 1.6
_+ 0.80 _ 0.85 +- 0.14 __ 0.15 -+ 0.17 -+ 0.18
Diclofenac Sodium (DS) (n = 54) 5.3 7.3 1.3 1.7 1.7 1.7
+_ 0.73 +_ 0.87 +_ 0.15 _+ 0.18 +_ 0.20 -+ 0.19
Placebo (n = 46) 2.6 5.2 0.9 1.4 1.3 1.5
_+ 0.83 +_ 0.84 -+ 0.15 _+ 0.16 -+ 0.22 +- 0.21
SPID = sum of pain intensity differences; TOTPAR = total pain relief; MAXPID = maximum pain intensity difference; MAXPAR = maximum paLn relief.
440
R. BAKSHI ET AL.
pain from those with severe baseline pain. The results, in general, did not differ greatly from those obtained without stratification; however, the analgesic effects of the two diclofenac formulations were more pronounced in the subgroup of patients with moderate initial pain intensity. Three patients (6%) in the DP group, 1 patient (2%) receiving DS, and 3 patients (7%) on placebo reported adverse effects that were assessed as possibly or probably related to the trial medication. Details of adverse effects, all mild to moderate in severity, are provided in Table V. DISCUSSION
The conventional enteric-coated formulation of diclofenac sodium, although primarily recommended for the long-term management of chronic rheumatic disorders, has also been shown to be effective for the treatment of nonrheumatic painful conditions including postextraction dental pain. a-s In order to hasten the onset of absorption and thereby therapeutic effect, a formulation without enteric coating (eg, sugar-coated diclofenac potassium) may be more appropriate for such indications. The standardized dental surgery pain model was chosen to evaluate whether the observed pharmacokinetic difference between enteric-coated diclofenac sodium and sugar-coated diclofenac potassium in terms of time to maximal plasma concentration results in a clinically meaningful outcome vis-h-vis analgesic efficacy. In the present study, both formulations of diclofenac have been demonstrated to be significantly better than placebo on most of the efficacy parameters. Nevertheless, it must be noted that diclofenac potassium led to an earlier onset of pain relief coupled with other trends of greater analgesic effect in comparison with diclofenac sodium, for example, higher values for SPID and TOTPAR, lower frequency of rescue analgesic con-
Table V. Adverse effects (possibly or probably related to trial medication).
Diclofenac Potassium ( D P )
DiclofenacSodium (DS)
Placebo
(n = 51)
(n = 54)
(n = 46)
No.
No.
No.
Adverse Effect Abdominal pain Nausea Vomiting Dizziness Vertigo Palpitations Chills Patients with one or more adverse effects
1 1 1 1 1 0 0
0 0 0 0 0 1 0
2 0 0 0 0 0 1
3 (6%)
1 (2%)
3 (7%)
441
EFFICACYOFDICLOFENACIN POSTOPERATIVEDENTALPAIN
sumption, and better overall efficacy ratings. The results of this trial confirm the observations in other studies with diclofenac potassium for postextraction dental pain 9'1° in which clear superiority of this formulation over placebo has been shown; similarly, a relative delay in the onset of analgesic effect has also been noted with enteric-coated diclofenac sodium in the same pain model. 11 The incidence of adverse effects related to the test medication was expectedly low in this single-dose study and practically similar for the three treatment groups. In conclusion, both enteric-coated diclofenac sodium and diclofenac potassium are effective analgesics for the treatment of postsurgical pain after extraction of an impacted third molar, but the latter formulation may be more suited for the initial/short-term treatment of acute painful nonrheumatic conditions because of its quicker onset of analgesic effect. References:
1. Kantor TG. Use of diclofenac in analgesia. A m J Med 1986; 80(Suppl. 4B):64-69. 2. Data on File, Ciba-Geigy Limited, Basel, Switzerland, 1989. 3. Cooper SA. Models for clinical assessment of oral analgesics. A m J Med 1983; 75(Suppl. 5A):24-29. 4. Henrikson P-A, Thilander H, Wahlander LA. Absorption and effect of diclofenac sodium after surgical removal of a lower wisdom tooth. Curr Ther Res 1982; 31(1):20-26. 5. Henrikson P-A, Thilander H, Wahlander LA. Voltaren as an analgesic after surgical removal of a lower wisdom tooth. Int J Oral Surg 1985; 14:333-338. 6. Frame JW, Rout PGJ. A comparison of the analgesic efficacy of flurbiprofen, diclofenac, dihydrocodeine/paracetamol and placebo following oral surgery. B r J Clin Pract 1986; 40(11):463-467. 7. Waiter SL, Cooper SA, Finizio TA, et al. Analgesic efficacy of 50 and 100 mg diclofenac sodium compared to aspirin 650 mg in dental pain. (Abstract) Clin Pharmacol Ther 1987; 41(2):230. 8. Adair SF, Mehlisch DR, Brandes S, et al. Diclofenac sodium (Voltaren) shows analgesic efficacy in dental pain model. (Abstract) J Clin Pharmacol 1988; 28(10):915. 9. Adair SF, Mehlisch DR, Brandes S, et al. Analgesic efficacy of diclofenac potassium in dental pain trial. (Abstract) Clin Pharmacol Ther 1989; 45(2):176. 10. Adair SF, Nelson SL, Brahim JS, et al. Dose-ranging study measuring the analgesic efficacy of diclofenac potassium. (Abstract) Clin Pharmacol Ther 1990; 47(2):163. 11. Mehlisch D, Kiersch T, Brown P, et al. Pain relief following dental impaction surgery using naproxen, diclofenac sodium (enteric-coated), or placebo. (Abstract) J Clin Pharmacol 1991; 31(9):856.
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