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Flurbiprofen, aspirin, codeine, and placebo for postpartum uterine pain
Flurbiprofen, Aspirin, Codeine, and Placebo for Postpartum Uterine Pain
SAUL S. BLOOMFIELD, M.D. JEANEl-fE MITCHELL, L.P.N. GAIL C&SELL, R.N. TOM P. BARDEN, M.D. Cincinnati,
Ohio
From the Division of Clinical Pharmacology and Toxicology, Department of Internal Medicine and Department of Obstetrics and Gynecology, Universky of Cincinnati Medical Center, Cincinnati, Ohio. This article was presented, in part, at the 82nd Annual Meeting of the American Society for Clinical Pharmacology and Therapeutics, New Orleans, Louisiana, March, 1961. The research was supported, in part, by a grant from The Upjohn Company. Requests for reprints should be addressed to Dr. Saul S. Bloomfield, 5502 Medical Sciences Building, University of Cincinnati Medical Center, Cincinnati, Ohio 45267-0576. The work presented was based on the administration of Ansaid tablets, a registered trademark of The Upjohn Company.
Flurbiprofen (Ansaid, Upjohn), a substituted phenyl propionic acid, is a new analgesic/anti-inflammatory agent. To evaluate its relative efficacy in noninflammatory pain, 159 hospitalized women with moderate or severe postpartum uterine cramps were given single oral doses of 60 mg of flurbiprofen, 650 mg of aspirin, 60 or 120 mg of codeine sulfate, or placebo in a parallel, stratified, randomized block, placebo-controlled, double-blind trial. Patients rated pain intensity, pain relief, and side effects in uniform interviews for six hours after treatment. All measures of peak and summed analgesia exhibited significant differences among the five treatments. Flurbiprofen and aspirin showed the greatest analgesic response and were significantly superior to placebo. Results of codeine treatment were equivocal with no evidence of a positive dose response. Side effects were unremarkable except for dizziness and drowsiness after the 120.mg codeine dose. These findings suggest that flurbiprofen as an analgesic for patients with postpartum uterine pain is equivalent to asplrfn and superior to codeine. Flurbiprofen (Ansaid, Upjohn), 2-(2-fluoro4-biphenylyl) propionic acid, is a new analgesic/anti-inflammatory’agent that, like aspirin and other compounds in this chemical class, inhibits prostaglandin synthetase (cyclooxygenase) [l]. In laboratory animals, flurbiprofen exhibits analgesic, anti-inflammatory, and antipyretic activity [2,3]. The analgesic action appears to be peripheral rather than central, and the anti-inflammatory activity does not involve the adrenal cortex. Flurbiprofen has significant antithrombotic activity due to its inhibition of platelet aggregation [4]. In humans, carefully controlled clinical studies in the United States [5,6] and abroad [7,8], along with over eight years of European clinical experience, indicate that flurbiprofen is a safe and effective analgesic for patients with various rheumatic diseases, including both the inflammatory and degenerative arthritides. Other studies have shown that flurbiprofen is well tolerated, with minimal effects on the gastrointestinal tract.and a notable absence of ulceration or blood loss [9]. Since a need exists for pain relievers that are safe and effective alternatives to narcotics, the analgesic response to flurbiprofen in patients with nonrheumatic pain was evaluated. We conducted a phase II clinical study comparing flurbiprofen’s efficacy, safety, and time course of analgesia with those of aspirin and codeine, two standard reference analgesics, in 159 hospitalized women experiencing moderate or severe postpartum uterine cramping-a form of noninflammatory, nonarthritic pain that may be mediated by a second messenger-prostaglan-
March
24, 1966
The American
Journal
of Medicine
Volume
99
(suppl 3A)
65
SYMPOSIUM
ON FLURBIPROFEN-BLOOMFIELD
ET AL
din system. Single oral doses of 50 mg of flurbiprofen, 650 mg of aspirin, 60 and 120 mg of codeine sulfate, and placebo were compared in a parallel, stratified, randomized block, placebo-controlled, double-blind trial [lo-181.
PATIENTS AND METHODS Patient Selection. Patients were selected
consecutively from a homogeneous population of healthy, consenting, postpartum women, 18 years or older, who were admitted to the obstetrics service of the University of Cincinnati Hospital. All patients were interviewed within 72 hours of uncomplicated delivery. Only those complaining of moderate or severe uterine pain (afterbirth cramps) were enrolled in the study; mild pain was not considered suitable. Patients with concurrent episiotomies were included only if that pain was judged weaker than afterbirth pain at the time of enrollment. To avoid confusion, these patients were not questioned further about episiotomy pain. Exclusion criteria included a history of hypersensitivity to aspirin or codeine; known drug dependence; use of analgesics, sedatives, or other psychotropic drugs within six hours of enrollment; and breastfeeding. Ferrous sulfate was given routinely during the postpartum period but, unless necessary, all other drugs were avoided. Provision was made to remove women requiring “rescue” analgesics from the study. For the first two hours after enrollment, patients were confined to bed, but were intermittently ambulatory for the remaining study hours. Study Design. The trial involved a concurrent comparison of five treatment groups, including a test group and positive and negative control groups, under strict double-blind conditions. On enrollment, patients underwent a two-way stratification according to morning or afternoon shifts of the two clinical research nurse observers, and according to moderate or severe pretreatment pain intensity. Within these four strata, individual patients were randomly assigned to one of the five treatment groups on a balanced schedule. The purpose of the stratified, balanced randomization was to ensure even matching of all treatment groups for variations between observers and levels of initial (hour zero) pain intensity. Additionally, according to this design, all treatment groups were approximately equal in sample size, consisting of 30 to 34 patients each. Because the trial was a parallel betweensubject comparison, only one of the five treatments was given to each patient. Study medications included single oral doses of 50 mg of flurbiprofen (two 25-mg tablets), 650 mg of aspirin (two 325-mg tablets), 60 mg of codeine sulfate (one 60-mg tablet and one placebo tablet), 120 mg of codeine sulfate (two 60-mg tablets), and two placebo tablets. Tablets, prepackaged in code-numbered individual dose vials, were identical in appearance and taste. The code for an individual could be broken without revealing the treatment received by other patients. All doses were given with eight ounces of water, and patients were instructed to lie on their right side for two hours thereafter. Evaluation of Response. Subjective reports were used as indices of response. Changes in pain intensity, pain relief, and development of side effects associated with treatment
66
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The American
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were evaluated for a total of six hours in uniformly conducted interviews [I 1 ,I 21 by the two clinical nurse observers. For any individual patient, interviews were performed by only one of these nurses. Each patient was interviewed before dosing at hour zero and seven times thereafter at intervals of one-half or one hour; when necessary, patients were awakened. At each observation time, the patient reported her afterbirth pain intensity since the last interview (for hour zero, the hour before enrollment), and pain relief as compared with initial pain. Pain intensity and pain relief levels were measured on a four-point verbal ordinal rating scale with 0 = none, 1 = slight, 2 = moderate, and 3 = severe pain or complete pain relief. From the original observations at each time point, pain intensity difference, sum of pain intensity difference, and sum of pain relief scores, derived from standard methods of calculation [12], were used to determine relative efficacy, including peak effect, and to plot the time course of analgesia. Thus, pain intensity difference and pain relief scores and their respective summary variables provided graded measurements of analgesia. At the end of the last interview, each patient also verbally rated the global effect of the drug with 0 = “the worst” and 10 = “the best pain reliever ever taken.” Side effects elicited were graded on a four-point verbal ordinal rating scale of severity; minimal use was made of leading questions and a checklist of possible side effects was not invoked. Vital signs, including arterial pressure, pulse and respiratory rates, and oral body temperature, were obtained before, and one, two, and six hours after treatment. Recording and Analysis of Data. Data were recorded on case report forms specifically designed for computer application. Ordinal data were analyzed statistically for treatment group differences by nonparametric statistical tests [13], including the Kruskal-Wallis one-way analysis of variance by ranks applied at each observation point and, if statistically justified, the Mann-Whitney test corrected with Bonferroni’s procedure [14] for pairwise contrasts between treatments. Frequency data were analyzed by the Chi-square test, and vital signs data by conventional one-way analysis of variance applied at each observation period.
RESULTS Background Characteristics and Results of Randomization. Demographic and other background characteristics of patients in the five treatment groups were compared, including age, weight, race, parity, type of labor and delivery, and time-lapse between delivery and enrollment in the study. There were no important differences in these background characteristics among the five treatment groups. On enrollment, 80 of the 159 patients had moderate initial pain and 79 had severe initial cramp pain. Patients in each of these pain strata were equally distributed among the treatment groups with 50 percent of patients in each group having moderate pain and 50 percent severe pain. These data were combined for analysis and presentation. Of the 159 cases, 125 were enrolled by the morning nurse and 34 by the afternoon nurse. After crossvalidation between nurses, their data were combined.
66
(suppl 3A)
SYMPOSIUM
Pain Intensity Scores after Treatment with Flurbiprofen, Aspirin, Codeine, and Placebo Codeine
Aspirin
Placebo Time (hours) 0 0.5 1 2 3 4 5 6
TABLE II
ET AL
better than to placebo or either codeine dose. Relative efficacy based on the highest mean sum of pain relief and sum of pain intensity difference scores (Table II) showed that flurbiprofen and aspirin were most effective. The performances of these two drugs were virtually equal with a small, though not significant, sum of pain relief difference favoring flurbiprofen. The two codeine doses were ranked between aspirin and placebo, and did not exhibit a positive dose-response slope. These results are mirrored by the mean global rating (Table II), which reflects the excellent response to flurbiprofen and aspirin, with equivocal responses to codeine. Such data lend support to the significant superiority of flurbiprofen and aspirin over placebo. Time Course of Analgesic Response. Flurbiprofen and aspirin appeared to have similar time-effect patterns with regard to both pain relief (Figure 1) and pain intensity difference (Figure 2) variables. Each drug’s peak effect was attained at the second or third hour and separation from placebo was distinct at all but two time points; this advantage was consistent and greater after the third hour than before, despite the natural tendency toward return of pain as reflected in the placebo curve. The peak effect of flurbiprofen tended to exceed that of aspirin, although not significantly. In contrast, the performance of codeine was less consistent; an early advantage of the 60-mg dose
Among the 159 patients, nine had no pain relief, received rescue analgesic medication, and were removed from the study before the end of the six-hour observation period. Of these patients, five-had received placebo, two were given aspirin, one took 60 mg of codeine and another was treated with 120 mg of codeine. No patient in the flurbiprofen group required rescue analgesic medication. Although these nine patients were withdrawn before completion of the study, they were included in the data analysis without qualification, but interviews were discontinued. The pain intensity score for each unperformed interview was adjusted to the pretreatment value, and the adjusted scores were analyzed with the earlier recorded data (Table I). Pain relief scores and other data were handled in a corresponding fashion. One patient in the placebo group was inadvertently enrolled in the study less than six hours (4.2 hours) from the time of her last regularly prescribed analgesic, 60 mg of codeine. Despite the oversight, interviews were performed and all data for this patient were included in the analysis without qualification. Analgesic Response and Relative Efficacy. Initial pain intensity (hour zero) mean values were almost identical in all treatment groups, ranging from 2.47 to 2.53 (Table I). Changes from baseline after dosing indicate that the overall responses to flurbiprofen and aspirin were consistently TABLE I
ON FLURBIPROFEN-BLOOMFIELD
60 mg (n = 32)
(n = 32) 2.47 1.53 0.94 0.81 ,0.84 1.31 1.31 1.25
+ + k + 2 + * +
0.09 0.18 0.17 0.18 0.18 0.20 0.20 0.20
120 mg (n = 31)
2.50 -t 0.09 0.94 k 0.18 0.94 k 0.18 0.89 f 0.14 0.78 + 0.17 1.00 2 0.17 1.03 f 0.19 1.28 f 0.18
2.52 1.26 1.06 0.97 0.90 1.03 1.13 1.35
-r+ k + ? ? + +
Flurbipmfen
650 mp (n = 34)
0.09 0.19 0.18 0.20 0.18 0.20 0.19 0.19
2.53 + 0.09 0.94 f 0.18 0.94 -e 0.17 0.79 k 0.17 0.82 + 0.18 0.82 2 0.17 0.71 k 0.19 0.79 rt 0.19
50 mu (n = 30) 2.47 1.27 1.10 0.80 0.63 0.40 0.50 0.47
f 0.09 + 0.18 -+ 0.17 -c 0.18 5 0.19 2 0.14 2 0.18 XIZ0.16
Mean Scores of Summary Variables with Flurbiprofen, Aspirin, Codeine, and Placebo Codeine
Asplrin
Flurbipmfen
666 mg (n = 34)
50 mu (n = 30)
Placebo
scorn Sum of pain relief Sum of pain intensitydifference Globalrating ‘p 50.05. +p ~0.05 (versusaspirin)and p ~0.01 *p 50.02. §p SO.01 (versusplacebo).
60
mu
(n = 32)
(n = 32) 11.6 9.3 8.0
12.7' 10.8 7.0'
120 mg
(n = 31) 11.9+ 9.9 7.3
14.6* 12.3* 7.9*
15.6* 12.3' 8.3"
(versusflurbiprofen).
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ol Medicine
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(suppl3A)
67
SYMPOSIUM
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ET AL
0.02*
1.2
d I,, , , , , D-------a
Flurbiprofen 50 mg (n=30) 0 Aspirin 650 mg (n=34) A-L.------ACodeine 60 mg (n=32) t--
-
A--.---.--*Codeine 0-C
0.8 1.0
(n=32)
*Paired comparisons Mann-Whitney test.
0.
1
2
3
Observation
TABLE
120 mg (n=31)
Placebo
III
Incidence
4
5
by
Figure 1. Pain relief versus time with single doses of flurbipfofen, aspirin, codeine, and placebo in patients with postpartum uterine cramp pain.
6
Time (hr)
of Side Effects with Flurbiprofen,
Aspirin,
Codeine,
Cedelne
and Placebo Aspirin
Flurblpmfen
656 mg (n = 34)
50 mg (n = 30)
Total (n = 166)
6 4** 1 0 1 1 0 0
57 41 20 4 3 2 2 4
Placebo Side Effect
(n = 32)
Any side effect Drowsiness Dizziness Nausea Fatigue Nervousness Sweating Other Note: ‘Two +Two *One *Five **One trTwo **Six ~TWO
so
some mild, mild, mild, mild, mild, mild, mild, mild.
60 mg (n = 32)
120 mg (n = 31)
10 7t 4f’ 0 0 0 1 0
27 16* 13** 4 2 1 1 2
6
75 25s 0 0 0 0 1
patients reported more than one side effect. three moderate. one moderate, four severe. 11 moderate, six severe (p ~0.001 versus placebo and aspirin; p ~0.02 versus 60 mg of codeine). one moderate, one severe. two moderate, one severe. one moderate, one severe. three moderate, four severe (p co.001 versus placebo and aspirin; p ~0.05 versus 60 mg of codeine).
March
24,1966
The Amwloan
Journal
of Medicine
Volume
80
(suppl3A)
SYMPOSIUM
0 ----Xl t-4 A-.-.-A &..-..-A o--
ON FLURSIPROFEN-BCOOMFIELD
ET AL
Flurbiprofen 50 mg (n=30) Aspirin 650 mg (n=34) Codeine 60 mg (n=32) Codeine 120 mg (n=31) Placebo (n=32) * Paired comparisons by Mann-Whitney test.
1.8!z 0 ii n h s 2
1.6-
1.4-
2 3 4 Observation Time (hr)
,
,
5
6
over placebo at 30 minutes did not persist, and thereafter neither the 60-mg nor the 120-mg dose of codeine separated convincingly from placebo. These results suggest that 50 mg of flurbiprofen was equivalent to aspirin and superior to codeine for patients with postpartum uterine cramps. On the other hand, 120 mg of codeine was ineffective, and the effect of the 60-mg dose, if any, was very short. Lasting, positive responses to aspirin and flurbiprofen were seen. Side Effects. The most common side effects were drowsiness and dizziness, reported by 41 and 20 patients, respectively (Table Ill). CMthe five treatments, 120 mg of codeine was clearly associated with the highest incidence of side effects, with 16 cases of drowsiness and 13 of dizziness. The incidence of these or any other side effect after flurbiprofen or aspirin was not significant. In addition, no significant or clinically important differences in vital signs were detected among the treatment groups.
March
24,1966
Flgure 2. Pain intensity difference (P/D) versus time with single doses of flurbiprofen, aspirin, codeine, and placebo in patients with postpartum uterine cramp pain.
COMMENTS
Our results suggest that single 50.mg doses of flurbiprofen provide effective analgesia for up to six hours, which is comparable to 650 mg of aspirin, for the relief of postpartum uterine pain. Peak effects of flurbiprofen exceeded those of aspirin by a small, nonsignificant margin. Side effects after administration of flurbiprofen and aspirin were not significant. In vitro and in vivo studies have shown that flurbiprofen inhibits prostaglandin biosynthesis [l]. Since prostaglandins have been recognized as intrinsic myometrial stimulants [15], and are implicated in dysmenorrhea 1161 and the initiation of labor [17], they are probably also at the root of postpartum uterine pain. This may explain the effectiveness of flurblprofen in our postpartum uterine pain model. Codeine’s failure to relieve postpartum uterine cramps in this study confirms our earlier reported findings [18].
The
American
Journal
of Medicine
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66 (ruppl3A)
69
SYMPOSIUM
1.
2.
3. 4.
5.
6.
7.
8.
9.
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ET AL
NOZU K: Flurbiprofen: a highly potent inhibitor of prostaglandin synthesis, Biwhem Biophys Acta 1978; 529: 493496. Adams SS, McCullough KF, Nicholson JS: Some biological properties of flurbiprofen, an anti-inflammatory, analgesic, and antipyretic agent. Arzneimittelforsch 1975; 25: 17861791. VanMiort AS, Van Duin CT: The antipyretic effect of flurbiprofen. Eur J Pharmacol 1977; 44: 197-204. Pitney WR, Nicol M, Dean S, Hickey A: Effect of flurbiprofen on bleeding time and platelet aggregation. Thromb Res 1978; 811-819. Mena HR, Ehrlich GE, Giansiracusa J: Response of osteoarthritis to ibuprofen or flurbiprofen. J Int Med Res 1976; 4: 152157. Mena HR, Ward JR, Zuckner J: Treatment of rheumatoid arthrit&r with flurbiprofen or ibuprofen. J Clin Pharmacol 1977; 17: 56-62. Brewis IQL: A comparative study of flurbiprofen and indomethatin in rheumatoid arthritis. Curr Med Res Opin 1977; 5: 4852. Lenaghan E, Barraclough DRE, Muirden KO: A comparison of flurbiprofen and aspirin in the treatment of rheumatoid arthritis. Int Congr Rheumatol 1973; 13: 186-187. Vakil BJ, Shah PN, Dalal NJ: Endoscopic study of gastrointestinal injury with non-steroidal anti-inflammatory drugs. Curr
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of Medlclne
Volume
10.
11.
12.
13. 14. 15.
16.
17. 18.
Med Res Opin 1977; 5: 38-42. Bloomfield SS, Barden TP, Mitchell J, Bichlmeir G: Flurbiprofen, aspirin, and codeine in postpartum pain (abstr). Clin Pharmacol Ther 1981; 29: 234-235. Bloomfield SS, Barden TP, Hille R: Clinical evaluation of flufenisal, a long-acting oral analgesic. Clin Pharmacol Ther 1970; 11: 747-754. Bloomfield SS, Barden TP, Mitchell J: Aspirin and codeine in two postpartum pain models. Clin Pharmacol Ther 1976; 20: 499503. Siegel S: Nonparametric statistics for the behavioral sciences. New York: McGraw-Hill, 1956. Morrison DF: Multivariate statistical methods, 2nd edition. New York: McGraw-Hill, 1976. Martin J, Bygdeman M: The effect of locally administered PGE2 on the wntractitity of the non-pregnant uterus in vivo. Prostaglandins 1975; 10: 253-265. Lundstrom V, Green K: Endogenous levels of prostaglandin F2a and its main metabolites in plasma and endometrium of normal and dysmenorrhe’i women. Am J Obstet Gynecol 1978; 130: 640-648. Moghissi KS: Prostaglandins in reproduction. Obstet Gynecol Ann 1972; 1: 297-337. Bloomfield SS, Barden’TP, Mitchell J, Bichlmeir G: A wmparison of flurbiprofen, aspirin, and placebo in postpartum uterine pain. %urr Ther Res 1981; 30: 670-679.
80 (suppl
3A)
SAUL S. BLOOMFIELD, M.D. JEANEl-fE MITCHELL, L.P.N. GAIL C&SELL, R.N. TOM P. BARDEN, M.D. Cincinnati,
Ohio
From the Division of Clinical Pharmacology and Toxicology, Department of Internal Medicine and Department of Obstetrics and Gynecology, Universky of Cincinnati Medical Center, Cincinnati, Ohio. This article was presented, in part, at the 82nd Annual Meeting of the American Society for Clinical Pharmacology and Therapeutics, New Orleans, Louisiana, March, 1961. The research was supported, in part, by a grant from The Upjohn Company. Requests for reprints should be addressed to Dr. Saul S. Bloomfield, 5502 Medical Sciences Building, University of Cincinnati Medical Center, Cincinnati, Ohio 45267-0576. The work presented was based on the administration of Ansaid tablets, a registered trademark of The Upjohn Company.
Flurbiprofen (Ansaid, Upjohn), a substituted phenyl propionic acid, is a new analgesic/anti-inflammatory agent. To evaluate its relative efficacy in noninflammatory pain, 159 hospitalized women with moderate or severe postpartum uterine cramps were given single oral doses of 60 mg of flurbiprofen, 650 mg of aspirin, 60 or 120 mg of codeine sulfate, or placebo in a parallel, stratified, randomized block, placebo-controlled, double-blind trial. Patients rated pain intensity, pain relief, and side effects in uniform interviews for six hours after treatment. All measures of peak and summed analgesia exhibited significant differences among the five treatments. Flurbiprofen and aspirin showed the greatest analgesic response and were significantly superior to placebo. Results of codeine treatment were equivocal with no evidence of a positive dose response. Side effects were unremarkable except for dizziness and drowsiness after the 120.mg codeine dose. These findings suggest that flurbiprofen as an analgesic for patients with postpartum uterine pain is equivalent to asplrfn and superior to codeine. Flurbiprofen (Ansaid, Upjohn), 2-(2-fluoro4-biphenylyl) propionic acid, is a new analgesic/anti-inflammatory’agent that, like aspirin and other compounds in this chemical class, inhibits prostaglandin synthetase (cyclooxygenase) [l]. In laboratory animals, flurbiprofen exhibits analgesic, anti-inflammatory, and antipyretic activity [2,3]. The analgesic action appears to be peripheral rather than central, and the anti-inflammatory activity does not involve the adrenal cortex. Flurbiprofen has significant antithrombotic activity due to its inhibition of platelet aggregation [4]. In humans, carefully controlled clinical studies in the United States [5,6] and abroad [7,8], along with over eight years of European clinical experience, indicate that flurbiprofen is a safe and effective analgesic for patients with various rheumatic diseases, including both the inflammatory and degenerative arthritides. Other studies have shown that flurbiprofen is well tolerated, with minimal effects on the gastrointestinal tract.and a notable absence of ulceration or blood loss [9]. Since a need exists for pain relievers that are safe and effective alternatives to narcotics, the analgesic response to flurbiprofen in patients with nonrheumatic pain was evaluated. We conducted a phase II clinical study comparing flurbiprofen’s efficacy, safety, and time course of analgesia with those of aspirin and codeine, two standard reference analgesics, in 159 hospitalized women experiencing moderate or severe postpartum uterine cramping-a form of noninflammatory, nonarthritic pain that may be mediated by a second messenger-prostaglan-
March
24, 1966
The American
Journal
of Medicine
Volume
99
(suppl 3A)
65
SYMPOSIUM
ON FLURBIPROFEN-BLOOMFIELD
ET AL
din system. Single oral doses of 50 mg of flurbiprofen, 650 mg of aspirin, 60 and 120 mg of codeine sulfate, and placebo were compared in a parallel, stratified, randomized block, placebo-controlled, double-blind trial [lo-181.
PATIENTS AND METHODS Patient Selection. Patients were selected
consecutively from a homogeneous population of healthy, consenting, postpartum women, 18 years or older, who were admitted to the obstetrics service of the University of Cincinnati Hospital. All patients were interviewed within 72 hours of uncomplicated delivery. Only those complaining of moderate or severe uterine pain (afterbirth cramps) were enrolled in the study; mild pain was not considered suitable. Patients with concurrent episiotomies were included only if that pain was judged weaker than afterbirth pain at the time of enrollment. To avoid confusion, these patients were not questioned further about episiotomy pain. Exclusion criteria included a history of hypersensitivity to aspirin or codeine; known drug dependence; use of analgesics, sedatives, or other psychotropic drugs within six hours of enrollment; and breastfeeding. Ferrous sulfate was given routinely during the postpartum period but, unless necessary, all other drugs were avoided. Provision was made to remove women requiring “rescue” analgesics from the study. For the first two hours after enrollment, patients were confined to bed, but were intermittently ambulatory for the remaining study hours. Study Design. The trial involved a concurrent comparison of five treatment groups, including a test group and positive and negative control groups, under strict double-blind conditions. On enrollment, patients underwent a two-way stratification according to morning or afternoon shifts of the two clinical research nurse observers, and according to moderate or severe pretreatment pain intensity. Within these four strata, individual patients were randomly assigned to one of the five treatment groups on a balanced schedule. The purpose of the stratified, balanced randomization was to ensure even matching of all treatment groups for variations between observers and levels of initial (hour zero) pain intensity. Additionally, according to this design, all treatment groups were approximately equal in sample size, consisting of 30 to 34 patients each. Because the trial was a parallel betweensubject comparison, only one of the five treatments was given to each patient. Study medications included single oral doses of 50 mg of flurbiprofen (two 25-mg tablets), 650 mg of aspirin (two 325-mg tablets), 60 mg of codeine sulfate (one 60-mg tablet and one placebo tablet), 120 mg of codeine sulfate (two 60-mg tablets), and two placebo tablets. Tablets, prepackaged in code-numbered individual dose vials, were identical in appearance and taste. The code for an individual could be broken without revealing the treatment received by other patients. All doses were given with eight ounces of water, and patients were instructed to lie on their right side for two hours thereafter. Evaluation of Response. Subjective reports were used as indices of response. Changes in pain intensity, pain relief, and development of side effects associated with treatment
66
March
24,1986
The American
Journal
of Medicine
Volume
were evaluated for a total of six hours in uniformly conducted interviews [I 1 ,I 21 by the two clinical nurse observers. For any individual patient, interviews were performed by only one of these nurses. Each patient was interviewed before dosing at hour zero and seven times thereafter at intervals of one-half or one hour; when necessary, patients were awakened. At each observation time, the patient reported her afterbirth pain intensity since the last interview (for hour zero, the hour before enrollment), and pain relief as compared with initial pain. Pain intensity and pain relief levels were measured on a four-point verbal ordinal rating scale with 0 = none, 1 = slight, 2 = moderate, and 3 = severe pain or complete pain relief. From the original observations at each time point, pain intensity difference, sum of pain intensity difference, and sum of pain relief scores, derived from standard methods of calculation [12], were used to determine relative efficacy, including peak effect, and to plot the time course of analgesia. Thus, pain intensity difference and pain relief scores and their respective summary variables provided graded measurements of analgesia. At the end of the last interview, each patient also verbally rated the global effect of the drug with 0 = “the worst” and 10 = “the best pain reliever ever taken.” Side effects elicited were graded on a four-point verbal ordinal rating scale of severity; minimal use was made of leading questions and a checklist of possible side effects was not invoked. Vital signs, including arterial pressure, pulse and respiratory rates, and oral body temperature, were obtained before, and one, two, and six hours after treatment. Recording and Analysis of Data. Data were recorded on case report forms specifically designed for computer application. Ordinal data were analyzed statistically for treatment group differences by nonparametric statistical tests [13], including the Kruskal-Wallis one-way analysis of variance by ranks applied at each observation point and, if statistically justified, the Mann-Whitney test corrected with Bonferroni’s procedure [14] for pairwise contrasts between treatments. Frequency data were analyzed by the Chi-square test, and vital signs data by conventional one-way analysis of variance applied at each observation period.
RESULTS Background Characteristics and Results of Randomization. Demographic and other background characteristics of patients in the five treatment groups were compared, including age, weight, race, parity, type of labor and delivery, and time-lapse between delivery and enrollment in the study. There were no important differences in these background characteristics among the five treatment groups. On enrollment, 80 of the 159 patients had moderate initial pain and 79 had severe initial cramp pain. Patients in each of these pain strata were equally distributed among the treatment groups with 50 percent of patients in each group having moderate pain and 50 percent severe pain. These data were combined for analysis and presentation. Of the 159 cases, 125 were enrolled by the morning nurse and 34 by the afternoon nurse. After crossvalidation between nurses, their data were combined.
66
(suppl 3A)
SYMPOSIUM
Pain Intensity Scores after Treatment with Flurbiprofen, Aspirin, Codeine, and Placebo Codeine
Aspirin
Placebo Time (hours) 0 0.5 1 2 3 4 5 6
TABLE II
ET AL
better than to placebo or either codeine dose. Relative efficacy based on the highest mean sum of pain relief and sum of pain intensity difference scores (Table II) showed that flurbiprofen and aspirin were most effective. The performances of these two drugs were virtually equal with a small, though not significant, sum of pain relief difference favoring flurbiprofen. The two codeine doses were ranked between aspirin and placebo, and did not exhibit a positive dose-response slope. These results are mirrored by the mean global rating (Table II), which reflects the excellent response to flurbiprofen and aspirin, with equivocal responses to codeine. Such data lend support to the significant superiority of flurbiprofen and aspirin over placebo. Time Course of Analgesic Response. Flurbiprofen and aspirin appeared to have similar time-effect patterns with regard to both pain relief (Figure 1) and pain intensity difference (Figure 2) variables. Each drug’s peak effect was attained at the second or third hour and separation from placebo was distinct at all but two time points; this advantage was consistent and greater after the third hour than before, despite the natural tendency toward return of pain as reflected in the placebo curve. The peak effect of flurbiprofen tended to exceed that of aspirin, although not significantly. In contrast, the performance of codeine was less consistent; an early advantage of the 60-mg dose
Among the 159 patients, nine had no pain relief, received rescue analgesic medication, and were removed from the study before the end of the six-hour observation period. Of these patients, five-had received placebo, two were given aspirin, one took 60 mg of codeine and another was treated with 120 mg of codeine. No patient in the flurbiprofen group required rescue analgesic medication. Although these nine patients were withdrawn before completion of the study, they were included in the data analysis without qualification, but interviews were discontinued. The pain intensity score for each unperformed interview was adjusted to the pretreatment value, and the adjusted scores were analyzed with the earlier recorded data (Table I). Pain relief scores and other data were handled in a corresponding fashion. One patient in the placebo group was inadvertently enrolled in the study less than six hours (4.2 hours) from the time of her last regularly prescribed analgesic, 60 mg of codeine. Despite the oversight, interviews were performed and all data for this patient were included in the analysis without qualification. Analgesic Response and Relative Efficacy. Initial pain intensity (hour zero) mean values were almost identical in all treatment groups, ranging from 2.47 to 2.53 (Table I). Changes from baseline after dosing indicate that the overall responses to flurbiprofen and aspirin were consistently TABLE I
ON FLURBIPROFEN-BLOOMFIELD
60 mg (n = 32)
(n = 32) 2.47 1.53 0.94 0.81 ,0.84 1.31 1.31 1.25
+ + k + 2 + * +
0.09 0.18 0.17 0.18 0.18 0.20 0.20 0.20
120 mg (n = 31)
2.50 -t 0.09 0.94 k 0.18 0.94 k 0.18 0.89 f 0.14 0.78 + 0.17 1.00 2 0.17 1.03 f 0.19 1.28 f 0.18
2.52 1.26 1.06 0.97 0.90 1.03 1.13 1.35
-r+ k + ? ? + +
Flurbipmfen
650 mp (n = 34)
0.09 0.19 0.18 0.20 0.18 0.20 0.19 0.19
2.53 + 0.09 0.94 f 0.18 0.94 -e 0.17 0.79 k 0.17 0.82 + 0.18 0.82 2 0.17 0.71 k 0.19 0.79 rt 0.19
50 mu (n = 30) 2.47 1.27 1.10 0.80 0.63 0.40 0.50 0.47
f 0.09 + 0.18 -+ 0.17 -c 0.18 5 0.19 2 0.14 2 0.18 XIZ0.16
Mean Scores of Summary Variables with Flurbiprofen, Aspirin, Codeine, and Placebo Codeine
Asplrin
Flurbipmfen
666 mg (n = 34)
50 mu (n = 30)
Placebo
scorn Sum of pain relief Sum of pain intensitydifference Globalrating ‘p 50.05. +p ~0.05 (versusaspirin)and p ~0.01 *p 50.02. §p SO.01 (versusplacebo).
60
mu
(n = 32)
(n = 32) 11.6 9.3 8.0
12.7' 10.8 7.0'
120 mg
(n = 31) 11.9+ 9.9 7.3
14.6* 12.3* 7.9*
15.6* 12.3' 8.3"
(versusflurbiprofen).
March
24,1986
The American
Journal
ol Medicine
Volume
60
(suppl3A)
67
SYMPOSIUM
ON FLURBIPROFEN-BLOOMFIELD
ET AL
0.02*
1.2
d I,, , , , , D-------a
Flurbiprofen 50 mg (n=30) 0 Aspirin 650 mg (n=34) A-L.------ACodeine 60 mg (n=32) t--
-
A--.---.--*Codeine 0-C
0.8 1.0
(n=32)
*Paired comparisons Mann-Whitney test.
0.
1
2
3
Observation
TABLE
120 mg (n=31)
Placebo
III
Incidence
4
5
by
Figure 1. Pain relief versus time with single doses of flurbipfofen, aspirin, codeine, and placebo in patients with postpartum uterine cramp pain.
6
Time (hr)
of Side Effects with Flurbiprofen,
Aspirin,
Codeine,
Cedelne
and Placebo Aspirin
Flurblpmfen
656 mg (n = 34)
50 mg (n = 30)
Total (n = 166)
6 4** 1 0 1 1 0 0
57 41 20 4 3 2 2 4
Placebo Side Effect
(n = 32)
Any side effect Drowsiness Dizziness Nausea Fatigue Nervousness Sweating Other Note: ‘Two +Two *One *Five **One trTwo **Six ~TWO
so
some mild, mild, mild, mild, mild, mild, mild, mild.
60 mg (n = 32)
120 mg (n = 31)
10 7t 4f’ 0 0 0 1 0
27 16* 13** 4 2 1 1 2
6
75 25s 0 0 0 0 1
patients reported more than one side effect. three moderate. one moderate, four severe. 11 moderate, six severe (p ~0.001 versus placebo and aspirin; p ~0.02 versus 60 mg of codeine). one moderate, one severe. two moderate, one severe. one moderate, one severe. three moderate, four severe (p co.001 versus placebo and aspirin; p ~0.05 versus 60 mg of codeine).
March
24,1966
The Amwloan
Journal
of Medicine
Volume
80
(suppl3A)
SYMPOSIUM
0 ----Xl t-4 A-.-.-A &..-..-A o--
ON FLURSIPROFEN-BCOOMFIELD
ET AL
Flurbiprofen 50 mg (n=30) Aspirin 650 mg (n=34) Codeine 60 mg (n=32) Codeine 120 mg (n=31) Placebo (n=32) * Paired comparisons by Mann-Whitney test.
1.8!z 0 ii n h s 2
1.6-
1.4-
2 3 4 Observation Time (hr)
,
,
5
6
over placebo at 30 minutes did not persist, and thereafter neither the 60-mg nor the 120-mg dose of codeine separated convincingly from placebo. These results suggest that 50 mg of flurbiprofen was equivalent to aspirin and superior to codeine for patients with postpartum uterine cramps. On the other hand, 120 mg of codeine was ineffective, and the effect of the 60-mg dose, if any, was very short. Lasting, positive responses to aspirin and flurbiprofen were seen. Side Effects. The most common side effects were drowsiness and dizziness, reported by 41 and 20 patients, respectively (Table Ill). CMthe five treatments, 120 mg of codeine was clearly associated with the highest incidence of side effects, with 16 cases of drowsiness and 13 of dizziness. The incidence of these or any other side effect after flurbiprofen or aspirin was not significant. In addition, no significant or clinically important differences in vital signs were detected among the treatment groups.
March
24,1966
Flgure 2. Pain intensity difference (P/D) versus time with single doses of flurbiprofen, aspirin, codeine, and placebo in patients with postpartum uterine cramp pain.
COMMENTS
Our results suggest that single 50.mg doses of flurbiprofen provide effective analgesia for up to six hours, which is comparable to 650 mg of aspirin, for the relief of postpartum uterine pain. Peak effects of flurbiprofen exceeded those of aspirin by a small, nonsignificant margin. Side effects after administration of flurbiprofen and aspirin were not significant. In vitro and in vivo studies have shown that flurbiprofen inhibits prostaglandin biosynthesis [l]. Since prostaglandins have been recognized as intrinsic myometrial stimulants [15], and are implicated in dysmenorrhea 1161 and the initiation of labor [17], they are probably also at the root of postpartum uterine pain. This may explain the effectiveness of flurblprofen in our postpartum uterine pain model. Codeine’s failure to relieve postpartum uterine cramps in this study confirms our earlier reported findings [18].
The
American
Journal
of Medicine
Volume
66 (ruppl3A)
69
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ON FLURBIPROFEN-BLOOMFIELD
ET AL
NOZU K: Flurbiprofen: a highly potent inhibitor of prostaglandin synthesis, Biwhem Biophys Acta 1978; 529: 493496. Adams SS, McCullough KF, Nicholson JS: Some biological properties of flurbiprofen, an anti-inflammatory, analgesic, and antipyretic agent. Arzneimittelforsch 1975; 25: 17861791. VanMiort AS, Van Duin CT: The antipyretic effect of flurbiprofen. Eur J Pharmacol 1977; 44: 197-204. Pitney WR, Nicol M, Dean S, Hickey A: Effect of flurbiprofen on bleeding time and platelet aggregation. Thromb Res 1978; 811-819. Mena HR, Ehrlich GE, Giansiracusa J: Response of osteoarthritis to ibuprofen or flurbiprofen. J Int Med Res 1976; 4: 152157. Mena HR, Ward JR, Zuckner J: Treatment of rheumatoid arthrit&r with flurbiprofen or ibuprofen. J Clin Pharmacol 1977; 17: 56-62. Brewis IQL: A comparative study of flurbiprofen and indomethatin in rheumatoid arthritis. Curr Med Res Opin 1977; 5: 4852. Lenaghan E, Barraclough DRE, Muirden KO: A comparison of flurbiprofen and aspirin in the treatment of rheumatoid arthritis. Int Congr Rheumatol 1973; 13: 186-187. Vakil BJ, Shah PN, Dalal NJ: Endoscopic study of gastrointestinal injury with non-steroidal anti-inflammatory drugs. Curr
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24, 1986
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Journal
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Volume
10.
11.
12.
13. 14. 15.
16.
17. 18.
Med Res Opin 1977; 5: 38-42. Bloomfield SS, Barden TP, Mitchell J, Bichlmeir G: Flurbiprofen, aspirin, and codeine in postpartum pain (abstr). Clin Pharmacol Ther 1981; 29: 234-235. Bloomfield SS, Barden TP, Hille R: Clinical evaluation of flufenisal, a long-acting oral analgesic. Clin Pharmacol Ther 1970; 11: 747-754. Bloomfield SS, Barden TP, Mitchell J: Aspirin and codeine in two postpartum pain models. Clin Pharmacol Ther 1976; 20: 499503. Siegel S: Nonparametric statistics for the behavioral sciences. New York: McGraw-Hill, 1956. Morrison DF: Multivariate statistical methods, 2nd edition. New York: McGraw-Hill, 1976. Martin J, Bygdeman M: The effect of locally administered PGE2 on the wntractitity of the non-pregnant uterus in vivo. Prostaglandins 1975; 10: 253-265. Lundstrom V, Green K: Endogenous levels of prostaglandin F2a and its main metabolites in plasma and endometrium of normal and dysmenorrhe’i women. Am J Obstet Gynecol 1978; 130: 640-648. Moghissi KS: Prostaglandins in reproduction. Obstet Gynecol Ann 1972; 1: 297-337. Bloomfield SS, Barden’TP, Mitchell J, Bichlmeir G: A wmparison of flurbiprofen, aspirin, and placebo in postpartum uterine pain. %urr Ther Res 1981; 30: 670-679.
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