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ORIGINAL RESEARCH |
From the Scirex Corporation, Austin, Texas; and Pharmacia, Skokie, Illinois.
Address reprint requests to: David P. Recker, MD, Clinical Research and Development, Pharmacia Corporation, 5200 Old Orchard Road, Skokie, IL 60077; E-mail: david.p.recker{at}pharmacia.com.
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ABSTRACT |
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 ABSTRACT PATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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METHOD: This single-center, double-blind, placebo-controlled, randomized, crossover study compared the efficacy and safety of single oral doses of valdecoxib 20 mg and 40 mg with naproxen sodium 550 mg, or placebo, with an option of treatment for up to 3 days, twice daily. Efficacy was assessed by time-weighted sum of total pain relief, sum of pain intensity difference, time-specific pain relief, and pain intensity difference over 12 hours, time to rescue medication or first re-medication, the percentage of patients taking rescue medication, and patient’s global evaluation of study medication.
RESULTS: Mean time-weighted sum of total pain relief and sum of pain intensity difference were significantly superior to placebo for the first 8 and 12 hours after the initial dose of valdecoxib 20 mg (P < .01) and 40 mg (P < .001). Valdecoxib 20 mg and 40 mg were comparable to naproxen sodium 550 mg for all efficacy measures. Other differences in efficacy measures favoring the higher dose of valdecoxib did not achieve statistical significance, with the exception of sum of pain intensity difference-12. Both doses of valdecoxib were well tolerated.
CONCLUSIONS: Both valdecoxib 20- and 40-mg doses were effective and well tolerated for the treatment of primary dysmenorrhea. Valdecoxib 20 mg and 40 mg demonstrate analgesic efficacy, based on onset, magnitude, and duration of analgesia that is similar to naproxen sodium, making it a potential choice for treating women with primary dysmenorrhea.
Dysmenorrhea affects approximately 50% of reproductive-aged women, and in 10% of women it is severe enough to interfere with their daily activity.1 Affected individuals experience a range of associated symptoms including nausea, dizziness, and headache. Primary dysmenorrhea is characterized clinically as painful uterine cramping during the menstrual cycle in the absence of pelvic pathology, and is due to excessive secretion of uterine prostaglandins.1 Prostaglandin synthesis is mediated primarily by two distinct isoforms of cyclooxygenase (COX-1 and COX-2), which catalyze the metabolism of arachidonate to prostaglandin H2.2–5 Conventional nonsteroidal anti-inflammatory drugs (NSAIDs)–which are nonselective inhibitors of both isoforms of COX–have been the primary modality used to treat primary dysmenorrhea, providing pain relief and reducing interference in daily activity.6 However, even after short-term use, conventional NSAIDs are associated with poor gastrointestinal tolerability in some patients.7,8
Cyclooxygenase-2 is expressed in inflamed tissue and is the target for NSAID-mediated anti-inflammatory responses.9,10 In contrast, COX-1 is constitutively expressed in many tissues, including platelets and the gastric mucosa, and it is critical for homeostasis.10 Many of the adverse effects observed with conventional NSAIDs, particularly disruption of platelet function, and gastrointestinal ulceration and bleeding, are a result of inhibition of COX-1.11–15
Valdecoxib is a novel potent COX-2-specific inhibitor, which is approximately 28,000-fold more selective against COX-2 (half-maximal inhibitory concentration using human recombinant enzymes [IC50] = 0.005 µM) than COX-1 (hIC50 = 140 µM).16 Cyclooxygenase-2-specific inhibitors have been shown to be effective in treating pain, including menstrual pain, in women suffering from primary dysmenorrhea.17–19 Valdecoxib has been developed for the treatment of inflammation and pain and has demonstrated efficacy, based on onset, magnitude, and duration of analgesia, in a variety of postsurgical settings. Valdecoxib also exhibits an improved gastrointestinal and platelet safety profile compared with conventional NSAIDs.20,21
This study evaluated the efficacy and tolerability of two dose regimes of valdecoxib (20 mg and 40 mg) in treating primary dysmenorrhea compared with placebo and naproxen sodium, a conventional NSAID that represents the current standard-of-care.22 Up to two doses daily of study medication could be taken, as required, for up to 3 days. Standard measures were used to evaluate analgesic efficacy.
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PATIENTS AND METHODS |
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ABSTRACTPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Patients provided complete medical and gynecologic history and underwent a complete physical and gynecologic examination during the screening visit. Those patients who had dysmenorrhea secondary to organic pathology, such as endometriosis, were excluded. Patients with chronic abdominal pain, inflammatory bowel disease, irritable bowel syndrome, or who had a history of vomiting during menses were also excluded. Patients could not have a contraceptive implant (eg, Norplant, Wyeth-Ayerst Laboratories, Philadelphia, PA) within 6 months or an injectable device (eg, Depo Provera, Pharmacia & Upjohn, Kalamazoo, MI) within 3 months before study entry, or have used an intrauterine device within 3 months before the study. Patients who had an active peptic ulcer or any gastrointestinal disease associated with significant blood loss were excluded from participating in the study.
This was a double-blind, placebo-controlled, randomized, crossover study, conducted at a single center (SCI-REX Clinical Research Center, Austin, TX) in the United States. It compared the efficacy and safety of valdecoxib 20 mg taken twice daily as needed or valdecoxib 40 mg taken twice daily as needed with placebo or naproxen sodium 550 mg twice daily as needed. Each patient was randomized to one of the four treatment sequences and received each of the four treatments in the sequence to which they were assigned. The trial was conducted in accordance with the principles of good clinical practice and the Declaration of Helsinki and approved by the Quorum International Review Board (Seattle, WA). Study medication sufficient for 3 days plus one extra dose was packaged in two bottles, labeled A and B. Each dose of study medication consisted of two tablets from bottle A and two capsules from bottle B, the content of each bottle depended on the assigned treatment. Each eligible patient was randomized to study medication, received a treatment diary, instructions for self-evaluation and treatment of menstrual cramping pain due to dysmenorrhea, and two urine ß-human chorionic gonadotrophin (ß-HCG) test kits to be performed during each treated menstrual cycle, before dosing.
Patients were assigned into treatment sequence in the order in which they were enrolled, according to a computer-generated randomization schedule prepared at G.D. Searle & Co. (Skokie, IL) before the start of the study. Patients were randomized into one of the following four treatment sequence groups where each sequence, as well as each treatment period, was a complete randomized block in a 4 x 4 balanced Latin square in the generalized Youden square design (see Figure 1
).
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The magnitude of analgesia was assessed by time-weighted sum of pain relief and time-weighted sum of pain intensity difference at 8 and 12 hours after the first dose of study medication. Time-specific pain relief and time-specific pain intensity difference were analyzed at scheduled intervals (below) over the 12-hour study period after administration of the initial dose of study medication. Time-specific pain intensity difference was calculated by subtracting time-specific pain intensity from baseline pain intensity. Patients assessed their pain intensity on a 4-point categorical scale of 0 to 3, where 0 = no pain, 1 = mild pain, 2 = moderate pain, and 3 = severe pain, and these assessments were recorded into their treatment diary. Pain assessments were made before the initial dose (hour 0) and 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, and 12 hours after the initial dose of study medication. Patients recorded their level of pain relief at the above time points using a 5-point categorical scale of 0 to 4 where 0 = none (0% reduction), 1 = a little (25% reduction), 2 = some (50% reduction), 3 = a lot (75% reduction), and 4 = complete (100% reduction).
Time to rescue medication or first re-medication, which ever came first, and the percentage of patients taking rescue medication before the second dose of study medication, were monitored. Patients completed a Global Evaluation of Study Medication before rescue medication or a second dose of study re-medication on day 1. Patients assessed their study medication on a 4-point scale of 1 to 4, where 1 = poor, 2 = fair, 3 = good, and 4 = excellent.
Adverse events were monitored throughout the study. Clinical laboratory tests were carried out at screening, and at final assessment. Urine pregnancy tests were performed at screening, baseline, and at each postcycle visit to the study facility.
The sample size calculation was based on four primary efficacy variables: time-weighted sum of pain relief-8 and -12 and time-weighted sum of pain intensity difference-8 and -12 for valdecoxib 20 mg twice daily as necessary and valdecoxib 40 mg twice daily as necessary versus placebo. A sample size of 92 patients per treatment was needed to detect a difference of at least 3 in time-weighted sum of pain intensity difference-8 between valdecoxib 20 mg or 40 mg and placebo, with an estimate of variability of at most 5.7, with 90% power and type I error of 0.025 (for a two-sided test adjusted for two comparisons). It was also sufficient to detect a difference of at least 4.9 in time-weighted sum of pain relief-8 between valdecoxib 20 mg or 40 mg and placebo, with an estimate of variability of at most 8.54, with the same type I error and power.22 Assuming a 20% dropout rate, a sample size of 116 patients was required.
Baseline demographic variables were compared across treatment sequence using analysis of variance (ANOVA), with treatment sequence as the factor, for continuous variables (including age, weight, age at onset of dysmenorrhea, number of days of menstrual cramping pain per cycle, average length of cycle), and a Fisher exact test for categorical variables (race). A Cochran-Mantel-Haenszel test adjusted for treatment sequence was used to compare baseline pain intensity across treatments.
Efficacy analyses were carried out on a modified intent-to-treat cohort using the last-observation-carried-forward method. The last-observation-carried-forward approach was only applied within each treatment period and was not used for cross-period missing values imputation. The modified intent-to-treat cohort comprised all patients who were randomized and received one dose of study medication and who completed one evaluable cycle for each of the four study medications in the order of the sequence group in which they were assigned. A cycle was evaluable if patients treated their menstrual pain with study medication and did not take rescue medication or re-medicate within 1 hour of the first dose of study medication. Time-weighted sum of pain relief, time-weighted sum of pain intensity difference, pain relief, pain intensity difference, and patient’s global evaluation of study medication, before rescue or re-medication on day 1, were analyzed using ANOVA, with fixed effects for baseline pain intensity, treatment, period, sequence, and random effect for patients. Fisher protected least significant difference multiple comparison procedure was used for pairwise comparisons of the model-adjusted treatment means. The crossover effects were examined by using ANOVA with fixed effects of baseline pain intensity, treatment, period, sequence, and carryover effect, plus random effect for patient and were found not to be significant, so analyses were performed excluding carryover effects in the model.
Time to rescue or first re-medication was analyzed using survival methods. The median time to each event for each treatment was calculated using the Kaplan-Meier product limit estimator. For time-to-event variables a traditional log-rank test does not take the crossover model into account and so was not appropriate. A Cox regression model stratified by patients with treatment and period effects was applied instead.
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RESULTS |
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). Ninety-six patients completed all four cycles, defined as the 12-hour study period after initial dose on day 1, and were included in the efficacy analysis (Figure 1
). Twenty-six patients entered the multiple-dose phase at some point during the four cycles: nine entered the multiple-dose phase during their placebo cycle, five in the valdecoxib 20-mg cycle, seven in the valdecoxib 40-mg cycle, and five in the naproxen sodium cycle. One patient each in the placebo group and valdecoxib 40-mg group took a third dose of study medication. Furthermore, statistical analysis failed to identify any evidence for carryover effect. There was no difference in the percentage of patients reporting severe menstrual pain at baseline in the four treatment groups (range 19–24%; P = .85).
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Twice-daily, as-needed doses of valdecoxib 20 mg (P < .01) and valdecoxib 40 mg (P < .001) produced mean time-weighted sum of pain relief scores that were significantly greater than for placebo in the first 8 (time-weighted sum of pain relief-8) and 12 hours (time-weighted sum of pain relief-12) (Table 2). Both doses of valdecoxib were comparable to twice-daily naproxen sodium 550 mg, with respect to time-weighted sum of pain relief at 8 and 12 hours after study drug administration (Table 2).
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). Time-weighted sum of pain intensity difference scores at 8 and 12 hours for valdecoxib 20 mg were also significantly greater than placebo (P < .01) and similar to naproxen sodium. The time-weighted sum of pain intensity difference-12 score for valdecoxib 40 mg was significantly greater than for the 20-mg dose (P < .05).
Both doses of valdecoxib achieved a rapid onset of pain relief, as demonstrated by the time-specific pain relief and pain intensity difference curves (Figure 2). The mean pain intensity difference and pain relief scores for twice-daily, as-needed valdecoxib 40 mg were statistically superior to placebo from 30 minutes after study drug administration (P < .05). In contrast, twice-daily, as-needed doses of valdecoxib 20 mg and naproxen sodium 550 mg demonstrated a similar but slightly slower onset of action than valdecoxib 40 mg, with significant pain relief and improved pain intensity scores occurring 1.5 hours after study drug administration (P < .05). Although there was a lag period in onset of pain intensity difference and time-specific pain relief between valdecoxib 40 mg and the valdecoxib 20 mg or naproxen sodium treatment arms, it should be noted that there was no significant difference between active treatments.
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). Time to rescue medication for the valdecoxib 40 mg treatment group was comparable with that of naproxen sodium and significantly longer than for valdecoxib 20 mg. Time to rescue medication for the valdecoxib 20 mg group was not significantly different from placebo. Additionally, the percentage of patients requiring rescue medication was statistically lower in all treatment groups versus placebo: valdecoxib 40 mg (17%), valdecoxib 20 mg (27%); naproxen sodium (21%), placebo (38%).
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. The incidence of adverse events reported by valdecoxib treatment groups was similar to that of placebo and naproxen sodium. The most common adverse effect was headache.
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DISCUSSION |
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The discovery that prostaglandin levels are elevated in the endometrium and in menstrual blood of women with primary dysmenorrhea, suggests a role for COX inhibitors such as conventional NSAIDs in treating menstrual pain.1,23 Naproxen sodium, ibuprofen, and diclofenac have all been used routinely to relieve pain associated with primary dysmenorrhea.24–26 Data from this study confirmed a previous report, demonstrating COX-2-specific inhibitors to be as effective as the conventional NSAID naproxen sodium in treating primary dysmenorrhea.6 These data suggest that COX-2 plays a critical role in the development of menstrual pain, and that a correlation can be made between inhibition of prostaglandin production and pain relief.
Several studies have demonstrated the efficacy of parecoxib sodium, the injectable prodrug of valdecoxib, in treating moderate to severe postoperative pain in various surgical pain models, including abdominal hysterectomy surgery as well as oral, orthopedic, and general surgery models.27–29 Pain associated with primary dysmenorrhea is more moderate than in most surgical models, but despite this the medical, social, and economic consequences are far reaching and distressing to patients. The efficacy of valdecoxib demonstrated in this study suggests that it will be a useful therapeutic agent for the treatment of acute pain, including menstrual pain associated with primary dysmenorrhea.
Valdecoxib was not only efficacious in relieving menstrual pain but had a rapid onset and a long duration of action. Onset of analgesia in response to active treatments was rapid in patients treated with either valdecoxib 20 mg or naproxen sodium 550 mg; significant analgesia was experienced within 1.5 hours of receiving the initial dose. Patients in the valdecoxib 40 mg group experienced a faster onset of action with significant analgesia occurring 30 minutes after the initial dose (ie, at the earliest measured time point). Although valdecoxib 40 mg achieved a more rapid onset than valdecoxib 20 mg or naproxen sodium, this difference was not significant.
As expected, fewer patients in the valdecoxib and naproxen sodium groups required rescue medication compared with placebo, and the rate at which placebo patients required rescue medication or early re-medication was significantly faster than for active treatments. As menstrual pain associated with primary dysmenorrhea is generally acute and transient, the long duration of action of valdecoxib should be more than sufficient for managing menstrual pain in most women. The clinical importance of improved pain relief, rapid onset, and sustained duration of action of valdecoxib is supported by the levels of patient satisfaction. Specifically, significantly more patients receiving valdecoxib (20 mg or 40 mg) rated their study medication as good or excellent compared with placebo.
Valdecoxib 20 mg and 40 mg were similar to naproxen sodium for all efficacy measures assessed. Both valdecoxib 20 mg and 40 mg provided good efficacy in treating menstrual pain; however, some women achieved better pain relief with 40 mg. Although there were no differences between valdecoxib 40 mg and naproxen sodium in magnitude of pain relief, duration of action, or overall patient satisfaction, the quicker onset of pain relief of valdecoxib 40 mg compared with naproxen sodium suggests a possible clinical advantage for valdecoxib. Moreover, conventional NSAIDs such as naproxen sodium, are associated with potentially significant clinical adverse effects, especially related to low gastrointestinal tolerability and platelet aggregation, even with short-term use.7,8 At supratherapeutic doses of 80 mg daily, valdecoxib is not associated with these adverse consequences due to COX-1 sparing properties.20,21 Thus, valdecoxib represents a therapeutic alternative to conventional NSAIDs in treating menstrual pain associated with primary dysmenorrhea.
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Footnotes |
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Received July 12, 2001. Received in revised form December 10, 2001. Accepted January 17, 2002.
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REFERENCES |
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2. DeWitt DL, Smith WL. Primary structure of prostaglandin G/H synthase from sheep vesicular gland determined from the complementary DNA sequence. Proc Natl Acad Sci U S A 1988;85:1412–6.
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20. Goldstein JL. Significant upper gastrointestinal events associated with conventional NSAID versus celecoxib. J Rheumatol Suppl 2000;60:25–8.[Medline]
21. Leese P, Talwalker S, Recker D, et al. Valdecoxib, a novel COX-2 specific inhibitor, does not impair platelet function in healthy adults: Results of a randomized controlled trial. Am J Em Med 2001;[In press].
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