Primary dysmenorrhea, or cramping pain with the onset of menstruation, can be an incapacitating problem.1
The results of the present study demonstrate that a single 20-mg or 40-mg dose of valdecoxib, a COX-2 specific inhibitor, is effective in relieving moderate or severe menstrual cramping pain from primary dysmenorrhea. Both doses of valdecoxib were effective in treating menstrual pain, as evidenced by significant differences from placebo in the TOTPAR and SPID scores at 8 and 12 hours postdose. The results of this study confirm those of another recent study of valdecoxib 20 mg and 40 mg and naproxen 550 mg (all dosed bid prn) in primary dysmenorrhea.13
In the present study, significant differences in PID and PR scores from 1 hour through 12 hours show the rapid onset and long duration of the analgesic effect of each dose of valdecoxib. The onset, magnitude, and duration of action of valdecoxib and naproxen sodium were similar. In addition, the occurrence of adverse events was low and similar across all treatments. There was a high degree of compliance with the study, as 87 of 92 patients completed the study.
Significantly fewer patients required rescue medication or remedication following active treatment than following placebo, and additional medication was required significantly earlier following placebo than following active treatments. Although the study design allowed patients 2 doses per day, only 15% of patients in the valdecoxib 20 mg and 20% of patients in both the valdecoxib 40 mg group and the naproxen sodium 550 mg group required remedication within the first 12 hours. In addition, patient satisfaction with study medication was significantly higher for both doses of valdecoxib than placebo and was similar to that reported for naproxen sodium.
In this study, the occurrence of adverse events, ranging from 12.9% to 17.6% for active treatments and placebo, was not significantly different between groups. However, use of nonspecific NSAIDs can result in potentially significant side effects—particularly related to GI tolerability, GI ulcers, and reduced platelet aggregation.14
The results of several studies have demonstrated that these complications may arise even with short-term use. One study showed a increase in GI and operative site bleeding in just over 5 or more days of consistent use of nonspecific NSAIDs.15
Another study demonstrated a significant increase in incidence of gastroduodenal ulcers in patients who took naproxen 500 mg bid compared with those who took valdecoxib 40 mg bid or placebo after only 6.5 consecutive days.16
The combined effect on the GI mucosa and platelet function, resulting from COX-1 inhibition by nonspecific NSAIDs, can multiply the overall risk of excessive GI bleeding. Valdecoxib and other COX-2 specific inhibitors have demonstrated improved GI safety profiles compared with nonspecific NSAIDs due to their COX-1-sparing effects.11,17,18
Naproxen was chosen as the comparator in this study for several reasons. A 550-mg dose of naproxen sodium twice daily is indicated for treatment of primary dysmenorrhea, as is valdecoxib 20 mg twice daily (or 40 mg daily), and the duration of effect for naproxen is similar to the duration of effect for valdecoxib.13
These were important considerations for blinding. Naproxen has been shown to be at least as effective as ibuprofen in the treatment of menstrual cramping associated with primary dysmenorrhea. A study comparing naproxen with ibuprofen, acetaminophen, and placebo for treatment of primary dysmenorrhea in a total of 443 female patients revealed that naproxen provided significantly greater PR than ibuprofen at 6 hours postdose.19
More recently, COX-2 specific inhibitors have been demonstrated to be effective treatment for primary dysmenorrhea, suggesting that COX-2-derived prostanoids play a role in the pathophysiology of primary dysmenorrhea.7,13
This study was not designed to examine cost-effectiveness of valdecoxib use for primary dysmenorrhea but rather to strengthen the concept of strong analgesic efficacy via COX-2 inhibition. While no empirical research to this effect has been done, certain subgroups of patients would likely benefit from the use of valdecoxib rather than a nonspecific NSAID to treat primary dysmenorrhea. These subgroups would include patients with known GI risk factors such as active ulcer, patients being treated concomitantly with corticosteroids or coagulants, and those who take nonspecific NSAIDs chronically for other conditions. It has been observed that up to 81% of patients who were hospitalized with serious GI complications such as GI bleeding had no prior GI symptoms or warning signs,20
indicating that there is a level of risk associated with use of nonspecific NSAIDs even in patients who are not suspected to have any preexisting GI risk factors. There is evidence for slightly increased incidence of GI and operative site bleeding with 5 or fewer days of consecutive use of nonspecific NSAIDs.15
In light of this, increased risk of incidence of GI adverse events with even 1 dose of a nonspecific NSAID cannot be ruled out.
Those patients with menorrhagia who require multiple doses of anti-inflammatory medication can also avoid the potential risk of serious GI adverse events with nonspecific NSAIDs by taking a COX-2 specific inhibitor instead. This is particularly relevant to any patient who has a history of GI ulcers. It is estimated that impaired platelet aggregation is an underlying cause of menorrhagia in approximately 20% to 30% of patients.21
COX-2 specific inhibitors, in contrast to nonspecific NSAIDs, have been shown not to interfere with platelet aggregation,12,22
thus offering another potential benefit to menorrhagic patients.
COX-2 specific inhibitors have the ability to cross the blood-brain barrier and inhibit prostanoid production in the central nervous system (CNS).23,24
It has been postulated that general feelings of illness coinciding with the inflammatory response are due not to direct neural transmission of peripheral nerve impulses to the CNS, but to a signal molecule produced at the local site of inflammation, which crosses the blood-brain barrier and induces COX-2 expression in the CNS.25
Nonspecific NSAIDs are known to reduce peripheral inflammation, but it is unclear to what extent they do so in the CNS. If COX-2 specific inhibitors are more effective at reducing prostanoid production in the CNS, they may be more effective at reducing the general effects of inflammatory pain, such as fever, lethargy, and general muscle and joint pain.26
In conclusion, valdecoxib 20 mg and 40 mg doses were superior to placebo and similar to naproxen sodium 550 mg for all efficacy measures. Both doses were well tolerated and provided rapid and effective relief of menstrual pain with no significant differences between the 2 doses. Because menstrual pain tends to be transient, the rapid onset and long duration of action demonstrated in this study with valdecoxib are important characteristics for improving the management of pain associated with primary dysmenorrhea. On the basis of these results, valdecoxib appears to be a viable new therapeutic agent for the treatment of pain associated with primary dysmenorrhea.