Clinical Review

NSAIDs: Is newer better for dysmenorrhea?

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In recent years, the range of nonsteroidal anti-inflammatory drugs has broadened considerably. But when it comes to menstrual pain, the most reliable agents are not necessarily the newest.



Key points
  • Nonsteroidal anti-inflammatory drugs (NSAIDs) can prevent dysmenorrhea, unlike other agents that simply relieve symptoms.
  • Although NSAIDs in one form or another have been used for centuries, agents introduced in the past 50 years have significantly improved efficacy and safety profiles.
  • A greater understanding of the role of prostaglandins in physiologic and pathophysiologic processes can enhance the selection of appropriate therapeutic agents.
  • Some drugs can selectively block the cyclooxygenase-2 (COX-2) isoform of the enzyme instrumental in the production of prostaglandins.

A major shift in the way menstrual pain is viewed and treated took place in the 1970s and ’80s, with a greater understanding of the role of prostaglandins and more effective nonsteroidal anti-inflammatory drugs (NSAIDs). Subjective studies of pain and objective studies of uterine activity established a firm connection between the two. These studies also amply demonstrated the ability of NSAIDs to alter the physiology of dysmenorrhea, making it possible to prevent—rather than simply relieve—pain.

Yet, these agents still are not universally used in the treatment of dysmenorrhea, despite more than 20 years of experience with them. Moreover, the introduction of new NSAIDs has clouded rather than clarified the issue of their relative efficacy. Drugs that are welldesigned for the suppression of chronic inflammation (e.g., arthritis therapies) are not very effective for dysmenorrhea, and vice versa. Even so, it is possible to apply the findings of published studies and an understanding of the pathophysiology of dysmenorrhea to demystify the range of options.

The therapeutic effects of NSAIDs come from their ability to inhibit the production of prostaglandin.

A brief history

The term “dysmenorrhea” is derived from a Greek root meaning “difficult monthly flow,” but it did not make its appearance in the English language until about 1810. Therapies for dysmenorrhea ranged from the plausible and somewhat effective to the outlandish and useless. Everything from cauterizing the middle turbinate of the nose,1 exercise programs,2 and presacral sympathectomy3,4 to uterine-relaxing factor,5 vasodilators,6,7 tranquilizers,8 and hormones9-11 have been tried. Today’s effective therapies against primary dysmenorrhea are an outgrowth of earlier observations of uterine activity and the presence of a menstrual “toxin.” That toxin was later identified as prostaglandin.

Endometrial prostaglandin production is tied to changes throughout the menstrual cycle. Prostaglandin is stored in the endometrium as it thickens in preparation for implantation or menstruation. With the onset of menstruation, preformed prostaglandins are liberated and large amounts of arachidonic acid are released from the cell walls of sloughed endometrial cells. This large increase in arachidonic acid substrate results in a tremendous rise in prostaglandin production, which augments the supplies of preformed prostaglandins liberated from the sloughed endometrial cells.

The causative role of prostaglandin F in dysmenorrhea was confirmed when researchers triggered dysmenorrhea-like pain and uterine activity after intravenous (IV) injection of prostaglandins.12 (Current evidence indicates that women with primary dysmenorrhea make 2 to 7 times the normal amount of prostaglandin F.) Excess prostaglandins also may be responsible for the smooth-muscle activity noted in the gastrointestinal (GI) tracts of these women. Hypermobility of the gut may be responsible for the frequent coexistence of nausea, vomiting, and diarrhea in these patients. In addition, prostaglandins appear to act as initiators and potentiators of nociceptive pain signals, further contributing to the symptoms of dysmenorrhea.

In 1967, Pickles demonstrated that prostaglandin levels were lower during anovulatory cycles, prompting the use of oral contraceptives (OCs) to suppress ovulation and relieve menstrual pain.13,14 Although this approach is usually successful, not all women want to—or can—use OCs. NSAIDs more directly alter the physiologic sequence leading to discomfort by inhibiting the production and/or action of prostaglandins. Moreover, NSAIDs generally are well-tolerated and need only be taken at the time of menstruation. While OCs act to reduce the substrate available to the reaction, NSAIDs act to block the pathway at 2 later enzymatic steps.

In 1979, Jacobson et al reported successful pain relief in 64% to 100% of patients from 16 studies of NSAIDs in dysmenorrhea.15 Unfortunately, few of those studies were double-blinded, and many failed to report the incidence of side effects. Dingfelder evaluated 23 trials published from 1970 to 1980 and found a 67% to 86% rate of pain relief.16 In a more thorough review, Owen presented data from 51 reports and attempted to analyze the diverse methods, designs, and outcomes.17 She found an 87% rate of “excellent” pain relief for the fenamates versus 56%, 68%, and 56% for ibuprofen, indomethacin, and naproxen, respectively. Unfortunately, she lumped together 2 different drugs (tolfenamic and mefenamic acids) and misinterpreted some primarily methodological reports. More recent attempts to analyze existing studies have failed to further clarify the issue.18,19


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