NSAIDs: Is newer better for dysmenorrhea?
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.
- 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 F2α 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 F2α.) 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
Prostaglandin synthesis: the basic ingredients
Prostaglandins are made throughout the body and are important autocrine and paracrine regulators of cellular and organ function. As depicted below, the main substrate for their production is arachidonic acid, a major constituent of cell walls. Under some circumstances, phospholipase A2 also can be used as a substrate for prostaglandin production.
Cyclooxygenase, also called prostaglandin H synthase, is the first enzymatic step in the conversion of arachidonic acid into prostaglandins. This enzyme folds the arachidonic acid molecule (cyclization) and oxygenates it to produce prostaglandin H2 (PGH2).
All other members of the prostaglandin family are then formed from PGH2. Arachidonic acid also is the substrate for the production of leukotrienes and 5-hydroxyeicosatetraenoic acid (5-HETE) through the 5-lipooxygenase pathway. Like prostaglandins F2α and E2, the products of the lipooxygenase pathway are potent vasoconstrictors and stimulators of uterine contractions.—Roger P. Smith, MD, and Jeffrey Ellis, MD
The link between uterine activity and menstrual pain
Increased uterine activity was first hypothesized as a cause of dysmenorrhea in 1932. By the late 1930s, objective findings began to support that hypothesis.1 The correlation between uterine activity and menstrual pain was strengthened when Jacobson et al studied simultaneous electrical and mechanical changes within the uterus.2,3 Using an intrauterine air-filled balloon system, Wilson and Kurzrok also noted the relationship between maximal uterine activity and pain.4,5 Despite the strength of these investigations, few changes occurred in the way dysmenorrhea was viewed or treated.
In the late 1940s, Liessé demonstrated that women with dysmenorrhea not only had a greater degree of uterine electrical and mechanical activity, but that this activity correlated with the pain of menstruation.6 Liessé found minimal activity between pains and as many as 30 irregular electrical discharges per second during pain, suggesting a cause (electrical) for dysmenorrhea but offering no clue to the underlying physiologic disturbance that might account for it.
The most detailed and influential studies of dysmenorrhea and uterine activity came in 1947 in a trial conducted by Woodbury.7 His findings of a direct correlation between pressure, pattern of contractions, resting tone, and pain became a standard reference.
After Woodbury, the stage was set for a connection to be made between uterine activity and prostaglandins. That happened in 1965, when Pickles reported elevated levels of prostaglandin F2αin the menstrual fluid of dysmenorrheic women.8
During the past 2 decades, more sophisticated analytic techniques have been applied to intrauterine pressure data, 9,10 and strong correlations between uterine activity and pain have been reported.11,12 The basic assertion that menstrual pain is caused by increased intrauterine pressure, poor relaxation, and more frequent, irregular contractions appears to be valid.—Roger P. Smith, MD, and Jeffrey Ellis, MD
1. Novac E, Reynolds SRM. The cause of primary dysmenorrhea. JAMA. 1932;99:1466.-
2. Jacobson E, Lackner JE, Sinykin MB. Electrical and mechanical activity of the human non-pregnant uterus. Am J Obstet Gynecol. 1939;38:1008.-
3. Jacobson E, Lackner JE, Sinykin MB. Activity of the human non-pregnant uterus. Am J Physiol. 1940;53:407.-
4. Wilson L, Kurzrok R. Studies on the motility of the human uterus in vivo. Endocrinology. 1938;23:79.-
5. Wilson L, Kurzrok R. Uterine contractility in functional dysmenorrhea. Endocrinology. 1940;27:23.-
6. Liessé A. L’Activité électrique de l’uterus dans la dysmenorrhee functionnelle. Gynec et Obstet. 1948;47:850.-
7. Woodbury RA, Torpin R, Child GP, Watson H, Jarboe M. Myometrial physiology and its relation to pelvic pain. JAMA. 1947;134:1081-1085.
8. Pickles VR, Hall WJ, Best FA, Smith GN. Prostaglandins in endometrium and menstrual fluid from normal and dysmenorrheic subjects. J Obstet Gynaecol Br Comm. 1965;72:185.-
9. Smith RP. Intrauterine pressure analysis in nonpregnant dysmenorrheic women. Med Instr. 1984;185:137-139.
10. Smith RP. Distribution analysis of intrauterine pressure in nonpregnant dysmenorrheic women. Am J Obstet Gynecol. 1984;150:271-273.
11. Smith RP. The dynamics of nonsteroidal anti-inflammatory therapy for primary dysmenorrhea. Obstet Gynecol. 1987;70:785-788.
12. Smith RP, Powell JR. Simultaneous objective and subjective evaluation of meclofenamate sodium in the treatment of primary dysmenorrhea. Am J Obstet Gynecol. 1987;157:611-616.
Classes of NSAIDs
Although aspirin was synthesized in 1853 and incorporated into medical practice in 1899, its history goes back even farther. That fact—along with the introduction of newer agents—ensured that NSAIDs became the mainstays of medical therapy for fever, pain, and inflammation. In the United States, NSAIDs are among the most widely prescribed drugs, with more than 70 million prescriptions and more than 30 billion over-the-counter tablets sold each year.20 Most of their therapeutic effects come from their ability to inhibit the production of prostaglandins.21
Interestingly, some drugs with the ability to inhibit prostaglandin synthesis have little clinical usefulness. Some have weak antiprostaglandin activity, require metabolic transformation to become active, or have side effects that limit their usefulness. While these drugs can be used to treat dysmenorrhea, they generally have been replaced by more effective agents.
There are 2 broad classes of NSAIDs: enolic acids and carboxylic acids. Each class can be further subcategorized (Table 1).
Enolic acids. With the exception of the newer cyclooxygenase-2 (COX-2) selective agents, drugs of the enolic-acid type are primarily type II inhibitors of prostaglandin synthesis. That means they impede the isomerase/reductase step in the formation of prostaglandins E2 (PGE2) and F2α (PGF2α). The most frequently used agents in the enolic-acid group are phenylbutazone and piroxicam.
Phenylbutazone was discovered in the 19th century during a search for a substitute for quinine. (Quinine had become popular for the treatment of fever; however, uncontrolled cutting of the Peruvian cinchona tree dramatically increased its cost.) While phenylbutazone is an effective shortterm analgesic for musculoskeletal pain (through antiprostaglandin activity), its relative toxicity has limited its use in dysmenorrhea and general therapy.
Piroxicam has a long half-life (50 hours), making once-daily dosing possible. Its action as an anti-inflammatory drug for the treatment of arthritis is well-established, but its use as an analgesic for acute pain therapy or for dysmenorrhea has not been fully evaluated. Based on the pharmacodynamics of drug absorption and action, one would anticipate its efficacy in that regard to be poor. In general, drugs in the pyrazolone group have a higher incidence of blood dyscrasias, limiting their broad utility.
Celecoxib is structurally similar to phenylbutazone and was the first selective COX-2 inhibitor approved by the Food and Drug Administration (FDA). It has been studied in dental pain models and the treatment of osteoarthritis. In these trials, celecoxib performed as well as naproxen and slow-release diclofenac, but with fewer GI side effects. No data on its use in dysmenorrhea is available.
Chemically related but less similar to the enolic acids is refecoxib. Like celecoxib, it has been studied in the treatment of osteoarthritis, where it was comparable in efficacy to ibuprofen and diclofenac, but with side-effect rates similar to placebo therapy. In studies of women with primary dysmenorrhea, rofecoxib has proved to be statistically superior to placebo but indistinguishable from naproxen (Figure 1).22 Peak blood levels are achieved in 2 to 3 hours (delayed by 1 to 2 hours by a fatty meal), but a steady state is not achieved until day 4 of continuous therapy. When the drug is used to treat women who have a rapid onset of symptoms, the significance of this delay is unclear but is a potential drawback. In addition, the dosage of rofecoxib for the treatment of pain or dysmenorrhea is generally much larger than that required for the treatment of arthritis. Thus, the risk of side effects may be increased.