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.
A third selective COX-2 inhibitor, meloxicam, was introduced into the US market solely for the treatment of osteoarthritis. This drug is marketed on the basis of its more favorable side-effect profile rather than its selectivity in blocking the COX-2 isoform.
Carboxylic acids. The first of the carboxylic acid subgroups are the salicylic acids. The use of salicylates derived from the bark or leaves of the Salic alba or S. fragilis dates back to Biblical times. Salicylates were formally introduced into medical use in 1763 by the Reverend Edmund Stone.23
The relatively low potency of aspirin for reducing prostaglandin synthesis in the uterus limits its clinical utility in preventing moderate or severe dysmenorrhea. In contrast, diflunisal has a long half-life, making twice-daily dosing possible. However, its slow onset of action limits use for most patients with menstrual pain.
The indoleacetic acid subgroup offers increased potency against dysmenorrhea. Most of these drugs have a direct effect rather than requiring metabolism into an active form.
Indomethacin was one of the first NSAIDs widely used to treat dysmenorrhea, but a moderate incidence of side effects limits its use—and that of most of the other drugs in this family.
No NSAID completely eliminates gastric cyclooxygenase activity.
The most commonly used drugs for dysmenorrhea come from the 2 remaining carboxylate groups: arylalkanoic acids (propionic acid derivatives) and anthranilic acids (fenamates). Of the propionic acid derivatives currently available, ibuprofen and naproxen are commonly used for dysmenorrhea. Other drugs of this class have been used for pain relief or arthritis therapy, but are not currently FDA-approved for dysmenorrhea. The subset of drugs that are phenylpropionic acid derivatives are associated with a higher incidence of GI side effects and skin reactions.
Mefenamic acid was the first alternative synthesized in an effort to reduce the gastric irritation caused by acetylsalicylic acid.24 Mefenamic acid and meclofenamate sodium—both fenamates—are potent prostaglandin synthetase inhibitors. In addition, they have been shown to antagonize already formed prostaglandins, providing a dual mode of action.25-28 This ability to block the action of existing prostaglandins produces a more rapid onset of uterine relaxation. Some of the first studies of NSAIDs in dysmenorrhea used these agents.29,30 In fact, they are some of the most thoroughly investigated drugs for the treatment of dysmenorrhea, shown to be consistently effective in reducing its subjective discomfort.31-35