Clinical Review

NSAIDs: Is newer better for dysmenorrhea?

OBG Manag. 2002 July;14(7):71-81

References

1. Mayer E. The intranasal treatment of dysmenorrhea. With a report of ninety-three cases. JAMA. 1914;62:6.-

2. Miller NF, et al. Dysmenorrhea. Am J Obstet Gynecol. 1953;65:505.-

3. Cotte G. La sympathectomie hypogastrique: A-t-elle sa place dans la therapeutique gynecologique? Presse Med. 1925;33:98.-

4. Black WT, Jr. Use of presacral sympathectomy in the treatment of dysmenorrhea: a second look after twenty-five years. Am J Obstet Gynecol. 1964;89:16.-

5. Hayden GE. Relief of primary dysmenorrhea. Obstet Gynecol. 1960;16:730.-

6. Schuck F. Pain and pain relief in essential dysmenorrhea. Am J Obstet Gynecol. 1951;62:559.-

7. Voulgaris DM. Dysmenorrhea. Treatment with isoxsuprine. Obstet Gynecol. 1960;15:220.-

8. Champlin WD, Corbit JP. Chlorpromazine and chlorpromazine combinations in the treatment of dysmenorrhea. Am J Obstet Gynecol. 1957;74:419.-

9. Filler W. The treatment of dysmenorrhea. With special reference to the primary type. Med Clin North Am. 1951;35:861.-

10. Menaker JS, Powers KD. Management of primary dysmenorrhea. Obstet Gynecol. 1962;20:66.-

11. Molla LA, Donald JF. A comparative study of ibuprofen and paracetamol in primary dysmenorrhea. J Int Med Res. 1974;2:395.-

12. Roth-Brandel U, Bygdman M, Wiqvist N. Effect of intravenous administration of prostaglandin E1 and F2 on the contractility of the nonpregnant human uterus in vivo. Acta Obstet Gynecol Scand Suppl. 1970;49(5):19.-

13. Filler W. The treatment of dysmenorrhea. With special reference to the primary type. Med Clin North Am. 1951;35:861.-

14. Menaker JS, Powers KD. Management of primary dysmenorrhea. Obstet Gynecol. 1962;20:66.-

15. Jacobson J, Cavalli-Bjorkman K, Lundstrom V, Nilsson B, Norbeck M. Prostaglandin synthetase inhibitors and dysmenorrhea. Acta Obstet Gynecol Scand. 1979;87(suppl):73.-

16. Dingfelder JR. Primary dysmenorrhea treatment with prostaglandin inhibitors: a review. Am J Obstet Gynecol. 1981;140:874.-

17. Owen PR. Prostaglandin synthetase inhibitors in the treatment of primary dysmenorrhea. Am J Obstet Gynecol. 1984;148:96.-

18. Dawood MY. Nonsteroidal anti-inflammatory drugs and reproduction. Am J Obstet Gynecol. 1993;169:1255-1265.

19. Zhang WY, Po ALW. Efficacy of minor analgesics in primary dysmenorrhoea: a systematic review. Br J Obstet Gynaecol. 1998;105:780-789.

20. Lichtenstein DR, Syngal S, Wolfe MM. Nonsteroidal anti-inflammatory drugs and the gastrointestinal tract: the double-edged sword. Arthritis Rheumk. 1995;38:5-18.

21. Vane JR. Inhibition of prostaglandin synthesis as a mechanism of action for the aspirin-like drugs. Nature. 1971;231:232-235.

22. Morrison BW, Daniels SE, Kotey P, Cantu N, Seidenberg B. Rofecoxib, a specific cyclooxygenase-2 inhibitor, in primary dysmenorrhea: a randomized controlled trial. Obstet Gynecol. 1999;94:504-508.

23. Stone E. An account of the success of the bark of the willow in the cure of agues. Philosophical Transactions of the Royal Society. 1763;53:195-200.

24. Winder CV, Wax J, Scotti L, Scherrer RA, Jones EM, Short FW. Antiinflammatory, antipyretic, and antinociceptive properties of N-(2,3-xylyl) anthranilic acid (mefenamic acid). J Pharm Exp Ther. 1962;138:405-413.

25. Collier HOJ, Sweatmon WJF. Antagonism by fenamates of prostaglandin F 2α and of slow-reacting substance on human bronchial muscle. Nature. 1968;219:864.-

26. Vane JR. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nature New Biol. 1971;231:232.-

27. Tolman EL, Partridge R. Multiple sites of interaction between prostaglandins and nonsteroidal anti-inflammatory drugs. Prostaglandins. 1975;9:349.-

28. Ferreira SH, Vane JR. New aspects of the mode of action of nonsteroidal anti-inflammatory drugs. Ann Rev Pharmacol. 1973;14:57.-

29. Schwartz A, Zor U, Lindner HR, Naor S. Primary dysmenorrhea. Alleviation by an inhibitor of prostaglandin synthesis and action. Obstet Gynecol. 1974;44:709.-

30. Kauppila A, Ylikorkala O. Indomethacin and tolfenamic acid in primary dysmenorrhea. Eur J Obstet Gynecol Reprod Biol. 1977;7:59.-

31. Anderson ABM, Haynes PJ, Fraser IS, Turnbull AC. Trial of prostaglandin-synthetase inhibitors in primary dysmenorrhea. Lancet. 1978;1:345.-

32. Kapadia L, Elder MG. Flufenamic acid in treatment of primary spasmodic dysmenorrhea. Lancet. 1978;1:348.-

33. Budoff PW. Use of mefenamic acid in the treatment of primary dysmenorrhea. JAMA. 1979;241:2713.-

34. Powell JR, Smith RP. Mefenamic acid (Ponstel) for treating primary spasmodic dysmenorrhea. Curr Ther Res. 1981;29:544.-

35. Roy S. A double-blind comparison of a propionic acid derivative (ibuprofen) and a fenamate (mefenamic acid) in the treatment of dysmenorrhea. Obstet Gynecol. 1983;61:628.-

36. 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.-

37. Smith RP. The dynamics of nonsteroidal anti-inflammatory therapy for primary dysmenorrhea. Obstet Gynecol. 1987;70:785.-

38. Boctor AM, Eickholt M, Pugsley TA. Meclofenamate sodium is an inhibitor of both the 5-lipooxygenase and cyclooxygenase pathways of the arachidonic acid cascade in vitro. Prostaglandins, Leukotrienes & Med. 1986;23:229.-

39. Myers RF, Siegel MI. Differential effects of anti-inflammatory drugs on lipooxygenase and cyclooxygenase activities of neutrophils from a reverse passive Arthus reaction. Biochemical Biophysical Res Comm. 1983;112:586.-

40. Feldman M, McMahon AT. Do cyclooxygenase-2 inhibitors provide benefits similar to those of traditional nonsteroidal anti-inflammatory drugs, with less gastrointestinal toxicity? Ann Intern Med. 2000;132:134-143.

41. Bannwarth B. Are COX-2 inhibitors as effective as conventional NSAIDs in acute pain states? [letter] Arch Intern Med. 2001;161:127-128.

42. Lipsky PE, Brooks P, Crofford LJ, DuBois R, Graham D, Simon LS, van de Putte LBA, Abramson SB, et al. Unresolved issues in the role of cyclooxygenase-2 in normal physiologic processes and disease. Arch Intern Med. 2000;160(7):913-920.

43. Cryer B, Feldman M. Cyclooxygenase-1 and cyclooxygenase-2 selectivity of widely used nonsteroidal anti-inflammatory drugs. Am J Med. 1998;104(5):413-421.

44. Fraser IS, Pearse C, Shearman RP, Elliott PM, McIlveen J, Markham R. Efficacy of mefenamic acid in patients with a complaint of menorrhagia. Obstet Gynecol. 1981;58:543-551.

45. Fraser IS, McCarron G, Markham R, Robinson M, Smyth E. Long-term treatment of menorrhagia with mefenamic acid. Obstet Gynecol. 1983;61:109-112.

46. Vargyas JM, Campeau JD, Mishell DR Jr. Treatment of menorrhagia with meclofenamate sodium. Am J Obstet Gynecol. 1987;157:944-950.

47. Van Eijkeren MA, Christiaens GCML, Geuze HJ, Haspels AA, Sixma JJ. Effects of mefenamic acid on menstrual hemostasis in essential menorrhagia. Am J Obstet Gynecol. 1992;166:1419-1428.

48. Al-Waili NS. Treatment of menstrual migraine with prostaglandin synthesis inhibitor mefenamic acid: double-blind study with placebo. Eur J Med Res. 2000;5:176-182.

49. Wood C, Jakubowicz D. The treatment of premenstrual symptoms with mefenamic acid. Br J Obstet Gynaecol. 1980;87:627-630.

50. Jakubowicz DL, Godard E, Dewhurst J. The treatment of premenstrual tension with mefenamic acid: analysis of prostaglandin concentrations. Br J Obstet Gynaecol. 1984;91:78-84.

51. Mira M, McNeil D, Fraser IS, Vizzard J, Abraham S. Mefenamic acid in the treatment of premenstrual syndrome. Obstet Gynecol. 1986;68:395-398.

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 F_2α 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 F_2αin 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

REFERENCES

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.