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Nonsteroidal anti-inflammatory drugs are the most common treatment for menstrual pain, though research continues on alternative treatments.
By Roger P. Smith, MD
Dr. Smith is the Robert A. Munsick Professor of Clinical Obstetrics & Gynecology, Vice Chair for Faculty Development, and Director, Division of General Obstetrics & Gynecology, Department of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis.
For women in their late teens and early 20s, dysmenorrhea represents the single greatest cause of time lost from work or school. The incidence of dysmenorrhea in this group may be as high as 70%, with up to half of women experiencing loss of ability to perform daily activities.1 The true overall incidence of dysmenorrhea is difficult to estimate, but most authors feel that between 50% and 90% of women will suffer disability (ie, interruption of normal activity or function) at least once during their reproductive years.
The magnitude of this problem can be appreciated considering that there are more than 40 million women of reproductive age in the United States.
This article looks at current evidence for established strategies for treating primary and secondary dysmenorrhea, ranging from nonsteroidal anti-inflammatory drugs (NSAIDs) to transcutaneous electrical nerve stimulation (TENS), and also reviews a new medical therapy on the horizon.
Successful treatment of primary dysmenorrhea is predicated on a correct initial diagnosis and understanding of the underlying pathophysiology. When secondary dysmenorrhea is identified, the best therapeutic approach is one directed toward the clinically identified pathology.
Only when the definitive therapy is not practical or available (eg, multiple fibroids in a patient wishing to avoid hysterectomy or impaired fertility) are analgesics or modifications of the menstrual cycle indicated. These latter interventions are often adequate but they are frequently less than completely successful.
Overproduction of (and possibly a heightened sensitivity to) prostaglandin F2a is well established as the underlying cause of painful uterine activity in primary dysmenorrhea. As with secondary dysmenorrhea, the most effective therapy for primary dysmenorrhea is directed toward this biochemical cause. It would seem logical that if prostaglandin synthesis could be reduced, menstrual pain could be lessened. The observation that prostaglandin levels are lower during anovulatory cycles prompted the use of oral contraceptives (OCs) to suppress ovulation and relieve menstrual pain.2,3 While this approach is usually successful, not all women are able or willing to take OCs.
By directly suppressing uterine activity it is possible to interrupt the process by which primary dysmenorrhea occurs. Drugs such as calcium channel antagonists (nifedipine) or spasmolytic agents (isoxuprine, papaverine, ritodrine) may suppress uterine activity in the laboratory, but side effects limit their clinical usefulness.
A more direct method of altering the sequence leading to discomfort comes in the form of NSAIDs. These agents inhibit the production and/or the action of prostaglandins. The body of evidence seems to slightly favor fenamates (mefenamic acid, meclofenamate) over propionic acid agents (ibuprofen, naproxen, ketoprofen), but both groups are sufficiently effective that the differences may be moot.
When NSAID therapy was first being evaluated, Dingfelder evaluated 23 trials published from 1970 to 1980 and found 67% to 86% pain relief with these agents.4 In a more thorough review, Owen presented data from 51 reports and attempted to analyze the diverse methods, designs, and outcomes.5 Patients reported pain relief of 87% for the fenamates versus 56%, 68%, and 56% for ibuprofen, indomethacin, and naproxen, respectively, although the summary contains some minor misinterpretations of at least one primarily methodologic report. Response rates still varied widely from study to study. Differences in study design, dependent variables, inclusion and exclusion criteria, and the very nature of subjective pain studies make decisive data illusive.
Once an agent has been selected it should be tried over 2 to 4 menstrual cycles before its effects can be appraised. If therapy is unsuccessful, some patients may still respond favorably to another NSAID. For the best chance of success, the second drug should be chosen from a different chemical class.
Selective COX-2 inhibitors seem to be safe and effective for short-term use. But concerns exist about their adverse effects. For example, evidence has emerged about the potential for coronary heart disease with prolonged use, which may not be the case with older agents.6,7 Despite a decreased incidence of gastrointestinal (GI) side effects with COX-2 inhibitors, their use by patients with active GI ulcers, infection with Helicobacter pylori, or inflammatory bowel disease has not been adequately studied. Studies have demonstrated that all NSAIDs, including the selective COX-2 inhibitors, do not spare gastric cyclooxygenase activity at therapeutic concentrations.8
As more data emerge about the physiologic roles of COX-1 and –2, there are growing concerns that COX-2 function is not restricted to inflammation and pathology, suggesting the possibility of unanticipated adverse effects of selective inhibition. For example, there is evidence of constitutive expression of COX-2 in the kidney and brain, and essential physiologic roles in ovulation and implantation.9 The higher cost of these agents combined with the lack of clinical efficacy studies on COX-2 inhibitors suggests that they should be used as second-line therapy for dysmenorrhea.
Physicians should be aware of the potential for adverse effects with COX-2 inhibitors, as with any medication. While the adverse effects tend to be infrequent and generally mild and the duration of dysmenorrhea therapy is usually short, the risk of serious problems still exists. Patients with aspirin-sensitive asthma, ulcers, significant renal impairment, or inflammatory bowel disease should not use these drugs.
Women who do not achieve adequate pain relief with NSAIDs and hormonal contraceptives should be reevaluated for secondary dysmenorrhea. This reappraisal should include a repeat, focused pelvic examination and may include discussion of family, school, and other potential sources of stress, which may exacerbate symptoms.
Pelvic imaging, including ultrasonography, is generally not indicated unless the clinical examination is inadequate. The likelihood of occult pelvic pathology is high in women with secondary dysmenorrhea. For example, one study of 100 women with pelvic pain who did not have adequate pain relief with NSAIDs (some were also treated with OCs) found that approximately 80% had documented endometriosis at laparoscopy.10
Given the high likelihood of the presence of pelvic disease, diagnostic laparoscopy is reasonable for women with dysmenorrhea who have not had adequate relief with 2 to 4 cycles of NSAIDs and OCs.11
Intrauterine progestin delivery systems (levonorgestrel intrauterine system [LNG-IUS]) have demonstrated some efficacy in women with dysmenorrhea secondary to either proven or suspected endometriosis.12 A discussion of the treatment of endometriosis is beyond the scope of this review.
Exercise and diet
A systematic review of exercise for relief of dysmenorrhea included a single randomized trial that provided evidence that exercise reduces menstrual symptoms.13,14 Most observational studies have reported decreased prevalence of dysmenorrhea and/or improved symptomatology with exercise.15 However, the quality of this trial and these studies was low.
A variety of dietary and vitamin therapies may reduce the severity of menstrual pain, but data are limited to a few small studies of low-fat vegetarian diets, vitamins E, B1 and B6, fish oil supplements, and Japanese herbal combinations. Three small randomized trials found that magnesium was more effective than placebo for relief of dysmenorrhea and was well tolerated.16 However, the trials’ small sizes, high dropout rates, and varying designs precluded a definite recommendation for use of magnesium or the optimum dose or regimen.
A recent study comparing the effect of mefenamic acid and ginger on pain relief in primary dysmenorrhea found comparable efficacy, but the way the ginger was administered may limit the generalizability of the findings.17 Even self-administered massage has been suggested as an alternative option.18
Although the limited available data appear promising for some of these interventions, they remain unproven. Despite this, there is no reason not to recommend a healthy lifestyle.
The application of heat to treat dysmenorrhea has a venerated history of success, but low levels of use. For centuries, Chinese physicians have treated dysmenorrhea with moxibustion, which involves placing burning moxa or mugwort-Artemisia vulgaris, a species of chrysanthemum used as incense-on acupuncture points on the lower abdomen. Three-thousand-year-old hieroglyphs of acupuncture and moxibustion have been found on bones and tortoise shells from China’s Shang dynasty, indicating that the practice predates that time. Soranus of Ephesus in the second century of the modern era advised local application of heat using an animal bladder filled with hot oil and held over the lower abdomen.19
Despite this, historically heat therapy has not been evaluated rigorously or systematically in the scientific literature, and there are only a few case reports.20,21 Even when heat therapy has been endorsed, the practicalities of rapidly cooling hot-water bottles and the inconvenience of heating pads have limited the utility of this option.
The development of small wearable devices capable of supplying a low level of topical heat at a constant temperature over a prolonged period now makes this modality portable enough to be a viable treatment option. A study by Akin and associates showed that continuous, low-level, topical heat was similar or superior to oral ibuprofen therapy for menstrual pain.22 The topical heat treatment used in this study appeared to have an additive effect with ibuprofen, as the time to onset of pain relief was significantly shorter with combination heat/ibuprofen therapy compared with ibuprofen treatment alone.
In addition, the pain relief in the heat/ibuprofen group on the first day of treatment was directionally higher than that in the unheated/ibuprofen group. Thus, low-level topical heat therapy can provide relief for dysmenorrhea that is comparable or superior to therapy with NSAIDs.
Unlike NSAIDs, which are more effective for primary versus secondary dysmenorrhea and which may cause GI upset, heat therapy should be equally effective in cases of secondary dysmenorrhea without any side effects. Topical heat therapy can be used safely by patients with known or suspected GI disorders, which is not the case with NSAIDs. The heat may help with some GI symptoms as well, although trials of heat therapy in patients with GI diseases such as irritable bowel syndrome are lacking.
Transcutaneous electrical nerve stimulation
TENS is thought to have two effects: 1) It raises the threshold for pain signals from uterine hypoxia and hypercontractility by sending a volley of afferent impulses through the large-diameter sensory fibers of the same nerve root, resulting in lower perception of painful uterine signals; and 2) It stimulates release of endorphins from the peripheral nerves and the spinal cord.23 Intrauterine pressure studies indicate that TENS therapy had no significant effect on uterine contractile activity.24
A meta-analysis from the Cochrane database including three trials (N = 124 women) found that high-frequency TENS was more effective than placebo TENS for relief of dysmenorrhea.25 This modality appears to be a useful alternative in women who cannot or will not take oral analgesics. The degree of pain relief obtained with TENS therapy alone is lower than that with drugs; however, some women may be able to lower their analgesic dose with combined therapy.
Long-cycle hormonal therapies
Combination hormonal contraceptives are reasonable primary or secondary therapies for women who are not trying to conceive. Estrogen-progestin hormonal contraceptives can be administered in monthly cycles, extended cycles, or continuously.
Depot medroxyprogesterone acetate and the LNG-IUS represent alternatives to combination hormonal contraceptives. The major disadvantage to use of long- or extended-cycle therapy is that many women develop breakthrough spotting/bleeding, many days per week. This bleeding, which decreases as women continue use of extended OCs, is the main reason women using OCs in a long-cycle format discontinue the medication.
Accordingly, counseling women regarding this common side effect will likely improve patient satisfaction and continuation of this approach.
Surgical interruption of pelvic nerve pathways
A systematic review of two trials (N = 68 patients) found some evidence of the effectiveness of laparoscopic uterine nerve ablation (LUNA) at 12 months when compared to untreated controls (OR 6.12, 95% CI 1.78-21.03) for dysmenorrhea.26 Short-term effects at 6 months and quality-of-life assessments at 12 months were similar for both groups. The wide confidence intervals and lack of long-term improvement in quality of life indicate that the efficacy of this surgical approach is uncertain.
When LUNA was compared to laparoscopic presacral neurectomy (LPSN), patients undergoing LPSN were significantly more likely to have pain relief at 12 months. LUNA combined with presacral neurectomy is not more effective than LUNA alone.27 For both LUNA and LPSN, observational series have shown that success rates declined rapidly over time (years), possibly due to regrowth of nerves or to pain signals being transferred via alternative routes.28,29
More evidence is needed before these procedures can be recommended.
The principle of NSAID therapy for dysmenorrhea has been to inhibit the production of prostaglandins by interfering with the enzymatic production process.
The recent availability of an agent that can modify the prostaglandin receptor itself has opened the possibility of targeted intervention at the receptor level. A recent trial of such an agent showed significant effect on uterine activity in a small group of women with primary dysmenorrhea.30 Further research is needed to define the role of such agents in clinical practice.
1. Andersch B, Milson I: An epidemiologic study of young women with dysmenorrhea. Amer J Obstet Gynecol. 1982;144:655.
2. Filler W: The treatment of dysmenorrhea. With special reference to the primary type. M Clin North America. 1951;35:861.
3. Menaker JS, Powers KD: Management of primary dysmenorrhea. Obstet Gynecol. 1962;20:66.
4. Dingfelder JR: Primary dysmenorrhea treatment with prostaglandin inhibitors: A review. Amer J Obstet Gynecol. 1981;140:874.
5. Owen PR: Prostaglandin synthetase inhibitors in the treatment of primary dysmenorrhea. Amer J Obstet Gynecol. 1984;148:96.
6. Garcia Rodriguez LA, Varas-Lorenzo C, Maguire A, Gonzalez-Perez A. Nonsteroidal antiinflammatory drugs and the risk of myocardial infarction in the general population. Circulation. 2004 Jun 22;109(24):3000-6. Epub 2004 Jun 14.
7. Chan AT, Manson JE, Albert CM. et al. Nonsteroidal antiinflammatory drugs, acetaminophen, and the risk of cardiovascular events. Circulation. 2006 Mar 28;113(12):1578-1587.
8. 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.
9. Lipsky PE, Brooks P, Crofford LJ. et al. Unresolved issues in the role of cyclooxygenase-2 in normal physiologic processes and disease. Arch Intern Med. 2000;16;0:913-920.
10. Ling FW, for the Pelvic Pain Study Group. Randomized controlled trial of depot leuprolide in patients with chronic pelvic pain and clinically suspected endometriosis. Obstet Gynecol. 1999;93:51.
11. ACOG Practice Bulletin Number 11. Medical Management of Endometriosis. December 1999.
12. Brown J, Farquhar C. An overview of treatments for endometriosis. JAMA. 2015;313:296.
13. Israel RG, Sutton M, O'Brien KF. Effects of aerobic training on primary dysmenorrhea symptomatology in college females. J Am Coll Health. 1985; 33:241.
14. Brown J, Brown S. Exercise for dysmenorrhoea. Cochrane Database Syst Rev. 2010:CD004142.
15. Golomb LM, Solidum AA, Warren MP. Primary dysmenorrhea and physical activity. Med Sci Sports Exerc. 1998;30:906.
16. Proctor, ML, Murphy, PA. Herbal and dietary therapies for primary and secondary dysmenorrhoea. Cochrane Database Syst Rev. 2001:CD002124.
17. Shirvani MA, Motahari-Tabari N, Alipour A. The effect of mefenamic acid and ginger on pain relief in primary dysmenorrhea: a randomized clinical trial. Arch Gynecol Obstet. 2014 Nov 16. [Epub ahead of print]
18. Sadeghi Aval Shahr H, Saadat M, Kheirkhah M, Saadat E. The effect of self-aromatherapy massage of the abdomen on the primary dysmenorrhoea. J Obstet Gynaecol. 2014;25:1.
19. O’Dowd MJ, Philipp EE. The History of Obstetrics and Gynaecology. New York: The Parthenon Publishing Group, 1994.
20. Lehman JF, de Lateur BJ. Ultrasound, shortwave, microwave, laser superficial heat, and cold in the treatment of pain. In: Wall PD, Melzack R, eds. Textbook of Pain, ed 3. Edinburgh: Churchill-Livingstone; 1994;1239.
21. Vance AR, Hayes SH, Spielholz NI. Microwave diathermy treatment for primary dysmenorrhea. Phys Ther. 1996;76:1003.
22. Akin MD, Weingand KW, Hengehold DA, et al. Use of continuous low-level topical heat in the treatment of dysmenorrhea. Obstet Gynecol. 2001;97:343.
23. Dawood, MY. Primary dysmenorrhea: advances in pathogenesis and management. Obstet Gynecol. 2006;108:428.
24. Smith RP, Heltzel J. Interrelation of analgesia and uterine activity in women with primary dysmenorrhea. A preliminary report. J Reprod Med. 1991;36:260-264.
25. Proctor, ML, Smith, CA, Farquhar, CM, Stones, RW. Transcutaneous electrical nerve stimulation and acupuncture for primary dysmenorrhoea. Cochrane Database Syst Rev. 2002:CD002123.
26. Proctor, ML, Latthe, PM, Farquhar, CM, et al. Surgical interruption of pelvic nerve pathways for primary and secondary dysmenorrhoea. Cochrane Database Syst Rev. 2005:CD001896.
27. Juang, CM, Chou, P, Yen, MS, et al. Laparoscopic uterosacral nerve ablation with and without presacral neurectomy in the treatment of primary dysmenorrhea: a prospective efficacy analysis. J Reprod Med. 2007;52:591.
28. Chen, FP, Chang, SD, Chu, KK, Soong, YK. Comparison of laparoscopic presacral neurectomy and laparoscopic uterine nerve ablation for primary dysmenorrhea. J Reprod Med. 1996;41:463.
29. Papasakelariou, C. Long-term results of laparoscopic uterosacral nerve ablation. Gynaecol Endosc. 1996;5:177.
30. Böttcher B, Laterza RM, Wildt L, et al. A first-in-human study of PDC31 (prostaglandin F2α receptor inhibitor) in primary dysmenorrhea. Hum Reprod. 2014;29(11):2465.