Ouch! Best approaches to menstrual pain

 

Dysmenorrhea is painfully prevalent among modern women who are limiting numbers of pregnancies and the time they spend breastfeeding. In a study of college students, 84% of those surveyed reported having experienced dysmenorrhea; only 9% missed exams due to dysmenorrhea, but 48.7% reported poor satisfaction with their academic performance because of menstrual pain.[1] Younger patients lose days at school, and older patients are hampered at home and in the workplace.  We all know that dysmenorrhea has physiologic causes, but not everyone else is aware that the causes are not psychological. Greater awareness of the fact brings earlier recognition and treatment, as well as more support, or at least understanding of those close to the sufferer. Even though dysmenorrhea is an ancient Greek word, dysmenorrhea has only recently been recognized as a medical problem. Before the 1970s, there were virtually no scientific articles studying any aspect of the condition, say Anita Nelson and Lee Shulman in the latest edition of Contraceptive Technology.[2] The latest Canadian Society of Obstetrics and Gynecology guidelines report that both primary and secondary dysmenorrhea are likely to respond to the same medical therapies, so initiation of therapy should not depend on establishing a precise diagnosis.[3] However, the choice of therapy should reflect the desire for fertility. Ovulation suppression or, better yet, menstrual suppression is usually effective.[4]

Primary Dysmenorrea

Measurements with intrauterine pressure catheters demonstrate that women with primary dysmenorrhea generate intrauterine pressures with menstrual contractions similar to intrauterine pressures seen during the second stage of labor.

Progesterone stimulates the production of prostaglandins, which are released as the functional layer is sloughed. Persons with primary dysmenorrhea produce excessive amounts of prostaglandin F2.[5] Prostaglandin F2α increases the force of uterine contractions. These strong uterine contractions reduce uterine blood flow to the myometrium, causing ischemia. This ischemia directly causes pain and sensitizes afferent nerve fibers in the uterus to other painful stimuli, which augments the patient’s perception of pain. When uterine contractions inject these same prostaglandins into the general circulation, they can cause headache, nausea, vomiting, and diarrhea. Other etiologies of early onset dysmenorrhea, such as structural abnormalities of the uterus (blind horns), cervix (stenotic os), or vagina (transverse septa), can usually be ruled out by a careful pelvic examination and radiographic studies.

Regular exercise is likely to improve dysmenorrhea symptoms and should be recommended.[6] Prostaglandin synthetase inhibitors such as NSAIDs are first-line medical therapy for most women; approximately 80% of women with dysmenorrhea feel relief from cramping pain, backache, headaches, and blood loss with these agents. All currently available NSAIDs are of comparable efficacy and safety.² In contrast, aspirin is no more effective than placebo for dysmenorrhea and can increase menstrual blood loss. While COX-2 inhibitors also significantly reduce dysmenorrhea, they have been linked to cardiovascular risk and are more expensive, so they are generally not prescribed for this indication.

Suppression of ovulation is associated with decreased menstrual pain.² Hormonal contraceptives have been used extensively off-label to reduce menstrual cramping and have been shown to be effective in a placebo-controlled, double-blind clinical trial.[7] A review of studies using lower dose formulations (especially when they were used for extended periods of time) concluded that COCs were the preferred therapy for dysmenorrhea for women who wish to use contraception, because the additional benefit of such relief was not linked to any other risks and eliminated the risks of NSAID use.³

Amenorrhea induced by any medication is beneficial for treatment of primary dysmenorrhea.² Women can achieve profound relief from dysmenorrhea by using extended cycles of COCs or contraceptive vaginal rings.[8] DMPA is also helpful in treating dysmenorrhea.[9] After their third injections, nearly half of DMPA users become amenorrheic and avoid dysmenorrhea entirely. The high-dose LNG IUS is also an excellent choice for patients with dysmenorrhea, because menstrual blood loss and duration of bleeding are significantly reduced over time. By 12 months of use, 20% of users have amenorrhea. The contraceptive implant has been found to reduce dysmenorrhea symptoms in over 80% of users.[10] Other therapies that have been studied as treatments for dysmenorrhea include vasopressin antagonists,[11] progesterone receptor modulators,[12] and dienogest.[13]

Alternative complementary therapies include dietary supplements, acupuncture, and high-frequency transcutaneous electrical nerve stimulation. A recent systematic review studied the effectiveness of a full range of dietary supplements in treating dysmenorrhea, including herbs or other botanicals, vitamins, minerals, enzymes, and amino acids; traditional Chinese medications were excluded. The bottom line was that there is no high-quality evidence to support the effectiveness or safety of any dietary supplement for dysmenorrhea.[14]

Trials with acupuncture compared to sham (placebo) procedures have not consistently demonstrated effectiveness.[15] However, many case reports and some placebo-controlled studies have shown that acupuncture reduced pain and related menstrual symptoms. A four-arm dose-finding study without a placebo arm showed that every acupuncture method studied at every intensity reduced menstrual pain intensity and duration.[16] A smart phone app-based self-acupressure therapy was recently found to reduce mean pain intensity more than did the usual cure in a randomized but not blinded study.[17]

Surgical approaches provide relief for patients who do not respond to medical therapies. Endometrial ablation can reduce dysmenorrhea when it occurs in conjunction with heavy or prolonged menstrual bleeding. Some evidence exists to support the effectiveness of laparoscopic nerve ablation in selected cases. Hysterectomy is the definitive, effective treatment for primary dysmenorrhea when other measures fail.

Secondary Dysmenorrhea

Patients with secondary dysmenorrhea also complain of painful uterine cramping with menses but may have other accompanying complaints, such as dyspareunia or non-menstrual pelvic pain. By definition, the pain that patients experience with secondary dysmenorrhea is due to uterine or other pathology.  The most common causes of secondary dysmenorrhea are adenomyosis, endometriosis, pelvic adhesions, and neoplasia. Adenomyosis is the presence of endometrial glands and stroma deep in the myometrium. With endometriosis, the endometrial glands and stoma implant outside the uterus on the serosa of the uterus, the fallopian tubes, the ovaries, the intestines, and other peritoneal surfaces. The endometrial cells within the endometriotic implants proliferate early in the cycle and are sloughed at the end of the cycle into the surrounding tissue; this induces intense, usually painful, local inflammation. Long-term, extensive adhesive disease, nodules, or ovarian endometriomas may develop.

Progestin-only pills that suppress ovulation (desogestrel) have been found to be better than cyclic combined estrogen-progestin contraceptive pills.[18] In particular, Depo-subQ provera 104 is an FDA-approved therapy for the treatment of dysmenorrhea associated with endometriosis. The magnitude of pain reduction seen in the clinical trials with Depo-subQ provera 104 matched the pain score reductions seen with gonadotropin releasing hormone (GnRH) agonists with fewer adverse hypoestrogenic impacts.⁷ In clinical trials, the high-dose LNG IUD has been effective in the treatment of dysmenorrhea caused by endometriosis, and also has shrunk the size of endometriotic implants, particularly those that are located near the uterus. In a comparative trial of extended cycle use of the vaginal contraceptive ring vs. oral contraceptives, mean pain score reductions were greater among ring users.⁶ The contraceptive implant is as effective as DMPA in treating dysmenorrhea associated with endometriosis.[19]

Other medications are available to treat dysmenorrhea by inducing amenorrhea, but their use is limited by side effects and cost. GnRH agonists induce amenorrhea and, thereby, eliminate dysmenorrhea. However, GnRH use is limited to 4 to 6 months because it causes hypoestrogenic side effects such as vasomotor symptoms (hot flashes), vaginal dryness, and loss of bone mineralization. GnRH agonists have been combined with either progestin-only or combined estrogen/progestin add-back therapy for long-term treatment of endometriosis.[20] Danazol, an androgen that was used more frequently in the past to treat endometriosis, effectively induces amenorrhea but can be used for only 4 to 6 months due to androgenic side effects, such as acne, hirsutism, oily skin, clitoral enlargement, and voice deepening. Other therapies on the horizon, especially for endometriosis-related dysmenorrhea include selective progesterone (or estrogen) receptor modulators, aromatase inhibitors, immunomodulators and antiangiogenic agents.[21]

If medical therapies are not effective, or if the patient wants to become pregnant, more definitive surgical approaches may be needed. For example, secondary dysmenorrhea caused by pelvic scarring may benefit from surgical lysis of adhesions, although recurrence of such adhesions is very common. Hysterectomy is reserved for treatment of incapacitating dysmenorrhea unresponsive to more conservative measures and is appropriate only for patients who do not desire future childbearing.

[1] Kamel DM, Tantawy SA, Abdelsamea GA. Experience of dysmenorrhea among a group of physical therapy students from Cairo University: an exploratory study. J Pain Res 2017;10:1079–1085.

[2] Nelson A, Shulman L. Menstrual Cycle: Normal Patterns, Menstrual Disorders, and Menstrually-Related Problems. In: Hatcher RA, Nelson AL, Trussell J, Cwiak C, Cason P, Policar MS, Edelman A, Aiken ARA, Marrazzo J, Kowal D, eds. Contraceptive technology. 21st ed. New York, NY: Ayer Company Publishers, Inc., 2018.

Policar MS, Edelman A, Aiken ARA, Marrazzo J, Kowal D, eds. Contraceptive

[3] Burnett M, Lemyre M. No. 345-Primary dysmenorrhea consensus guideline. J Obstet Gynaecol Can 2017;39:585–595.

[4] Coffee AL, Sulak PJ, Kuehl TJ. Long-term assessment of symptomatology and satisfaction of an extended oral contraceptive regimen. Contraception 2007;75:444–9.

[5] Sultan C, Gaspari L, Paris F. Adolescent dysmenorrhea. Endocr Dev 2012;22:171–80.

[6] Geneen LJ, Moore RA, Clarke C, Martin D, Colvin LA, Smith BH. Physical activity and exercise for chronic pain in adults: an overview of Cochrane Reviews. Cochrane Database Syst Rev 2017;4:CD011279.pub3.

[7] Harada T, Momoeda M. Evaluation of an ultra-low-dose oral contraceptive for dysmenorrhea: a placebo-controlled, double-blind, randomized trial. Fertil Steril 2016;106:1807–1814.

[8] Priya K, Rajaram S, Goel N. Comparison of combined hormonal vaginal ring and low dose combined oral hormonal pill for the treatment of idiopathic chronic pelvic pain: a randomised trial. Eur J Obstet Gynecol Reprod Biol 2016;207:141–146.

[9] Schlaff WD, Carson SA, Luciano A, Ross D, Bergqvist A. Subcutaneous injection of depot medroxyprogesterone acetate compared with leuprolide acetate in the treatment of endometriosis-associated pain. Fertil Steril 2006;85:314–25.

[10] Funk S, Miller MM, Mishell DR Jr, et al. Safety and efficacy of Implanon, a single-rod implantable contraceptive containing etonogestrel. Contraception 2005;71:319–26.

[11] Johnson PS, Ryckmans T, Bryans J, et al. Discovery of PF-184563, a potent and selective V1a antagonist for the treatment of dysmenorrhoea. The influence of compound flexibility on microsomal stability. Bioorg Med Chem Lett 2011;21:5684–7.

[12] Fu J, Song H, Zhou M, et al. Progesterone receptor modulators for endometriosis. Cochrane Database Syst Rev 2017;7:CD009881.pub2.

[13] Osuga Y, Watanabe M, Hagino A. Long-term use of dienogest in the treatment of painful symptoms in adenomyosis. J Obstet Gynaecol Res 2017;43:1441–48.

[14] Pattanittum P, Kunyanone N, Brown J, et al. Dietary supplements for dysmenorrhoea. Cochrane Database Syst Rev 2016;3:CD002124.pub2.

[15] Smith CA, Armour M, Zhu X, Li X, Lu ZY, Song J. Acupuncture for dysmenorrhoea. Cochrane Database Syst Rev 2016;4:CD007854.pub3.

[16] Armour M, Dahlen HG, Zhu X, Farquhar C, Smith CA. The role of treatment timing and mode of stimulation in the treatment of primary dysmenorrhea with acupuncture: An exploratory randomised controlled trial. PLoS One 2017;12:e0180177.

[17] Blödt S, Pach D, Eisenhart-Rothe SV, et al. Effectiveness of app-based self-acupressure for women with menstrual pain compared to usual care: A randomized pragmatic trial. Am J Obstet Gynecol 2017:Epub ahead of print.

[18] Casper RF. Progestin-only pills may be a better first-line treatment for endometriosis than combined estrogen-progestin contraceptive pills. Fertil Steril 2017;107:533–536.

[19] Walch K, Unfried G, Huber J, et al. Implanon versus medroxyprogesterone acetate: effects on pain scores in patients with symptomatic endometriosis—a pilot study. Contraception 2009;79:29–34.

[20] Soliman AM, Bonafede M, Farr AM, Castelli-Haley J, Winkel C. Analysis of adherence, persistence, and surgery among endometriosis patients treated with leuprolide acetate plus norethindrone acetate add-back therapy. J Manag Care Spec Pharm 2016;22:573–87.

[21] Bedaiwy MA, Alfaraj S, Yong P, Casper R. New developments in the medical treatment of endometriosis. Fertil Steril 2017;107:555–565.