Primary dysmenorrhea is the most common cause of pelvic pain in women. It is estimated that 50–90% of the female population has this condition, and 10% are severely affected for 1–3 days per month as a consequence.1 This has both psychological and economic effects, because the resulting absenteeism causes severe economic loss each month. In one study, dysmenorrhea accounted for 600 million lost work hours and $2 billion annually in the United States.2
Primary dysmenorrhea is most commonly attributable to excess prostaglandin production at the time of menstruation. Prostaglandin overproduction causes abnormal uterine contractions and increased intrauterine pressure, vasoconstriction of small uterine vessels leading to decreased uterine blood flow, increased sensitivity of pain receptors, and ischemia of the uterine muscle, which consequently contribute to pelvic pain.3,4 During uterine contractions, endometrial blood flow decreases, indicating that ischemia caused by the hypercontractility is the primary cause of the pain.3,5 Preventing menstruation thus may be a viable treatment option.
Oral contraceptives are frequently prescribed for this condition, but they are not always effective.6 We theorized that cyclic oral contraceptive pills (OCPs) that induce withdrawal bleeding occasionally allow the production of prostaglandins and persistent pain. Continuous OCPs have not been studied as a primary treatment of primary dysmenorrhea, although recent studies show their superiority to cyclic regimens in the treatment of endometriosis.7–9 We hypothesized that continuous administration of OCPs will result in more pain relief than cyclic 21 days of active pills and 7 days of placebo pills administered in primary dysmenorrhea patients. We hypothesized secondarily that the differences in uterine artery pulsatility index measured by color Doppler ultrasonography would be significant between treatment groups at the end of the trial period, compared with the beginning of the trial, and that the patient self-evaluation of menstrual symptoms as determined by a standardized questionnaire would be more favorable in the continuous group compared with the cyclic 21-7 regimen group.
MATERIALS AND METHODS
The study was approved by the Institutional Review Board at Penn State Hersey Medical Center and by the Ethics Committee at Nova Gradiska General Hospital, Croatia, where it was conducted. Participants were recruited from the obstetrics and gynecology department at Nova Gradiska General Hospital from December 2007 to May 2010. A number of women who participated in the study were presenting for their annual screening and reporting dysmenorrhea, whereas others were referred to the clinic for evaluation of dymenorrhea. All participants gave written informed consent.
We conducted a double-blind, randomized, controlled trial of two treatment regimens of monophasic OCPs (gestodene 0.075 mg and ethinyl estradiol [E2] 20 micrograms) in 38 primary dysmenorrhea patients with an allocation ratio of 1:1. The randomization list was created by our biostatistician at Penn State (A.R.K.), who sent the list to the certified research pharmacy in Croatia (Magdis, Sveta Nedjelja) and who overencapsulated the OCPs to blind the treatment and then sent them to the research site. To preserve the blinding, we overencapsulated the commercially purchased intact gestodene 0.075-mg and ethinyl E2 20-microgram OCPs and identical-appearing placebo pills. Adherence was assessed with pill counts confirmed at each visit. The research pharmacy also kept the randomization list. Both participants and care providers in the study were blinded to the treatment. The patients were randomized into the study group of continuous OCPs and the control group of cyclic OCPs based on a randomization table with a block size of four, known only by the biostatistician. Patients in the continuous group received 28 active pills (0.075-mg gestodene and 20-microgram ethinyl E2, a monophasic OCP), whereas patients in the cyclic OCP group received 21 active pills and 7 placebo pills. Gestodene-containing oral contraceptives currently are not available in United States; however, they are marketed in Croatia, where the study was conducted (and we chose this because we wanted a low-dose ethinyl E2 pill and this was the only 20-microgram ethinyl E2 available in Croatia).
Participants were in good health, their age was 18–35 years, and they had a history of primary dysmenorrhea (onset less than 3 years after menarche). They had regular (25–31 days) menstrual cycles for the 3-month period preceding enrollment, with symptoms of moderate to severe primary dysmenorrhea during those cycles. The pain associated with primary dysmenorrhea was abdominal or pelvic, could radiate to the back and along the thighs, could begin up to 1 day before menses, and could last for the first 3 days of bleeding. The pain could be accompanied with systemic symptoms, including nausea, vomiting, diarrhea, headache, fatigue, nervousness, and dizziness.
Exclusion criteria were contraindications to OCP therapy (as described in the drug label), known or suspected secondary dysmenorrhea (major abdominal or pelvic surgery, endometriosis, pelvic inflammatory disease, ovarian cysts, pathological vaginal secretion, chronic abdominal pain, inflammatory bowel disease, irritable bowel syndrome), concomitant treatment with OCPs, gonadotropin-releasing hormone agonists and antagonists, antiandrogens, gonadotropins, and antiobesity drugs, the use of contraceptive implants, injectable contraceptives or intrauterine devices (the washout period on all these medications was 3 months), smoking (because we were uncertain about the risk–benefit of continuous OCP use in this population), migraine, increased severity of headaches, depression requiring hospitalization or associated with suicidal ideation during previous estrogen or OCP use, and known or suspected hypersensitivity to trial drug. Patients enrolled simultaneously into other investigative studies that require medications or otherwise prevent compliance with the protocol were also excluded.
Patients had a screening visit in which inclusion and exclusion criteria were determined and informed consent signed, a randomization visit, and three study visits (after 1 month, 3 months, and 6 months). At the screening visit, patients were asked to define pain they were feeling for the past three cycles, on a categorical scale presented, as none, mild, moderate, or severe. They were allowed to participate in the study if they rated their pain as moderate or severe. The first two OCP boxes were dispensed at the randomization visit, and patients were advised to take one pill daily (and two pills if a day was missed) starting on the first day of their next period.
At first study visit, scheduled between days 25 and 28 of the study, visual analog scale and Moos Menstrual Distress Questionnaire were administered for current bleeding, if it happened, and for previous bleeding at days 1–4 of the study. Other visits were scheduled at days 53–56, 81–84, and 165–168 of the study. Participants kept vaginal bleeding diaries that were reviewed at each study visit. On each page of the bleeding diary, patients had three pictures of sanitary pads and three pictures of tampons (for analysis they were named spotting, moderate, and heavy bleeding), indicating the amount of blood staining. They were asked to make a mark for each pad or tampon they have used that had blood staining that was similar to that shown in the picture, underneath the appropriate picture, and across from the correct date. Color Doppler ultrasonography also was performed at each study visit using an Aloka 2000 color Doppler ultrasonography with 7.5-MHz vaginal transducer. The scanning technique was as follows: after excluding uterine and ovarian pathology with the conventional ultrasonography, uterine arteries were visualized laterally in the transverse section of the cervicocorporeal junction. Measurements of the pulsatility index (pulsatility index=maximal systolic flow−minimal diastolic flow/mean flow) were made after at least three consecutive blood flow velocity waveforms were analyzed.
The primary outcome was the difference in subjective perception of pain as measured by the visual analog scale over a period of 6 months, whereas the secondary outcomes were the differences in menstrual-related symptoms as determined by Moos Menstrual Distress Questionnaire and in ultrasound parameters (endometrial thickness, uterine artery pulsatility index). The visual analog scale is a validated pain scale10 used widely in clinical trials assessing the intensity of pain, especially in trials with patients with primary dysmenorrhea. The visual analog scale uses an analog linear scale to assess pain intensity. The scale is 100 mm long; the extremes of the scale are to the left (“no pain”) and to the right (“worst pain I have ever felt”). A score itself is determined by measuring the distance from the left side of the scale to the point that the patient marked.
At baseline, at 3 months, and at 6 months, patients completed the Moos Menstrual Distress Questionnaire,11 a validated questionnaire of menstrual-related symptoms that is often used in the dysmenorrhea trials. In a questionnaire, patients are asked to quantify their symptoms related to the cycle for 4 days before the current bleeding, for the time of the bleeding, and for the rest of the cycle, describing it as 0 (no experience of symptom), 1 (present, mild), 2 (present, moderate), 3 (present, strong), and 4 (present, severe).
A modified intention-to-treat approach, defined before study initiation, was used for efficacy analyses. The predefined modified intention-to-treat approach included for analysis all participants who used the medication they were randomized to and who recorded at least one primary outcome score after the dose. Baseline values were not imputed or carried forward. All analyses were performed using SAS statistical software.
Linear mixed-effects models were fit to the data to assess between-group (treatment regimen) and within-group differences over time for all continuous outcomes.12 The independent variables for these models were treatment regimen, time (month), and the interaction of treatment regimen and time. From these linear mixed-effects models that included the two main effects and their interaction, contrasts were constructed to assess changes from baseline to each specific postrandomization month to compare within and between the treatment regimens. The linear mixed-effects models used a spatial power law covariance structure to account for unequally spaced repeated measurements (ie, visits) over time.13 Poisson regression models were fit to assess differences in treatment regimens with respect to bleeding day outcomes, in which bleeding days were represented as the total number of bleeding days over the 6-month study time interval. Effect sizes from the Poisson regression models were quantified using rate ratios14 and 95% confidence intervals (CIs).
We estimated that 38 participants would be needed to detect a 30-mm difference in visual analog scale between the continuous and cyclic 21–7 OCP treatment regimens with 90% power using a two-sided test having a significance level of 0.05. The power calculation assumed a visual analog scale standard deviation (SD) of 25 mm and factored in an anticipated 15% participant dropout for the trial.
RESULTS
Forty-three women were screened, 38 were randomized, and 29 completed the study (Fig. 1). Three of the 38 randomized women never returned for a postdose visit assessment and therefore were excluded in the modified intention-to-treat analysis. Baseline descriptives are presented in Table 1. There were no significant changes from baseline between the two groups after 6 months of treatment for any of the following blood tests: bilirubin, alkaline phosphatase, alanine aminotransferase, glucose, total cholesterol, low-density lipoprotein, high-density lipoprotein, triglycerides, thyroid-stimulating hormone, T3, T4, blood urea nitrogen, creatinine, and complete blood count.
;)
Fig. 1: Flow of participants through the study. *N=3 participants who did not return for a follow-up visit after randomization and were excluded from the analysis per the modified intent-to-treat (mITT) approach.Fig. 1. Dmitrovic. Oral Contraceptives for Primary Dysmenorrhea. Obstet Gynecol 2012.
Table 1: Baseline Characteristics of Patients by Treatment Regimen
Mean visual analog scale score (SD) in the cyclic regimen was 64.4 (SD 31.9) at screening visit, 19.0 (SD 24.8) after 1 month, and 5.2. (SD 9.5) at the end of the study. Mean visual analog scale score in the continuous group was 75.6 (SD 16.7) at screening visit, 3.1 (SD 5.8) after 1 month, and 0.8 (SD 1.4) at the end of the study. In both groups, pain reduction measured by visual analog scale was significant compared with baseline (Table 2). The continuous regimen was superior to the cyclic regimen when comparing pain reduction after 1 and 3 months of treatment, and had marginal statistical significance after 6 months of treatment (Fig. 2).
Table 2: Linear Mixed-Effects Model–Based Differences in Key Outcomes of Treatment Compared With Baseline by Treatment Group and Difference Between Groups
Fig. 2: Comparisons between the two groups in visual analog scale scores (VAS) at varying time points in the study. Asterisks signify that all P-values were rounded to two decimal places. The P-value for the comparison at 6 months was rounded to 0.05; however, it is actually slightly larger than 0.05, which is why it was reported that after 6 months only marginal statistical significance was reached.Fig. 2. Dmitrovic. Oral Contraceptives for Primary Dysmenorrhea. Obstet Gynecol 2012.
The changes in Moos Menstrual Distress Questionnaire scores over time were the same for the continuous and cyclic groups, with no changes between the groups (Table 2). We did note a significant increase in weight and body mass index (calculated as weight (kg)/[height (m)]2), and a decrease in systolic blood pressure at 6 months between the study groups (all P<.05; Table 3). There were no significant changes from baseline between the two groups after 6 months of treatment for ovarian volume and endometrial thickness, or for uterine artery resistance and pulsatility indices (data not shown). Within both groups, there was a significant decrease in endometrial thickness after 6 months of treatment (continuous: −3.7, 95% CI −5.4 to −2.0, P<.001; cyclic: −3.4, 95% CI −5.2 to −1.7, P<.001), with no difference between treatments. We observed more bleeding and spotting days in continuous compared with cyclic regimens over the period of 6 months, as shown in Table 4.
Table 3: Linear Mixed-Effects Model–Based Differences in Safety Outcomes of Treatment Compared With Baseline and Difference Between Groups*
Table 4: Differences in Vaginal Bleeding Days by Treatment Group Based on Poisson Regression Models
DISCUSSION
This is a randomized trial of continuous compared with cyclic OCPs in the treatment of primary dysmenorrhea. Our results show that in healthy young women, both regimens of OCPs are effective in the treatment of primary dysmenorrhea at 6 months, although the continuous OCP regimen is superior in pain relief compared with cyclic OCPs in the short term (up to 3 months), with no differences in quality of life as determined by the Moos Menstrual Distress Questionnaire between groups. Further, we noted in the continuous group greater weight gain and more bleeding or spotting days, but a decrease in systolic blood pressure compared with the cyclic group.
Dysmenorrhea has been successfully treated with OCPs. Davis et al15 assessed whether a low-dose OCP is more effective than placebo treatment for dysmenorrhea pain in adolescents, and they reported that the mean Moos Menstrual Distress Questionnaire pain score was lower (less pain) in the OCP group than the placebo group, comparable with our findings in both groups. Our findings also are consistent with other studies of other gynecologic disorders with chronic pain. For instance, several studies addressed the use of a continuous OCP regimen in patients with endometriosis, which is associated with pelvic pain, dysmenorrhea, dyspareunia, and infertility.7–9 They found less endometriosis-associated dysmenorrhea in the continuous contraceptive groups, which is comparable with our findings. Kwiecien et al,16 in a study of bleeding patterns and patient acceptability of standard or continuous dosing regimens of a low-dose OCP, examined symptoms of menstrual pain. At the conclusion of the study, participants completed a satisfaction questionnaire, and significantly less menstrual pain was noted in the continuous group.
Under social, cultural, and religious influences, women traditionally have been prescribed OCPs in a pattern of 21 days of active pills with 7 days of inactive pills as a way of mimicking the natural menstrual cycle.17 However, in dysmenorrhea patients, this may attenuate the full pain benefit of OCPs. The continuous administration may reduce dysmenorrhea by eliminating withdrawal bleeding and associated uterine contractions, as well as by preventing rebound ovarian function during the pill-free interval, which may stimulate the growth of the endometrium.18 Previous studies in other populations have shown greater satisfaction and quality of life with extended cycle regimens.19–21 A multicenter randomized trial22 of an extended-cycle OCP assessed patient satisfaction with the continuous regimen. Patients reported a preference for the reduced frequency of menstrual periods, and that they would prefer to have fewer menstrual periods after completion of the study.
We found no or only modest differences between the groups in premenstrual and intermenstrual symptoms that constitute the Moos Menstrual Distress Questionnaire, which is different from other studies.18,23 However, some studies did not find that OCP use alters the incidence or severity of premenstrual change in Moos Menstrual Distress Questionnaire.24 The reason for this may be our small sample size and also the subjective nature of the questionnaire.
Our patients in the continuous group gained weight, whereas patients in the cyclic group did not. We did not note this in our previous trial;18 moreover, a recent meta-analysis25 did not find evidence to support a large weight change using OCPs. Although this reflect improved appetite because of decreased pelvic pain, this may be a chance finding because of our small sample size and also the consequence of weighing women when the two groups were in different endocrinologic milieus (in the continuous group always using active pills, in the cyclic group using placebo pills [ie, the last 4 days of each pill cycle]). Women in the cyclic group had an increase in both systolic and diastolic blood pressure, which is expected, because OCPs are associated with a small but significant increase in blood pressure. Recent studies26,27 confirmed this; however, although this may be true for cyclic regimens of OCPs, continuous regimens, as in our study, may not change blood pressure to the same degree.18,28
Although ultrasonography has been the most important diagnostic tool in gynecology in the past decades, it has little value in the diagnosis of primary dysmenorrhea. Its main contribution in such patients is in excluding the patients with secondary dysmenorrhea by positively identifying endometriomas, uterine leiomyomas, adenomyosis, and other abnormalities. This was confirmed in this study, because the only significant change we observed was a change in endometrial thickness for both groups compared with baseline after 6 months of treatment, a common change in these studies.29,30
Women in our study reported more bleeding days and more spotting on continuous regimen than previously reported.16 However, this was likely a minor distraction, without involvement of the myometrium and prostaglandin production, given the significant reduction in visual analog scale and the lack of difference in the quality of life as reported on the Moos Menstrual Distress Questionnaire. Further, there was no significant difference in the total number of moderate or heavy bleeding days in our study between regimens, although previously we noted fewer days.18 However, we were studying healthy women and using a different OCP formulation.
In conclusion, patients with primary dysmenorrhea may benefit from continuous administration of OCPs compared with cyclic OCPs by a more rapid achievement in pain reduction. However, because primary dysmenorrhea therapy is a long-term therapy, and because continuous regimen could be associated with unpleasant side effects such as weight gain, women should be counseled about this. In the clinical setting, they may be less tolerant to side effects and thus discontinue the OCPs. Further larger randomized trials are needed to establish the risk-to-benefit ratio of longer use of extended-cycle OCP regimens for primary dysmenorrhea.
REFERENCES
1. Andersch B, Milsom I. An epidemiologic study of young women with dysmenorrhea. Am J Obstet Gynecol 1982;144;:655–60.
2. Dawood MY. Ibuprofen and dysmenorrhea. Am J Med 1984;77:87–94.
3. Hauksson A, Akerlund M, Melin P. Uterine blood flow and myometrial activity at menstruation, and the action of vasopressin and a synthetic antagonist. Br J Obstet Gynaecol 1988;95:898–904.
4. Pulkkinen MO. Prostaglandins and the non-pregnant uterus. The pathophysiology of primary dysmenorrhea. Acta Obstet Gynecol Scand Suppl 1983;113:63–7.
5. Akerlund M.Vascularization of human endometrium. Uterine blood flow in healthy condition and in primary dysmenorrhoea. Ann N Y Acad Sci 1994;734:47–56.
6. Wong CL, Farquhar C, Roberts H, Proctor M. Oral contraceptive pill for primary dysmenorrhoea. The Cochrane Database of Systematic Reviews 2009, Issue 4. Art. No.: CD002120. DOI: 10.1002/14651858.CD002120.pub3.
7. Wiegratz I, Kuhl H. Long-cycle treatment with oral contraceptives. Drugs 2004;64:2447–62.
8. Vercellini P, De Giorgi O, Mosconi P, Stellato G, Vicentini S, Crosignani PG. Cyproterone acetate versus a continuous monophasic oral contraceptive in the treatment of recurrent pelvic pain after conservative surgery for symptomatic endometriosis. Fertil Steril 2002;77:52–61.
9. Vercellini P, Frontino G, De Giorgi O, Pietropaolo G, Pasin R, Crosignani PG. Continuous use of an oral contraceptive for endometriosis-associated recurrent dysmenorrhea that does not respond to a cyclic pill regimen. Fertil Steril 2003;80:560–3.
10. Littman GS, Walker BR, Schneider BE. Reassessment of verbal and visual analog ratings in analgesic studies. Clin Pharmacol Ther 1985;38:16–23.
11. Markum RA. Assessment of the reliability of and the effect of neutral instructions on the symptom ratings on the Moos Menstrual Distress Questionnaire. Psychosom Med 1976;38:163–72.
12. Laird NM, Ware JH. Random-effects models for longitudinal data. Biometrics 1982;38:963–74.
13. Littell RC, Stroup WW, Wolfinger RD, Schabenberger O. SAS for mixed models. 2nd edition. Cary (NC): SAS Institute Inc; 2006.
14. Hilbe J. Negative binomial regression. Cambridge (UK): Cambridge University Press; 2007.
15. Davis AR, Westhoff C, O'Connell K, Gallagher N. Oral contraceptives for dysmenorrhea in adolescent girls: a randomized trial. Obstet Gynecol 2005;106:97–104.
16. Kwiecien M, Edelman A, Nichols MD, Jensen JT. Bleeding patterns and patient acceptability of standard or continuous dosing regimens of a low-dose oral contraceptive: a randomized trial. Contraception 2003;67:9–13.
17. Thomas SL, Ellertson C. Nuisance or natural and healthy: should monthly menstruation be optional for women? Lancet 2000;355:922–4.
18. Legro RS, Pauli JG, Kunselman AR, Meadows JW, Kesner JS, Zaino RJ, et al.. Effects of continuous versus cyclical oral contraception: a randomized controlled trial. J Clin Endocrinol Metab 2008;93:420–9.
19. Kaunitz AM. Menstruation: choosing whether.and when. Contraception 2000;62:277–84.
20. Loudon NB, Foxwell M, Potts DM, Guild AL, Short RV. Acceptability of an oral contraceptive that reduces the frequency of menstruation: the tri-cycle pill regimen. BMJ 1977;2:487–90.
21. Hamerlynck JV, Vollebregt JA, Doornebos CM, Muntendam P. Postponement of withdrawal bleeding in women using low-dose combined oral contraceptives. Contraception, 1987;35:199–205.
22. Anderson FD, Hait H. A multicenter, randomized study of an extended cycle oral contraceptive. Contraception 2003;68:89–96.
23. Barbosa IC, Filho CI, Faggion D Jr, Baracat EC. Prospective, open-label, noncomparative study to assess cycle control, safety and acceptability of a new oral contraceptive containing gestodene 60 microg and ethinylestradiol 15 microg (Minesse). Contraception 2006;73:30–3.
24. Ross C, Coleman G, Stojanovska C. Prospectively reported symptom change across the menstrual cycle in users and non-users of oral contraceptives. J Psychosom Obstet Gynaecol 2003;24:15–29.
25. Gallo MF, Lopez LM, Grimes DA, Schulz KF, Helmerhorst FM. Combination contraceptives: effects on weight. The Cochrane Database of Systematic Reviews 2011, Issue 9. Art. No.: CD003987. DOI: 10.1002/14651858.CD003987.pub4.
26. Boldo A, White WB. Blood pressure effects of the oral contraceptive and postmenopausal hormone therapies. Endocrinol Metab Clin North Am 2011;40:419–32, ix.
27. Hickson SS, Miles KL, McDonnell BJ, Yasmin, Cockcroft JR, Wilkinson IB, et al.. Use of the oral contraceptive pill is associated with increased large artery stiffness in young women: the ENIGMA study. J Hypertens 2011;29:1155–9.
28. Machado RB, Fabrini P, Cruz AM, Maia E, da Cunha Bastos A. Clinical and metabolic aspects of the continuous use of a contraceptive association of ethinyl estradiol (30 microg) and gestodene (75 microg). Contraception 2004;70:365–70.
29. Rabe T, Nitsche DC, Runnebaum B. The effects of monophasic and triphasic oral contraceptives on ovarian function and endometrial thickness. Eur J Contracept Reprod Health Care 1997;2:39–51.
30. Grow DR, Iromloo K. Oral contraceptives maintain a very thin endometrium before operative hysteroscopy. Fertil Steril 2006;85:204–7.
