University of Auckland, Obstetrics and Gynaecology, FMHS Park Road, Grafton, AucklandNew Zealand, 1003 Show
Faculty of Medicine and Health Sciences University of Auckland, Obstetrics & Gynaecology, Private Bag 92019, AucklandNew Zealand, 1003 Department of Corrections, Psychological Service, PO Box 302457, North Harbour, AucklandNew Zealand, 1310 Chooi L Wong, Email: zn.ca.dnalkcua.ce@461nowc. Author information Copyright and License information Disclaimer FMHS, O & G, AucklandNew Zealand University of Auckland, Obstetrics and Gynaecology, FMHS Park Road, Grafton, AucklandNew Zealand, 1003 Faculty of Medicine and Health Sciences University of Auckland, Obstetrics & Gynaecology, Private Bag 92019, AucklandNew Zealand, 1003 Department of Corrections, Psychological Service, PO Box 302457, North Harbour, AucklandNew Zealand, 1310 Chooi L Wong, Email: zn.ca.dnalkcua.ce@461nowc.  Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. This article is an update of "Oral contraceptive pill as treatment for primary dysmenorrhoea." on page CD002120. AbstractBackgroundDysmenorrhoea (painful menstrual cramps) is common. Combined OCPs are recommended in the management of primary dysmenorrhoea. ObjectivesTo determine the effectiveness and safety of combined oral contraceptive pills for the management of primary dysmenorrhoea. Search methodsWe conducted electronic searches for randomised controlled trials (RCTs) in the Cochrane Menstrual Disorders and Subfertility Group Register of controlled trials CENTRAL, CCTR, MEDLINE, EMBASE, and CINAHL (first conducted in 2001, updated on 5 November 2008). Selection criteriaRCTs comparing all combined OCPs with other combined OCPs, placebo, no management, or management with nonsteroidal anti‐inflammatories (NSAIDs) were considered. Data collection and analysisTwenty three studies were identified and ten were included. Six compared the combined OCP with placebo and four compared different dosages of combined OCP. Main resultsOne study of low dose oestrogen and four studies of medium dose oestrogen combined OCPs compared with placebo, for a combined total of 497 women, reported pain improvement. For the outcome of pain relief across the different OCPs the pooled OR suggested benefit with OCPs compared to placebo (7 RCTs: Peto OR 2.01 [95% CI 1.32, 3.08]).The Chi‐squared test for heterogeneity showed there is significant heterogeneity with an I2 statistic of 64% and a significant chi‐square test (14.06, df=5, p=0.02). A sensitivity analysis removing the studies with inadequate allocation concealment suggested significant benefit of treatment with the pooled OR of 2.99 (95% CI 1.76, 5.07) and heterogeneity no longer statistically significant and I2 statistic of 0%. Three studies reported adverse effects (Davis 2005; Hendrix 2002; GPRG 1968) The adverse effects were nausea, headaches and weight gain. Two studies reported if women experienced any side effect and no evidence of an effect was found (3 RCTs: OR = 1.45 (95% 0.71, 2.94). There was no evidence of statistical heterogeneity. There were no studies identified that compared combined OCP versus non steroidal anti‐inflammatory drugs There was no evidence of a difference for the pooled studies for 3rd generation pro gestagens (OR = 1.11 (95% CI 0.79 ‐ 1.57)). For the 2nd generation versus 3rd generation the OR was 0.44 (95% CI 0.23‐0.84) suggesting benefit of the 3rd generation OCP but this was for a single study (Winkler 2003). Authors' conclusionsThere is limited evidence for pain improvement with the use of the OCP (both low and medium dose oestrogen) in women with dysmenorrhoea. There is no evidence of a difference between different OCP preparations. Plain language summaryCombined oral contraceptive pill (OCP) as treatment for primary dysmenorrhoea Dysmenorrhoea is painful menstruation (woman's monthly bleeding) with the symptoms including cramping, headaches, nausea and vomiting. An excess of the hormone prostaglandin is a known cause. The synthetic hormones in combined oral contraceptive pills suppress ovulation, which could result in a reduction in dysmenorrhoea. The OCP reduces the amount of prostaglandin produced by glands in the lining of the uterus; which then reduces both uterine blood flow and cramps. The preparations of OCP with doses less than 35 mcg were effective and should be the preparation of choice. BackgroundDescription of the condition Dysmenorrhoea is the term for describing painful menstrual cramps. It is a common gynaecological problem that can affect as many as 50% of women, and 15% of these women suffer severely enough to temporarily render them incapacitated which, results in absences from work or school (Dawood 2006). The impacts are significant both in terms of quality of life and global economy. In the US alone it was estimated that there is an annual loss of 600 million work hours costing over 2 billion dollars (Dawood 1984). The initial onset of primary dysmenorrhoea is usually at or shortly after (6 to 12 months) menarche, when ovulatory cycles are established. The pain duration commonly ranges from 8 to 72 hours and is associated with menstrual flow. In contrast secondary dysmenorrhoea is more likely to develop years after the onset of menarche and occur premenstrually as well as during menstruation. Aetiology of the condition The aetiology (cause) of primary dysmenorrhoea has been the subject of considerable debate. Experimental and clinical research has identified the over‐production or imbalanced amount of uterine prostaglandins as a substantial contributing factor to the painful cramps that are the major symptom of dysmenorrhoea (Dawood 2006). Prostaglandin production is controlled by progesterone; immediately prior to menstruation progesterone levels drop causing prostaglandin production to increase. If these prostaglandins are overproduced cramping can occur. The process of ovulation is also implicated; dysmenorrhoea mostly only occurs in ovulatory cycles, which helps explain why the initial onset of primary dysmenorrhoea occurs shortly after menarche, when ovulatory cycles become established (Dawood 1990). Description of the intervention Research as early as 1937 has shown that dysmenorrhoea responds favourably to ovulation inhibition (Karnaky 1975), and that the synthetic hormones in the combined oral contraceptive pill can be used to manage dysmenorrhoea. These hormones act by suppressing ovulation and lessening of the endometrial lining of the uterus. Therefore menstrual fluid volume decreases along with the amount of prostaglandins produced, which then reduces dysmenorrhoea by decreasing uterine motility, and uterine cramping. The use of combined oral contraceptive pills (OCP) has been advocated as a treatment for primary dysmenorrhoea since their introduction for general use in 1960. However this type of long term hormonal/endocrine therapy is viewed by some as only potentially useful if long term contraception is also desired (Chan 1981). OCP use for secondary dysmenorrhoea is also questioned, as although this type of treatment may have some favourable effect on dysmenorrhoea ultimately the organic cause of the pain must be addressed (Smith 1993). Adverse effects of intervention One potential drawback of the use of OCPs is the possible adverse effects that can accompany the two hormones used. Oestrogen related side effects may include nausea, vomiting, headaches, breast tenderness, and changes in body weight; progesteronic side effects may include acne, weight gain, increased hair growth, and depression. Citing a cause‐and‐effect relationship between OCPs and these adverse effects may be misleading as they are also observed in women with dysmenorrhoea. Placebo‐controlled double‐blind studies suggesting that many of these adverse effects can also occur with similar frequency in placebo‐using control groups, and even in the general population (Goldzieher 1971; Goldzieher 1995). More potentially serious complications of oestrogens are deep venous thrombosis (blood clotting in the veins), and arterial disease such as heart attacks and stroke, although these are rare. In order to lessen any potential side effects lower dose OCPs have been developed. In contrast to older OCPs, which contain 50‐150 micrograms of oestrogen, modern pills are low dose (<35 micrograms). The level of progestogen has also decreased along with a move from first or second generation progestogens (such as norgestrel, levonorgestrel, norethisterone) to third generation progestogens (such as desogestrel, gestodene) which are more selective and have different effects on metabolic parameters. Therefore combined OCPs can be categorised according to the level of oestrogen and the type of progestogen they contain. How the intervention might work Clinical trials show that OCPs effectively treat dysmenorrhoea by inhibiting ovulation and reducing prostaglandin levels. In an open trial of 661 women from the general population, 63% experienced dysmenorrhoea pre‐treatment but after 12 months of OCP treatment only 12% still experienced dysmenorrhoea (Gauthier 1992). In an open clinical trial of a low dose OCP involving 100,000 women, of those who had dysmenorrhoea as a pre‐existing condition, 65% (23,500 women) of the dysmenorrhoeic sample who were first time users of oral contraceptives felt relief from dysmenorrhoea as a result of treatment (Brill 1991). Therefore there is some evidence in general populations that combined OCPs can effectively treat dysmenorrhoea. Why it is important to do this review Although combined oral contraceptives have long been promoted as the management for primary dysmenorrhoea, very few trials have been conducted to study efficacy and associated adverse events of their use. In addition, most of these trials are of poor methodological quality which exposes them to various biases. It is important to recognize that in this review. Dysmenorrhoea is a debilitating gynaecological condition that impacts significantly on women around the world. Not only does it cause great loss in personal health, but having to take time off work or school has also resulted in loss of productivity, eventually leading to economic loss. Proper management of dysmenorrhoea will therefore be beneficial to individuals and society. There has also been a lot of debate around the issue of the risks of adverse events, if they were worth the benefits of OCPs in managing dysmenorrhoea. This review therefore aimed to establish the usefulness of OCPs in managing dysmenorrhoea in general population by comparing all relevant randomised controlled trials. ObjectivesTo determine the effectiveness and safety of combined oral contraceptive pills for the management of primary dysmenorrhoea. MethodsCriteria for considering studies for this reviewTypes of studiesRandomised controlled trials that compare all types of combined oral contraceptives (oestrogen/progestogen) with other combined oral contraceptives, placebo, no treatment, or treatment with nonsteroidal anti‐inflammatory drugs (NSAIDs) in the treatment of primary dysmenorrhoea. Cross‐over trials will only be included if pre and post crossover data available and there was a washout period of two cycles. Types of participantsInclusion criteria: Women in the trials had to meet these inclusion criteria for the trial to be included in the review. Exclusion criteria: If more than 20% of women in the trial meet any of the exclusion criteria the trial was not included in the review. Types of interventionsCombined oral contraceptives versus placebo, versus no treatment, versus NSAIDs, versus other combined OCPs. The types of interventions were analysed according to the level and type of hormones used in the oral contraceptive: 1. Combined OCP compared with placebo or no treatment. 2. OCP compared with NSAIDs 3. OCP compared with OCP For comparison 1‐3, then stratification will be according to the type of OC: i. low oestrogen (< or equal to 35 micrograms of oestrogen) and 1st/2nd generation progestogen ii. low oestrogen (< or equal to 35 micrograms of oestrogen) and 3rd generation iii. moderate oestrogen (>35 mcg and < 100 mcg) and 1st/2nd generation Oral contraceptives containing 100mcg or more of oestrogen have been discontinued due to the increased risk of adverse effects associated with high levels of oestrogen and will be excluded from this review. Types of outcome measuresPrimary outcomes: 1. Pain improvement‐ measured with the visual analogue scale (VAS), Moos Menstrual Disorder Questionnaires (MMDQ) or as dichotomous data (pain improvement). Pain measured with the VAS is preferable as it is a more objective and sensitive measure than dichotomous data (Melzack 1994). 2. Adverse side effects from treatment (incidence of side effects and type of side effects) Secondary outcomes: 1. Requirements for additional medication (measured as a number of women requiring analgesics additional to their assigned treatment) Search methods for identification of studiesAll reports which described (or might have described) randomised controlled trials of combined oral contraceptives in the treatment of primary dysmenorrhoea were obtained using the following search strategy. The original search was performed in 2001. Updated searches were completed in 5th November 2008. The search was not restricted by language. Search strategies were revised and redeveloped in the update of the review. Please refer to previous version of review for details on old search strategies. Electronic Searches (details of specific search strategies for each database/register) Keywords CONTAINS "dysmenorrh" or "pelvic pain" or "menstrual cramps" or "menstrual pain" or"pain‐pelvic" or (Title CONTAINS "dysmenorrh" or "pelvic pain" or "menstrual cramps" or "menstrual pain" or"pain‐pelvic") AND Keywords CONTAINS "combined oral contraceptive" or "oral contraceptive" or "progestagen" or "Progesterone" or "progestin" or "progestogen" or "Norgestrel" or "norethisterone" or "desogestrel" or "gestodene" or "estrogen" or "oestrogen" or "oestrodiol" or "Estradiol" or "non steroidal" or "NSAID" or "mefenamic acid" or "naproxen" or "ibuprofen" or "Flurbiprofen" or "Meclofenamic Acid" or "Meclofenamate" or "diclofenac" or "acetly salicylic acid" or "aspirin" or Title CONTAINS "combined oral contraceptive" or "oral contraceptive" or "progestagen" or "Progesterone" or "progestin" or "progestogen" or "Norgestrel" or "norethisterone" or "desogestrel" or "gestodene" or "estrogen" or "oestrogen" or "oestrodiol" or "Estradiol" or "non steroidal" or "NSAID" or "mefenamic acid" or "naproxen" or "ibuprofen" or "Flurbiprofen" or "Meclofenamic Acid" or "Meclofenamate" or "diclofenac" or "acetly salicylic acid" or "aspirin" 2) EMBASE (1980 to 2008 Week 06): 3) MEDLINE (1950 to January Week 5 2008): 4) CINAHL ‐ Cumulative Index to Nursing & Allied Health Literature (1982 to December Week 1 2007): 5) The Cochrane Central Register of Controlled Trials (1st Quarter 2008) Searching other resources 2) The citation lists of relevant publications, review articles, abstracts of scientific meetings and included studies were also searched. Data collection and analysisSelection of studiesThe selection of trials for inclusion in the update of review was performed by the two reviewers (CW and CF) after employing the search strategy described previously. This was done previously by the two original reviewers (MW and CF). Data extraction and managementIncluded trials were analysed for the following quality criteria and methodological details. This information is presented in the table of included studies and provides a context for discussing the reliability of results: Trial characteristics Characteristics of the study women Interventions used Outcomes Assessment of risk of bias in included studiesThe Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2008) recommends the explicit reporting of:
Was sequence generation adequate (e.g. use of a random number table, a computer random number generator or coin tossing), inadequate (e.g. use of date of birth or clinical record number) or unclear (insufficient information about the process of sequence generation)?
Was allocation concealment adequate (e.g. use of central allocation or opaque sealed envelopes), inadequate (e.g. use of an open random allocation schedule, date of birth or case record number) or unclear (insufficient information about the process of allocation concealment)?
Was blinding adequate (e.g. participants and researchers were all blinded and it was unlikely that blinding could have been broken, either participants or some researchers are not blinded but outcome assessment was blinded or no blinding was used but this is not likely to influence outcomes), inadequate (e.g. no blinding or incomplete blinding and outcomes are likely to be influenced by this) or unclear (insufficient information about the process of blinding)?
Was outcome data addressed adequately (e.g. there was no missing outcome data, reasons for missing outcome data were unlikely to be related to true outcome or missing outcome data was balanced in numbers across intervention groups), inadequate (e.g. reasons for missing outcome data were likely to be related to true outcome) or unclear (insufficient information about the process of addressing outcome data)?
Was the study free of selective reporting? Adequate (e.g. the study protocol is available and all pre‐specified outcomes have been reported or the study protocol is not available but it is clear that all pre‐specified outcomes have been reported), inadequate (e.g. not all pre‐specified primary outcomes have been reported) or unclear (insufficient information about the process of outcome reporting).
Was the study free of other bias? Adequate (the study seems to be free of other bias), inadequate (e.g. extreme baseline imbalance, a potential source of bias related to the specific study design used or early stopping) or unclear (insufficient information about other sources of bias). Each of these domains as assessed as 'Yes' (indicating a low risk of bias), 'Unclear' (indicating an uncertain risk of bias) or 'No' (indicating a high risk of bias). No study was automatically excluded as a result of a rating of 'Unclear' or 'No'. Where it was unclear, authors of studies were contacted about the methods used and also any missing data was sought.The risk of bias assessment in the 'Characteristics of included studies' tables in the review have been completed, including commentary about each of the domains where possible. This will lead to an overall assessment of the risk of bias of included. A summary of the risk of bias table has been added to the figure section. Measures of treatment effectWhen extracting data from the trials for the outcome of pain relief it was decided a priori to only count substantial changes in pain as pain relief, if the trial reported sufficient data. For example the number of women changing from severe pain to mild or no pain would be included as experiencing pain relief, but not women changing from severe to moderate pain. The OR has been used for dichotomous outcomes and weighted mean difference for continuous outcomes. In the case of missing variance such as standard deviations the measure was imputed from the other similar studies. (The use of the imputation method was added in the update of 2008). Unit of analysis issuesNo unit of analysis issues were identified in this review. Dealing with missing dataWhere missing data was reported, the analysis was performed using the initial number of patients who were randomised. Assessment of heterogeneityThe overlap of the confidence intervals for the results of individual studies will be visually inspected as a general indication the presence of statistical heterogeneity. More formally, a statistical test for heterogeneity, the chi‐squared test will be included in the graphical output of the review. The chi‐squared test assesses whether observed differences in results are compatible with chance alone. A low p‐value (or a large chi‐squared statistic relative to its degree of freedom) provides evidence of heterogeneity of treatment effects (variation in effect estimates beyond chance). An I² statistic describing the percentage of the variability in effect estimates that is due to heterogeneity rather than sampling error (chance) will be calculated. A value greater than 50% may be considered substantial heterogeneity. A priori, it was planned to look at the possible contribution of differences in trial design to any heterogeneity identified in this manner. Where possible, the outcomes were pooled statistically. Data synthesisStatistical analysis was performed in accordance with the guidelines for statistical analysis developed by the Cochrane Collaboration and published in the handbook. For dichotomous data (for example, proportion of women with a specific adverse effect), results for each study were expressed as an odds ratio with 95% confidence intervals and combined for meta‐analysis with RevMan software using the Peto Mantel‐Haenszel method. Continuous differences between groups in the meta‐analysis were shown as a weighted mean difference (WMD). where the same scales are applied, and 95% confidence interval. A fixed approach was used for primary analysis. Where statistical heterogeneity was observed, sensitivity to the choice of model was assessed by comparison with a random effects analysis. If other scales or labels were used these were collapsed into dichotomous data if possible, based on the authors descriptions of the scale. If outcomes were presented in terms of pain intensity rather than pain relief these were considered and where possible converted into dichotomous categories. Subgroup analysis and investigation of heterogeneityNo subgroup analyses were planned. Sensitivity analysisSensitivity analyses were planned on the basis of allocation of concealment only. ResultsDescription of studiesTwenty three studies were considered for inclusion and ten met the inclusion criteria. One of the studies had three reports, the first related to pain outcomes and the second publication reported treatment discontinuation rates and losses to follow up of the original study and third providing further outcome data on pain and adverse events. (Davis 2005). Two of the studies reported some pain outcomes for a subgroup of women who had dysmenorrhoea but pain improvement and pain scores were not reported and therefore no data could be usefully extracted (Bassol 2000, Hendrix 2002). TRIALS EXCLUDED FROM THE REVIEW TRIALS INCLUDED IN THE REVIEW All assessments of the quality of trials and data extraction were performed independently by the two reviewers (CW and CF) using forms designed according to Cochrane guidelines. This was done previously by the two original reviewers (MW and CF). Additional information on trial methodology or original trial data was to be sought from the principal author of trials. However, for the trials that were more than 20 years old this was not deemed to be feasible, therefore four of the authors were not written to as their trials (GPRG 1968; Nakano 1971; Buttram 1969a; Cullberg 1972) were published more than 20 years ago. Out of the remaining six authors who were being contacted, three of them responded. (Hendrix 2002; Davis 2005; Winkler 2003) Types of intervention Of the ten included studies, six compared combined oral contraceptives with placebo as treatment for primary dysmenorrhoea (GPRG 1968; Nakano 1971; Buttram 1969a; Cullberg 1972; Hendrix 2002; Davis 2005), two compared combined oral contraceptives with different types of progestogens (Serfaty 1998; Endrikat 1999) and two compared combined oral contraceptives with different doses of estrogen.(Bassol 2000; Winkler 2003) One study also had a sequential arm combined OCP (Buttram 1969a). See table of included studies for more detail No studies were identified comparing OCP and NSAIDs. Study design Treatment length and follow up Study location and sources of women The included studies originated from a wide variety of countries; USA, UK, Sweden, Japan, Germany, Argentina, Brazil, Chile, Mexico, France, Austria, Switzerland, Italy, and the Netherlands. The women in the studies were also recruited from a variety of sources; student nurses, private practice patients and the local hospital (Buttram 1969a); local telephone company, student nurses, university students and two hospitals (Cullberg 1972); general practitioner's patients (GPRG 1968); hospital outpatients (Nakano 1971); college students (Davis 2005). The remaining five studies did not state from where the women were recruited. Six of the studies made explicit attempts in the form of clinical or pelvic exams to rule out pelvic pathology as a cause for dysmenorrhoea (Buttram 1969a; Nakano 1971; Hendrix 2002; Bassol 2000; Endrikat 1999; Serfaty 1998). One other study included very little information on the selection of women other than they had dysmenorrhoea (GPRG 1968), while Cullberg 1972 stated that women had to be absent of disease but included no information on how this was assessed. One study stated that pelvic examinations were not done to exclude secondary causes of dysmenorrhoea to avoid discouraging enrolments by younger adolescents (Davis 2005). The other study did not include any information on if any pelvic exams were done (Winkler 2003). Other exclusion criteria included planned or suspected pregnancy, contraindications to OCPs use, use of drugs that would interfere with pharmacokinetics of OCPs, recent miscarriage or abortion, abnormal genital bleeding, injectable hormonal contraceptives users, drugs use and abnormal genital bleeding. Severity of dysmenorrhoea Outcome measures Two trials reported mean change in pain scores as its primary outcome for pain relief (Davis 2005;Hendrix 2002 ). For two of the trials included in the meta‐analysis for the comparison of 1st /2nd generation progestogens versus placebo, only women experiencing complete relief were included as those experiencing pain relief (GPRG 1968; Nakano 1971); one trial was included that reported the number of women changing from severe pain to no pain/mild pain (Buttram 1969a); the other trial in the meta‐analysis categorised women as those whose pain improved or did not improve (Cullberg 1972). This trial may be a source of heterogeneity as its categorisation of dysmenorrhoea was not as sophisticated as the other trials. For trials with different comparisons, one trial also grouped women as those whose pain improved or did not improve (Winkler 2003); one trial included those who experienced complete relief or improvement in pain as those experiencing pain relief (Serfaty 1998); the other trial reported the number of women who experienced relief or no relief (Endrikat 1999). Three studies reported adverse effects by group (Davis 2005, GPRG 1968; Hendrix 2002), additional use of analgesics (Davis 2005; GPRG 1968) and absence from work or school (Hendrix 2002; GPRG 1968) although three additional studies reported withdrawing from the study as a result of adverse events (GPRG 1968; Hendrix 2002). Davis 2005; Endrikat 1999; Serfaty 1998; Winkler 2003) Withdrawals: For the GPRG 1968 trial a number of women dropped out of the trial before completing three months of treatment, therefore the meta‐analysis only included those who completed three full months of treatment. Adverse events were not a reason for withdrawal. One study reported 4/22 women (18%) withdrawing from the final analysis, however two of these women were excluded due to breakthrough bleeding (Nakano 1971). Cullberg 1972 had 23 drop outs out of the 322 women initially randomised, however only 213 of the 322 women had dysmenorrhoea and results were reported for only 203 of those women. Therefore dropouts from the dysmenorrhoea group were less than 10%, while dropouts from the overall trial were only 7%. Reasons given for withdrawals varied (from the overall group there were five pregnancies, six women who disappeared, four with somatic complaints such as bleeding, skin troubles or nausea, three with "interfering illness", and four who changed their minds). This data was not suitable for inclusion in the analysis. Hendrix 2002 reported 25/77 women (32%) not being included in the final analysis; four were excluded due to protocol violations, and the rest discontinued the treatment due to various reasons (non‐compliance, personal reasons, pre‐existing pregnancy and unknown reasons). The text specifically states that there were no withdrawals for adverse events. Only 7/76 women discontinued in Davis 2005 and only 2 of them were not included in the final analysis due to lost to follow up and pregnancy and three were for adverse events. Three studies (Bassol 2000; Endrikat 1999; Winkler 2003) included women with no dysmenorrhoea in the trials, therefore although withdrawals of the women were mentioned, but no number was reported specifically for the dysmenorrhoea group. The percentage of withdrawals was therefore applied to the subgroup of women with dysmenorrhoea. For example, in Endrikat 1999 13% of women withdrew and this percentage was assumed to apply to the women with dysmenorrhoea. Serfaty 1998 stated that only 213 out of 1016 women initially randomised had dysmenorrhoea and 40 of them dropped out of the study prior to completion. Most common reasons for withdrawals were unacceptable bleeding problems and adverse events. The one remaining study did not report withdrawals (Buttram 1969a). For the Cullberg 1972 trial, data on pain relief was reported as a percentage of the women in the group and these percentages had to be recalculated into numbers of women to be included in the meta‐analysis. In the meta‐analysis for the comparison of 1st/2nd generation progestogens versus placebo, the placebo group for the Cullberg 1972 trial was evenly split between the three different types of progestogens evaluated in the trial. This was done to allow comparisons to be made and to ensure that the women in the placebo group were not over represented in the summary statistic. Baseline comparability Types of compounds used A number of different types of oestrogen/progestogen compounds were used and four of the trials (Buttram 1969a; GPRG 1968; Cullberg 1972; Nakano 1971) used medium doses of oestrogen and 1st or 2nd generation progestogens. Of these trials, mestranol 0.08mg and chlormadinone acetate 2mg taken sequentially was used in one arm of a trial and combined mestranol 0.1mcg and norethindrone was used in another arm and compared with a third placebo arm (Buttram 1969a). Mestranol 0.05mg and norethisterone 1mg was used in one trial (GPRG 1968). 0.05 mg of mestranol is equivalent to 35mcg of ethinyl estradiol. Two other trials included 0.05mg ethinyl oestradiol with different levels of the progestogen norgestrel; 1mg, 0.5mg and 0.06mg (Cullberg 1972); 0.5mg (Nakano 1971). The remaining trials all used low doses of ethinyl oestradiol and 1st or 2nd or 3rd generation progestogens. Hendrix 2002 used two doses of ethinyl estradiol, 0.02mg and 0.01mg, and 0.15mg desogestrel. Ethinyl estradiol 0.02mg and desogestrel 0.15mg was used in three trials (Endrikat 1999; Serfaty 1998; Bassol 2000) and they were compared against 0.075mg gestodene with same doses of ethinyl estradiol in two of them (Endrikat 1999; Serfaty 1998) while Bassol 2000 used 0.03mg ethinyl estradiol combined with 0.075mg gestodene. The remaining two trials included 0.02mg ethinyl estradiol with 0.01mg levonorgestrel (Davis 2005; Winkler 2003), and 0.15mg gestodene was used as a comparison in Winkler 2003. Compliance Risk of bias in included studiesAllocation concealment and randomisation methodFigure 1; Figure 2 Open in a separate window 1 Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies. Open in a separate window 2 Methodological quality summary: review authors' judgements about each methodological quality item for each included study. Blinding Power Calculation Effects of interventions1. Combined oral contraceptive pill versus placebo or no treatment Pain improvement Figure 3 Open in a separate window 3 Forest plot of comparison: 1 Combined OCP versus placebo or no treatment, outcome: 1.1 Pain improvement. Two studies of low dose oestrogen and five studies of medium dose oestrogen combined OCPs compared with placebo, for a combined total of 497 women, reported pain improvement. For the outcome of pain relief across the different OCPs the pooled OR suggested benefit with OCPs compared to placebo (Peto OR 2.01 [95% CI 1.32, 3.08]]). The Chi‐squared test for heterogeneity showed there is significant heterogeneity with an I2 statistic of 64% and a significant chi‐square test (14.06, df=5, p=0.02). One explanation for this is the disparate results of Cullberg 1972 and GPRG 1968. GPRG 1968 had a mistake with the blinding procedure although unbinding as a result seems unlikely to have occurred. A sensitivity analysis removing the studies without adequate allocation concealment resulted in Davis 2005; Cullberg 1972; Hendrix 2002; Nakano 1971 remaining and suggesting significant benefit of treatment with the pooled OR of 2.99 (95% CI 1.76, 5.07) and heterogeneity no longer statistically significant and I2 statistic of 0%. Pain scores Figure 4 Open in a separate window 4 Forest plot of comparison: 1 Combined OCP versus placebo or no treatment, outcome: 1.2 Pain score (mean change). The pooled pain scores of low dose oestrogen and 2nd and 3rd generation progestagen's reported pain scores with a weighted mean difference of ‐0.29 (95%CI ‐0.46, ‐0.12). Heterogeneity: Chi² = 2.38, df = 1 (P = 0.12); I² = 58%.Figure 5 Open in a separate window 5 Forest plot of comparison: 1 Combined OCP versus placebo or no treatment, outcome: 1.3 Additional analgesia required. Additional pain relief Three studies reported this outcome. In the study of low dose oestrogen and 1st/2nd generation progestogens there was reduced need for additional pain relief with an OR of 0.33 (95%CI 0.13,0.85) Davis 2005 but in the medium dose oestrogen pills there was no evidence of a benefit and the pooled OR was 0.75 (95% CI 0.39, 1.43) . There was significant statistical heterogeneity with a Chi‐square test=5.79, df=1 and I2 =83%. Once GPRG 1968 was removed from the analysis because of inadequate allocation concealment then only one study Davis 2005 remains (OR = 0.33 (95% CI 0.13‐0.85). Absence from school Figure 6 Open in a separate window 6 Forest plot of comparison: 1 Combined OCP versus placebo or no treatment, outcome: 1.4 Absence from school or work. Only two studies reported this outcome. (Hendrix 2002; GPRG 1968) The pooled OR for the two studies was 0.39 (95% 0.17,0.88) suggesting benefit with the OC pill. No evidence of statistical heterogeneity. Withdrawals from treatment Figure 7 Open in a separate window 7 Forest plot of comparison: 1 Combined OCP versus placebo or no treatment, outcome: 1.5 Withdrawals from treatment. Only two studies reported this outcome. (Davis 2005; Hendrix 2002) The pooled OR for the two studies was 2.06 (95% 0.18‐0.23.72) suggesting no evidence of increased withdrawals with the OC pill and no evidence of statistical heterogeneity. Adverse events Figure 8 Open in a separate window 8 Forest plot of comparison: 1 Combined OCP versus placebo or no treatment, outcome: 1.6 Adverse events. Three studies reported adverse effects (Davis 2005; Hendrix 2002; GPRG 1968) The adverse effects were nausea, headaches and weight gain. Two studies reported if women experienced any side effect and the there was no evidence of an effect with a pooled OR = 1.45 (95% 0.71, 2.94). There was no evidence of statistical heterogeneity. 2. Combined OCP versus non steroidal anti‐inflammatory drugs There were no studies identified for this comparison. 3. Combined OCP versus other combined OCP Pain improvement Figure 9 Open in a separate window 9 Forest plot of comparison: 2 Combined low dose OCP versus Combined low doseOCP, outcome: 2.1 Pain improvement. There was no evidence of a difference for the pooled studies for 3rd generation progestagen's (OR = 1.11 (95% CI 0.79 ‐ 1.57)). For the 2nd generation versus 3rd generation the OR was 0.44 (95% CI 0.23‐0.84) suggesting benefit of the 3rd generation OCP but this was for a single study (Winkler 2003). Withdrawals from treatment Three studies reported this outcome and there was no evidence of a difference for the pooled studies for 3rd generation progestagen's was OR = 1.11 (95% CI 0.79 ‐ 1.57)). and for the 2nd generation versus 3rd generation was OR 0.44 (95% CI 0.23‐0.84). None of studies reported any of the other considered outcomes of additional analgesics required and absence from work or school,or adverse events. Figure 10 Open in a separate window 10 Forest plot of comparison: 2 Combined low dose OCP versus Combined low doseOCP, outcome: 2.2 Withdrawals from treatment. DiscussionThe aim of this review was to investigate the effectiveness of combined oral contraceptive pills in the treatment of primary dysmenorrhoea, and to compare the effectiveness of OCPs that use different levels and types of oestrogen and progestogen. The paucity of RCTs investigating oral contraceptives, despite their apparent widespread clinical use, has meant this review is unable to achieve this objective. Summary of main results Ten RCTs were included in this review and six compared different OCP preparations with placebo and 4 compared different preparations with each other. No studies compared OCP with the NSAIDs. Only two of our initial hypotheses could be commented on with the available data from the ten trials. The trials included in this review indicate that both low and medium dose oestrogen pills may be more effective than placebo treatment. There is no evidence of a difference between the different pill preparations although the 3rd generation pills may be more effective in pain improvement. Overall completeness and applicability of evidence Another issue that needs to be considered is that the use of oral contraceptives as treatment for dysmenorrhoea does not just depend on their efficacy but also the suitability of oral contraceptives for the woman. If a woman wants a pregnancy or has contraindications to the OCP, then the OCP would be an unsuitable treatment option at that time. The lack of reporting of adverse effects experienced by the women in the trials is problematic. Only three placebo controlled trials reported adverse effects. There are also difficulties in extrapolating the results of this review to modern day populations as the majority of oral contraceptive pills prescribed today include much lower levels of oestrogen and progestogen and often different types of progestogens than some of the trials included in this review. Quality of the evidence Overall, three trials were methodologically sound (Cullberg 1972; Hendrix 2002; Davis 2005), but all of the other trials were of poor methodological quality and, in addition to that, three of them (GPRG 1968; Nakano 1971; Buttram 1969a) had small sample sizes. Potential biases in the review process Authors' conclusionsImplications for practiceCombined oral contraceptive pills of medium and low dose oestrogen with 2nd and 3rd generation progestogens may be more effective than placebo treatment for dysmenorrhoea but the interpretation of the results is limited because the variable quality of the RCTs included in this review. Implications for researchThere is a paucity of RCTs of the combined OCP for dysmenorrhoea. There is only one trial of a low dose oestrogen OCP and further placebo controlled trials of the low dose OCP for pain improvement of dysmenorrhoea would be welcome. Comparisons with other standard medical treatments such as nonsteroidal anti‐inflammatories would also be useful. Any future trials would need to be double blind, randomised controlled trials with adequate sample sizes, and use objective pain outcome measures such as the visual analogue scale or Moos Menstrual Distress Questionnaires (MMDQ). What's newDateEventDescription12 January 2009New citation required but conclusions have not changedNew author added Chooi Ling Wong HistoryProtocol first published: Issue 1, 2000 DateEventDescription8 November 2008New search has been performedThere were 5 studies in the first version of this review published in 2001. In the 2008 update one study was removed as not truly a RCT Matthews 1968 and 6 new studies were added. Bassol 2000; Davis 2005; Winkler 2003; Endrikat 1999; Serfaty 199825 June 2008AmendedConverted to new review format.18 February 2008New citation required and conclusions have changedSubstantive amendment AcknowledgementsThe authors acknowledge the helpful comments of those who refereed previous versions of this review, and the authors of included trials that supplied extra information and/or data. AppendicesAppendix 1. Embase search strategy1 exp Dysmenorrhea/ (3308) Appendix 2. Embase search strategy1 exp Dysmenorrhea/ (2343) Appendix 3. Cinahl search strategyexp Dysmenorrhea/ (277) Appendix 4. Specialised register1 exp Dysmenorrhea/ (247) NotesEdited (no change to conclusions) Data and analysesComparison 1Combined OCP versus placebo or no treatment Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size1 Pain improvement7497Odds Ratio (M‐H, Fixed, 95% CI)2.01 [1.32, 3.08]1.1 low dose oestrogen and 1st/2nd generation progestagen176Odds Ratio (M‐H, Fixed, 95% CI)1.83 [0.69, 4.83]1.2 low dose oestrogen and 3rd generation progestagen173Odds Ratio (M‐H, Fixed, 95% CI)0.0 [0.0, 0.0]1.3 medium dose oestrogen and 1st/2nd generation progestagen5348Odds Ratio (M‐H, Fixed, 95% CI)2.06 [1.28, 3.30]2 Pain score (mean change)2150Mean Difference (IV, Fixed, 95% CI)‐0.29 [‐0.46, ‐0.12]2.1 Low dose oestrogen and 1st/2nd generation progesterone174Mean Difference (IV, Fixed, 95% CI)1.50 [‐0.78, 3.78]2.2 Low dose oestrogen and 3rd generation progestagen176Mean Difference (IV, Fixed, 95% CI)‐0.3 [‐0.47, ‐0.13]2.3 Medium dose oestrogen and 1st/2nd generation progestagen00Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]3 Additional analgesia required2 Odds Ratio (M‐H, Fixed, 95% CI)Subtotals only3.1 low dose oestrogen and 1st/2nd generation progestagen174Odds Ratio (M‐H, Fixed, 95% CI)0.33 [0.13, 0.85]3.2 low dose oestrogen and 3rd generation progestagen00Odds Ratio (M‐H, Fixed, 95% CI)0.0 [0.0, 0.0]3.3 medium dose oestrogen and 1st/2nd generation progestagen189Odds Ratio (M‐H, Fixed, 95% CI)1.76 [0.66, 4.72]4 Absence from school or work2148Odds Ratio (M‐H, Fixed, 95% CI)0.39 [0.17, 0.88]4.1 low dose oestrogen and 1st/2nd generation progestagen159Odds Ratio (M‐H, Fixed, 95% CI)0.18 [0.01, 3.92]4.2 medium dose oestrogen and 1st/2nd generation progestagen189Odds Ratio (M‐H, Fixed, 95% CI)0.42 [0.18, 0.99]5 Withdrawals from treatment2134Odds Ratio (M‐H, Fixed, 95% CI)2.06 [0.18, 23.72]5.1 low dose oestrogen and 1st/2nd generation progestagen174Odds Ratio (M‐H, Fixed, 95% CI)2.06 [0.18, 23.72]5.2 low dose estrogen and 3rd generation progestagen160Odds Ratio (M‐H, Fixed, 95% CI)0.0 [0.0, 0.0]5.3 medium dose oestrogen and 1st/2nd generation progestagen00Odds Ratio (M‐H, Fixed, 95% CI)0.0 [0.0, 0.0]6 Adverse events3 Odds Ratio (M‐H, Fixed, 95% CI)Subtotals only6.1 Nausea3225Odds Ratio (M‐H, Fixed, 95% CI)0.91 [0.41, 2.03]6.2 Headaches2135Odds Ratio (M‐H, Fixed, 95% CI)1.56 [0.67, 3.67]6.3 Weight gain176Odds Ratio (M‐H, Fixed, 95% CI)2.17 [0.71, 6.65]6.4 Experienced any side effect2165Odds Ratio (M‐H, Fixed, 95% CI)1.45 [0.71, 2.94] Open in a separate window Open in a separate window 1.1 Analysis Comparison 1 Combined OCP versus placebo or no treatment, Outcome 1 Pain improvement. Open in a separate window 1.2 Analysis Comparison 1 Combined OCP versus placebo or no treatment, Outcome 2 Pain score (mean change). Open in a separate window 1.3 Analysis Comparison 1 Combined OCP versus placebo or no treatment, Outcome 3 Additional analgesia required. Open in a separate window 1.4 Analysis Comparison 1 Combined OCP versus placebo or no treatment, Outcome 4 Absence from school or work. Open in a separate window 1.5 Analysis Comparison 1 Combined OCP versus placebo or no treatment, Outcome 5 Withdrawals from treatment. Open in a separate window 1.6 Analysis Comparison 1 Combined OCP versus placebo or no treatment, Outcome 6 Adverse events. Comparison 2Combined low dose OCP versus Combined low doseOCP Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size1 Pain improvement3 Peto Odds Ratio (Peto, Fixed, 95% CI)Subtotals only1.1 3rd generation progestagens: 75mcg gestodene vs150mcg desogestrel2626Peto Odds Ratio (Peto, Fixed, 95% CI)1.11 [0.79, 1.57]1.2 2nd generation versus 3rd generation progestagens100mcg levonorgestrel vs 150mcg desogestrel1349Peto Odds Ratio (Peto, Fixed, 95% CI)0.44 [0.23, 0.84]2 Withdrawals from treatment3 Odds Ratio (M‐H, Fixed, 95% CI)Subtotals only2.1 3rd generation progestagens: 75mcg gestodene vs150mcg desogestrel2626Odds Ratio (M‐H, Fixed, 95% CI)1.15 [0.72, 1.83]2.2 2nd generation versus 3rd generation progestagens: 100mcg levonorgestrel vs 150mcg desogestrel1349Odds Ratio (M‐H, Fixed, 95% CI)4.41 [1.23, 15.77] Open in a separate window Open in a separate window 2.1 Analysis Comparison 2 Combined low dose OCP versus Combined low doseOCP, Outcome 1 Pain improvement. Open in a separate window 2.2 Analysis Comparison 2 Combined low dose OCP versus Combined low doseOCP, Outcome 2 Withdrawals from treatment. Characteristics of studiesCharacteristics of included studies [ordered by study ID]Bassol 2000 MethodsRandomisation list was prepared with random number tables. Buttram 1969a MethodsRandom ‐ unstated Buttram 1969b MethodsRandom ‐ unstated Cullberg 1972 MethodsRandomisation was done statistically by the pharmaceutical company, allocation concealment was via a secure code not broken until after all data was collected. Davis 2005 MethodsRandomisation list was prepared with random number tables. Endrikat 1999 MethodsRandomisation method not stated. GPRG 1968 MethodsAdministration of medicine was random however due to error each treatment had different numbers so were not identical Hendrix 2002 MethodsRandomisation list was generated by computer. Nakano 1971 MethodsRandomisation by 'envelope method' Serfaty 1998 MethodsRandomisation method not stated. Winkler 2003 MethodsRandomisation list was generated by computer. Characteristics of excluded studies [ordered by study ID]StudyReason for exclusionCreatsas 1998Study participants did not have dysmenorrhoeaFoidart 2000Only small number of women with dysmenorrhoea included in the study.Iannotti 1991Not a randomised or controlled clinical trial. No information on the oestrogen/progestagen compound used. Differences between protocol and reviewIn the update in 2008, the comparisons were restructured. The outcome of pain relief was changed to pain improvement in the 2008 update. The title was changed from 'Combined oral contraceptive pill (OCP) as treatment for primary dysmenorrhoea' to 'Oral contraceptive pill as treatment for primary dysmenorrhoea'. A new author was added Chooi Ling Wong. Contributions of authorsMichelle Proctor: Took the lead in writing the initial protocol and review, performed initial searches of databases for trials, was involved in selecting trials for inclusion, performed independent data extraction and quality assessment of the included trials, was responsible for statistical analysis and interpretation of the data. Sources of supportInternal sources
External sources
Declarations of interestHelen Roberts has received funding from Schering, Wyeth, Pharmaco Organanon, and Pharmacia Upjohn in the past. ReferencesReferences to studies included in this reviewBassol 2000 {published data only}
Buttram 1969a {published data only}
Buttram 1969b {published data only}
Cullberg 1972 {published data only}
Davis 2005 {published and unpublished data}
Endrikat 1999 {published data only}
GPRG 1968 {published data only}
Hendrix 2002 {published data only}
Nakano 1971 {published data only}
Serfaty 1998 {published data only}
Winkler 2003 {published and unpublished data}
References to studies excluded from this reviewCreatsas 1998 {published data only}
Foidart 2000 {published data only}
Iannotti 1991 {published data only}
Karasawa 1968 {published data only}
Kaunitz 2000 {published data only}
Kremser 1971 {published data only}
Kristjansdottir 2000 {published data only}
Kwiecien 2003 {published data only}
La Guardia 2003 {published data only}
Matthews 1968 {published data only}
Moore 1999 {published data only}
Reisman 1999 {published data only}
Tallian 1994 {published data only}
Additional referencesBrill 1991
Chan 1981
Coco 1999
Dawood 1984
Dawood 1990
Dawood 2006
Gauthier 1992
Goldzieher 1971
Goldzieher 1995
Karnaky 1975
Melzack 1994
Milsom 1984
Milsom 1990
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