Review question
Is nifedipine safe and effective for the relief of pain associated with primary dysmenorrhoea (also known as period pain or menstrual cramps)?
Background
Primary dysmenorrhoea is pain associated with menstruation (periods) due to cramping of the uterus (womb). It is a common condition in women of reproductive age, and can have a significant impact on normal activities. Nifedipine is a medication that is effective at slowing contractions of the uterus in pregnant women with preterm labour. This review addresses whether nifedipine also helps with relieving uterine contractions during menstruation.
Study characteristics
We found three randomised controlled trials (experiments where each person has an equal chance of being chosen to receive the treatment or a comparator). They compared the use of nifedipine with placebo (dummy pill) for primary dysmenorrhoea. A total of 106 women were included in the trials; however only information from two trials containing a total of 66 women was available for analysis. In one of these trials, randomisation was very unbalanced between groups: only five women received placebo whereas 19 received nifedipine. Our search for trials was done on 31 January 2019, and repeated on 5 June 2020 and 25 November 2021. One trial was identified through discussion with colleagues.
Key results
Overall we are uncertain of the effectiveness of nifedipine for relief of pain in primary dysmenorrhoea. Nifedipine may be effective for overall pain relief, and for obtaining the subsets of "good" or "excellent" pain relief. Caution is needed in drawing conclusions from this as the analysis is based on very low participant numbers. In the study where the question was asked, women who received nifedipine were more likely to prefer to continue taking the medication for future cycles than women taking the placebo (12/19 women taking nifedipine, versus 0/5 women taking placebo). In one study, participants taking nifedipine who were usually severely incapacitated by periods had a significant improvement in the ability to carry out daily activities compared to those assigned to placebo. In both trials where adverse effects were assessed there was a high, and similar, rate of adverse physical symptoms associated with menstruation both in women taking nifedipine and those taking placebo.
Quality of the evidence
We rated the quality of the evidence as very low. There was generally inadequate reporting of study methods, and one trial did not report results in a way that could be analysed. Results for analysis were drawn from only two trials, which included a total of 66 women, one of which had unbalanced randomisation.
The evidence is insufficient to confirm whether nifedipine is a possible medical treatment for primary dysmenorrhoea. The trials included in this review had very low numbers and were of low quality. Notably, there was a large imbalance in numbers randomised between placebo and treatment groups in one of the two trials with data available for analysis. While there was no evidence of a difference noted in adverse effects between groups, more data from larger participant numbers are needed for this outcome. Larger, more well-conducted trials are required to elucidate the potential role of nifedipine in the treatment of this common condition, as it could be a useful addition to the therapeutic options available if shown to be well tolerated and effective. The safety of nifedipine in women of reproductive age is well established from trials of its use in preterm labour, and clinicians are accustomed to off-label use for this indication. The drug is inexpensive and readily available. Other options for relief of primary dysmenorrhoea are not suitable for all women; NSAIDs and the oral contraceptive pill (OCP) are contraindicated for some women, and the OCP is not suitable for women who are trying to conceive. In addition, the trials examined suggest there may be a participant preference for nifedipine.
Dysmenorrhoea (period pain) is a common condition with a substantial impact on the well-being and productivity of women. Primary dysmenorrhoea is defined as recurrent, cramping pelvic pain that occurs with periods, in the presence of a normal uterus, ovaries and fallopian tubes. It is thought to be caused by uterine contractions (cramps) associated with a high level of production of local chemicals such as prostaglandins. The muscle of the uterus (the myometrium) responds to these high levels of prostaglandins by contracting forcefully, causing low oxygen levels and consequently pain. Nifedipine is a calcium channel blocker in widespread clinical use for preterm labour due to its ability to inhibit uterine contractions in that setting. This review addresses whether this effect of nifedipine also helps with relief of the uterine contractions during menstruation
To assess the effectiveness and safety of nifedipine for primary dysmenorrhoea.
We searched for all published and unpublished randomised controlled trials (RCTs) of nifedipine for dysmenorrhoea, without language restriction and in consultation with the Cochrane Gynaecology and Fertility Group (CGF) Information Specialist.
The following databases were searched to 25 November 2021: the Cochrane Gynaecology and Fertility Group (CGF) Specialised Register of Controlled Trials, CENTRAL, MEDLINE, Embase, PsycINFO, and CINAHL. Also searched were the international trial registers: ClinicalTrials.gov, and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) search portal, the Web of Science, OpenGrey, LILACS database, PubMed and Google Scholar. We checked the reference lists of relevant articles.
We included RCTs comparing nifedipine with placebo for the treatment of primary dysmenorrhoea.
The primary outcomes to be assessed were pain, and health-related quality of life. Secondary outcomes were adverse effects, satisfaction, and need for additional medication. The two review authors independently assessed the included trials. There were insufficient data to allow meaningful meta-analysis.
The evidence assessed was of very low quality overall. We examined three small RCTs, with a total of 106 participants. Data for analysis could be extracted from only two of these trials (with a total of 66 participants); two trials were published in the 1980s, and the third in 1993. Nifedipine may be effective for "any pain relief" compared to placebo in women with primary dysmenorrhoea (odds ratio (OR) 9.04, 95% confidence interval (CI) 2.61 to 31.31; 2 studies, 66 participants; very low-quality evidence). The evidence suggests that if the rate of pain relief using placebo is 40%, the rate using nifedipine would be between 64% and 95%. For the outcome of "good" or "excellent" pain relief, nifedipine may be more effective than placebo; the confidence interval was very wide (OR 43.78, 95% CI 5.34 to 259.01; 2 studies, 66 participants; very low-quality evidence). We are uncertain if the use of nifedipine was associated with less requirement for additional analgesia use than placebo (OR 0.54, 95% CI 0.07 to 4.20, 1 study, 42 participants; very low-quality evidence). Participants indicated that they would choose to use nifedipine over their previous analgesic if the option was available. There were similar levels of adverse effects and menstruation-related symptoms in the placebo and intervention groups (OR 0.94, 95% CI 0.08 to 10.90; 1 study, 24 participants; very low-quality evidence); if the chance of adverse effects with placebo is 80%, the rate using nifedipine would be between 24% and 98%. There were no results regarding formal assessment of health-related quality of life.