Jane Marjoribanks, Reuben Olugbenga Ayeleke, Cindy Farquhar, Michelle Proctor

Dysmenorrhoea is a common gynaecological problem consisting of painful cramps accompanying menstruation, which in the absence of any underlying abnormality is known as primary dysmenorrhoea. Research has shown that women with dysmenorrhoea have high levels of prostaglandins, hormones known to cause cramping abdominal pain. Nonsteroidal anti-inflammatory drugs (NSAIDs) are drugs that act by blocking prostaglandin production. They inhibit the action of cyclooxygenase (COX), an enzyme responsible for the formation of prostaglandins. The COX enzyme exists in two forms, COX-1 and COX-2. Traditional NSAIDs are considered 'non-selective' because they inhibit both COX-1 and COX-2 enzymes. More selective NSAIDs that solely target COX-2 enzymes (COX-2-specific inhibitors) were launched in 1999 with the aim of reducing side effects commonly reported in association with NSAIDs, such as indigestion, headaches and drowsiness. To determine the effectiveness and safety of NSAIDs in the treatment of primary dysmenorrhoea. We searched the following databases in January 2015: Cochrane Menstrual Disorders and Subfertility Group Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL, November 2014 issue), MEDLINE, EMBASE and Web of Science. We also searched clinical trials registers (ClinicalTrials.gov and ICTRP). We checked the abstracts of major scientific meetings and the reference lists of relevant articles. All randomised controlled trial (RCT) comparisons of NSAIDs versus placebo, other NSAIDs or paracetamol, when used to treat primary dysmenorrhoea. Two review authors independently selected the studies, assessed their risk of bias and extracted data, calculating odds ratios (ORs) for dichotomous outcomes and mean differences for continuous outcomes, with 95% confidence intervals (CIs). We used inverse variance methods to combine data. We assessed the overall quality of the evidence using GRADE methods. We included 80 randomised controlled trials (5820 women). They compared 20 different NSAIDs (18 non-selective and two COX-2-specific) versus placebo, paracetamol or each other. NSAIDs versus placeboAmong women with primary dysmenorrhoea, NSAIDs were more effective for pain relief than placebo (OR 4.37, 95% CI 3.76 to 5.09; 35 RCTs, I(2) = 53%, low quality evidence). This suggests that if 18% of women taking placebo achieve moderate or excellent pain relief, between 45% and 53% taking NSAIDs will do so.However, NSAIDs were associated with more adverse effects (overall adverse effects: OR 1.29, 95% CI 1.11 to 1.51, 25 RCTs, I(2) = 0%, low quality evidence; gastrointestinal adverse effects: OR 1.58, 95% CI 1.12 to 2.23, 14 RCTs, I(2) = 30%; neurological adverse effects: OR 2.74, 95% CI 1.66 to 4.53, seven RCTs, I(2) = 0%, low quality evidence). The evidence suggests that if 10% of women taking placebo experience side effects, between 11% and 14% of women taking NSAIDs will do so. NSAIDs versus other NSAIDsWhen NSAIDs were compared with each other there was little evidence of the superiority of any individual NSAID for either pain relief or safety. However, the available evidence had little power to detect such differences, as most individual comparisons were based on very few small trials. Non-selective NSAIDs versus COX-2-specific selectorsOnly two of the included studies utilised COX-2-specific inhibitors (etoricoxib and celecoxib). There was no evidence that COX-2-specific inhibitors were more effective or tolerable for the treatment of dysmenorrhoea than traditional NSAIDs; however data were very scanty. NSAIDs versus paracetamolNSAIDs appeared to be more effective for pain relief than paracetamol (OR 1.89, 95% CI 1.05 to 3.43, three RCTs, I(2) = 0%, low quality evidence). There was no evidence of a difference with regard to adverse effects, though data were very scanty.Most of the studies were commercially funded (59%); a further 31% failed to state their source of funding. NSAIDs appear to be a very effective treatment for dysmenorrhoea, though women using them need to be aware of the substantial risk of adverse effects. There is insufficient evidence to determine which (if any) individual NSAID is the safest and most effective for the treatment of dysmenorrhoea. We rated the quality of the evidence as low for most comparisons, mainly due to poor reporting of study methods.