Abstract: We included four studies, all of which enrolled adults with frequent episodic TTH. They all specified using the IHS diagnostic criteria and reported mean baseline pain of at least moderate intensity. While 1253 people with TTH participated in these studies, the numbers available for any analysis were lower than this because outcomes were inconsistently reported and because many participants received active comparators. None of the included studies were at low risk of bias across all domains considered, although for most studies and domains this was likely to be due to inadequate reporting rather than poor methods. We judged one study to be at high risk of bias due to small size. Useful information was available only for ketoprofen 25 mg. For the IHS preferred outcome of being pain-free at two hours the NNT for ketoprofen 25 mg compared with placebo was 9.0 (95% confidence interval (CI) 4.8 to 72) in two studies (272 participants; low quality evidence). The NNT was 3.7 (95% CI 2.6 to 6.3) for pain-free or mild pain at two hours in two studies (272 participants; moderate quality evidence). Fewer people needed rescue medication with ketoprofen 25 mg than with placebo, with a number needed to treat to prevent one event (NNTp) of 6.2 (95% CI 4.3 to 11) in three studies (605 participants; moderate quality evidence). The number of participants reporting any adverse event was higher with ketoprofen 25 mg than placebo (NNH 15, (95% CI 8.7 to 45)) in three studies (651 participants with 66 events; low quality evidence). Most events were of mild to moderate intensity. Ketoprofen 25 mg was not different from paracetamol 1000 mg in two studies with 276 participants for any efficacy outcomes (low to moderate quality evidence); the RR for pain-free at two hours was 1.3 (95% CI 0.9 to 2.0). The number of participants reporting any adverse event was higher with ketoprofen 25 mg than with paracetamol (NNH 17, 95% CI 8.9 to 130)) in two studies (582 participants, 68 events; low quality evidence). Studies reported no serious adverse events. We judged the quality of the evidence comparing ketoprofen 25 mg with placebo or paracetamol 1000 mg as moderate to very low. Where evidence was downgraded it was because of the small number of studies and events. Ketoprofen 25 mg provided a small benefit compared with placebo in terms of being pain-free at two hours or having mild or no pain at two hours for people with frequent episodic TTH who have an acute headache of moderate or severe intensity. Its use was associated with more people experiencing adverse events. Ketoprofen 25 mg was not superior to paracetamol 1000 mg for any efficacy outcome.

Plain-language summary: In May 2016, we searched the medical literature and found four studies involving 1253 participants looking at ketoprofen for frequent episodic tension-type headache. Only a fraction of the participants were involved in comparisons between ketoprofen 25 mg and placebo (a dummy tablet). Results were usually reported two hours after taking the medicine or placebo. The International Headache Society recommends the outcome of being pain-free two hours after taking a medicine, but other outcomes are also suggested. Few studies reported these recommended outcomes, so there was limited information to analyse for some outcomes. The outcome of being pain-free at two hours was reported by 27 in 100 people taking ketoprofen 25 mg, and in 16 out of 100 people taking placebo, meaning that only 11 in 100 people benefited because of ketoprofen 25 mg (low quality evidence). The outcome of being pain-free or having only mild pain at two hours was reported by 66 in 100 people taking ketoprofen 25 mg, and in 38 out of 100 people taking placebo (moderate quality evidence), meaning that 28 in 100 people benefited because of ketoprofen 25 mg. About 14 in 100 people taking ketoprofen 25 mg reported having a side effect, which was slightly more than with placebo (7 in 100 people) (low quality evidence). Most side effects were mild or moderate in intensity. No side effects were serious. Ketoprofen 25 mg was not different from paracetamol 1000 mg for any measure of headache relief (moderate and low quality evidence), but was associated with more side events (low quality evidence). The quality of the evidence for being pain-free at two hours was low quality, and for having mild pain at two hours was moderate quality. Moderate quality evidence means that we are reasonably confident about the results. Low quality evidence means that we are not very certain about the results and they could change with more information.