Abstract

Background

Tension‐type headache (TTH) affects about 1 person in 5 worldwide. It is divided into infrequent episodic TTH (fewer than one headache day per month), frequent episodic TTH (2 to 14 headache days per month), and chronic TTH (15 headache days a month or more). Ketoprofen is one of a number of analgesics suggested for acute treatment of headaches in frequent episodic TTH.

Objectives

To assess the efficacy and safety of ketoprofen for treatment of episodic TTH in adults compared with placebo or any active comparator.

Search methods

We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, and the Oxford Pain Relief Database up to May 2016, and also reference lists of relevant published studies and reviews. We sought unpublished studies by asking personal contacts and searching online clinical trial registers and manufacturers' websites.

Selection criteria

We included randomised, double‐blind, placebo‐controlled studies (parallel‐group or cross‐over) using oral ketoprofen for symptomatic relief of an acute episode of TTH. Studies had to be prospective, with participants aged 18 years or over, and include at least 10 participants per treatment arm.

Data collection and analysis

Two review authors independently assessed studies for inclusion and extracted data. We used the numbers of participants achieving each outcome to calculate the risk ratio (RR) and number needed to treat for one additional beneficial outcome (NNT) or one additional harmful outcome (NNH) for oral ketoprofen compared to placebo or an active intervention for a range of outcomes, predominantly those recommended by the International Headache Society (IHS).

We assessed the evidence using GRADE and created a 'Summary of findings' table.

Main results

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.

Authors' conclusions

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.

Author(s)

Lucy Veys, Sheena Derry, R Andrew Moore

Abstract

Plain language summary

Oral ketoprofen for treatment of acute episodic tension‐type headache in adults

Bottom line

This review found that few people with 2 to 14 tension‐type headaches a month get good pain relief from taking ketoprofen 25 mg. There are questions about how studies of this type of headache are conducted. These questions involve the type of people chosen for the studies and the types of outcomes reported. This limits the usefulness of the results, especially for people who just have an occasional headache.

Background

People with frequent episodic tension‐type headache have between 2 and 14 headaches days every month. Tension‐type headache stops people concentrating and working properly, and results in much disability. When headaches do occur, they get better over time, even without treatment.

Ketoprofen is a commonly used painkiller, available by prescription in most parts of the world but without prescription (over‐the‐counter) in some. The usual dose is 25 mg or 50 mg taken by mouth.

Study characteristics

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.

Key results

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).

Quality of the 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.

Author(s)

Lucy Veys, Sheena Derry, R Andrew Moore

Reviewer's Conclusions

Authors' conclusions 

Implications for practice 

For people with frequent episodic tension‐type headache

Ketoprofen 25 mg may relieve headache pain, but the chance of the pain being relieved entirely by two hours is low, about 3 in 10 (27%), and this is only very slightly greater than the proportion with placebo (about 2 in 10, or 16%). We do not know how or if these results can be extrapolated to people with an occasional headache. Its use is probably associated with more adverse events than placebo.

For clinicians

Ketoprofen may provide headache relief to about 10% more people with frequent episodic tension‐type headache than placebo, but at the expense of increased adverse events. It may be that a different dose or formulation of ketoprofen, or a combination with paracetamol or caffeine might be better, but evidence on this is lacking.

For policy makers

There is insufficient information on drugs, doses, formulations, or outcomes for policy makers to be able to make strong recommendations. Policy should reflect the finding of no or little clinically useful benefit.

For funders

Because of the very limited information and small degree of efficacy found for ketoprofen, it is highly unlikely that the treatment could be regarded as cost effective even considering that this is a generic drug.

Implications for research 

General

Frequent episodic tension‐type headache (TTH) is common and debilitating. The amount of evidence was limited by reporting issues, particularly of outcomes; this is a general finding for all TTH studies, not just those involving ketoprofen. It is not sufficient just to call for more studies. What is needed is a better understanding of TTH studies, in terms of the outcomes that can be reported from clinical trials, and often are not, and the differential effects of treatments in people with different degrees of headache frequency. This can be done from individual participant‐level analyses. Given that few modern studies have been completed or are underway involving ketoprofen or other drugs, this would appear to be the research priority before new studies are commissioned.

Design

The design of studies was generally good, although some were small. Future studies should be adequately powered to detect the magnitude of any effect, not simply a statistical difference from placebo, and could usefully investigate using different doses and formulations.

Measurement (endpoints)

The measurement of pain is not a major issue as most studies, especially modern studies, have used standard pain intensity and pain relief scales. What is at issue are the outcomes reported using those pain measurements. It is not clear that the International Headache Society preferred outcome of being free of pain at two hours is entirely appropriate, and while it is reasonable by analogy with migraine, it requires substantiating.

Comparison between active treatments

No authoritative comparisons between active treatments is possible in the present state of knowledge.

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