Abstract

Background

Combining two different analgesics in fixed doses in a single tablet can provide better pain relief than either drug alone in acute pain. This appears to be broadly true across a range of different drug combinations, in postoperative pain and migraine headache. A new combination of dexketoprofen (a nonsteroidal anti‐inflammatory drug) plus tramadol (an opioid) has been tested in acute postoperative pain conditions. It is not yet licensed for use. This review is one of a series on oral analgesics for acute postoperative pain. Individual reviews have been brought together in two overviews to provide information about the relative efficacy and harm of the different interventions.

Objectives

To assess the analgesic efficacy and adverse effects of a single fixed‐dose of oral dexketoprofen plus tramadol, compared with placebo, for moderate to severe postoperative pain in adults, using methods that permit comparison with other analgesics evaluated in standardised trials using almost identical methods and outcomes. A secondary objective was to compare the combination with the individual analgesics alone.

Search methods

We searched the Cochrane Central Register of Controlled Trials (CENTRAL) via CRSO, MEDLINE via Ovid, and Embase via Ovid from inception to 31 May 2016. We also searched the reference lists of retrieved studies and reviews, and two online clinical trial registries.

Selection criteria

Randomised, double‐blind trials of oral dexketoprofen plus tramadol administered as a single oral dose, for the relief of acute postoperative pain in adults, and compared to placebo.

Data collection and analysis

Two review authors independently considered trials for inclusion in the review, examined issues of study quality and potential bias, and extracted data. For dichotomous outcomes, we calculated risk ratio (RR) and number needed to treat for an additional beneficial outcome (NNT) for dexketoprofen plus tramadol, compared with placebo with 95% confidence intervals (CI). We collected information on the number of participants with at least 50% of the maximum possible pain relief over six hours, the median time to use of rescue medication, and the proportion of participants requiring rescue medication. We also collected information on adverse events and withdrawals. We assessed the quality of the evidence using GRADE and created a 'Summary of findings' table.

We also collected information on the number of participants with at least 50% of the maximum possible pain relief over six hours for dexketoprofen alone and tramadol alone.

Main results

We included three studies with 1853 participants who had undergone surgical removal of impacted wisdom teeth, hip replacement, or hysterectomy. The overall risk of bias across the three included studies was low, with unclear risk of bias in relation to the size of the three studies. Two studies did not report all our prespecified outcomes, which limited the analyses we could do.

The proportion of participants achieving at least 50% pain relief over six hours with dexketoprofen 25 mg plus tramadol 75 mg was 66%, compared to 32% with placebo, giving an NNT of 3.0 (95% CI 2.5 to 3.7) (RR 2.1 (95% CI 1.7 to 2.4); 748 participants; 3 studies) (moderate quality evidence). The response rate with dexketoprofen 25 mg alone was 53% (RR 1.3 (95% CI 1.1 to 1.4); 744 participants; 3 studies) and with tramadol alone was 45% (RR 1.5 (95% CI 1.3 to 1.7); 741 participants; 3 studies) (moderate quality evidence). We downgraded the evidence because of some inconsistency in the results.

The median time to use of rescue medication could not be estimated exactly, but was probably eight hours or more, indicating a long duration of effect (moderate quality evidence). We downgraded the evidence because it was not possible to estimate the effect exactly in the two multiple dose studies, resulting in imprecision. Fewer participants used rescue medication with higher doses of active treatment (summary statistic not calculated; 123 participants; 1 study) (very low quality evidence). We downgraded the evidence because the data came from a single study with few participants and events.

Adverse events and serious adverse events were not reported consistently for the single dose phase of the studies. In the single dose study, 11% of participants experienced adverse events with dexketoprofen 25 mg plus tramadol 75 mg, which were mostly mild or moderate nausea, vomiting, or dizziness, and typical with these medicines. Rates were lower with placebo and lower doses (very low quality evidence). We downgraded the evidence because the data came from a single study with few participants and events. Information on multiple dosing over three and five days supported a low event rate with the combination. Overall, rates were generally low in all treatment arms, as they were for withdrawals for adverse events or other reasons.

Authors' conclusions

A single oral dose of dexketoprofen 25 mg plus tramadol 75 mg provided good levels of pain relief with long duration of action to more people than placebo or the same dose of dexketoprofen or tramadol alone. The magnitude of the effect was similar to other good analgesics. Adverse event rates were low.

There is modest uncertainty about the precision of the point estimate for efficacy, but the NNT of 3 is consistent with other analgesics considered effective and commonly used.

Author(s)

Sheena Derry, Tess E Cooper, Tudor Phillips

Abstract

Plain language summary

Fixed‐dose oral dexketoprofen plus tramadol for acute postoperative pain in adults

Bottom line

This review found that most people with moderate or severe pain after an operation get good pain relief from taking dexketoprofen 25 mg plus tramadol 75 mg.

Background

Acute pain is short‐lived pain often felt soon after injury, including after operations. Most people who have an operation have moderate or severe pain afterwards. Painkillers are tested in people with acute pain, often following the removal of wisdom teeth. This pain is usually treated with painkillers taken by mouth. We believe these results can be applied to other acute painful conditions.

The use of two different painkillers in a single tablet at fixed doses has been found to provide good pain relief to a high proportion of people with moderate or severe pain after an operation. This review examined a new fixed‐dose combination of two painkillers, a nonsteroidal anti‐inflammatory medicine (dexketoprofen) with an opioid medicine (tramadol).

Study characteristics

In May 2016, we found three studies involving 1853 people. The main comparison was between the fixed‐dose of dexketoprofen 25 mg plus tramadol 75 mg and placebo (a dummy treatment). The studies tested single doses after wisdom tooth extraction, hip replacement operations, and gynaecological (female reproductive system) operations. Studies included adults over a range of ages, and 7 out of 10 participants were women. The main outcome was the number of participants having at least half of the maximum possible pain relief over the first six hours after taking the tablets.

Key results

All three studies reported the main outcome for dexketoprofen 25 mg plus tramadol 75 mg. There were 748 participants in the comparison with placebo. About 7 in 10 people achieved this outcome with dexketoprofen 25 mg plus tramadol 75 mg, compared with 3 in 10 with placebo. The combination was significantly better than placebo, and better than either dexketoprofen or tramadol alone. The pain relief lasted a long time, probably eight hours or more, but the exact duration could not be determined. Fewer people needed to take additional painkillers with the combination treatment than with placebo.

About 1 in 10 people had side effects with dexketoprofen 25 mg plus tramadol 75 mg. These were mostly mild or moderate nausea (feeling sick), vomiting (being sick), and dizziness, which are typical with these medicines. Serious side effects were uncommon. Few people dropped out of the studies.

Quality of the evidence

We judged the quality of the evidence as moderate for the painkilling effect of dexketoprofen 25 mg plus tramadol 75 mg. For side effects we judged the quality of the evidence about a single dose as very low because there were so few participants and events, but we judged it as moderate when we included evidence from the three‐ and five‐day studies. Moderate quality evidence means that more information might change our estimate of the effect. Very low quality evidence means that we are very uncertain about the results.

Author(s)

Sheena Derry, Tess E Cooper, Tudor Phillips

Reviewer's Conclusions

Authors' conclusions 

Implications for practice 

For people with moderate to severe acute pain

A single oral dose of dexketoprofen 25 mg plus tramadol 75 mg provided good levels of pain relief to more people than placebo or the same dose of dexketoprofen or tramadol alone. The magnitude of the effect is similar to other analgesics generally considered effective in postoperative pain.

For clinicians

A single oral dose of dexketoprofen 25 mg plus tramadol 75 mg provided good levels of pain relief with long duration of action to more people than the same dose of dexketoprofen or tramadol alone. The magnitude of the effect is similar to other good analgesics, as reported in Cochrane reviews of individual analgesics and in two overviews. Adverse event rates were low, and possibly lower than with single drugs, but this was based on very low and moderate quality evidence and should be interpreted with caution.

For policy makers

Dexketoprofen 25 mg plus tramadol 75 mg is an effective analgesic in acute pain when compared with placebo. There is modest uncertainty about the precision of the point estimate for efficacy, but the number needed to treat for an additional beneficial outcome (NNT) of 3 is consistent with other analgesics considered effective and commonly used.

For funders

Dexketoprofen 25 mg plus tramadol 75 mg is an effective analgesic in acute pain when compared with placebo. There is modest uncertainty about the precision of the point estimate for efficacy, but the NNT of 3 is consistent with other analgesics considered effective and commonly used.

Implications for research 

General

This review confirms that fixed‐dose combination analgesics provide good levels of pain relief in a large proportion of people with acute pain. It is not clear from the available data whether lower doses of dexketoprofen and tramadol in the combination can provide the same level of efficacy as standard doses of the individual drugs, possibly with reduced adverse events. Studies with larger numbers of participants in treatment arms using low‐dose combinations would be required to investigate this.

Design

The current design of acute pain studies is well understood, and has proven to be robust.

Measurement (endpoints)

Endpoints in these studies have been extensively validated, as have standard pain scoring systems. The main outcome used is one valued by people with pain, and has economic benefits in most circumstances.

Comparison between active treatments

The standardised nature of the study design means that indirect comparisons with placebo are valid, as evidenced by independent research. There is, however, a very large body of information amenable to network meta‐analysis. While unlikely to provide much in the way of new insights, it could prove an invaluable tool for testing network meta‐analytical methods.

Reporting

The studies in this review demonstrate that adherence to CONSORT and similar guidelines, and the extensive use of online supplementary material, provides a case study on good reporting of clinical trial methods and results.

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