Systematic Review of Dexketoprofen in Acute and Chronic Pain

R. Andrew Moore; Jodie Barden

Disclosures

BMC Clin Pharmacol 

In This Article

Abstract and Introduction

Abstract

Background: Dexketoprofen, an NSAID used in the management of acute and chronic pains, is licensed in several countries but has not previously been the subjected of a systematic review. We used published and unpublished information from randomised clinical trials (RCTs) of dexketoprofen in painful conditions to assess evidence on efficacy and harm.
Methods: PubMed and Cochrane Central were searched for RCTs of dexketoprofen for pain of any aetiology. Reference lists of retrieved articles and reviews were also searched. Menarini Group produced copies of published and unpublished studies (clinical trial reports). Data were abstracted into a standard form. For studies reporting results of single dose administration, the number of patients with at least 50% pain relief was derived and used to calculate the relative benefit (RB) and number-needed-to-treat (NNT) for one patient to achieve at least 50% pain relief compared with placebo.
Results: Thirty-five trials were found in acute pain and chronic pain; 6,380 patients were included, 3,381 receiving dexketoprofen. Information from 16 trials (almost half the total patients) was obtained from clinical trial reports from previously unpublished trials or abstracts. Almost all of the trials were of short duration in acute conditions or recent onset pain.
All 12 randomised trials that compared dexketoprofen (any dose) with placebo found dexketoprofen to be statistically superior. Five trials in postoperative pain yielded NNTs for 12.5 mg dexketoprofen of 3.5 (2.7 to 4.9), 25 mg dexketoprofen of 3.0 (2.4 to 3.9), and 50 mg dexketoprofen of 2.1 (1.5 to 3.5). In 29/30 active comparator trials, dexketoprofen at the dose used was at least equivalent in efficacy to comparator drugs. Adverse event withdrawal rates were low in postoperative pain and somewhat higher in trials of longer duration; no serious adverse events were reported.
Conclusion: Dexketoprofen was at least as effective as other NSAIDs and paracetamol/opioid combinations. While adverse event withdrawal was not different between dexketoprofen and comparator analgesics, the different conditions and comparators studies precluded any formal analysis. Exposure was limited, and no conclusions could be drawn about safety in terms of serious adverse events like gastrointestinal bleeding or cardiovascular events.

Introduction

Racemic ketoprofen is used as an analgesic and an anti-inflammatory agent, and is one of the most potent in vitro inhibitors of prostaglandin synthesis, but is also implicated as having an association with higher risk of serious gastrointestinal bleeding events than other NSAIDs.[1,2] The analgesic effect is due to the S(+)-enantiomer (dexketoprofen), while the R(-)-enantiomer is devoid of analgesic activity.[3] Because the R(-)-enantiomer does appear to have ulcerogeneic activity, at least in the rat,[3,4] the implication is that use of dexketoprofen alone should produce equivalent analgesia to double-dose ketoprofen, but at lower risk of harm. At least one case-control study in Spain appears to confirm a lower rate of serious gastrointestinal harm with dexketoprofen than ketoprofen, but with overlapping confidence intervals and small numbers of events.[2] Other authorities regard the approach of using an active enantiomer as a tromethamine salt as attractive on theoretical grounds.[4]

Formulation is important, especially the use of the trometamol salt for rapid absorption.[3] In healthy volunteers absorption of dexketoprofen from dexketoprofen trometamol capsules was similar to ketoprofen, while the extent of absorption of dexketoprofen free acid was significantly lower than that for ketoprofen.[5] Dexketoprofen trometamol showed the most rapid absorption rate, with highest maximum plasma concentration and shortest time to maximum values, while ketoprofen had an intermediate absorption rate, and dexketoprofen free acid the slowest absorption rate. After repeated-dose administration of dexketoprofen trometamol, the pharmacokinetic parameters were similar to those obtained after single doses, indicating that no drug accumulation occurred.[5] Food slowed absorption of dexketoprofen, even from the trometamol salt.[6]

Dexketoprofen is licensed in a number of countries around the world. Oral dexketoprofen was approved in the European Countries through a Mutual Recognition Procedure on 13th February 1998 and the injectable formulation on 25th October 2002. Dexketoprofen has not been subjected to the scrutiny of a systematic review, and not reviewed at all since preclinical and clinical development studies were reviewed over a decade ago.[7] We sought to obtain published and unpublished information from randomised clinical trials of dexketoprofen to assess the available evidence on efficacy and harm.

Systematic reviews are useful for pulling together all the studies on a topic - here randomised, double blind comparative trials of dexketoprofen in painful conditions. By assessing trial quality and validity[8,9] it is possible to eliminate trials likely to be biased, and biased trials are much more likely to over-estimate treatment effects. Accumulating many similar trials together reduces the possibility of variation in efficacy estimates because of the random play of chance, and should improve assessment of harm.

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