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Systematic Review of Dexketoprofen in Acute

and Chronic Pain
R. Andrew Moore; Jodie Barden

BMC Clin Pharmacol

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We used published and unpublished information from randomised clinical trials (RCTs) of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Group produced copies of published and unpublished studies (clinical trial reports).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patients) was obtained from clinical trial reports from previously unpublished trials or abstracts.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.

Methods

We searched PubMed, and Cochrane Central up to October 2008 for randomised controlled trials
using dexketoprofen to treat pain of any aetiology. The detailed search strategy included use of
the drug name dexketoprofen anywhere in an article, together with the publication descriptor of
randomised trial; this was modified for the different databases. Reference lists of retrieved
articles and reviews were also searched for relevant trials. In addition, Menarini Group also
produced copies of published and unpublished studies, the latter in the form of clinical trial
reports.

For inclusion, trials had to be at least randomised, and use dexketoprofen to treat adult patients
with pain of any origin. Trials had to have a minimum of 10 patients per treatment arm, and at
least one dose of dexketoprofen given by any route of administration, at any dose, and with any
comparator.

The abstracts were read, and potentially useful reports retrieved in full paper copy. No
information was taken from posters or abstracts unless supplemented by details from a clinical
trial report. Decisions on inclusion or exclusion of trials, assessment of trial quality and validity
and all data extraction were made independently by both reviewers, with discrepancies resolved
by consensus.

Methodological quality of included studies was assessed using the validated 5-point Oxford
quality scale[8] utilising reporting of randomisation, blinding and withdrawals. The maximum
score possible was 5 points, and no study could be included with fewer than 2 points (one for
randomisation and one for blinding). Study validity was assessed using the validated Oxford Pain
Validity Scale (OPVS) 16-point scale.[9] Only trials that were both randomised and double blind
were used for calculation of numbers needed to treat.

Data were abstracted into a standard form. Information was extracted from the trials according to
painful condition, with details of drugs, dose, route of administration, patient numbers, treatment
and observation schedule, outcomes measured, and main efficacy and safety results.

For studies reporting results of single dose administration we sought to the outcome of at least
50% pain relief. For each report, mean TOTPAR (total pain relief) or SPID (summed pain
intensity difference) for active and placebo groups were converted to %maxTOTPAR or
%maxSPID by division into the calculated maximum value.[10] The proportion of patients in each
treatment group who achieved at least 50%maxTOTPAR was calculated using verified
equations.[11-13] These proportions were then converted into the number of patients achieving at
least 50%maxTOTPAR by multiplying by the total number of patients in the treatment group.
Information on the number of patients with at least 50%maxTOTPAR for active treatment and
placebo was then used to calculate relative benefit (RB) and number needed-to-treat (NNT). Pain
measures accepted for the calculation of TOTPAR or SPID were:

 5-point categorical pain relief (PR) scales with comparable wording to "none, slight,
moderate, good or complete"
 4-point categorical pain intensity (PI) scales with comparable wording to "none, mild,
moderate, severe"
 Visual analogue scales (VAS) for pain relief
 VAS for pain intensity
 5-point categorical global scale with the wording "poor, fair, good, very good,
excellent"[14]
Other measures of pain relief were abstracted where reported and appropriate. Secondary
outcomes were withdrawals (all cause, lack of efficacy and adverse events) and adverse events
(patients with at least one adverse event, serious adverse events, and specific adverse events).
We anticipated that reporting of adverse events would vary between trials with regard to the
terminology used, method of ascertainment, and categories reported (e.g. occurring in ≥ 5% of
patients or where there was a statistically significant difference between treatment groups).

Guidelines for quality of reporting of meta-analyses were followed where appropriate.[15] The
prior intention was to pool data where there was clinical and methodological homogeneity, with
similar patients, dose, duration, outcomes, and comparators, but not where numbers of events
were small, and random chance could dominate effects of treatment.[16] Homogeneity tests and
funnel plots, though commonly used in meta-analysis, were not used here because they have
been found to be unreliable.[17,18] Instead clinical homogeneity was examined graphically.[19]
Relative benefit (or risk) and number-needed-to-treat or harm (NNT or NNH) were calculated
with 95% confidence intervals. Relative benefit or risk was calculated using a fixed effects
model,[20] with no statistically significant difference between treatments assumed when the 95%
confidence intervals included unity. We added 0.5 to treatment and comparator arms of trials in
which at least one arm had no events. Number-needed-to-treat (or harm) was calculated by the
method of Cook and Sackett[21] using the pooled number of observations only when there was a
statistically significant difference of relative benefit or risk (where the confidence interval did
not include 1). There was a prior intention to carry out sensitivity analyses for high versus low
trial quality (< 3 vs ≥ 3), dose, and condition. Information would be reported with any number of
patients, but not regarded unless there was a minimum of two trials or 250 patients.[16]

Results

Thirty-five trials were found in acute and chronic pain, 32 of which had reporting quality of 3/5
or better and 30 of which had OPVS score of at least 9/16 ( ). Ten trials had individual group
sizes of 100 patients or more. The total number of patients was 6,380, of whom 3381 received
dexketoprofen ( ). More patients were in trials of oral therapies (4,249 total, 2,270 on
dexketoprofen) than trials of intramuscular or intravenous therapies (2,131 total, 1,111 on
dexketoprofen). Information from 16 trials (46%) with 3,253 patients (51%) was obtained from
clinical trial reports from previously unpublished trials, or trials published only as abstracts. All
16 clinical trial reports had a quality score of at least 3/5 and an OPVS score of at least 9/16.
Almost all of the trials were of short duration in acute conditions, or for recent onset pain. Only
two, in osteoarthritis, investigated efficacy in chronic painful conditions.

Table 1. Summary Table of Randomised Trials Included in the Review

Number of
At least
Number of: patients
Better than equivalent to
Studie Studie Trial placebo/tot effective
s with s with s of In Given al analgesic/tot
Pain Studie QS ≥ OPVS grou tota dexketoprof comparison al
condition s 3/5 ≥ 9/16 p l en s comparisons
 size
≥ 100
Dental pain 7 6 6 0 994 618 4/4 3/4
218
Postsurgical 13 11 11 2 1022 7/7 11/11
5
Renal colic 3 3 3 3 838 526 3/3
Gynaecolog
2 2 1 1 350 200 1/1 2/2
ic pain
Lower limb
1 1 1 0 122 65 1/1
injury
Ankle
1 1 1 1 209 106 1/1
sprain
Acute bone
pain in 1 1 1 0 115 57 1/1
cancer
Acute low 126
5 5 5 3 635 5/5
back pain 7
OA/RA 2 2 2 0 300 152 2/2
638
Total 35 32 31 10 3381 12/12 29/30
0

QS = quality score; OPVS = Oxford Pain Validity Score; OA = osteoarthritis; RA = rheumatoid

arthritis

Table 1. Summary Table of Randomised Trials Included in the Review

Number of
Number of: patients
Trial At least
s of Better than equivalent to
Studie Studie grou placebo/tot effective
s with s with p In Given al analgesic/tot
Pain Studie QS ≥ OPVS size tota dexketoprof comparison al
condition s 3/5 ≥ 9/16 ≥ 100 l en s comparisons
Dental pain 7 6 6 0 994 618 4/4 3/4
 218
Postsurgical 13 11 11 2 1022 7/7 11/11
5
Renal colic 3 3 3 3 838 526 3/3
Gynaecolog
2 2 1 1 350 200 1/1 2/2
ic pain
Lower limb
1 1 1 0 122 65 1/1
injury
Ankle
1 1 1 1 209 106 1/1
sprain
Acute bone
pain in 1 1 1 0 115 57 1/1
cancer
Acute low 126
5 5 5 3 635 5/5
back pain 7
OA/RA 2 2 2 0 300 152 2/2
638
Total 35 32 31 10 3381 12/12 29/30
0

QS = quality score; OPVS = Oxford Pain Validity Score; OA = osteoarthritis; RA = rheumatoid

arthritis

All 12 randomised trials that compared dexketoprofen, at any dose, with placebo found
dexketoprofen to be statistically superior ( ). More common was a comparison of dexketoprofen
with an active comparator, which happened in 30 trials. In 29 of these 30 trials, dexketoprofen at
the dose used was at least equivalent in efficacy to the comparator drugs with known analgesic
efficacy.

Table 1. Summary Table of Randomised Trials Included in the Review

Number of
Number of: patients
Trial At least
s of Better than equivalent to
Studie Studie grou placebo/tot effective
s with s with p In Given al analgesic/tot
Pain Studie QS ≥ OPVS size tota dexketoprof comparison al
condition s 3/5 ≥ 9/16 ≥ 100 l en s comparisons
Dental pain 7 6 6 0 994 618 4/4 3/4
218
Postsurgical 13 11 11 2 1022 7/7 11/11
5
Renal colic 3 3 3 3 838 526 3/3
Gynaecolog
2 2 1 1 350 200 1/1 2/2
ic pain
Lower limb
1 1 1 0 122 65 1/1
injury
Ankle
1 1 1 1 209 106 1/1
sprain
Acute bone
pain in 1 1 1 0 115 57 1/1
cancer
Acute low 126
5 5 5 3 635 5/5
back pain 7
OA/RA 2 2 2 0 300 152 2/2
638
Total 35 32 31 10 3381 12/12 29/30
0

QS = quality score; OPVS = Oxford Pain Validity Score; OA = osteoarthritis; RA = rheumatoid

arthritis

Single and Multiple Dose Trials in Dental Pain

Seven randomised trials[22-29] examined the analgesic efficacy of oral dexketoprofen in 994
patients studied in the third molar extraction pain model, 618 of whom received dexketoprofen
(Additional file 1). One trial was published as an abstract,[29] with data taken from a clinical trial
report.[23] Six of the seven trials were both randomised and double blind, and had quality scores
of 4 or 5 of the maximum 5 points and had OPVS scores of at least 9/16. One open trial[27]
scored only 1 out of 5.

Three good quality trials were standard pain models reporting pain intensity or pain relief for
four to six hours after the initial dose, had patients with moderate or severe pain at entry, and
measured pain intensity and pain relief over six hours.[24,25,28] In these three trials dexketoprofen
at doses of 10 or 12.5 mg (Figure 1), 20 or 25 mg (Figure 2), and 50 mg were all significantly
superior to placebo, with NNTs for at least 50% pain relief over six hours compared with
placebo of 3.0 (2.3 to 4.4), 2.6 (2.0 to 3.5), and 2.1 (1.5 to 3.5) respectively ( ). One trial[28] used
ketoprofen 50 mg, and that was also significantly better than placebo. The one other trial that
used placebo[26] reported data at eight hours, and appeared to measure pain scores after use of
remedication. Despite that, dexketoprofen 25 mg was significantly better than placebo.

Table 2. Results of Single Dose Trials in Dental and Postsurgical Pain for Comparison of
Dexketoprofen With Placebo, and Dexketoprofen With Ketoprofen

Dexketoprofen versus placebo

Percent of patients with at Relativ
Number of
least 50% pain relief e
benefit
Trial Patient Dexketoprofe (95% NNT
Dexketoprofen dose (mg) s s n Placebo CI) (95% CI)
All trials
3.4 (2.2 3.5 (2.7 to
10/12.5 mg 5 462 45 17
to 5.6) 4.9)
3.9 (2.4 3.0 (2.4 to
20/25 mg 5 455 50 17
to 6.3) 3.9)
6.7 (1.7 2.1 (1.5 to
50 mg 1 67 56 8
to 26) 3.5)
Dental
3.5 (2.2 3.0 (2.3 to
10/12.5 mg 3 261 47 13
to 5.6) 4.4)
3.9 (2.4 2.6 (2.0 to
20/25 mg 3 254 52 13
to 6.3) 3.5)
6.7 (1.7 2.1 (1.5 to
50 mg 1 67 56 8
to 26) 3.5)
Postsurgical
2.1 (1.4 4.4 (2.8 to
10/12.5 mg 2 201 43 21
to 3.3) 9.7)
2.3 (1.5 3.7 (2.5 to
20/25 mg 2 201 47 21
to 3.6) 7.0)
Dexketoprofen versus ketoprofen
Percent of patients with at Relativ
Number of
least 50% pain relief e
benefit
Dexketoprofen/ketoprofe Trial Patient Dexketoprofe Ketoprofe (95% NNT
n dose (mg) s s n n CI) (95% CI)
All trials
 not
0.8 (0.5
12.5 vs 50 3 287 44 35 calculate
to 1.2)
d
not
1.1 (0.7
25 vs 50 3 284 51 35 calculate
to 1.5)
d
not
1.1 (0.9
50 vs 100 1 247 82 77 calculate
to 1.2)
d
1.2 (1.1 8.8 (5.1 to
25/50 vs 50/100 4 531 65 54
to 1.4) 33)

L'Abbé plot of individual trials of dexketoprofen 10/12.5 mg compared with placebo in dental
and postsurgical pain. Inset scale shows size of trial. Light symbols = dental trials, dark symbols
= postsurgical trials.
L'Abbé plot of individual trials of dexketoprofen 20/25 mg compared with placebo in dental and
postsurgical pain. Inset scale shows size of trial. Light symbols = dental trials, dark symbols =
postsurgical trials.

Dexketoprofen 12.5 mg and 25 mg were both superior to dipyrone 575 mg in the single dose
phase of a multiple dose trial.[22] There was no difference between use of pre and postsurgical
dexketoprofen in another trialsup>.[23,29] The final trial[27] compared dexketoprofen 25 mg with
ibuprofen 600 mg, but no interpretation could be made in this case because it included patients
with mild pain which is known to desensitise pain trials.

Single and Multiple Dose Trials in Postsurgical Pain

Thirteen randomised trials[30-43] examined the analgesic efficacy of dexketoprofen in 2135

patients studied in postsurgical pain, 997 of whom received dexketoprofen (Additional file 2).
One trial was published as an abstract[31] with data taken from a clinical trial report.[42] Twelve of
the 13 trials were both randomised and double blind, and 11 had quality scores of three or more
of the maximum 5 points and at least 9 on an OPVS ( ). Eight trials (1212 patients) used oral
dexketoprofen and four (923 patients) intramuscular or intravenous dexketoprofen. Eight of the
13 trials were in major orthopaedic surgery (mainly knee and hip surgery), the others involving
arthroscopy, bunionectomy, hernias, abdominal hysterectomy, and abdominal surgery.

Summary Table of Randomised Trials Included in the Review

Number of
Number of: patients
Trial At least
s of Better than equivalent to
Studie Studie grou placebo/tot effective
s with s with p In Given al analgesic/tot
Pain Studie QS ≥ OPVS size tota dexketoprof comparison al
condition s 3/5 ≥ 9/16 ≥ 100 l en s comparisons
Dental pain 7 6 6 0 994 618 4/4 3/4
218
Postsurgical 13 11 11 2 1022 7/7 11/11
5
Renal colic 3 3 3 3 838 526 3/3
Gynaecolog
2 2 1 1 350 200 1/1 2/2
ic pain
Lower limb
1 1 1 0 122 65 1/1
injury
Ankle
1 1 1 1 209 106 1/1
sprain
Acute bone
pain in 1 1 1 0 115 57 1/1
cancer
Acute low 126
5 5 5 3 635 5/5
back pain 7
OA/RA 2 2 2 0 300 152 2/2
638
Total 35 32 31 10 3381 12/12 29/30
0

QS = quality score; OPVS = Oxford Pain Validity Score; OA = osteoarthritis; RA = rheumatoid

arthritis

Two good quality trials were standard pain models reporting pain intensity or pain relief for four
to six hours after the initial dose, had patients with moderate or severe pain at entry, and
measured pain intensity and pain relief over six hours.[32,34] In these trials oral dexketoprofen at
doses of 10 or 12.5 mg (Figure 1) and 20 or 25 mg (Figure 2) were significantly superior to
placebo, with NNTs for at least 50% pain relief over six hours compared with placebo of 4.4 (2.8
to 9.7) and 3.7 (2.5 to 7.0) respectively ( ). Four of the nine oral trials used placebo, and in these
dexketoprofen was significantly better than placebo on at least one measure in three trials,[34,39,43]
but not in the fourth.[32] Ketoprofen 50 mg was not significantly better than placebo in the two
trials that used it.[32,34]

Table 2. Results of Single Dose Trials in Dental and Postsurgical Pain for Comparison of
Dexketoprofen With Placebo, and Dexketoprofen With Ketoprofen

Dexketoprofen versus placebo

Percent of patients with at Relativ
Number of
least 50% pain relief e
benefit
Trial Patient Dexketoprofe (95% NNT
Dexketoprofen dose (mg) s s n Placebo CI) (95% CI)
All trials
3.4 (2.2 3.5 (2.7 to
10/12.5 mg 5 462 45 17
to 5.6) 4.9)
3.9 (2.4 3.0 (2.4 to
20/25 mg 5 455 50 17
to 6.3) 3.9)
6.7 (1.7 2.1 (1.5 to
50 mg 1 67 56 8
to 26) 3.5)
Dental
3.5 (2.2 3.0 (2.3 to
10/12.5 mg 3 261 47 13
to 5.6) 4.4)
3.9 (2.4 2.6 (2.0 to
20/25 mg 3 254 52 13
to 6.3) 3.5)
6.7 (1.7 2.1 (1.5 to
50 mg 1 67 56 8
to 26) 3.5)
Postsurgical
2.1 (1.4 4.4 (2.8 to
10/12.5 mg 2 201 43 21
to 3.3) 9.7)
2.3 (1.5 3.7 (2.5 to
20/25 mg 2 201 47 21
to 3.6) 7.0)
Dexketoprofen versus ketoprofen
Percent of patients with at Relativ
Number of
least 50% pain relief e
benefit
Dexketoprofen/ketoprofe Trial Patient Dexketoprofe Ketoprofe (95% NNT
n dose (mg) s s n n CI) (95% CI)
All trials
not
0.8 (0.5
12.5 vs 50 3 287 44 35 calculate
to 1.2)
d
not
1.1 (0.7
25 vs 50 3 284 51 35 calculate
to 1.5)
d
not
1.1 (0.9
50 vs 100 1 247 82 77 calculate
to 1.2)
d
1.2 (1.1 8.8 (5.1 to
25/50 vs 50/100 4 531 65 54
to 1.4) 33)

Where there was an active comparator, dexketoprofen 25 mg appeared to be equivalent to

tramadol 50 mg,[42,33] diclofenac 50 mg,[36] and paracetamol 500 mg plus codeine 22.5 mg.[38]
Three trials compared dexketoprofen 25 mg with ketoprofen 50 mg; while there was no
difference in one small trial,[41] ketoprofen appeared to be less effective in two others.[32,34]

Two trials[35,40] used intramuscular administration of dexketoprofen at doses of 25 mg or 50 mg

twice a day, and two[30,37] intravenous administration of 50 mg three times a day, or 50 mg twice
a day. Time intervals between doses were 6-8 h and 12 hours in the different studies.
Three[35,37,40] made a comparison with placebo, and in all three doses of dexketoprofen were
significantly better than placebo on at least one measure of efficacy. All four trials had an active
comparator, and dexketoprofen at the dose studied was at least as effective as ketoprofen 100
mg,[30,40] tramadol 100 mg,[37] and diclofenac 75 mg twice a day.[35] There was a suggestion of
somewhat better efficacy between three and eight hours, and lower morphine requirements, than
diclofenac 75 mg twice a day.[35]

Overall Results of Single Dose Dexketoprofen in Acute Pain, and Comparison With
Ketoprofen

Combining three third molar extraction and two postsurgical trials ( ) gave NNTs for at least
50% pain relief 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). The overlapping confidence intervals and
formal testing[44] for difference between NNTs showed no statistical difference between 12.5 mg
and 25 mg doses.

Table 2. Results of Single Dose Trials in Dental and Postsurgical Pain for Comparison of
Dexketoprofen With Placebo, and Dexketoprofen With Ketoprofen

Dexketoprofen versus placebo

Percent of patients with at Relativ NNT
Number of
Dexketoprofen dose (mg) least 50% pain relief e (95% CI)
 benefit
Trial Patient Dexketoprofe (95%
s s n Placebo CI)
All trials
3.4 (2.2 3.5 (2.7 to
10/12.5 mg 5 462 45 17
to 5.6) 4.9)
3.9 (2.4 3.0 (2.4 to
20/25 mg 5 455 50 17
to 6.3) 3.9)
6.7 (1.7 2.1 (1.5 to
50 mg 1 67 56 8
to 26) 3.5)
Dental
3.5 (2.2 3.0 (2.3 to
10/12.5 mg 3 261 47 13
to 5.6) 4.4)
3.9 (2.4 2.6 (2.0 to
20/25 mg 3 254 52 13
to 6.3) 3.5)
6.7 (1.7 2.1 (1.5 to
50 mg 1 67 56 8
to 26) 3.5)
Postsurgical
2.1 (1.4 4.4 (2.8 to
10/12.5 mg 2 201 43 21
to 3.3) 9.7)
2.3 (1.5 3.7 (2.5 to
20/25 mg 2 201 47 21
to 3.6) 7.0)
Dexketoprofen versus ketoprofen
Percent of patients with at Relativ
Number of
least 50% pain relief e
benefit
Dexketoprofen/ketoprofe Trial Patient Dexketoprofe Ketoprofe (95% NNT
n dose (mg) s s n n CI) (95% CI)
All trials
not
0.8 (0.5
12.5 vs 50 3 287 44 35 calculate
to 1.2)
d
not
1.1 (0.7
25 vs 50 3 284 51 35 calculate
to 1.5)
d
not
1.1 (0.9
50 vs 100 1 247 82 77 calculate
to 1.2)
d
 1.2 (1.1 8.8 (5.1 to
25/50 vs 50/100 4 531 65 54
to 1.4) 33)

Several trials used both dexketoprofen and ketoprofen. also shows the comparisons between 12.5
mg and 25 mg dexketoprofen and 50 mg ketoprofen, and 50 mg dexketoprofen and 100 mg
ketoprofen. While the proportion of patients achieving at least 50% pain relief was consistently
higher with dexketoprofen, this did not reach statistical significance with any comparison.
However, when 25 mg or 50 mg dexketoprofen were compared with 50 mg or 100 mg
ketoprofen (that is, double the dose, Figure 3), statistical significance was achieved, with a
number needed to treat of 8.8 (5.1 to 33). That means that for every nine persons treated with 25
mg or 50 mg dexketoprofen, one more would have at least 50% pain relief than if the same nine
patients were treated with ketoprofen 50 mg or 100 mg.

Table 2. Results of Single Dose Trials in Dental and Postsurgical Pain for Comparison of
Dexketoprofen With Placebo, and Dexketoprofen With Ketoprofen

Dexketoprofen versus placebo

Percent of patients with at Relativ
Number of
least 50% pain relief e
benefit
Trial Patient Dexketoprofe (95% NNT
Dexketoprofen dose (mg) s s n Placebo CI) (95% CI)
All trials
3.4 (2.2 3.5 (2.7 to
10/12.5 mg 5 462 45 17
to 5.6) 4.9)
3.9 (2.4 3.0 (2.4 to
20/25 mg 5 455 50 17
to 6.3) 3.9)
6.7 (1.7 2.1 (1.5 to
50 mg 1 67 56 8
to 26) 3.5)
Dental
3.5 (2.2 3.0 (2.3 to
10/12.5 mg 3 261 47 13
to 5.6) 4.4)
3.9 (2.4 2.6 (2.0 to
20/25 mg 3 254 52 13
to 6.3) 3.5)
6.7 (1.7 2.1 (1.5 to
50 mg 1 67 56 8
to 26) 3.5)
Postsurgical
2.1 (1.4 4.4 (2.8 to
10/12.5 mg 2 201 43 21
to 3.3) 9.7)
 2.3 (1.5 3.7 (2.5 to
20/25 mg 2 201 47 21
to 3.6) 7.0)
Dexketoprofen versus ketoprofen
Percent of patients with at Relativ
Number of
least 50% pain relief e
benefit
Dexketoprofen/ketoprofe Trial Patient Dexketoprofe Ketoprofe (95% NNT
n dose (mg) s s n n CI) (95% CI)
All trials
not
0.8 (0.5
12.5 vs 50 3 287 44 35 calculate
to 1.2)
d
not
1.1 (0.7
25 vs 50 3 284 51 35 calculate
to 1.5)
d
not
1.1 (0.9
50 vs 100 1 247 82 77 calculate
to 1.2)
d
1.2 (1.1 8.8 (5.1 to
25/50 vs 50/100 4 531 65 54
to 1.4) 33)
L'Abbé plot of individual trials of dexketoprofen compared with double dose of ketoprofen in
dental and postsurgical pain. Inset scale shows size of trial. Light symbols = 25 mg vs 50 mg,
dark symbols = 50 mg vs 100 mg.

Single Dose Trials in Pain of Renal Colic

Three randomised trials[45-47] examined the analgesic efficacy of dexketoprofen 25 mg and 50 mg

intramuscularly, and 25 mg and 50 mg intravenously, in 838 patients studied in pain of renal
colic, 526 of whom received dexketoprofen (Additional file 3). All of the trials were both
randomised and double blind, all had quality scores of three or more of the maximum 5 points
and at least 9 points on an OPVS. One trial[45] used intramuscular dexketoprofen and two[46,47]
intravenous dexketoprofen.
None of the trials had a placebo control, and all examined efficacy over six hours after a single
dose n pain of moderate or severe intensity. Intramuscular dexketoprofen 25 mg and 50 mg were
indistinguishable from intramuscular dipyrone 2000 mg.[45] Intravenous dexketoprofen 25 mg or
50 mg were indistinguishable from intravenous dipyrone 2000 mg or more,[46] and intravenous
dexketoprofen 50 mg was indistinguishable from intravenous ketoprofen 100 mg.[47]

Multiple Dose Trials in Acute Low Back Pain

Five trials[48-53] examined short-term use of dexketoprofen in acute low back pain, generally over
about a week (Additional file 4); one was published in German,[50] but data were taken from a
clinical trial report.[49] All of the trials were both randomised and double blind, all had quality
scores of three or more of the maximum 5 points and at least 9 points on an OPVS. One shorter
trial compared 50 mg twice-daily intramuscular dexketoprofen with 75 mg diclofenac in almost
400 patients.[48] Four oral comparisons of dexketoprofen 25 mg three times daily over 4-7 days in
patients with pain of acute onset back pain of at least moderate severity showed similar efficacy
to diclofenac 150 mg daily,[51] tramadol 150 mg daily,[49,52] and paracetamol 800 mg plus
dextropropoxyphene 60 mg daily.[53]

Single and Multiple Dose Trials in Other Acute Painful Conditions

Five randomised trials[54-58] have examined the analgesic efficacy in other acute painful
conditions in 796 patients, 428 of whom received oral dexketoprofen, mainly at 25 mg
(Additional file 5). All of the trials were both randomised and double blind, all had quality scores
of three or more of the maximum 5 points and at least 9 points on an OPVS. Only one trial[54]
was placebo controlled, and looked at efficacy of 12.5 mg and 25 mg of dexketoprofen in
comparison with 50 mg ketoprofen in 52 women with dysmenorrhoea; all three active treatments
were superior to placebo, but not different one from another.

Dexketoprofen 25 mg orally was found to be superior to injections of mepivacaine into the

uterine cervix in producing significantly lower pain scores over 30-120 minutes after
hysteroscopy[55] as well as being better than 50 mg diclofenac for lower limb injury between 15
and 60 minutes.[56] Over four days there was no difference between three times daily ketoprofen
25 mg or paracetamol 500 mg plus codeine 60 mg in the treatment of ankle sprains.[57] In patients
with cancer who developed bone cancer pain of at least moderate intensity, and who had not
previously been treated with a continuous regimen of opioids or NSAIDs in the previous 15
days, there was no difference between 25 mg dexketoprofen and 10 mg ketorolac over seven
days.[58]

Multiple Dose Trials in Arthritis

Two trials tested dexketoprofen 25 mg three times a day against ketoprofen 150 mg daily and
diclofenac 150 mg daily in patients with established arthritis[59,60](Additional file 6). Both trials
were randomised and double blind, all had quality scores of three or more of the maximum 5
points and at least 9 points on an OPVS. The trials had a flare design in which patients
discontinued previous treatment. Over two or three weeks of treatment there were no differences
between dexketoprofen and diclofenac at these doses,[60] though dexketoprofen 75 mg daily was
superior to ketoprofen 150 mg daily.[59]

Overall Comparison Between Dexketoprofen and Ketoprofen

The main comparisons between dexketoprofen and ketoprofen occurred within the dental trials
and those in postsurgical pain. There were three other comparisons. One comparison of
intravenous administration in renal colic showed no difference between dexketoprofen 50 mg
and ketoprofen 100 mg.[47] Of the two oral comparisons there was no difference between
dexketoprofen 12.5 mg or 25 mg and ketoprofen 50 mg,[54] while the one comparison between 25
mg dexketoprofen with 50 mg ketoprofen in arthritis showed better results for dexketoprofen.[59]

Adverse Events

Additional file 1, Additional file 2, Additional file 3, Additional file 4, Additional file 5,
Additional file 6 records adverse events reported in the trials, in terms of the numbers of patients
reporting at least one adverse event, all cause withdrawals, and withdrawal due to an adverse
event. Adverse event reporting was generally poor. Because trials varied from single dose to
three weeks duration, with different routes of administration, drug doses, comparators, and
condition, sensible analysis of adverse events were not possible. Because adverse event
withdrawal is a significant event, and attempt was made to examine adverse event withdrawal
rates in trials where at least two doses of drug were given. Because the rate of adverse event
withdrawals is likely to be a function of the number of doses given, these were split by relatively
shorted duration studies predominantly less than two days (dental and postsurgical pain) and
relatively longer studies predominantly more two days or longer (acute painful conditions, back
pain, and arthritis) ( ).

Adverse Event Withdrawal Rates in Trials Where at Least Two Doses of Drug Were
Given

Dental and postsurgical pain Other acute, back pain, arthritis

Number of Adverse event Number of Adverse event
Drug patients withdrawal (%) patients withdrawal (%)
Placebo 236 2.5 no data
Dexketoprofen 652 1.8 844 3.2
Ketoprofen 301 1.3 152 7.9
Diclofenac 80 0.0 272 3.7
Tramadol 72 1.4 247 9.7
Paracetamol +
100 0.0 167 1.2
opioid
The choice of two doses was simply because withdrawal is not really an option after a single
dose and is unlikely to be recorded in the same was as in multiple dose studies.

In both comparisons dexketoprofen (all doses) provided the about half the total number of
patients ( ). Adverse event withdrawal rates were low, at about 2% or below in dental and
postsurgical pain, and somewhat higher in trials of longer duration. The adverse event
withdrawal rate for dexketoprofen was not out of line with other drugs, though limited numbers
prevented any firm conclusions, and statistical tests were not deemed sensible.

Adverse Event Withdrawal Rates in Trials Where at Least Two Doses of Drug Were
Given

Dental and postsurgical pain Other acute, back pain, arthritis

Number of Adverse event Number of Adverse event
Drug patients withdrawal (%) patients withdrawal (%)
Placebo 236 2.5 no data
Dexketoprofen 652 1.8 844 3.2
Ketoprofen 301 1.3 152 7.9
Diclofenac 80 0.0 272 3.7
Tramadol 72 1.4 247 9.7
Paracetamol +
100 0.0 167 1.2
opioid

No serious adverse events, like gastrointestinal bleeding, myocardial infarction, or death, were
reported in any trial.

Discussion

This review found reports of 34 randomised trials of dexketoprofen, predominantly of

sufficiently high reporting quality to avoid bias.[9,61] To be comprehensive any randomised trial
was included, but only higher quality trials (randomised, double blind) were used to calculate
NNTs. Almost half the trials and just over half the patients (51%) were in trials that had not
previously been published in full, and so this review doubles the amount of information
previously available on dexketoprofen. Significant numbers of otherwise unpublished pain trials
have been found before in systematic reviews.[62,63]

Nearly all trials appeared to be valid as judged by quality scores and OPVS scores. The two
arthritis trials, at three weeks, were considerably shorter than the current norm in arthritis trials,
which now is 6-12 weeks. The trials tended to be relatively small, with an average of 190
patients split between several treatment groups, and while they were sufficient to yield statistical
results regarding the direction of any effect, they were not individually large enough to comment
sensibly on its magnitude.[16] While 10 trials had group sizes of at least 100 patients, these were
spread throughout the different conditions studied ( ).

Table 1. Summary Table of Randomised Trials Included in the Review

Number of
Number of: patients
Trial At least
s of Better than equivalent to
Studie Studie grou placebo/tot effective
s with s with p In Given al analgesic/tot
Pain Studie QS ≥ OPVS size tota dexketoprof comparison al
condition s 3/5 ≥ 9/16 ≥ 100 l en s comparisons
Dental pain 7 6 6 0 994 618 4/4 3/4
218
Postsurgical 13 11 11 2 1022 7/7 11/11
5
Renal colic 3 3 3 3 838 526 3/3
Gynaecolog
2 2 1 1 350 200 1/1 2/2
ic pain
Lower limb
1 1 1 0 122 65 1/1
injury
Ankle
1 1 1 1 209 106 1/1
sprain
Acute bone
pain in 1 1 1 0 115 57 1/1
cancer
Acute low 126
5 5 5 3 635 5/5
back pain 7
OA/RA 2 2 2 0 300 152 2/2
638
Total 35 32 31 10 3381 12/12 29/30
0

QS = quality score; OPVS = Oxford Pain Validity Score; OA = osteoarthritis; RA = rheumatoid

arthritis
The small size and generally short duration of the trials limits transfer of knowledge to clinical
practice. The trials tell us about whether dexketoprofen is an analgesic. They do not tell us how
best to use it in any particular painful condition.

Meta-analysis of all trials was not possible because of the differences between them in terms of
painful condition being treated, dose and route of administration of dexketoprofen, duration of
therapy, and outcomes reported. Vote counting only was possible, and this showed that all 12
trials with a placebo comparison showed dexketoprofen to be better than placebo, and that 29/30
trials showed dexketoprofen to be at least equivalent to an active comparator of known analgesic
efficacy ( ).

Table 1. Summary Table of Randomised Trials Included in the Review

Number of
Number of: patients
Trial At least
s of Better than equivalent to
Studie Studie grou placebo/tot effective
s with s with p In Given al analgesic/tot
Pain Studie QS ≥ OPVS size tota dexketoprof comparison al
condition s 3/5 ≥ 9/16 ≥ 100 l en s comparisons
Dental pain 7 6 6 0 994 618 4/4 3/4
218
Postsurgical 13 11 11 2 1022 7/7 11/11
5
Renal colic 3 3 3 3 838 526 3/3
Gynaecolog
2 2 1 1 350 200 1/1 2/2
ic pain
Lower limb
1 1 1 0 122 65 1/1
injury
Ankle
1 1 1 1 209 106 1/1
sprain
Acute bone
pain in 1 1 1 0 115 57 1/1
cancer
Acute low 126
5 5 5 3 635 5/5
back pain 7
OA/RA 2 2 2 0 300 152 2/2
638
Total 35 32 31 10 3381 12/12 29/30
0
QS = quality score; OPVS = Oxford Pain Validity Score; OA = osteoarthritis; RA = rheumatoid
arthritis

The one area where meta-analysis was possible was that of single dose oral administration in
dental and postsurgical pain ( ). Based on limited data there appeared to be a dose-response, with
better (lower) NNTs with higher doses of dexketoprofen. The best general comparison with other
analgesics probably comes from the dental pain model, because these trials are consistently
conducted in very similar patients, using similar methods and outcomes, and tried and tested
methods.[64,65] The NNT for dexketoprofen compared with placebo for at least 50% pain relief
over 4-6 hours was 2.6, comparable to ibuprofen 200-600 mg (NNTs 2.2-2.8) and diclofenac 50
mg (NNT 2.1), and better than paracetamol 1000 mg (NNT 3.7).[64] Limited numbers of patients
for some of these drugs and doses make it invidious to push these comparisons too far, but at
least it can be said that oral dexketoprofen 25 mg is an effective analgesic according to present
standards. As yet we do not have sufficient or consistent information across systematic reviews
of single dose analgesics to make comparisons of duration of analgesia (median time to
remedication, or percentage of patients remedicating in a fixed time, for instance), though this
would be useful additional information.[66]

Table 2. Results of Single Dose Trials in Dental and Postsurgical Pain for Comparison of
Dexketoprofen With Placebo, and Dexketoprofen With Ketoprofen

Dexketoprofen versus placebo

Percent of patients with at Relativ
Number of
least 50% pain relief e
benefit
Trial Patient Dexketoprofe (95% NNT
Dexketoprofen dose (mg) s s n Placebo CI) (95% CI)
All trials
3.4 (2.2 3.5 (2.7 to
10/12.5 mg 5 462 45 17
to 5.6) 4.9)
3.9 (2.4 3.0 (2.4 to
20/25 mg 5 455 50 17
to 6.3) 3.9)
6.7 (1.7 2.1 (1.5 to
50 mg 1 67 56 8
to 26) 3.5)
Dental
3.5 (2.2 3.0 (2.3 to
10/12.5 mg 3 261 47 13
to 5.6) 4.4)
 3.9 (2.4 2.6 (2.0 to
20/25 mg 3 254 52 13
to 6.3) 3.5)
6.7 (1.7 2.1 (1.5 to
50 mg 1 67 56 8
to 26) 3.5)
Postsurgical
2.1 (1.4 4.4 (2.8 to
10/12.5 mg 2 201 43 21
to 3.3) 9.7)
2.3 (1.5 3.7 (2.5 to
20/25 mg 2 201 47 21
to 3.6) 7.0)
Dexketoprofen versus ketoprofen
Percent of patients with at Relativ
Number of
least 50% pain relief e
benefit
Dexketoprofen/ketoprofe Trial Patient Dexketoprofe Ketoprofe (95% NNT
n dose (mg) s s n n CI) (95% CI)
All trials
not
0.8 (0.5
12.5 vs 50 3 287 44 35 calculate
to 1.2)
d
not
1.1 (0.7
25 vs 50 3 284 51 35 calculate
to 1.5)
d
not
1.1 (0.9
50 vs 100 1 247 82 77 calculate
to 1.2)
d
1.2 (1.1 8.8 (5.1 to
25/50 vs 50/100 4 531 65 54
to 1.4) 33)

There available evidence is that analgesia with dexketoprofen is equivalent to analgesia obtained
with double the dose of ketoprofen. In single doses in acute pain, there is a hint even of superior
analgesia than double dose ketoprofen (Figure 3, ), and there is at least equivalence in three other
trials.

Table 2. Results of Single Dose Trials in Dental and Postsurgical Pain for Comparison of
Dexketoprofen With Placebo, and Dexketoprofen With Ketoprofen

Dexketoprofen versus placebo

Percent of patients with at Relativ NNT
Number of
Dexketoprofen dose (mg) least 50% pain relief e (95% CI)
 benefit
Trial Patient Dexketoprofe (95%
s s n Placebo CI)
All trials
3.4 (2.2 3.5 (2.7 to
10/12.5 mg 5 462 45 17
to 5.6) 4.9)
3.9 (2.4 3.0 (2.4 to
20/25 mg 5 455 50 17
to 6.3) 3.9)
6.7 (1.7 2.1 (1.5 to
50 mg 1 67 56 8
to 26) 3.5)
Dental
3.5 (2.2 3.0 (2.3 to
10/12.5 mg 3 261 47 13
to 5.6) 4.4)
3.9 (2.4 2.6 (2.0 to
20/25 mg 3 254 52 13
to 6.3) 3.5)
6.7 (1.7 2.1 (1.5 to
50 mg 1 67 56 8
to 26) 3.5)
Postsurgical
2.1 (1.4 4.4 (2.8 to
10/12.5 mg 2 201 43 21
to 3.3) 9.7)
2.3 (1.5 3.7 (2.5 to
20/25 mg 2 201 47 21
to 3.6) 7.0)
Dexketoprofen versus ketoprofen
Percent of patients with at Relativ
Number of
least 50% pain relief e
benefit
Dexketoprofen/ketoprofe Trial Patient Dexketoprofe Ketoprofe (95% NNT
n dose (mg) s s n n CI) (95% CI)
All trials
not
0.8 (0.5
12.5 vs 50 3 287 44 35 calculate
to 1.2)
d
not
1.1 (0.7
25 vs 50 3 284 51 35 calculate
to 1.5)
d
not
1.1 (0.9
50 vs 100 1 247 82 77 calculate
to 1.2)
d
 1.2 (1.1 8.8 (5.1 to
25/50 vs 50/100 4 531 65 54
to 1.4) 33)

Again, the varied nature of the studies precluded any formal meta-analysis of adverse events.
What could be done was a descriptive analysis of adverse event withdrawals in trials with at least
two doses of dexketoprofen. The split by relatively short term studies in dental and postsurgical
pain, and somewhat longer studies in acute pain, back pain, and arthritis ( ) appeared to make
sense, as withdrawal rates tended to be somewhat higher in the longer duration studies.
Dexketoprofen adverse event withdrawals were not higher than other effective analgesics, based
on the limited data available.

Adverse Event Withdrawal Rates in Trials Where at Least Two Doses of Drug Were
Given

Dental and postsurgical pain Other acute, back pain, arthritis

Number of Adverse event Number of Adverse event
Drug patients withdrawal (%) patients withdrawal (%)
Placebo 236 2.5 no data
Dexketoprofen 652 1.8 844 3.2
Ketoprofen 301 1.3 152 7.9
Diclofenac 80 0.0 272 3.7
Tramadol 72 1.4 247 9.7
Paracetamol +
100 0.0 167 1.2
opioid

No conclusions could be drawn about serious adverse events like serious gastrointestinal
bleeding, cardiovascular events, or mortality. Gastrointestinal bleeding and cardiovascular events
tend to occur at a rate of about 1% a year in randomised trials in arthritis.[67] Trials of
dexketoprofen lasted only three weeks with arthritis, and barely a week with most trials. In that
circumstance, the rate of a serious adverse event would be expected in about 1 in 5,000 patients
(1 in 100 multiplied by 50), and only 3,200 patients were in trials other than dental or
postsurgical pain. Additionally, a number of those trials were in patients substantially younger
than those in arthritis trials, with substantially lower baseline risk, decreasing the potential risk
even lower than 1 in 5,000. The absence of serious events should not, therefore, be taken as an
absence of risk, because the quantity, type and duration of studies precludes any such conclusion.

Conclusion

This review doubles the amount of information available concerning analgesic efficacy of
dexketoprofen. That efficacy was apparent in single dose in dental and postsurgical pain, where
NNTs for at least 50% pain relief over 4-6 hours compared with placebo were similar to other
effective analgesics. In vote-counting, dexketoprofen was at least as effective as other analgesics
in 29/30 trials. While adverse event withdrawal was not different between dexketoprofen and
comparator analgesics, the different conditions and comparators studies precluded any formal
analysis. The amount of exposure was limited, and no conclusions could be drawn about safety
in terms of serious adverse events like gastrointestinal bleeding or cardiovascular events.

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Funding information

Pain Research is supported in part by the Oxford Pain Research Trust, and this work was also
supported by an unrestricted educational grant from Menarini Group. Neither organisation had
any role in design, planning, execution of the study, or in writing the manuscript. The terms of
financial support included freedom for authors to reach their own conclusions, and an absolute
right to publish the results of their research, irrespective of any conclusions reached.

Reprint Address

R Andrew Moore, [email protected]

BMC Clin Pharmacol © 2008 Moore and Barden; licensee BioMed Central Ltd.

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