BMC Clinical Pharmacology BioMed Central

Research article Open Access

Systematic review of dexketoprofen in acute and chronic pain
R Andrew Moore*† and Jodie Barden†

Address: Pain Research and Nuffield Department of Anaesthetics, University of Oxford, Level 6, West Wing, John Radcliffe Hospital, Oxford OX3
9DU, UK
Email: R Andrew Moore* - andrew.moore@pru.ox.ac.uk; Jodie Barden - jodie.barden@balliol.ox.ac.uk
* Corresponding author †Equal contributors

Published: 31 October 2008 Received: 25 March 2008

Accepted: 31 October 2008
BMC Clinical Pharmacology 2008, 8:11 doi:10.1186/1472-6904-8-11
This article is available from: http://www.biomedcentral.com/1472-6904/8/11
© 2008 Moore and Barden; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0),
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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used published and unpublished information from randomised clinical trials (RCTs) of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produced copies of published and unpublished studies (clinical trial reports).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obtained from clinical trial reports from previously unpublished trials or abstracts.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

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Introduction mulating many similar trials together reduces the possibil-

Racemic ketoprofen is used as an analgesic and an anti- ity of variation in efficacy estimates because of the
inflammatory agent, and is one of the most potent in vitro random play of chance, and should improve assessment
inhibitors of prostaglandin synthesis, but is also impli- of harm.
cated as having an association with higher risk of serious
gastrointestinal bleeding events than other NSAIDs [1,2]. Methods
The analgesic effect is due to the S(+)-enantiomer (dexke- We searched PubMed, and Cochrane Central up to Octo-
toprofen), while the R(-)-enantiomer is devoid of analge- ber 2008 for randomised controlled trials using dexketo-
sic activity [3]. Because the R(-)-enantiomer does appear profen to treat pain of any aetiology. The detailed search
to have ulcerogeneic activity, at least in the rat [3,4], the strategy included use of the drug name dexketoprofen
implication is that use of dexketoprofen alone should anywhere in an article, together with the publication
produce equivalent analgesia to double-dose ketoprofen, descriptor of randomised trial; this was modified for the
but at lower risk of harm. At least one case-control study different databases. Reference lists of retrieved articles and
in Spain appears to confirm a lower rate of serious gas- reviews were also searched for relevant trials. In addition,
trointestinal harm with dexketoprofen than ketoprofen, Menarini Group also produced copies of published and
but with overlapping confidence intervals and small num- unpublished studies, the latter in the form of clinical trial
bers of events [2]. Other authorities regard the approach reports.
of using an active enantiomer as a tromethamine salt as
attractive on theoretical grounds [4]. For inclusion, trials had to be at least randomised, and use
dexketoprofen to treat adult patients with pain of any ori-
Formulation is important, especially the use of the gin. Trials had to have a minimum of 10 patients per treat-
trometamol salt for rapid absorption [3]. In healthy vol- ment arm, and at least one dose of dexketoprofen given by
unteers absorption of dexketoprofen from dexketoprofen any route of administration, at any dose, and with any
trometamol capsules was similar to ketoprofen, while the comparator.
extent of absorption of dexketoprofen free acid was signif-
icantly lower than that for ketoprofen [5]. Dexketoprofen The abstracts were read, and potentially useful reports
trometamol showed the most rapid absorption rate, with retrieved in full paper copy. No information was taken
highest maximum plasma concentration and shortest from posters or abstracts unless supplemented by details
time to maximum values, while ketoprofen had an inter- from a clinical trial report. Decisions on inclusion or
mediate absorption rate, and dexketoprofen free acid the exclusion of trials, assessment of trial quality and validity
slowest absorption rate. After repeated-dose administra- and all data extraction were made independently by both
tion of dexketoprofen trometamol, the pharmacokinetic reviewers, with discrepancies resolved by consensus.
parameters were similar to those obtained after single
doses, indicating that no drug accumulation occurred [5]. Methodological quality of included studies was assessed
Food slowed absorption of dexketoprofen, even from the using the validated 5-point Oxford quality scale [8] utilis-
trometamol salt [6]. ing reporting of randomisation, blinding and withdraw-
als. The maximum score possible was 5 points, and no
Dexketoprofen is licensed in a number of countries study could be included with fewer than 2 points (one for
around the world. Oral dexketoprofen was approved in randomisation and one for blinding). Study validity was
the European Countries through a Mutual Recognition assessed using the validated Oxford Pain Validity Scale
Procedure on 13th February 1998 and the injectable for- (OPVS) 16-point scale [9]. Only trials that were both ran-
mulation on 25th October 2002. Dexketoprofen has not domised and double blind were used for calculation of
been subjected to the scrutiny of a systematic review, and numbers needed to treat.
not reviewed at all since preclinical and clinical develop-
ment studies were reviewed over a decade ago [7]. We Data were abstracted into a standard form. Information
sought to obtain published and unpublished information was extracted from the trials according to painful condi-
from randomised clinical trials of dexketoprofen to assess tion, with details of drugs, dose, route of administration,
the available evidence on efficacy and harm. patient numbers, treatment and observation schedule,
outcomes measured, and main efficacy and safety results.
Systematic reviews are useful for pulling together all the
studies on a topic – here randomised, double blind com- For studies reporting results of single dose administration
parative trials of dexketoprofen in painful conditions. By we sought to the outcome of at least 50% pain relief. For
assessing trial quality and validity [8,9] it is possible to each report, mean TOTPAR (total pain relief) or SPID
eliminate trials likely to be biased, and biased trials are (summed pain intensity difference) for active and placebo
much more likely to over-estimate treatment effects. Accu- groups were converted to %maxTOTPAR or %maxSPID

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by division into the calculated maximum value [10]. The which at least one arm had no events. Number-needed-to-
proportion of patients in each treatment group who treat (or harm) was calculated by the method of Cook and
achieved at least 50%maxTOTPAR was calculated using Sackett [21] using the pooled number of observations
verified equations [11-13]. These proportions were then only when there was a statistically significant difference of
converted into the number of patients achieving at least relative benefit or risk (where the confidence interval did
50%maxTOTPAR by multiplying by the total number of not include 1). There was a prior intention to carry out
patients in the treatment group. Information on the sensitivity analyses for high versus low trial quality (< 3 vs
number of patients with at least 50%maxTOTPAR for ≥ 3), dose, and condition. Information would be reported
active treatment and placebo was then used to calculate with any number of patients, but not regarded unless
relative benefit (RB) and number needed-to-treat (NNT). there was a minimum of two trials or 250 patients [16].
Pain measures accepted for the calculation of TOTPAR or
SPID were: Results
Thirty-five trials were found in acute and chronic pain, 32
• 5-point categorical pain relief (PR) scales with compara- of which had reporting quality of 3/5 or better and 30 of
ble wording to "none, slight, moderate, good or com- which had OPVS score of at least 9/16 (Table 1). Ten trials
plete" had individual group sizes of 100 patients or more. The
total number of patients was 6,380, of whom 3381
• 4-point categorical pain intensity (PI) scales with com- received dexketoprofen (Table 1). More patients were in
parable wording to "none, mild, moderate, severe" trials of oral therapies (4,249 total, 2,270 on dexketopro-
fen) than trials of intramuscular or intravenous therapies
• Visual analogue scales (VAS) for pain relief (2,131 total, 1,111 on dexketoprofen). Information from
16 trials (46%) with 3,253 patients (51%) was obtained
• VAS for pain intensity from clinical trial reports from previously unpublished tri-
als, or trials published only as abstracts. All 16 clinical trial
• 5-point categorical global scale with the wording "poor, reports had a quality score of at least 3/5 and an OPVS
fair, good, very good, excellent" [14] score of at least 9/16. Almost all of the trials were of short
duration in acute conditions, or for recent onset pain.
Other measures of pain relief were abstracted where Only two, in osteoarthritis, investigated efficacy in
reported and appropriate. Secondary outcomes were with- chronic painful conditions.
drawals (all cause, lack of efficacy and adverse events) and
adverse events (patients with at least one adverse event, All 12 randomised trials that compared dexketoprofen, at
serious adverse events, and specific adverse events). We any dose, with placebo found dexketoprofen to be statis-
anticipated that reporting of adverse events would vary tically superior (Table 1). More common was a compari-
between trials with regard to the terminology used, son of dexketoprofen with an active comparator, which
method of ascertainment, and categories reported (e.g. happened in 30 trials. In 29 of these 30 trials, dexketopro-
occurring in ≥ 5% of patients or where there was a statisti- fen at the dose used was at least equivalent in efficacy to
cally significant difference between treatment groups). the comparator drugs with known analgesic efficacy.

Guidelines for quality of reporting of meta-analyses were Single and multiple dose trials in dental pain
followed where appropriate [15]. The prior intention was Seven randomised trials [22-29] examined the analgesic
to pool data where there was clinical and methodological efficacy of oral dexketoprofen in 994 patients studied in
homogeneity, with similar patients, dose, duration, out- the third molar extraction pain model, 618 of whom
comes, and comparators, but not where numbers of received dexketoprofen (Additional file 1). One trial was
events were small, and random chance could dominate published as an abstract [29], with data taken from a clin-
effects of treatment [16]. Homogeneity tests and funnel ical trial report [23]. Six of the seven trials were both ran-
plots, though commonly used in meta-analysis, were not domised and double blind, and had quality scores of 4 or
used here because they have been found to be unreliable 5 of the maximum 5 points and had OPVS scores of at
[17,18]. Instead clinical homogeneity was examined least 9/16. One open trial [27] scored only 1 out of 5.
graphically [19]. Relative benefit (or risk) and number-
needed-to-treat or harm (NNT or NNH) were calculated Three good quality trials were standard pain models
with 95% confidence intervals. Relative benefit or risk was reporting pain intensity or pain relief for four to six hours
calculated using a fixed effects model [20], with no statis- after the initial dose, had patients with moderate or severe
tically significant difference between treatments assumed pain at entry, and measured pain intensity and pain relief
when the 95% confidence intervals included unity. We over six hours [24,25,28]. In these three trials dexketopro-
added 0.5 to treatment and comparator arms of trials in fen at doses of 10 or 12.5 mg (Figure 1), 20 or 25 mg (Fig-

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Table 1: Summary table of randomised trials included in the review

Number of: Number of patients

Pain Studies Studies Studies with Trials of In total Given Better than At least equivalent
condition with QS OPVS ≥ 9/16 group size ≥ dexketoprofen placebo/total to effective
≥ 3/5 100 comparisons analgesic/total
comparisons

Dental pain 7 6 6 0 994 618 4/4 3/4

Postsurgical 13 11 11 2 2185 1022 7/7 11/11
Renal colic 3 3 3 3 838 526 3/3
Gynaecologic 2 2 1 1 350 200 1/1 2/2
pain
Lower limb 1 1 1 0 122 65 1/1
injury
Ankle sprain 1 1 1 1 209 106 1/1
Acute bone 1 1 1 0 115 57 1/1
pain in cancer
Acute low 5 5 5 3 1267 635 5/5
back pain
OA/RA 2 2 2 0 300 152 2/2

Total 35 32 31 10 6380 3381 12/12 29/30

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

ure 2), and 50 mg were all significantly superior to profen. Eight of the 13 trials were in major orthopaedic
placebo, with NNTs for at least 50% pain relief over six surgery (mainly knee and hip surgery), the others involv-
hours compared with placebo of 3.0 (2.3 to 4.4), 2.6 (2.0 ing arthroscopy, bunionectomy, hernias, abdominal hys-
to 3.5), and 2.1 (1.5 to 3.5) respectively (Table 2). One terectomy, and abdominal surgery.
trial [28] used ketoprofen 50 mg, and that was also signif-
icantly better than placebo. The one other trial that used Two good quality trials were standard pain models report-
placebo [26] reported data at eight hours, and appeared to ing pain intensity or pain relief for four to six hours after
measure pain scores after use of remedication. Despite the initial dose, had patients with moderate or severe pain
that, dexketoprofen 25 mg was significantly better than at entry, and measured pain intensity and pain relief over
placebo. 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
Dexketoprofen 12.5 mg and 25 mg were both superior to 2) were significantly superior to placebo, with NNTs for at
dipyrone 575 mg in the single dose phase of a multiple least 50% pain relief over six hours compared with pla-
dose trial [22]. There was no difference between use of pre cebo of 4.4 (2.8 to 9.7) and 3.7 (2.5 to 7.0) respectively
and postsurgical dexketoprofen in another trial [23,29]. (Table 2). Four of the nine oral trials used placebo, and in
The final trial [27] compared dexketoprofen 25 mg with these dexketoprofen was significantly better than placebo
ibuprofen 600 mg, but no interpretation could be made in on at least one measure in three trials [34,39,43], but not
this case because it included patients with mild pain in the fourth [32]. Ketoprofen 50 mg was not significantly
which is known to desensitise pain trials. better than placebo in the two trials that used it [32,34].

Single and multiple dose trials in postsurgical pain Where there was an active comparator, dexketoprofen 25
Thirteen randomised trials [30-43] examined the analge- mg appeared to be equivalent to tramadol 50 mg [42,33],
sic efficacy of dexketoprofen in 2135 patients studied in diclofenac 50 mg [36], and paracetamol 500 mg plus
postsurgical pain, 997 of whom received dexketoprofen codeine 22.5 mg [38]. Three trials compared dexketopro-
(Additional file 2). One trial was published as an abstract fen 25 mg with ketoprofen 50 mg; while there was no dif-
[31] with data taken from a clinical trial report [42]. ference in one small trial [41], ketoprofen appeared to be
Twelve of the 13 trials were both randomised and double less effective in two others [32,34].
blind, and 11 had quality scores of three or more of the
maximum 5 points and at least 9 on an OPVS (Table 1). Two trials [35,40] used intramuscular administration of
Eight trials (1212 patients) used oral dexketoprofen and dexketoprofen at doses of 25 mg or 50 mg twice a day, and
four (923 patients) intramuscular or intravenous dexketo- two [30,37] intravenous administration of 50 mg three

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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

Number of Percent of patients with at least 50% pain

relief

Dexketoprofen dose Trials Patients Dexketoprofen Placebo Relative benefit NNT (95% CI)
(mg) (95% CI)

All trials
10/12.5 mg 5 462 45 17 3.4 (2.2 to 5.6) 3.5 (2.7 to 4.9)
20/25 mg 5 455 50 17 3.9 (2.4 to 6.3) 3.0 (2.4 to 3.9)
50 mg 1 67 56 8 6.7 (1.7 to 26) 2.1 (1.5 to 3.5)

Dental
10/12.5 mg 3 261 47 13 3.5 (2.2 to 5.6) 3.0 (2.3 to 4.4)
20/25 mg 3 254 52 13 3.9 (2.4 to 6.3) 2.6 (2.0 to 3.5)
50 mg 1 67 56 8 6.7 (1.7 to 26) 2.1 (1.5 to 3.5)

Postsurgical
10/12.5 mg 2 201 43 21 2.1 (1.4 to 3.3) 4.4 (2.8 to 9.7)
20/25 mg 2 201 47 21 2.3 (1.5 to 3.6) 3.7 (2.5 to 7.0)

Dexketoprofen versus ketoprofen

Number of Percent of patients with at least 50% pain

relief

Dexketoprofen/ Trials Patients Dexketoprofen Ketoprofen Relative benefit NNT (95% CI)
ketoprofen dose (mg) (95% CI)

All trials
12.5 vs 50 3 287 44 35 0.8 (0.5 to 1.2) not calculated
25 vs 50 3 284 51 35 1.1 (0.7 to 1.5) not calculated
50 vs 100 1 247 82 77 1.1 (0.9 to 1.2) not calculated

25/50 vs 50/100 4 531 65 54 1.2 (1.1 to 1.4) 8.8 (5.1 to 33)

times a day, or 50 mg twice a day. Time intervals between dexketoprofen of 3.0 (2.4 to 3.9), and 50 mg dexketopro-
doses were 6–8 h and 12 hours in the different studies. fen of 2.1 (1.5 to 3.5). The overlapping confidence inter-
Three [35,37,40] made a comparison with placebo, and in vals and formal testing [44] for difference between NNTs
all three doses of dexketoprofen were significantly better showed no statistical difference between 12.5 mg and 25
than placebo on at least one measure of efficacy. All four mg doses.
trials had an active comparator, and dexketoprofen at the
dose studied was at least as effective as ketoprofen 100 mg Several trials used both dexketoprofen and ketoprofen.
[30,40], tramadol 100 mg [37], and diclofenac 75 mg Table 2 also shows the comparisons between 12.5 mg and
twice a day [35]. There was a suggestion of somewhat bet- 25 mg dexketoprofen and 50 mg ketoprofen, and 50 mg
ter efficacy between three and eight hours, and lower mor- dexketoprofen and 100 mg ketoprofen. While the propor-
phine requirements, than diclofenac 75 mg twice a day tion of patients achieving at least 50% pain relief was con-
[35]. sistently higher with dexketoprofen, this did not reach
statistical significance with any comparison. However,
Overall results of single dose dexketoprofen in acute pain, when 25 mg or 50 mg dexketoprofen were compared with
and comparison with ketoprofen 50 mg or 100 mg ketoprofen (that is, double the dose, Fig-
Combining three third molar extraction and two postsur- ure 3), statistical significance was achieved, with a number
gical trials (Table 2) gave NNTs for at least 50% pain relief needed to treat of 8.8 (5.1 to 33). That means that for
for 12.5 mg dexketoprofen of 3.5 (2.7 to 4.9), 25 mg every nine persons treated with 25 mg or 50 mg dexketo-

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At least 50% pain relief with dexketoprofen

At least 50% pain relief with dexketoprofen 10/12.5 mg 100
100

80 80

60 60
200
40 300
100 40
200
20
0 100
20
0 0
0 20 40 60 80 100
At least 50% pain relief with placebo 0
0 20 40 60 80 100
L'Abbé
compared
Figure plot
1 withof individual
placebo intrials
dental
of dexketoprofen
and postsurgical10/12.5
pain mg At least 50% pain relief with ketoprofen
L'Abbé plot of individual trials of dexketoprofen 10/
L'Abbé
with
Figure
pain double
plot
3 of dose
individual
of ketoprofen
trials ofindexketoprofen
dental and postsurgical
compared
12.5 mg compared with placebo in dental and post-
L'Abbé plot of individual trials of dexketoprofen
surgical pain. Inset scale shows size of trial. Light symbols =
compared with double dose of ketoprofen in dental
dental trials, dark symbols = postsurgical trials.
and postsurgical pain. Inset scale shows size of trial. Light
symbols = 25 mg vs 50 mg, dark symbols = 50 mg vs 100 mg.

profen, one more would have at least 50% pain relief than
if the same nine patients were treated with ketoprofen 50
At least 50% pain relief with dexketoprofen 20/25 mg
mg or 100 mg.
100
Single dose trials in pain of renal colic
80 Three randomised trials [45-47] examined the analgesic
efficacy of dexketoprofen 25 mg and 50 mg intramuscu-
larly, and 25 mg and 50 mg intravenously, in 838 patients
60 studied in pain of renal colic, 526 of whom received
200 dexketoprofen (Additional file 3). All of the trials were
both randomised and double blind, all had quality scores
40
of three or more of the maximum 5 points and at least 9
100 points on an OPVS. One trial [45] used intramuscular
20 dexketoprofen and two [46,47] intravenous dexketopro-
0 fen.
0 None of the trials had a placebo control, and all examined
0 20 40 60 80 100 efficacy over six hours after a single dose n pain of moder-
At least 50% pain relief with placebo ate or severe intensity. Intramuscular dexketoprofen 25
mg and 50 mg were indistinguishable from intramuscular
dipyrone 2000 mg [45]. Intravenous dexketoprofen 25
L'Abbé
compared
Figure plot
2 withof individual
placebo intrials
dental
of dexketoprofen
and postsurgical20/25
pain mg mg or 50 mg were indistinguishable from intravenous
L'Abbé plot of individual trials of dexketoprofen 20/ dipyrone 2000 mg or more [46], and intravenous dexke-
25 mg compared with placebo in dental and postsur- toprofen 50 mg was indistinguishable from intravenous
gical pain. Inset scale shows size of trial. Light symbols = ketoprofen 100 mg [47].
dental trials, dark symbols = postsurgical trials.

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Multiple dose trials in acute low back pain treatment. Over two or three weeks of treatment there
Five trials [48-53] examined short-term use of dexketo- were no differences between dexketoprofen and
profen in acute low back pain, generally over about a week diclofenac at these doses [60], though dexketoprofen 75
(Additional file 4); one was published in German [50], mg daily was superior to ketoprofen 150 mg daily [59].
but data were taken from a clinical trial report [49]. All of
the trials were both randomised and double blind, all had Overall comparison between dexketoprofen and
quality scores of three or more of the maximum 5 points ketoprofen
and at least 9 points on an OPVS. One shorter trial com- The main comparisons between dexketoprofen and keto-
pared 50 mg twice-daily intramuscular dexketoprofen profen occurred within the dental trials and those in post-
with 75 mg diclofenac in almost 400 patients [48]. Four surgical pain. There were three other comparisons. One
oral comparisons of dexketoprofen 25 mg three times comparison of intravenous administration in renal colic
daily over 4–7 days in patients with pain of acute onset showed no difference between dexketoprofen 50 mg and
back pain of at least moderate severity showed similar effi- ketoprofen 100 mg [47]. Of the two oral comparisons
cacy to diclofenac 150 mg daily [51], tramadol 150 mg there was no difference between dexketoprofen 12.5 mg
daily [49,52], and paracetamol 800 mg plus dextropro- or 25 mg and ketoprofen 50 mg [54], while the one com-
poxyphene 60 mg daily [53]. parison between 25 mg dexketoprofen with 50 mg keto-
profen in arthritis showed better results for dexketoprofen
Single and multiple dose trials in other acute painful [59].
conditions
Five randomised trials [54-58] have examined the analge- Adverse events
sic efficacy in other acute painful conditions in 796 Additional files 1, 2, 3, 4, 5, 6 records adverse events
patients, 428 of whom received oral dexketoprofen, reported in the trials, in terms of the numbers of patients
mainly at 25 mg (Additional file 5). All of the trials were reporting at least one adverse event, all cause withdrawals,
both randomised and double blind, all had quality scores and withdrawal due to an adverse event. Adverse event
of three or more of the maximum 5 points and at least 9 reporting was generally poor. Because trials varied from
points on an OPVS. Only one trial [54] was placebo con- single dose to three weeks duration, with different routes
trolled, and looked at efficacy of 12.5 mg and 25 mg of of administration, drug doses, comparators, and condi-
dexketoprofen in comparison with 50 mg ketoprofen in tion, sensible analysis of adverse events were not possible.
52 women with dysmenorrhoea; all three active treat- Because adverse event withdrawal is a significant event,
ments were superior to placebo, but not different one and attempt was made to examine adverse event with-
from another. drawal rates in trials where at least two doses of drug were
given. Because the rate of adverse event withdrawals is
Dexketoprofen 25 mg orally was found to be superior to likely to be a function of the number of doses given, these
injections of mepivacaine into the uterine cervix in pro- were split by relatively shorted duration studies predomi-
ducing significantly lower pain scores over 30–120 min- nantly less than two days (dental and postsurgical pain)
utes after hysteroscopy [55] as well as being better than 50 and relatively longer studies predominantly more two
mg diclofenac for lower limb injury between 15 and 60 days or longer (acute painful conditions, back pain, and
minutes [56]. Over four days there was no difference arthritis) (Table 3).
between three times daily ketoprofen 25 mg or paraceta-
mol 500 mg plus codeine 60 mg in the treatment of ankle The choice of two doses was simply because withdrawal is
sprains [57]. In patients with cancer who developed bone not really an option after a single dose and is unlikely to
cancer pain of at least moderate intensity, and who had be recorded in the same was as in multiple dose studies.
not previously been treated with a continuous regimen of
opioids or NSAIDs in the previous 15 days, there was no In both comparisons dexketoprofen (all doses) provided
difference between 25 mg dexketoprofen and 10 mg the about half the total number of patients (Table 3).
ketorolac over seven days [58]. Adverse event withdrawal rates were low, at about 2% or
below in dental and postsurgical pain, and somewhat
Multiple dose trials in arthritis higher in trials of longer duration. The adverse event with-
Two trials tested dexketoprofen 25 mg three times a day drawal rate for dexketoprofen was not out of line with
against ketoprofen 150 mg daily and diclofenac 150 mg other drugs, though limited numbers prevented any firm
daily in patients with established arthritis [59,60](Addi- conclusions, and statistical tests were not deemed sensi-
tional file 6). Both trials were randomised and double ble.
blind, all had quality scores of three or more of the maxi-
mum 5 points and at least 9 points on an OPVS. The trials No serious adverse events, like gastrointestinal bleeding,
had a flare design in which patients discontinued previous myocardial infarction, or death, were reported in any trial.

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Table 3: Adverse event withdrawal rates in trials where at least two doses of drug were given

Dental and postsurgical pain Other acute, back pain, arthritis

Drug Number of patients Adverse event withdrawal (%) Number of patients Adverse event 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 + opioid 100 0.0 167 1.2

Discussion The one area where meta-analysis was possible was that of
This review found reports of 34 randomised trials of single dose oral administration in dental and postsurgical
dexketoprofen, predominantly of sufficiently high report- pain (Table 2). Based on limited data there appeared to be
ing quality to avoid bias [9,61]. To be comprehensive any a dose-response, with better (lower) NNTs with higher
randomised trial was included, but only higher quality tri- doses of dexketoprofen. The best general comparison with
als (randomised, double blind) were used to calculate other analgesics probably comes from the dental pain
NNTs. Almost half the trials and just over half the patients model, because these trials are consistently conducted in
(51%) were in trials that had not previously been pub- very similar patients, using similar methods and out-
lished in full, and so this review doubles the amount of comes, and tried and tested methods [64,65]. The NNT for
information previously available on dexketoprofen. Sig- dexketoprofen compared with placebo for at least 50%
nificant numbers of otherwise unpublished pain trials pain relief over 4–6 hours was 2.6, comparable to ibupro-
have been found before in systematic reviews [62,63]. fen 200–600 mg (NNTs 2.2–2.8) and diclofenac 50 mg
(NNT 2.1), and better than paracetamol 1000 mg (NNT
Nearly all trials appeared to be valid as judged by quality 3.7) [64]. Limited numbers of patients for some of these
scores and OPVS scores. The two arthritis trials, at three drugs and doses make it invidious to push these compar-
weeks, were considerably shorter than the current norm in isons too far, but at least it can be said that oral dexketo-
arthritis trials, which now is 6–12 weeks. The trials tended profen 25 mg is an effective analgesic according to present
to be relatively small, with an average of 190 patients split standards. As yet we do not have sufficient or consistent
between several treatment groups, and while they were information across systematic reviews of single dose anal-
sufficient to yield statistical results regarding the direction gesics to make comparisons of duration of analgesia
of any effect, they were not individually large enough to (median time to remedication, or percentage of patients
comment sensibly on its magnitude [16]. While 10 trials remedicating in a fixed time, for instance), though this
had group sizes of at least 100 patients, these were spread would be useful additional information [66].
throughout the different conditions studied (Table 1).
There available evidence is that analgesia with dexketo-
The small size and generally short duration of the trials profen is equivalent to analgesia obtained with double the
limits transfer of knowledge to clinical practice. The trials dose of ketoprofen. In single doses in acute pain, there is
tell us about whether dexketoprofen is an analgesic. They a hint even of superior analgesia than double dose keto-
do not tell us how best to use it in any particular painful profen (Figure 3, Table 2), and there is at least equivalence
condition. in three other trials.

Meta-analysis of all trials was not possible because of the Again, the varied nature of the studies precluded any for-
differences between them in terms of painful condition mal meta-analysis of adverse events. What could be done
being treated, dose and route of administration of dexke- was a descriptive analysis of adverse event withdrawals in
toprofen, duration of therapy, and outcomes reported. trials with at least two doses of dexketoprofen. The split by
Vote counting only was possible, and this showed that all relatively short term studies in dental and postsurgical
12 trials with a placebo comparison showed dexketopro- pain, and somewhat longer studies in acute pain, back
fen to be better than placebo, and that 29/30 trials pain, and arthritis (Table 3) appeared to make sense, as
showed dexketoprofen to be at least equivalent to an withdrawal rates tended to be somewhat higher in the
active comparator of known analgesic efficacy (Table 1). longer duration studies. Dexketoprofen adverse event
withdrawals were not higher than other effective analge-
sics, based on the limited data available.

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No conclusions could be drawn about serious adverse

events like serious gastrointestinal bleeding, cardiovascu- Additional file 2
lar events, or mortality. Gastrointestinal bleeding and car- Trials of oral and injected dexktoprofen in pain after surgery. The file
diovascular events tend to occur at a rate of about 1% a contains information on each included study, with reference, quality
score, design, treatments, main results, and comments.
year in randomised trials in arthritis [67]. Trials of dexke- Click here for file
toprofen lasted only three weeks with arthritis, and barely [http://www.biomedcentral.com/content/supplementary/1472-
a week with most trials. In that circumstance, the rate of a 6904-8-11-S2.pdf]
serious adverse event would be expected in about 1 in
5,000 patients (1 in 100 multiplied by 50), and only Additional file 3
3,200 patients were in trials other than dental or postsur- Trials of injected dexktoprofen in pain of renal colic. The file contains
gical pain. Additionally, a number of those trials were in information on each included study, with reference, quality score, design,
treatments, main results, and comments.
patients substantially younger than those in arthritis tri-
Click here for file
als, with substantially lower baseline risk, decreasing the [http://www.biomedcentral.com/content/supplementary/1472-
potential risk even lower than 1 in 5,000. The absence of 6904-8-11-S3.pdf]
serious events should not, therefore, be taken as an
absence of risk, because the quantity, type and duration of Additional file 4
studies precludes any such conclusion. Trials of intramuscular and oral dexktoprofen in acute back pain. The
file contains information on each included study, with reference, quality
score, design, treatments, main results, and comments.
Conclusion Click here for file
This review doubles the amount of information available [http://www.biomedcentral.com/content/supplementary/1472-
concerning analgesic efficacy of dexketoprofen. That effi- 6904-8-11-S4.pdf]
cacy was apparent in single dose in dental and postsurgi-
cal pain, where NNTs for at least 50% pain relief over 4–6 Additional file 5
hours compared with placebo were similar to other effec- Trials of oral dexktoprofen in gynaecological and other acute painful
tive analgesics. In vote-counting, dexketoprofen was at conditions. The file contains information on each included study, with
least as effective as other analgesics in 29/30 trials. While reference, quality score, design, treatments, main results, and comments.
Click here for file
adverse event withdrawal was not different between [http://www.biomedcentral.com/content/supplementary/1472-
dexketoprofen and comparator analgesics, the different 6904-8-11-S5.pdf]
conditions and comparators studies precluded any formal
analysis. The amount of exposure was limited, and no Additional file 6
conclusions could be drawn about safety in terms of seri- Trials of oral dexktoprofen in arthritis. The file contains information on
ous adverse events like gastrointestinal bleeding or cardi- each included study, with reference, quality score, design, treatments,
ovascular events. main results, and comments.
Click here for file
[http://www.biomedcentral.com/content/supplementary/1472-
Competing interests 6904-8-11-S6.pdf]
RAM has received research grants, consulting, or lecture
fees from pharmaceutical companies, government
sources, and charities. Neither author has any direct stock
holding in any pharmaceutical company. Acknowledgements
Pain Research is supported in part by the Oxford Pain Research Trust, and
Authors' contributions this work was also supported by an unrestricted educational grant from
RAM the original concept, planning the study, searching, Menarini Group. Neither organisation had any role in design, planning, exe-
data extraction, writing, analysis, and preparing a manu- cution of the study, or in writing the manuscript. The terms of financial sup-
port included freedom for authors to reach their own conclusions, and an
script; JB was involved with searching, data extraction,
absolute right to publish the results of their research, irrespective of any
writing, analysis, and preparing a manuscript. conclusions reached. Menarini did have the right to view the final manu-
script before publication, and did so.
Additional material
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58. Rodriguez MJ, Contreras D, Galvez R, Castro A, Camba MA, Bus- scientist can read your work free of charge
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59. Beltran J, Martin-Mola E, Figueroa M, Granados J, Sanmarti R, Artigas Your research papers will be:
R, Torres F, Forns M, Mauleon D: Comparison of dexketoprofen
trometamol and ketoprofen in the treatment of osteoarthri- available free of charge to the entire biomedical community
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