Etoricoxib - preemptive and postoperative analgesia (EPPA) in patients with laparotomy or thoracotomy - design and protocols
SEtutdoy rprioctoocoxl ib - preemptive and postoperative analgesia (EPPA) in patients with laparotomy or thoracotomy - design and protocols
Johannes Fleckenstein 0
Sybille Kramer 0
Martin Offenbächer 2
Gabriel Schober 0
Herbert Plischke 2
Matthias Siebeck 1
Thomas Mussack 1
Rudolf Hatz 4
Lukas Lehmeyer 0 3
Philip M Lang 0
Bernhard Heindl 0
Peter Conzen 0
Dominik Irnich 0
0 Department of Anaesthesiology, University of Munich , Germany
1 Department of General Surgery, Campus Innenstadt, University of Munich , Germany
2 Generation Research Project, University of Munich , Bad Tölz , Germany
3 Department for Anesthesia, Hawkes Bay Hospital , Hastings , New Zealand
4 Department of Surgery and General Thoracic Surgery, Campus Großhadern, University of Munich , Germany
Background and Objective: Our objective was to report on the design and essentials of the Etoricoxib protocolPreemptive and Postoperative Analgesia (EPPA) Trial, investigating whether preemptive analgesia with cox-2 inhibitors is more efficacious than placebo in patients who receive either laparotomy or thoracotomy. Design and Methods: The study is a 2 × 2 factorial armed, double blinded, bicentric, randomised placebo-controlled trial comparing (a) etoricoxib and (b) placebo in a pre- and postoperative setting. The total observation period is 6 months. According to a power analysis, 120 patients scheduled for abdominal or thoracic surgery will randomly be allocated to either the preemptive or the postoperative treatment group. These two groups are each divided into two arms. Preemptive group patients receive etoricoxib prior to surgery and either etoricoxib again or placebo postoperatively. Postoperative group patients receive placebo prior to surgery and either placebo again or etoricoxib after surgery (2 × 2 factorial study design). The Main Outcome Measure is the cumulative use of morphine within the first 48 hours after surgery (measured by patient controlled analgesia PCA). Secondary outcome parameters include a broad range of tests including sensoric perception and genetic polymorphisms. Discussion: The results of this study will provide information on the analgesic effectiveness of etoricoxib in preemptive analgesia and will give hints on possible preventive effects of persistent pain. Trial registration: NCT00716833
To achieve an adequate postoperative pain therapy is a
medical challenge. Acute postoperative pain is followed
by persistent pain in 10-50% of individuals after common
operations, such as groin hernia repair, breast and
thoracic surgery, leg amputation, and coronary artery bypass
surgery. Since chronic pain can be severe in about 2-10%
of these patients, persistent postsurgical pain represents a
major, largely unrecognised clinical problem [
]. There is
a discrepancy between the results of many
epidemiological surveys reporting persistent pain in a significant
portion of postoperative patients despite the fact that very
effective analgesic tools are available to treat
postoperative pain [
]. Postoperative analgesia improves patients
rehabilitation, shortens hospital stay, and potentially
decreases postoperative complications . In this
context, the acute pain management team responsible for the
patient's analgesic therapy can play an important role in
improving the patient's surgical outcomes [
Preemptive analgesia has become one of the most
promising strategies of pain management [
]. The precise
definition of preemptive analgesia remains controversial.
However, the explanatory concept behind it indicates that
an analgesic intervention begins before the noxious
stimulus arises which has beneficial effects reducing
postoperative pain and the occurrence of postoperative pain [
From a physiological view of pain, physical injury
generates a complex stress response that extends beyond the
nervous system contributing to the experience of
postoperative pain. This response comprises of
neurotransmitters, peptides, endocannabinoids, cytokines, and
hormones, all of which are operating in interdependent
nervous, endocrine, and immune processes to cope with
the injury [
]. The transition of acute postoperative pain
into a chronic pain state is a complex process that not
only involves the effects of one's physiological state but
also involves psychological and social-environmental
]. All these effects are supposed to induce
plasticity in spinal and supraspinal structures contributed to the
chronification of postoperative pain [
]. Therefore, in
using preemptive analgesia there is a partial stopping to
some of the influencing factors experienced; which in
turn, may already prevent the sensitizing effects of the
Systematic reviews suggest that current preemptive
analgetic therapy, e.g. systemic non-steroidal
anti-inflammatory drugs (NSAIDs), decreased analgesic
consumption but not postoperative pain scores [
]. This effect is
more pronounced when using invasive analgesia, e.g.
epidural analgesia [
]. Nevertheless, NSAIDs failed to
elicit significant effects in all of the outcome measured
values in the reviews; affected selected variables were
only mentioned. Although there is a widespread belief of
the efficacy of preemptive analgesia among clinicians,
large scale randomised controlled trials will be necessary
to prove the current concepts.
A multimodal approach which combines several agents
(non-opioid analgesics, opioids, local anaesthetics) and
delivery techniques (intravenous anaesthesia,
patientcontrolled anaesthesia, epidural and regional blocks) is
currently recognised as best practice in postoperative
pain management [
]. Traditional, nonspecific NSAIDs
are considered an important part of postoperative pain
management, resulting in improved clinical outcomes.
Otherwise their role is limited in the peri- and
postoperative setting due to (a) platelet dysfunction, (b) renal
impairment, (c) gastrointestinal disorders and (d)
bleeding complications [
]. There are concerns especially
with their effects on platelets which have limited their use
in the immediate preoperative period [
development of COX-2-selective agents has provided additional
options for the management of acute pain.
COX-2-inhibitors may offer benefits in the pre- and perioperative
settings because of their selective inhibition of COX-2.
Several studies report significantly lowered postoperative
pain scores such as a significantly reduced dose of
postoperative opioids [
]. In addition, their unique
pharmacologic profile makes them a promising alternative to
To our knowledge, there are only a limited number of
publications examining the preemptive effect of
COX-2inhibitors on the intensity of postoperative pain. All these
studies deal with orthopaedic surgery [
therefore carried out a novel study design to examine these
preemptive and postoperative analgetic effects of
COX-2inhibitors, in particular etoricoxib, in patients
programmed for abdominal or thoracic surgery. In addition,
we aimed to follow-up the occurrence of persistent pain.
Patients and Methods
The study is a 2 × 2 factorial armed, double blinded,
randomised placebo-controlled trial comparing (a)
etoricoxib and (b) placebo in a pre- and postoperative setting.
After randomisation, patients receive preemptive
medication of either (a) or (b). Medication will be given
postoperatively for additional three days. Additionally, all
patients receive morphine administered through Patient
Controlled Analgesia (PCA). Analysis of all records is
performed by blinded evaluators. The total follow-up
period per patient is 6 month. Trial registration is
For the included patients the following criteria must be
- Age ≥ 18 years
- Scheduled abdominal or thoracic surgery harming
peritoneum or pleura
- ASA classification I or II according to the American
Society of Anaesthesiologists
Main exclusion criteria are:
- Severe cardiac/pulmonary/renal or neurologic
- ASA score > II
- Patients with insulin-dependent diabetes mellitus or
other diseases influencing the peripheral sensibility
(e.g. polyneuropathy, chronic pain syndromes)
- Regional blocks
- Continuous use of analgesics
- Pregnancy or lactation
- Uncontrolled hypertension
- Contraindications listed in the product information
of etoricoxib, i.e. intolerance, ulcers or gastric
bleeding, inflammatory bowel diseases, anaphylactic
Information will be held on the vigil of surgery. If
criteria are appropriate and patients want to participate, they
give their written informed consent with sufficient time
Randomised treatment allocation, blinding and samplesize estimation
Patients are randomly allocated to either the preemptive
or the postoperative treatment group. These two groups
are each divided into two arms. Preemptive group
patients receive etoricoxib prior to surgery and either
etoricoxib again or placebo postoperatively. Postoperative
group patients receive placebo prior to surgery and either
placebo again or etoricoxib after surgery (2 × 2 factorial
study design, Figure 1). The randomisation procedure
into the two study arms was performed by the Institute of
Medical Information Technology, Biometry and
Epidemiology, University of Munich, Germany. The biometricians
compiled an allocation list which was the basis for the
pharmacists to prepare sequentially numbered envelopes
containing two boxes of study medication for pre- and
postoperative use. The boxes contained either a 120 mg
dose of etoricoxibe or an equivalent placebo pill. After
inclusion into the trial, the study physician assigned the
content of the lowest numbered envelope to the patient.
Neither the patient nor the study physician knew about
the content of the boxes, the pills were not
distinguishable. This procedure assured a complete blinding.
We conducted a 2 × 2 factorial-armed study which
should prove the superiority of preemptive versus
postoperative etoricoxib. The study was based on the
moderate effective size of pre-emptive etoricoxib vs.
postoperative etoricoxib in the reduction of the 48 hour
cumulative morphine consumption. A sample size of
S cre e n in g
B a selin e
R a n d o m isa tion
C um ulative m orphine consum ption
D G S S pain questionnaire
M orphine consum ption
P ain intensity
G lobal scale
Q uantitative S ensory T esting
Etoricoxib 120 mg
approximately 60 patients in the two arms (i.e. 30 patients
in each of the four arms) is anticipated taking a drop out
rate of 10% into account (this is a conservative estimate
based on the dropped out rate of 4% in the study by
Sinatra et al. [
]). With this sample size we would permit a
type I error of alpha = .05, and with the alternate
hypothesis, the null hypothesis would be retained with a type II
error of beta = .2 (i.e. power of 80%).
The calculation of the effective size is based on the data
of Sinatra et al. [
]. The authors found a mean reduction
of cumulative morphine consumption of 23 mg in the
treatment group (total morphine dose 45 mg, SD 14)
compared to the placebo group (total morphine dose 68
mg, SD 25).
Participating trial physicians are employees of the
Multidisciplinary Pain Centre, Department of Anaesthesiology,
University of Munich, Germany. Their average
qualification is at least equal to a 3rd year resident in the field of
anaesthesiology and specialised pain medicine. They
contributed to all medical duties.
Etoricoxib 120 mg
for three days
for three days
Etoricoxib 120 mg
for three days
for three days
day 1 – 2 – 3
Patients are randomly allocated to either the preemptive
or the postoperative treatment group. Preemptive group
patients get etoricoxib 120 mg p.o. prior to surgery (day
0). After surgical intervention, depending on their
respective allocation, patients receive either etoricoxib
120 mg p.o. or placebo for the next three postoperative
days (day 1-3). Postoperative group patients get placebo
prior to surgery and continue afterwards with either
placebo or etoricoxib 120 mg p.o. for three postoperative
days (2 × 2 factorial study design, Figure 1). All patients
will receive standardised morphine (patient controlled
analgesia PCA; bolus 2 mg; interval 10 min; max dosage
30 mg/4 h). Patients, study physicians and contributing
hospital staff are blinded regarding the treatment group
The study is performed according to the principles of the
Declaration of Helsinki (Version Edinburg 2000, cf. http:/
index.html) and according to common guidelines for
clinical trials (ICH-GCP). The protocols have been
approved by the Ethics Committee, University of Munich
and the national component authority (German Federal
Drug Administration [Bundesinstitut für Arzneimittel
und Medizinprodukte BfArM]). Written informed
consent is obtained from all patients.
Main outcome measure
The cumulative morphine consumption (mg) within the
first 48 hours after surgery (PCA)
Secondary outcome measure
- Baseline personal situation on the DGSS (German
Society for the Study of Pain) validated pain
], comprising inter alia the German versions
of questionnaires assessing demographic data, pain
variables (e. g. pain sites, temporal characteristics,
duration, intensity), pain associated symptoms,
affective and sensory qualities of pain (adjective list by
Geissner, SES), pain relieving and intensifying factors,
previous pain treatment procedures, pain-related
disability (Pain Disability Index), depression (Centre for
Epidemiological Studies Depression Test CES-D),
comorbid conditions, social factors (educational level,
occupation, retirement status, compensation or
litigation status, disability for work), health related quality
of life (SF-36).
- Systematic quantitative sensory testing (QST). The
detailed QST protocol including reference data is
reported elsewhere [
]. In brief, the following testing
procedures were performed:
a) Thermal Testing comprising cold and warm
detection thresholds (CDT, WDT), paradoxical heat sensations
(PHS) during the thermal sensory limen procedure (TSL)
of alternating warm and cold stimuli and cold and heat
pain thresholds (CPT, HPT);
b) Mechanical Testing comprising mechanical
detection thresholds (MDT), mechanical pain
thresholds (MPT), mechanical pain sensitivity (MPS),
dynamic mechanical allodynia (DMA), the wind-up
ratio (WUR), vibration detection thresholds (VDT)
and pressure pain thresholds (PPT).
- Pain intensity (visual analogue scale)
- Overall morphine consumption
- Side effects (documentation according to ICH
- Genetic polymorphisms: the metabolic profile of
etoricoxib involves cytochrome P450-dependent
hydroxylation and oxidation as primary clearance
]. Different genotypes might either be
the reason for individually different analgesic needs
or be considered as a risk factor for side effects [
Similar mechanisms have been described for the use
of opioids and so called multidrug resistance proteins
]. We therefore collected EDTA-blood
samples from all patients to analyse the different
expression of genotypes.
For time points please refer to Figure 1.
Descriptive analysis of the study population (including
means, standard deviations, median and frequencies) will
be made for all parameters.
Main outcome measures will be analysed with a 2 × 2
factorial ANOVA. Independent variables are time point
of medication uptake and allocated study arm, dependent
variable is the cumulative morphine consumption within
48 hours postoperatively.
Secondary outcome measures (QST, pain intensity) will
be analysed equivalent, taking into account the test
interval (repeated measurement ANOVA). ANOVA will be
adjusted according to Bonferroni using t-test for post-hoc
confirmation of significant alterations.
Ordinal scaled data will be analysed with Kruskal
Wallis test confirming significance with chi2 test.
For analyses of associative coherence we will use
Spearman's correlations coefficient, Wilcoxon-test or Kruskal
Wallis test. All reports will be performed according
intention-to treat analysis.
Data entry is done with SPSS statistical software system
(SPSS Inc., Chicago, IL; version 15.0). Data analysis will
be done with SAS/STAT® Software (SAS Institute Inc.,
Cary, NC, USA). All data entry will be carried out twice.
Internal and external audits will be held in order to assure
quality standards according to ICH-GCP guidelines, the
Declaration of Helsinki and governmental standards.
To our knowledge, the EPPA trial is the first clinical study
to investigate the preemptive analgesic effect of
etoricoxib on the cumulative postoperative morphine
consumption applying a 2 × 2 factorial study design. In
addition, our protocol takes into account individual
sensoric perception of the skin as well as genetically different
polymorphisms regarding the drug action.
Inclusion and exclusion criteria were deployed
pragmatically in order to facilitate screening and recruitment.
Exclusion criteria (besides standard items such as
pregnancy or contraindications to the study medication) are
either disease interfering with the patients' sensory
perception or with expected side effects or possible harm
related to etoricoxib. Our inclusion and exclusion criteria
are based on further trials and according to the summary
of product information [
Several COX-2-inhibitors have been shown to be
effective treating postoperative pain [
]. Data for the use
of etoricoxib seem to be promising; however, existing
results describing preemptive and postoperative effects
remain heterogeneous [
]. Etoricoxib is a
COX-2selective NSAID which is approached for treatment of
osteoarthritis, rheumatoid arthritis, acute gouty arthritis
and Morbus Bechterew. Numerous studies indicated that
etoricoxib has similar efficacy as traditional, unselective
NSAIDs have. It does not seem to elevate the risk of
severe side effects, i.e. in special vascular events [
The rates of thrombotic cardiovascular events in 34.000
patients with arthritis on etoricoxib were similar to those
in patients with long-term use of diclofenac . Ex vivo
whole-blood assays after multiple oral doses of etoricoxib
showed no important effects on bleeding time or platelet
]. Consequently, these drugs do not carry
the risk of blocking surgical interventions.
Additionally, etoricoxib demonstrated superior safety
in gastrointestinal toxicity due to its high selective COX-2
inhibition that is observed with its use. Other
NSAIDassociated effects, including renal adverse effects, appear
to be similar to those of other traditional NSAIDs [
The pharmacokinetic evaluation of etoricoxib indicates
a moderate rate of absorption and a t1/2 of approximately
20 hours that enables once-daily dosing [
We have chosen etoricoxib as verum treatment due to
the presented pharmacologic properties such as our own
clinical experience dealing with. Drug approval for
periand postoperative setting has not yet been authorised.
Quantitative sensory testing
Postoperative pain involves not only peripheral
mechanisms, most notably the sensitization of nociceptors due
to inflammation, but also secondary central mechanisms,
including hyperexcitability of nociceptive neurons (i.e.,
central sensitization, [
]). These processes play a
major role in postoperative pain, including spontaneous
pain and allodynia or hyperalgesia. In particular,
peripheral sensitization would explain the hyperalgesia
observed at the incision site (primary hyperalgesia),
whereas central sensitization would provide a major
mechanism of secondary hyperalgesia at distant
noninflammatory sites [
]; thus indicating a possible
pathway for the occurrence of prevalent pain.
From a clinical perspective, preoperative measurement
of sensoric perception may have some predictive value
regarding postoperative pain and, therefore, may also
predict perioperative analgesic requirement [
Martinez et al. showed that preoperative heat hyperalgesia
directly correlated with postoperative morphine
consumption after total knee arthroplasty [
]. These results
are in agreement with those of previous studies on the
prognostic value of preoperative pain for immediate
postoperative pain intensity with other types of surgery
]. Postoperative segmental secondary hyperalgesia
was detected in patients undergoing different types of
surgical interventions [
]. Several central and
peripheral pathophysiological actions play a role in the
development of acute and chronic postoperative pain.
Quantitative sensory testing (QST) allows precise
characterization of sensory deficits and painful symptoms and
may offer additional information on the pathophysiology
of postoperative pain. A follow-up sensory testing in our
trial is performed six months after intervention.
Therefore, we will be able to provide information regarding
long-term sensitisation after surgery, too. Taken together,
we will be able to evaluate possible predictive factors
related to patients' individual sensoric perception that
may influence the intensity of postoperative pain and
analgesic consumption such as characteristics that might
predict or prevent chronification.
Genetic polymorphisms in P-glycoprotein (P-gp), a
membrane-localised transporter codified by the gene MDR1
and Cytochrome P450 (CYP) genes, are involved in drug
metabolism and often account for variable drug response
or side effects. Some common drugs, including
non-steroidal anti-inflammatory drugs, are metabolised by the
P450 CYP2 C9 enzyme. There are mostly three variants
of CYP2C9 gene which show alternated drug response.
The variants CYP2C9*1, *2 and *3 occur most frequently
with those of a caucasian background [
enzymatic activity of *2 and *3 variant genes is decreased
significantly, and carriers of the *3 variant are at risk for
complications, such as bleeding after use of warfarin in
small amounts [
]. Newer COX-2 inhibitors have less
potential for causing gastrointestinal bleeding. The
COX2 inhibitor etoricoxib has plasma protein binding of
about 92% and is extensively metabolised, with only
about 1% being excreted in urine as parent drug. CYP3A4
plays a major role in the metabolism of etoricoxib (60%),
and CYP2C9, CYP2C19, CYP2D6 account for only a
minor fraction ( 10%) of etoricoxib's metabolic profile
]. Even though the pharmacokinetic profile is linear
and in vitro studies support that etoricoxib does minor
induction or inhibition of CYP isoenzymes, we want to
test whether the mentioned CYPs or the polymorphisms
of the MDR1 (e.g. C3435T) have a possible connection
with the outcome of postoperative pain management.
We have chosen a 2 × 2 factorial design for the following
reasons: the factorial design has several important
features. Firstly, it has great flexibility for exploring the
treatment effects in the trials. Whenever examining treatment
variations, factorial designs are strong candidates as the
design of choice. Secondly, factorial designs are efficient
due to the ability to combine multiple studies into one
rather than conducting a series of independent studies.
Finally, factorial designs are the only effective way to
examine interaction effects [
If the primary aim of a trial is to identify useful single
treatments, then it could possibly be more cost effective
to use a three-arm study than a 2 × 2 factorial design. In
this trial, it is of interest to detect the treatment
interaction, i.e. the opioid-sparing effect of a non-opioid
treatment. The chosen study design has the power to identify
such statistically significant differences between
etoricoxibe and placebo treatments [
]. While the methods are
developed for binary outcomes, they can be readily
adapted to outcomes based on continuous, ordinal or
time-to-event data using the methods for power
]. No attempt has been made to adjust for
multiple comparisons. However, this can be achieved by
simply changing the level of significance according to
some recognised procedures such as the Bonferroni
]. In our opinion, the study design allows to
obtain specific results regarding the preemptive and
postoperative analgesic effects of etoricoxib on (a) the
cumulative morphine consumption and (b) other parameters
as mentioned: predisposing characteristics influencing
postoperative pain (inter alia by means of
questionnaires), sensoric perception, genetic polymorphisms and
This study is a large-scale randomised placebo-controlled
trial to evaluate the efficacy of COX-2-inhibitors in
preemptive and postsurgical pain therapy. It can be expected
to provide new valuable information on clinical and
pathophysiological effects in postoperative pain, i.e. a)
the analgetic effectiveness of preemptive analgesia and b)
its relation to e.g. sensoric perception or genetical
predisposition as possible factors leading to persistent (chronic)
All authors declare that they have no competing interests and did not receive
any honorarium from MSD Sharp and Dome or other partners. The
investigator-initiated grant received by MSD Sharp and Dome guarantees independent
conceivability of the study design, its coordination, realisation and
independent report of the study results.
JF participated in the study design, patient recruitment and trial coordination,
and drafted the manuscript. SK, LL and PML conceived of the workflow and
acted as trial physicians. BH, HP, PC, MS, TM, PML and GS participated in the
design of the study. PC, MS and TM coordinated the study in their
departments. MO performed the sample size estimation and conceived of the
biometrical study design. DI is the principal investigator and initiator of the study,
obtained funding, designed the study and supervised and participated in
writing the manuscript. All authors read, and approved the final manuscript.
This study is supported by an investigator-initiated grant of MSD Sharp and
Dohme. Parts of the study constitute the topics of the medical thesis of Hanne
Schuller and Petra Meister. The authors thank Julia Hahn, Munich, Germany, for
her assistance while drafting the manuscript.
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