PANSAID – PAracetamol and NSAID in combination: study protocol for a randomised trial
Thybo et al. Trials
PANSAID - PAracetamol and NSAID in combination: study protocol for a randomised trial
Kasper Højgaard Thybo 0 3
Daniel Hägi-Pedersen 0 3
Jørn Wetterslev 2
Jørgen Berg Dahl 1
Henrik Morville Schrøder 7
Hans Henrik Bülow 6
Jan Gottfrid Bjørck 5
Ole Mathiesen 4
0 Department of Anaesthesiology, Naestved Hospital , Ringstedgade 61, 4700 Naestved , Denmark
1 Department of Anaesthesiology, Bispebjerg Hospital , Bispebjerg Bakke 23, 2400 Copenhagen, NV , Denmark
2 Copenhagen Trial Unit, Rigshospitalet, Department 7812 , Blegdamsvej 9, 2100 Copenhagen Ø , Denmark
3 Department of Anaesthesiology, Naestved Hospital , Ringstedgade 61, 4700 Naestved , Denmark
4 Department of Anaesthesiology, Zealand University Hospital Køge , Lykkebaekvej 1, 4600 Køge , Denmark
5 Department of Orthopedic Surgery, Nykøbing Falster Hospital , Fjordvej 15, 4800 Nykøbing Falster , Denmark
6 Department of Anaesthesiology, Holbaek Hospital , Smedelundsgade 60, 4300 Holbaek , Denmark
7 Department of Orthopedic Surgery, Naestved Hospital , Ringstedgade 61, 4700 Naestved , Denmark
Background: Effective postoperative pain management is essential for the rehabilitation of the surgical patient. No 'gold standard' exists after total hip arthroplasty (THA) and combinations of different nonopioid medications are used with virtually no evidence for additional analgesic efficacy compared to monotherapy. The objective of this trial is to investigate the analgesic effects and safety of paracetamol and ibuprofen alone and in combination in different dosages after THA. Methods: PANSAID is a placebo-controlled, parallel four-group, multicentre trial with centralised computergenerated allocation sequence and allocation concealment and with varying block size and stratification by site. Blinding of assessor, investigator, caregivers, patients and statisticians. Patients are randomised to four groups: (A) paracetamol 1 g × 4 and ibuprofen 400 mg × 4, (B) paracetamol 1 g × 4 and placebo, (C) placebo and ibuprofen 400 mg × 4 and (D) paracetamol 0.5 g × 4 and ibuprofen 200 mg. The two co-primary outcomes are 24-h consumption of morphine and number of patients with one or more serious adverse events within 90 days after surgery. Secondary outcomes are pain scores during mobilisation and at rest at 6 and 24 h postoperatively, and number of patients with one or more adverse events within 24 h postoperatively. Inclusion criteria are patients scheduled for unilateral, primary THA; age above 18 years; ASA status 1-3; BMI >18 and <40 kg/m2; women must not be pregnant; and provision of informed consent. Exclusion criteria are patients who cannot cooperate with the trial; participation in another trial; patients who cannot understand/speak Danish; daily use of strong opioids; allergy against trial medication; contraindications against ibuprofen; alcohol and/or drug abuse. A total of 556 eligible patients are needed to detect a difference of 10 mg morphine i.v. the first 24 h postoperatively with a standard deviation of 20 mg and a family wise type 1 error rate of 0.025 (two-sided) and a type 2 error rate of 0.10 for the six possible comparisons of the four intervention groups. Discussion: We started recruiting patients in December 2015 and expect to finish in September 2017. Data analysis will be from September 2017 to October 2017 and manuscript submission ultimo 2017.
Ibuprofen; Paracetamol; Total hip arthroplasty; Benefit; Harm; Multimodal analgesia; Postoperative pain
Effective postoperative pain management that promotes
early mobilisation, fluid and food intake, and the
resumptions of normal activities is essential for the
wellbeing and rehabilitation of the surgical patient  and is
a core component in enhanced recovery after surgery
programmes [2, 3]. In daily clinical practice, patients are
most often treated with different combinations of
nonopioid drugs and analgesic methods (‘multimodal
analgesia’) to achieve better analgesic effects and
lower opioid requirements including their well-known
The medical literature on postoperative multimodal
analgesia is, however, heterogenic and characterised
by typically small studies using a variety of different
combinations and techniques, and most often with
short follow-up times that lower the probability of
detecting relevant adverse effects. Consequently, most
combinations of analgesics are not well-documented
 and, therefore, it is a significant risk that patients’
pain is either treated insufficiently, or that patients
receive combinations of analgesics without additive
effects but with an increased risk of adverse effects .
It is documented that lack of systematic reporting of
adverse events (AE) is frequent , yet, the rate of
serious adverse events (SAEs) in a mixed orthopaedic
population was found to be as high as 6.2% in a
recent retrospective study .
The two most common drugs used as basic
nonopioid analgesics after surgery are paracetamol and
nonsteroidal anti-inflammatory drugs (NSAIDs). These
drugs have a proven analgesic and morphine-sparing
effect when administered individually [7, 8], whereas
evidence of an additive and improved analgesic effect
of their combination is virtually absent .
Furthermore, particularly the NSAIDs are associated with a
number of potential adverse effects, e.g.
gastrointestinal bleeding [9, 10], thromboembolic events [11, 12],
impaired renal function , anastomotic leakage
[14–17] and delayed bone-healing . It has further
been suggested that no safe treatment window exists,
even for short periods of NSAID therapy, in patients
with cardiovascular disease .
As stated above, the scientific evidence of a beneficial
effect of the combined use of paracetamol and NSAIDs
is limited. It is primarily based on two recent reviews: a
systematic, qualitative review of 21 trials including a
wide range of different pain models  and a Cochrane
review with meta-analysis of three trials of dental
surgical extraction  (Table 1).
The review by Ong et al.  included 1909
patients and, based on the available data, it concludes
that it was not possible to perform meta-analysis.
They conclude that the combination of paracetamol
and NSAIDs may provide superior analgesia
compared to either drug alone. The review is limited by a
qualitative approach including a wide range of acute
pain models, and pooling of both minor and major
surgical procedures in the analyses. Overall, 85% of
trials comparing paracetamol and a NSAID versus
paracetamol alone and 67% of trials comparing
paracetamol and a NSAID versus a NSAID alone,
provided more effective pain relief of the combination
compared to single drugs.
The Cochrane review with meta-analysis  included
1647 patients, and investigated the combined effects of
paracetamol and NSAIDs on established pain after
dental surgery, with surgical removal of at least three
impacted third molars. It was concluded that combination
therapy (both ibuprofen 200 mg/paracetamol 500 mg and
ibuprofen 400 mg/paracetamol 1000 mg) is more effective
than placebo (Number Needed to Treat ((NNT) 1.6 and
NNT 1.5, respectively) and that ibuprofen 400
mg/paracetamol 1000 mg is more effective than ibuprofen alone
(NNT 5.4). No comparison of combination therapy
versus paracetamol alone was included in this
metaTable 1 The most recent systematic reviews of combined paracetamol and a nonsteroidal anti-inflammatory drug (NSAID) versus
paracetamol or a NSAID alone in postoperative pain management, NNT Number Needed to Treat
Extraction Ibuprofen 200 mg and paracetamol
of at least 3 500 mg vs. placebo: NNT 1.6 (1.5–1.8)
impacted Ibuprofen 400 mg and paracetamol
third molars 1000 mg vs. placebo: NNT 1.5 (1.4–1.7)
Ibuprofen 400 mg and paracetamol 1000 mg
vs. ibuprofen 400 mg: NNT 5.4 (3.5–12.2)
Mixed Paracetamol and NSAID vs. paracetamol: 85%
surgical of studies showed that the combination had
populations better analgesic properties than paracetamol
alone Paracetamol and NSAID vs. NSAID: 64%
of these studies showed that the combination
had better analgesic properties than NSAID alone
Reduction in opioid
consumption is not
quantified in a
analysis. The trials included only investigated
relatively healthy and young adults.
Total hip arthroplasty (THA) is a common
procedure and may be associated with moderate to intense
postoperative pain. A large number of different
treatment options have been investigated for pain
following THA [21, 22] including opioids,
corticosteroids, NSAIDs, paracetamol and gabapentinoids and
various neuroaxial and peripheral nerve blocks.
However, no established ‘gold standard’ for pain
management after THA can be presented . The
most recent recommendation from postoppain.org
includes paracetamol, NSAIDs (either COX-2
selective or mixed type) and opioids as rescue . This
trial will potentially provide valuable information
about the optimal basic nonopioid combination
regimen for pain management after THA.
In the present trial, we have chosen THA as the
analgesic model for investigating benefit and harm of
short-term treatment of paracetamol and NSAIDs in
the trial: PANSAID – PAracetamol and NSAID in
combination: a randomised, blinded, parallel
fourgroup clinical trial.
The aim of the PANSAID trial, is to investigate the
analgesic effects and safety of paracetamol and ibuprofen
and their combination in different dosages after THA.
PANSAID is a randomised multicentre trial with a
central computer-generated allocation sequence,
concealed allocation, blinding of assessors,
investigators, caregivers, patients and statisticians in patients
having an elective total hip arthroplasty (Fig. 1).
Patients will be randomised with varying block size
and stratified according to site for treatment groups
receiving either paracetamol and ibuprofen,
paracetamol and placebo, placebo and ibuprofen or
paracetamol and ibuprofen in a reduced dosage.
We hypothesise that the combination of paracetamol
and ibuprofen is more effective than each drug alone
and will reduce opioid consumption and/or pain
levels. In addition, we hypothesise that a combination
of lower doses of paracetamol and ibuprofen will
Fig. 1 PANSAID flowchart
demonstrate analgesic efficacy comparable to higher
doses of each drug alone, and will reduce the risk of
adverse effects per se.
NSAIDs have anti-inflammatory, antipyretic and
analgesic properties and act by a reversible inhibition of the
cyclooxygenase (COX) enzyme, which mediates the
synthesis of prostaglandins and thromboxane A2. COX
exists (primarily) in two isoforms, COX-1 and COX-2, and
nonselective NSAIDs inhibit both isoforms (in varying
degrees), while COX-2-selective NSAIDs inhibit mostly
COX-2 [24, 25]. There are a number of potential adverse
effects of NSAID treatment, including increased risk of
cardiovascular events , gastrointestinal bleeding ,
ulcers , renal impairment , anastomotic leakage
[14–17] and possible impaired bone-healing .
Furthermore, although the cardiovascular and
gastrointestinal adverse effects are not well-characterised, there is
some evidence that none of the NSAIDs are completely
safe, especially for longer-term use [11, 27]. In the
existing medical literature, most of these adverse effects are
limited in description for short-term use in the
perioperative setting, and a number of them may be related
to NSAIDs with high COX-2 selectivity, e.g. diclofenac.
The European Medicines Agency has recognised an
increased cardiovascular risk in treatment with high-dose
ibuprofen (more than 2400 mg per day) . For
postoperative pain treatment; it may, therefore, be safest to
choose nonselective NSAIDs, like ibuprofen and
naproxen, and in lowest effective dose and for as short a
duration as possible, when NSAID treatment is needed.
Paracetamol has antipyretic and analgesic effects and
is generally recommended as the first-line drug in
nonopioid analgesic therapies including postoperative pain
management. Its mode of action is still controversial and
not yet fully understood. There may be a central effect
via cannabinoid and vanilloid receptors and/or
descending serotonergic pathways and, furthermore, a peripheral
and central COX-inhibition has been proposed .
Although paracetamol is considered to have few adverse
effects within the recommended dose range, liver failure
is a known adverse effect in the setting of overdose or in
specific patient populations (malnutrition, excess alcohol
intake, etc.) .
Paracetamol and ibuprofen are available as
‘over-thecounter’ medications in many countries and are standard
analgesic drugs used for postoperative pain treatment. In
this trial, paracetamol is administered in total doses of
2000 mg and 4000 mg, and ibuprofen in doses of
800 mg and 1600 mg per day. For both paracetamol and
ibuprofen these doses are within the range of
normally recommended and used postoperative doses
Scheduled for unilateral, primary THA
Aged over 18 years
Have an American Society of Anesthesiologists
(ASA) physical status classification score 1–3.
Have a Body Mass Index (BMI) >18 and <40 kg/m2
Women in the fertile age must have a negative
urinary human chorionic gonadotropin (HCG)
Patients must give written informed consent for
participation in the trial after having fully understood
the contents of the protocol and any restrictions
Patients who cannot cooperate with the trial (e.g.
use of the PCA-pump, understand the Visual
Analogue Scale (VAS) ruler, etc.)
Concomitant participation in another trial
Patients who cannot understand or speak Danish
Daily use of strong opioids (tramadol and codeine
Patients with allergy to the medicines used in
Contraindications against NSAIDs and paracetamol,
e.g. known heart failure, liver failure, renal failure
(estimated glomerular filtration rate (eGRF) <60 ml/
kg/1.73 m2), thrombocytopenia (<100 mia/L) or
previous gastric ulcer
Patients with alcohol and/or drug abuse – based
on the investigator’s judgement
Patients will be randomised to four groups at a 1:1:1:1
ratio with block randomisation of varying size and
stratified by site. Copenhagen Trial Unit (CTU),
Rigshospitalet, Denmark, provides a website for central computer
randomisation. Each patient entering the trial will be
given a unique randomisation number and a
corresponding ‘trial medicine number’.
Total need for morphine the first 24 h
postoperatively administered as both
patientcontrolled analgesia (PCA) and supplemental
morphine administered at the postanaesthesia
unit the first hour postoperatively
Serious adverse events, including death, within
90 days after surgery defined as a SAE (according to
International Conference on Harmonisation-Good
Clinical Practice (ICH-GCP) guidelines) except
‘prolongation of hospitalisation’
Level of nausea at 6 and 24 h postoperatively
Number of vomiting episodes (0–24 h) measured in
the periods 0–6 and 6–24 h postoperatively
Consumption of ondansetron in the period 0–24 h
Level of sedation at 6 and 24 h postoperatively
Level of dizziness at 6 and 24 h postoperatively
Blood loss during the surgical procedure
Days alive and outside hospital within 90 days after
Methods of measurements
The total dose of morphine (mg) in the period 0–24 h
postoperatively, including PCA-morphine and
nurseadministered supplemental morphine (bolus 2 mg) on
patient request for the first postoperative hour, is
recorded. Patients’ pain is recorded on a VAS of 100 mm,
where 0 = no pain and 100 = worst possible pain. Pain is
recorded at rest, and during 30° active flexion of the hip
and at rest.
Nausea, sedation and dizziness are recorded on a
verbal scale (none, mild, moderate, severe). The number of
productive vomiting events (volume estimated over
10 ml) is recorded corresponding to the periods 0–6 and
6–24 h postoperatively by interview with the patient.
Total use of ondansetron (mg) 0–24 h postoperatively is
recorded. Patient-reported adverse effects are recorded,
including gastrointestinal disturbances, neurological
disturbances and elevated serum creatinine.
Ninety-day mortality rate is recorded from the civil
registration system through Statistics Denmark. Serious
adverse events (SAEs) are recorded from the Danish
National Patient Registry. SAEs are defined as modified
SAEs according to the ICH-GCP guidelines excluding
‘prolongation of hospitalisation’, as we recognise that it
will be impossible to adjudicate such events.
Analgesic medication (paracetamol and NSAIDs) and
need for medical attention from discharge to the end of
trial period (90 days) are recorded from the patient
questionnaire. At sites where a 3-month clinical control
visit is part of the routine follow-up after THA the
questionnaire is returned. If no such visit is routine the
investigator at that site will telephone the patient or
contact the patient by mail.
The trial period is from randomisation to 90 days
postoperative. The intervention period is from
randomisation to 24 h postoperative.
Paracetamol 1000 mg + ibuprofen 400 mg given per os
starting 1 h before surgery and administered every 6 h
postoperatively (±1 h), i.e. a total of four times the first
Paracetamol 500 mg + ibuprofen 200 mg given per os
starting 1 h before surgery and administered every 6 h
postoperatively (±1 h), i.e. a total of four times the first
For spinal anaesthesia bupivacaine 0.5% plain,
10–15 mg is used and no opioids are added. If
sedation is needed propofol infusion is used
For general anaesthesia propofol infusion and
remifentanil infusion are used as needed. If needed,
sevofluranebased anaesthesia will alternatively be allowed and
Fifteen minutes before end of surgery sufentanil 0.3
mcg/kg intravenously (i.v.) is given to patients under
and will be reported to the relevant authorities according
to guidelines from ICH-GCP and the Danish Medicines
Standard postoperative pain and nausea management:
PCA-morphine, bolus 2 mg, lockout time 10 min.
Mixture: morphine 1 mg/ml.
If there is a need for morphine in addition to the
PCA pump in the first 1 h postoperatively at the
postanaesthesia care unit, additional bolus doses
of 2 mg morphine i.v. can be given on request by
Ondansetron 4 mg i.v. is administered at the first
indication of moderate-severe nausea and may then
be supplemented with 1 mg i.v. Maximal total dose
allowed is 8 mg over the first postoperative day
Pain treatment at the end of the intervention period
will follow departmental guidelines.
Analgesic medications other than the PCA-morphine,
including other opioids, chlorzoxazone, antidepressants,
steroids and gabapentinoids (gabapentin or pregabalin),
are not permitted during the intervention period.
Gabapentinoids and antidepressants are only permitted if the
patient continues an already instituted treatment from
All nonanalgesic medications are permitted at the
discretion of the attending physician.
The study medication will be masked by the pharmacy.
Participants, those administrating the intervention, other
caregivers, outcome assessors, data managers,
statisticians and investigators drawing conclusions will be
blinded to the intervention. The experimental medicine
will be packed and labelled by the Capital Region
Pharmacy in accordance with Good Manufacturing Practice
(GMP) hereof. The trial medication is packed in one box
per participant containing all medication for the
intervention period. CTU retains the nonblinded list of the
allocation sequence list stratified for sites, which will
only be revealed for the investigators when the data has
been analysed and abstracts  and conclusions
covering the different possibilities for interpreting the trial
results have been agreed upon by the Steering Committee/
investigators. The investigators, as well as Jørn
Wetterslev from CTU, have no access to the randomisation list.
Adverse events (AE), adverse reactions (AR), serious
adverse events (SAEs), serious adverse reactions (SARs)
and suspected unexpected serious adverse reactions
(SUSARs) will be recorded in the intervention period
Discontinuation of individual participants
If a SAE (according to the IHC-GCP definition) occurs
in the intervention period (0–24 h postoperatively) and
the investigator, after consultation with either principal
investigator or sponsor, finds it infeasible for the patient
to continue the trial, the medication will be discontinued
and the participant will be asked whether we may still
record data including follow-up data.
The blinding may only be broken if the continued
treatment of the patient requires knowledge of the
randomisation code. This can be done by the investigator
without restrictions. Breaking of the code is done by
contacting CTU by telephone.
A patient who has not completed the trial is a patient
included in the trial, i.e. one who has given informed
consent, been randomised but withdraws the consent and
does not allow for continued data recording after
discontinuing the trial medications.
If a patient does not complete the trial an account is
given as to whether and how this participant is followed
in the trial – this also applies to dropouts – as well as
what data has been collected from these participants.
The patient will be asked if the withdrawal is only for
the intervention/treatment and if they allow for further
data registration or if withdrawal is also for any further
Sample size estimation
Due to six possible comparisons and a wish to limit the
maximal family wise error rate to 0.025 (two-sided) for
each of the co-primary outcomes, for a power of 90% we
will need to randomise 556 patients (139 in each
intervention group) to detect or to discard a minimal
clinically relevant difference (10 mg) in 24-h morphine
consumption with a standard deviation of 20 mg over
24 h. However, for the coprimary outcome of patients
with one or more SAE we will collate events pending
the use of ibuprofen or not corresponding to one
comparison of 417 versus 139 patients. This comparison
addresses possible harm due to the use of ibuprofen versus
no use; a two-sided maximal type 1 error rate of 0.025
rendering a power of 80% to detect or discard an
increase in the number of patients with one or more SAE
from 10% to 20% will be used.
The trial will be completed when 556 patients are
included in the trial. The primary analysis will be a
modified (excluding patients randomised but not operated)
intention-to-treat comparing the co-primary outcome of
opioid consumption between the four groups and the
co-primary outcome of patients with one or more SAE
between collated groups randomised to ibuprofen versus
the group not receiving ibuprofen. If there are more
than 5% missing data or patients lost to follow-up and
Little’s test is statistically significant we will use multiple
imputations (MI) to impute missing data . Complete
case analysis will be performed as well but the results of
the analyses using MI-imputed datasets will be
considered the primary result of the trial. The primary analysis
of the continuous outcome of morphine consumption
within 24 h will be nonparametric pair-wise comparisons
between the median consumption of morphine between
the four groups (six analyses) stratified for sites with the
van Elteren test . If possible 99.6% and 95%
confidence intervals for the difference in medians will be
provided by boot-strapping.
Per-protocol analyses excluding patients with major
protocol violations will also be performed. Major
protocol violations are defined below. Per-protocol analyses
regarding SAEs and other safety variables will, however,
include patients with major protocol violation definition
number 3 (below).
Major protocol violations will be defined as:
1. Patients who did not get any of the dosages of the randomised allocated trial treatment
2. Patients withdrawing from the trial intervention but allowing the use of registered data
3. Patients undergoing surgery (besides the elective
THA) or a procedure in the intervention period that
requires anaesthesia or sedation and/or analgesia
The evaluability assessment of each patient in the
statistical analyses will be performed before the code is
broken. Excluded patients and missing, unused or false
data will be described. Data will be stored and evaluation
and statistical analysis will be made by a statistician
blinded for the interventions, where patient anonymity
will be preserved and local data legislation will be
Any change to the statistical plan will be accounted
for by publication. A detailed statistical analysis plan will
All data will be entered into an electronic Case Report
Form (eCRF) created and maintained by CTU (Fig. 2).
The eCRF will form the basis for the electronic database.
Data will be collected directly from the patients by trial
investigators or clinical personnel educated and
monitored by trial investigators and from the electronic
anaesthesia chart, the electronic patients chart, the civil
registration system through Statistics Denmark, and the
Danish National Patient Registry. All data will be
handled according to The Danish Data Protection agency
and local original data (e.g. Informed Consent Forms)
and records will be stored at trials sites for 5 years after
the completion of the study. The study database will be
anonymised and made publically accessible 18 months
following publication of the study.
The trial will be conducted in accordance with the
principles of the Declaration of Helsinki and in compliance
with the protocol approved by the competent authority
and Ethics Committee, and according to GCP standards
. No deviation from the protocol will be
implemented without the prior review and approval of the
regulatory authorities except where it may be
necessary to eliminate an immediate hazard to the trial
Data analysis and publication
Prior to breaking of the randomisation code an
independent statistician will perform the data analysis
according to a detailed statistical analysis plan. Based on
the masked result the Steering Committee will agree
upon abstracts covering all possible combinations and
then the blinding will be broken. The final manuscript
will contain the correct pre-made abstract. The protocol
followed the Standard Protocol Items:
Recommendations for Interventional trials (Additional file 1)  and
the manuscript will follow Consolidated Standards Of
reporting of Randomised Trials (CONSORT Statement)
. Authorship will be granted following the guidelines
from the International Committee of Medical Journal
Editors (ICMJE) . Funding sources will have no
influences on the interpretation of data.
The full, anonymised dataset will be published no
longer than 18 months after completion of the trial.
The trial is registered at clinicaltrials.gov with
Fig. 2 Screenshot of the electronic Case Report Form (eCRF)
1. A reanalysis of benefit outcomes (pain and opioid
consumption) with respect to the following
subgroups: sex, age, ASA-score, type of surgery
(uncemented, cemented or hybrid), surgical site
(posterior approach versus anterolateral approach)
and anaesthetic technique (general anaesthesia
versus spinal anaesthesia)
2. A reanalysis of harm (AEs and opioid-related side ef
fects) with respect to the following groups sex, age,
ASA-score, anaesthetic technique (general
anaesthesia versus spinal anaesthesia) and opioid
consumption (in the intervention period)
3. Longer follow-up than the specified 90 days (1 year)
4. An analysis of the association between VAS scores and opioid consumption
5. Time-to-event analyses regarding use of PCAmorphine
Fig. 3 Screenshot of the trial homepage, www.pansaid.dk
6. An analysis of the association between preoperative
analgesic use and pain/morphine consumption
7. An analysis of the individual patients: how many will
achieve ‘no worse than mild pain’ (NRS <3)
More substudies may be performed post hoc and they
will be clearly identified as such.
2015: application for approval from the Danish
Medicines Agency, the Ethics Committee and the Danish
Data Registration Agency. Development of an eCRF and
2015–2017: inclusion of patients
2018: data analysis, writing and submission of the
PANSAID will provide the first, large, high-quality data
regarding the combination of paracetamol and ibuprofen
used in a surgical setting. We expect this trial to supply
a significant contribution to a systematic and
evidencebased approach towards nonopioid multimodal analgesic
regimens for postsurgical treatment in a broader
Currently, more than 200 patients have been enrolled in
the trial. The trial status can be seen at the trial website
www.pansaid.dk (Fig. 3). We expect the enrolment
period to end in September 2017.
Additional file 1: SPIRIT 2013 Checklist: Recommended items to address
in a clinical trial protocol and related documents*. SPIRIT figure: PANSAID.
(ZIP 47 kb)
AE: Adverse events; AR: Adverse reactions; ASA: American Society of
Anesthesiologists; BMI: Body Mass Index; CONSORT: Consolidated Standards
of Reporting Trials; COX: Cyclooxygenase; CTU: Copenhagen Trial Unit;
DASAIM: The Danish Society of Anaesthesiology and Intensive care Medicine;
eCRF: Electronic Case Report Form; eGRF: Estimated glomerular filtration rate;
GCP: Good Clinical Practice; GMP: Good Manufacturing Practice; HCG: Human
chorionic gonadotropin; ICH: The International Conference on Harmonisation
of technical requirements for registration of pharmaceuticals for human use;
ICMJE: International Committee of Medical Journal Editors; MI: Multiple
imputations; NSAID: Nonsteroidal anti-inflammatory drugs; PCA:
Patientcontrolled analgesia; SAE: Serious adverse event; SAR: Serious adverse
reaction; SPIRIT: Standard Protocol Items: Recommendations for
Interventional Trials; SUSAR: Suspected unexpected serious adverse reaction;
THA: Total hip arthroplasty; VAS: Visual Analogue Scale
The trial is funded by departmental and external sources. No medical
company is supporting this trial. The following funds have until now
supported the trial: The Danish Society of Anaesthesiology and Intensive
Care Medicine (DASAIM), ‘Sophus Johansens Fond’, ‘Region Zealand Health
Scientific Research Foundation’, ‘The local research foundation at
NaestvedSlagelse-Ringsted Hospitals’, ‘The A.P. Møller Foundation for the
Advancement of Medical Science’ and ‘Aase og Ejnar Danielsens Fond’. The
funding sources will have no influences on trial design, data collection,
analysis or reporting.
KHT and OM drafted the protocol and the manuscript for this paper in close
collaboration with DHP, JBD and JW. HMS, HHB and JGB all made substantial
contributions to the process of developing the protocol and contributed
with scientific input for the protocol and this manuscript. All authors read
and approved the final manuscript. All authors are members of the PANSAID
Steering Committee. DHP is the sponsor, KHT is the principal investigator.
Ethics approval and consent to participate
The PANSAID trial was approved by the Regional Ethics Committee, Region
Zealand, SJ-462, on the 30 June 2015 (which covers all trial sites); approved
by the Danish Medicines Agency, journal no. 2015053406, EudraCT:
2015002239-16 on the 12 of August 2015; and approved by the Danish Data
Protection Agency, REG-33-2015, on the 30 of June 2015.
All participants considered for the trial will be provided with written and oral
information on the trial so that they can make an informed decision about
their participation in the trial. Written information and the Consent Form has
been approved by the Ethics Committee . This Consent Form must be
signed by the participant and by the investigator seeking the consent.
Patients will only be enrolled after written informed consent has been
1. Kehlet H , Dahl JB. Anaesthesia, surgery, and challenges in postoperative recovery . Lancet . 2003 ; 362 : 1921 - 8 .
2. Kehlet H , Wilmore DW. Evidence-based surgical care and the evolution of fast-track surgery . Ann Surg . 2008 ; 248 : 189 - 98 .
3. Aasvang EK , Luna IE , Kehlet H. Challenges in postdischarge function and recovery: the case of fast-track hip and knee arthroplasty . Br J Anaesth . 2015 ; 115 : 861 - 6 .
4. Dahl JB , Nielsen RV , Wetterslev J , Nikolajsen L , Hamunen K , Kontinen VK , Hansen MS , Kjer JJ , Mathiesen O , Scandinavian Postoperative Pain Alliance. Post-operative analgesic effects of paracetamol, NSAIDs, glucocorticoids, gabapentinoids and their combinations: a topical review . Acta Anaesthesiol Scand . 2014 ; 58 : 1165 - 81 .
5. Mathiesen O , Wetterslev J , Kontinen VK , Pommergaard HC , Nikolajsen L , Rosenberg J , Hansen MS , Hamunen K , Kjer JJ , Dahl JB , Scandinavian Postoperative Pain Alliance . Adverse effects of perioperative paracetamol, NSAIDs, glucocorticoids, gabapentinoids and their combinations: a topical review . Acta Anaesthesiol Scand . 2014 ; 58 : 1182 - 98 .
6. Hansen MS , Petersen EE , Dahl JB , Wetterslev J. Post-operative serious adverse events in a mixed surgical population-a retrospective register study . Acta Anaesthesiol Scand . 2016 ; 60 : 1209 - 21 .
7. Derry CJ , Derry S , Moore RA . Single dose oral ibuprofen plus paracetamol (acetaminophen) for acute postoperative pain . Cochrane Database Syst Rev . 2013 ; 6 : CD010210 .
8. Moore RA , Derry S , McQuay HJ , Wiffen PJ . Single dose oral analgesics for acute postoperative pain in adults . Cochrane Database Syst Rev . 2011 ; 9 : CD008659 .
9. Ofman JJ , MacLean CH , Straus WL , Morton SC , Berger ML , Roth EA , Shekelle P. A metaanalysis of severe upper gastrointestinal complications of nonsteroidal antiinflammatory drugs . J Rheumatol . 2002 ; 29 : 804 - 12 .
10. Scarpignato C , Hunt RH . Nonsteroidal antiinflammatory drug-related injury to the gastrointestinal tract: clinical picture , pathogenesis, and prevention. Gastroenterol Clin N Am . 2010 ; 39 : 433 - 64 .
11. Fosbol EL , Folke F , Jacobsen S , Rasmussen JN , Sorensen R , Schramm TK , Andersen SS , Rasmussen S , Poulsen HE , Kober L , et al. Cause-specific cardiovascular risk associated with nonsteroidal antiinflammatory drugs among healthy individuals . Circ Cardiovasc Qual Outcomes . 2010 ; 3 : 395 - 405 .
12. Fitzgerald GA . Coxibs and cardiovascular disease . N Engl J Med . 2004 ; 351 : 1709 - 11 .
13. Lee A , Cooper MC , Craig JC , Knight JF , Keneally JP . Effects of nonsteroidal anti-inflammatory drugs on postoperative renal function in adults with normal renal function . Cochrane Database Syst Rev 2004 : CD002765 .
14. Bhangu A , Singh P , Fitzgerald JE , Slesser A , Tekkis P. Postoperative nonsteroidal anti-inflammatory drugs and risk of anastomotic leak: metaanalysis of clinical and experimental studies . World J Surg . 2014 ; 38 : 2247 - 57 .
15. Burton TP , Mittal A , Soop M. Nonsteroidal anti-inflammatory drugs and anastomotic dehiscence in bowel surgery: systematic review and metaanalysis of randomized, controlled trials . Dis Colon Rectum . 2013 ; 56 : 126 - 34 .
16. Gorissen KJ , Benning D , Berghmans T , Snoeijs MG , Sosef MN , Hulsewe KW , Luyer MD . Risk of anastomotic leakage with non-steroidal anti-inflammatory drugs in colorectal surgery . Br J Surg . 2012 ; 99 : 721 - 7 .
17. Klein M , Gogenur I , Rosenberg J. Postoperative use of non-steroidal antiinflammatory drugs in patients with anastomotic leakage requiring reoperation after colorectal resection: cohort study based on prospective data . BMJ . 2012 ; 345 :e6166.
18. Kurmis AP , Kurmis TP , O'Brien JX , Dalen T. The effect of nonsteroidal antiinflammatory drug administration on acute phase fracture-healing: a review . J Bone Joint Surg Am . 2012 ; 94 : 815 - 23 .
19. Schjerning Olsen AM , Fosbol EL , Gislason GH . The impact of NSAID treatment on cardiovascular risk-insight from Danish observational data . Basic Clin Pharmacol Toxicol . 2014 ; 115 : 179 - 84 .
20. Ong CK , Seymour RA , Lirk P , Merry AF . Combining paracetamol (acetaminophen) with nonsteroidal antiinflammatory drugs: a qualitative systematic review of analgesic efficacy for acute postoperative pain . Anesth Analg . 2010 ; 110 : 1170 - 9 .
21. Hojer Karlsen AP , Geisler A , Petersen PL , Mathiesen O , Dahl JB . Postoperative pain treatment after total hip arthroplasty: a systematic review . Pain . 2015 ; 156 : 8 - 30 .
22. Fischer HB , Simanski CJ. A procedure-specific systematic review and consensus recommendations for analgesia after total hip replacement . Anaesthesia . 2005 ; 60 : 1189 - 202 .
23. PROSPECT: procedure specific postoperative pain management . http://www. postoppain.org/. Accessed 7 Oct 2016 .
24. Antman EM , DeMets D , Loscalzo J. Cyclooxygenase inhibition and cardiovascular risk . Circulation . 2005 ; 112 : 759 - 70 .
25. Antman EM , Bennett JS , Daugherty A , Furberg C , Roberts H , Taubert KA , American Heart Association. Use of nonsteroidal antiinflammatory drugs: an update for clinicians: a scientific statement from the American Heart Association . Circulation. 2007 ; 115 : 1634 - 42 .
26. Lee A , Cooper MG , Craig JC , Knight JF , Keneally JP . Effects of nonsteroidal anti-inflammatory drugs on postoperative renal function in adults with normal renal function . Cochrane Database Syst Rev 2007 : CD002765 .
27. Bhala N , Emberson J , Merhi A , Abramson S , Arber N , Baron JA , Bombardier C , Cannon C , et al. Vascular and upper gastrointestinal effects of nonsteroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials . Lancet . 2013 ; 382 : 769 - 79 .
28. European Medicines Agency. http://www.ema.europa.eu/docs/en_GB/ document_library/Press_release/2015/04/WC500185426.pdf. Accessed 7 Oct 2016 .
29. Graham GG , Davies MJ , Day RO , Mohamudally A , Scott KF . The modern pharmacology of paracetamol: therapeutic actions, mechanism of action, metabolism, toxicity and recent pharmacological findings . Inflammopharmacology . 2013 ; 21 : 201 - 32 .
30. Gotzsche PC . Blinding during data analysis and writing of manuscripts . Control Clin Trials . 1996 ; 17 : 285 - 90 . discussion 290 - 283 .
31. Schafer JL . Multiple imputation: a primer . Stat Methods Med Res . 1999 ; 8 : 3 - 15 .
32. Qu Y , Zhao YD , Rahardja D. Wilcoxon-Mann-Whitney test: stratify or not ? J Biopharm Stat . 2008 ; 18 : 1103 - 11 .
33. International Conference on Harmonisation Guideline for International conference on harmonisation of technical requirements for registration of pharmaceuticals for human use . Guideline for Good Clinical Practice E6 (R1). ICH Harmonised Tripartite Guideline . June 1996 . https://www.ich.org/ fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R1_ Guideline.pdf. Accessed 18 Feb 2016 .
34. Chan AW , Tetzlaff JM , Altman DG , Laupacis A , Gotzsche PC , Krleza-Jeric K , Hrobjartsson A , Mann H , Dickersin K , Berlin JA , et al. SPIRIT 2013 Statement: defining standard protocol items for clinical trials . Ann Intern Med . 2013 ; 158 : 200 - 7 .
35. Schulz KF , Altman DG , Moher D , Group C. CONSORT 2010 Statement: updated guidelines for reporting parallel group randomised trials . BMJ . 2010 ; 340 :c332.
36. International Committee of Medical Journal Editors. Uniform requirements for manuscripts submitted to Biomedica . http://www.icmje.org/. Accessed 4 Apr 2016 .
37. The National Committee on Health Research Ethics . http://www.dnvk.dk/. Accessed 18 Dec 2016 .