A Comparison of Analgesic and Respiratory Effects From Tapentadol Versus Oxycodone After Laparoscopic Hysterectomy.
Phase: PHASE4
Conditions: Pain, Postoperative, Pain Uterus, Pain, Acute, Opioid Use, Analgesics, Antipyretics, and Antirheumatics Causing Adverse Effects in Therapeutic Use, Visceral Pain
Sponsor: Oslo University Hospital

 
 
 A comparison of analgesic and respiratory effects from tapentadol versus 
oxycodone after laparoscopic hysterectomy. 
 
 
 
Protocol Identification Number:  Tapentadol study. 
EudraCT Number:  2017-001285-23. 
 
 
SPONSOR: 
Oslo University Hospital 
Kristin Sem Thagaard, Head of Department. 
 
 
Department of Anesthesiology 
 
 
Division of Emergencies and Critical Care 
 
 
Oslo University Hospital 
 
 
P.O.Box 4956, Nydalen 
 
 
0424 Oslo 
 
 
Telephone: 22 11 96 90 
 
 
E-mail: UXKRTH@ous-hf.no 
 
 
 
 
 
 
 
 
PROTOCOL VERSION NO. 170317-3.0  -  26.06.2017 

 
Tapentadol-study Version no. 3 – 26.06.17 
Page 2 of 51 
CONTACT DETAILS  
Sponsor: 
Kristin Sem Thagaard, Head of Department. 
Department of Anesthesiology 
Division of Emergencies and Critical Care 
Oslo University Hospital 
P.O.Box 4956, Nydalen 
0424 Oslo 
Telephone: 22 11 96 90 
E-mail: UXKRTH@ous-hf.no 
 
Principal investigator: 
 
 
 
 
 
 
 
 
 
Investigator: 
 
 
 
 
 
 
 
 
 
Investigator: 
 
 
 
 
 
 
 
 
 
Marlin Comelon, MD. 
Department of Anesthesiology 
Division of Emergencies and Critical Care 
Oslo University Hospital 
P.O.Box 4956, Nydalen 
0424 Oslo 
Telephone: 22 11 96 90  
E-mail: marlin.comelon@ous-hf.no 
 
Johan Ræder, Professor, MD. 
Department of Anesthesiology 
Division of Emergencies and Critical Care 
Oslo University Hospital 
P.O.Box 4956, Nydalen 
0424 Oslo 
Telephone: 22 11 96 90  
E-mail: johan.rader@medisin.uio.no 
 
Harald Lenz, MD, PhD 
Department of Anesthesiology 
Division of Emergencies and Critical Care 
Oslo University Hospital 
P.O.Box 4956, Nydalen 
0424 Oslo 
Telephone: 22 11 96 90  

 
Tapentadol-study Version no. 3 – 26.06.17 
Page 3 of 51 
 
 
Investigator: 
E-mail: harald.lenz@medisin.uio.no 
 
Tomas Drægni, CRNA/research nurse 
Department of Research and Development 
Division of Emergencies and Critical Care 
Oslo University Hospital 
P.O.Box 4956, Nydalen 
0424 Oslo 
Telephone: 22 11 96 90  
E-mail: TOMDRA@ous-hf.no 
 
Participating Departments: 
Department of Anesthesiology 
Division of Emergencies and Critical Care 
Oslo University Hospital 
P.O.Box 4956, Nydalen 
0424 Oslo 
Telephone: 22 11 96 90  
E-mail: marlin.comelon@ous-hf.no  
 
 
 
 
  
Participating Departments: 
Department of Gynaecology 
Women and Children’s Division 
Oslo University Hospital 
P.O.Box 4956, Nydalen 
0424 Oslo 
Telephone: 22 11 98 00 
E-mail: UXITLI@ous-hf.no 
 
Monitor: 
Department of Clinical Research Support  
Oslo University Hospital 
P.O.Box 4956, Nydalen 
0424 Oslo 
Telephone: 02770  
 

 
Tapentadol-study Version no. 3 – 26.06.17 
Page 4 of 51 
SIGNATURE PAGE 
 
Title 
A comparison of analgesic and respiratory effects from tapentadol versus oxycodone after 
laparoscopic hysterectomy. 
Protocol ID no: 
Tapentadol study.17031-2.  
EudraCT no: 
2017-001285-23. 
 
 
I hereby declare that I will conduct the study in compliance with the Protocol, ICH GCP and the 
applicable regulatory requirements: 
 
Name 
Title 
Role 
Signature 
Date 
Marlin Comelon 
MD 
Principal 
Investigator 
 
 
Kristin Sem Thagaard 
MD 
Sponsor’s 
representative 
 
 
 
 

 
Tapentadol-study Version no. 3 – 26.06.17 
Page 5 of 51 
PROTOCOL SYNOPSIS 
 
Title:  
A comparison of analgesic and respiratory effects from tapentadol versus oxycodone after laparoscopic 
hysterectomy. 
 
Sponsor: 
Kristin Sem Thagaard, Oslo University Hospital. 
Phase and study type 
Phase IV, interventional. 
Investigational Medical Product 
(IMP) (including active 
comparator and placebo):     
IMP:  
Palexia 50 mg® (tapentadol 50 mg) 
Palexia depot 50 mg® (tapentadol depot 50 mg) 
Active comparator: 
OxyNorm 10 mg® (oxycodone immediate-release 10 mg) 
OxyContin 10 mg® (oxycodone extended-release 10 mg) 
 
Centers: 
Oslo University Hospital, Oslo, Norway. 
Study Period: 
 
Estimated date of first patient enrolled: 01.09.17. 
Anticipated recruitment period: 1 year 6 months. 
Estimated date of last patient completed: 01.03.19. 
Treatment Duration: 
24 – 32 hours. 
Follow-up: 
End of treatment visit in person at 24 hours followed-up by a call at 32 hours. No 
further follow-up visits. 
Objectives  
The primary goal of the study is to examine the analgesic effects in patients receiving 
either tapentadol or oxycodone during the first postoperative day after hysterectomy.  
As a secondary goal we want to examine the respiratory depressive effect from 
tapentadol compared to oxycodone.  
 
Endpoints: 
Primary endpoint: Pain at rest 1 hour postoperatively. 
 
Secondary endpoints: Pain at rest and while coughing 1-24 hours postoperatively. 
Respiratory depression 1-24 hours postoperatively. Further, we will also examine 
other common opioid related side-effects: sedation, nausea, vomiting, pruritus, 
dizziness and headache. 

 
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Page 6 of 51 
Study Design: 
Randomized, double-blind, parallel-group, single-center study with two arms. 
Main Inclusion Criteria:    
Women, age 18-64 years, diagnosed with a benign gynecological condition, 
undergoing laparoscopic, supra-cervical or total hysterectomy in general anesthesia. 
ASA classification I-III. 
Main Exclusion Criteria 
• 
BMI > 31 and/or weight <55 kg, >85 kg.  
• 
Chronic pain syndromes related to organ systems other than the female 
reproductive system. 
• 
Chronic opioid therapy (codeine medication allowed up to 60 mg/day) or 
enteral steroid therapy.  
• 
Alcohol or medical abuse/addiction.  
• 
Pulmonary or neurological disease/condition known to predispose for 
respiratory depression.  
• 
Allergy or contraindication to any of the medications used in the study.  
• 
Lactose intolerance. 
• 
The concurrent use of monoamine oxidase inhibitors, serotonin 
norepinephrine reuptake inhibitors, benzodiazepines, barbiturates, 
              neuroleptics, phenytoin tricyclic antidepressants, gabapentanoids, tramadol, 
              clonidine, cimetidine, rifampicin, protease inhibitors, St John’s wort (Hyperi-  
              cum perforatum), macrolides and antimycotics is not allowed. 
 
 
 
Sample Size: 
90 patients. 
Efficacy Assessments: 
Verbal pain rating by the numerical rating scale (NRS) for pain. Rating of pain relief. 
Global medication performance after 24 hours. Time to first rescue medicine. Total 
rescue analgesic consumption IV and PO over 24 hours. 
Safety Assessments: 
Continuous monitoring with 3-lead ECG and oxygen saturation by pulse oximetry 
during anesthesia and in postoperative ward. Intermittent monitoring of blood 
pressure, respiratory rate, measurement of end-tidal carbon dioxide and evaluation of 
sedation using the Pasero opioid-induced sedation scale while in postoperative ward 
(30, 60, 120, 180 minutes postoperatively). In the gynecological ward oxygen 
saturation measured by pulse oximetry, sedation using the Pasero opioid-induced 
sedation scale and respiratory rate will be measured at rest at 24 hours 
postoperatively.  
Other Assessments:  
Not applicable. 

 
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Page 7 of 51 
TABLE OF CONTENTS 
CONTACT details ............................................................................................................................................................ 2 
Signature page ................................................................................................................................................................ 4 
PROTOCOL SYNOPSIS ................................................................................................................................................. 5 
TABLE OF CONTENTS ................................................................................................................................................... 7 
List of Abbreviations and Definitions of Terms ............................................................................................................... 10 
1 
introduction ......................................................................................................................................................... 11 
1.1 
Background – Postoperative pain ....................................................................................................................... 11 
1.2 
Background - Therapeutic Information ............................................................................................................... 11 
1.3 
Pre-Clinical & Clinical Experience with Tapentadol ............................................................................................ 11 
1.4 
Rationale for the Study and Purpose .................................................................................................................. 12 
2 
STUDY OBJECTIVES and related endpoints ..................................................................................................... 12 
2.1 
Primary Endpoint ................................................................................................................................................ 12 
2.2 
Secondary Endpoints ......................................................................................................................................... 13 
3 
Overall STUDY Design ....................................................................................................................................... 14 
4 
STUDY POPULATION ....................................................................................................................................... 14 
4.1 
Selection of Study Population ............................................................................................................................. 14 
4.2 
Number of Patients ............................................................................................................................................. 14 
4.3 
Inclusion Criteria ................................................................................................................................................. 14 
4.4 
Exclusion Criteria ................................................................................................................................................ 15 
5 
TREATMENT ...................................................................................................................................................... 15 
5.1 
Drug Identity, Supply and Storage ...................................................................................................................... 15 
5.2 
Dosage and Drug Administration ........................................................................................................................ 16 
5.3 
Duration of Therapy ............................................................................................................................................ 17 
5.4 
Premedication and Monitoring ............................................................................................................................ 18 
5.5 
Concomitant Medication ..................................................................................................................................... 18 
5.6 
Subject Compliance ............................................................................................................................................ 20 
5.7 
Drug Accountability ............................................................................................................................................. 20 
5.8 
Drug Labeling ..................................................................................................................................................... 21 
5.9 
Subject Numbering ............................................................................................................................................. 22 
6 
STUDY procedures ............................................................................................................................................ 23 
6.1 
Flow Chart .......................................................................................................................................................... 23 
6.2 
By Visit ............................................................................................................................................................... 24 
6.2.1 
Before Treatment Starts ............................................................................................................................... 25 
6.2.2 
During Treatment ......................................................................................................................................... 25 
6.2.3 
End of Treatment Visit .................................................................................................................................. 27 
6.2.4 
Withdrawal Visit ............................................................................................................................................ 29 
6.2.5 
After End of Treatment (Follow-up) .............................................................................................................. 29 

 
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6.3 
Criteria for Patient Discontinuation ..................................................................................................................... 29 
6.4 
Procedures for Discontinuation .......................................................................................................................... 29 
6.4.1 
Patient Discontinuation ................................................................................................................................. 29 
6.4.2 
Trial Discontinuation ..................................................................................................................................... 29 
6.5 
Laboratory Tests ................................................................................................................................................. 30 
7 
assessments....................................................................................................................................................... 30 
7.1 
Assessment of Efficacy Response ..................................................................................................................... 30 
7.2 
Safety and Tolerability Assessments .................................................................................................................. 31 
7.3 
Other Assessments ............................................................................................................................................ 32 
8 
Safety MONItoring and reporting ........................................................................................................................ 33 
8.1 
Definitions ........................................................................................................................................................... 33 
8.1.1 
Adverse Event (AE) ...................................................................................................................................... 33 
8.1.2 
Serious Adverse Event (SAE) ...................................................................................................................... 33 
8.1.3 
Suspected Unexpected Serious Adverse Reaction (SUSAR) ...................................................................... 34 
8.2 
Expected Adverse Events .................................................................................................................................. 34 
8.3 
Disease Progression/Recurrence ....................................................................................................................... 35 
8.4 
Time Period for Reporting AE and SAE.............................................................................................................. 35 
8.5 
Recording of Adverse Events ............................................................................................................................. 35 
8.6 
Reporting Procedure .......................................................................................................................................... 36 
8.6.1 
AEs and SAEs .............................................................................................................................................. 36 
8.6.2 
SUSARs ....................................................................................................................................................... 36 
8.6.3 
Annual Safety Report ................................................................................................................................... 37 
8.6.4 
Clinical Study Report .................................................................................................................................... 37 
8.7 
Procedures in Case of Emergency ..................................................................................................................... 37 
9 
Data management and monitoring ..................................................................................................................... 37 
9.1 
Case Report Forms ............................................................................................................................................ 37 
Case Report Forms (paper CRF/pCRF) ........................................................................................................................ 37 
9.2 
Source Data........................................................................................................................................................ 38 
9.3 
Study Monitoring ................................................................................................................................................. 38 
9.4 
Confidentiality ..................................................................................................................................................... 39 
9.5 
Database management ...................................................................................................................................... 39 
10 
Statistical methods and data analysis................................................................................................................. 40 
10.1 Determination of Sample Size ............................................................................................................................ 40 
10.2 Randomization .................................................................................................................................................... 40 
10.2.1 Allocation- sequence generation .................................................................................................................. 40 
10.2.2 Allocation- procedure to randomize a patient ............................................................................................... 40 
10.2.3 Blinding and emergency unblinding.............................................................................................................. 40 
10.3 Population for Analysis ....................................................................................................................................... 41 
10.4 Planned analyses ............................................................................................................................................... 41 

 
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10.5 Statistical Analysis .............................................................................................................................................. 41 
10.5.1 Primary analysis ........................................................................................................................................... 42 
10.5.2 Secondary analyses ..................................................................................................................................... 42 
11 
STUDY MANAGEMENT ..................................................................................................................................... 43 
11.1 Investigator Delegation Procedure ..................................................................................................................... 43 
11.2 Protocol Adherence ............................................................................................................................................ 43 
11.3 Study Amendments ............................................................................................................................................ 43 
11.4 Audit and Inspections ......................................................................................................................................... 43 
12 
Ethical and regulatory requirements ................................................................................................................... 43 
12.1 Ethics Committee Approval ................................................................................................................................ 43 
12.2 Other Regulatory Approvals ............................................................................................................................... 44 
12.3 Informed Consent Procedure ............................................................................................................................. 44 
12.4 Subject Identification .......................................................................................................................................... 44 
13 
Trial sponsorship and financing .......................................................................................................................... 44 
14 
Trial insurance .................................................................................................................................................... 44 
15 
Publication policy ................................................................................................................................................ 44 
16 
Conflict of interest ............................................................................................................................................... 45 
17 
REFERENCES ................................................................................................................................................... 45 
18 
LIST OF APPENDICES ...................................................................................................................................... 46 
APPENDIX A ................................................................................................................................................................. 47 
APPENDIX B ................................................................................................................................................................. 48 
   APPENDIX C ................................................................................................................................................................. 50 
 
 

 
Tapentadol-study Version no. 3 – 26.06.17 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
Abbreviation or special term 
Explanation 
AE 
Adverse Event  
ASA-classification 
American Society of Anesthesiologists physical status classification system 
BIS 
Bispectral index 
CRF 
Case Report Form (electronic/paper) 
CSA 
Clinical Study Agreement 
DAE 
Discontinuation due to Adverse Event 
ETCO2 
End-tidal carbon dioxide 
ECG 
Electrocardiogram 
GCP 
Good Clinical Practice 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IMP 
Investigational Medicinal Product (includes active comparator and placebo) 
IV 
Intra venous 
NRS 
Numerical Rating Scale for pain (range 0-10) 
PO 
Per oral 
PRN 
Pro re nata (when necessary) 
REK 
Regional Committees for Medical and Health Research Ethics 
SAE 
Serious Adverse Event   
SmPC 
Summary of Product Characteristics 
SOP 
Standard Operating Procedure 
SpO2 
Oxygen saturation 
 
 
 
 
 

 
Tapentadol-study Version no. 3 – 26.06.17 
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1 
INTRODUCTION 
1.1 
Background – Postoperative pain  
In the Norwegian population about 1 out of 10 will undergo surgery every year. Most of these patients will experience 
postoperative pain, which initiate different measures of prophylaxis and treatment. Postoperative pain is a major cause of 
postoperative suffering, prolonged hospitalization, complications and increased costs. It has been shown that 
postoperative pain is a frequent and unresolved problem in Norwegian hospitals, and so also internationally. Building 
knowledge on pain prophylaxis and treatment of postoperative pain is an area with substantial potential for improvement 
and affecting many patients. 
Opioids remain as first-line drugs for the treatment of moderate to severe postoperative pain, but the use is limited by 
well-known side-effects, most of which are dose-dependent. Opioids also carry an inherent risk of addiction. 
1.2 
Background - Therapeutic Information 
The opioid oxycodone (C18H21NO4. ACT: N02A A05) is used as standard therapeutic treatment for acute postoperative 
pain, either in immediate-release formulation, OxyNorm®, or as extended-release formulation, OxyContin®. Oxycodone 
is a pure opioid receptor agonist with central and peripheral effects. 
Tapentadol hydrochloride/depot (Palexia/depot®; 3-dimethylamino-1-ethyl-2-methyl-propyl-phenol hydrochloride. ACT: 
N02A X06) is a novel, centrally acting, strong analgesic with a dual mechanism of action. It is a µ-opioid receptor agonist 
with central and peripheral effects, and it also inhibits noradrenaline reuptake in the central nervous system. Tapentadol 
is an active compound, devoid of active metabolites and not reliant on enzyme systems.(1) For these reasons, it has a 
low drug interaction potential. 
Opioid receptors are usually not well expressed in non-inflamed peripheral tissue and they have limited effect on the 
peripheral pathophysiology and origin of acute wound pain. While postoperative pain basically is induced by relevant 
nociceptive pain nerve stimulation, there is also a neuropathic component in most cases. Opioids are not very effective 
in blocking neuropathic pain in low to moderate doses. Also, opioids do not have the potential to block the wind-up of 
pain when given before the start of surgical trauma.(2) The noradrenaline re-uptake inhibition (NRI) component of 
tapentadol is believed to have effect on descending pathways in the spinal cord. Such excitatory and inhibitory pathways 
act through monoamine systems mediated by noradrenaline and 5-hydroxytryptamine (5-HT). The inhibition of 
noradrenaline reuptake increases monoaminergic transmission in the descending pain inhibitory pathways, leading to 
reduced pain sensation. It seems like tapentadol produce not simply additive, but synergistic anti-nociceptive action by 
inhibitory actions in µ-opioid receptor agonism and NRI. While the effect on µ-opioid receptors is important in 
nociceptive pain, the NRI component seems to be especially relevant for both acute and persistent neuropathic pain.(3)  
The synergistic effect of µ-opioid receptor agonism and NRI translates clinically into less adverse effects than with pure 
opioid agonists. This is probably due to less µ-opioid receptor stimulation. 
We wish to compare the analgesic effect and side-effects of this new analgesic, tapentadol, to the standard treatment to 
day, oxycodone, in the acute postoperative period in patients with visceral pain.  
1.3 
Pre-Clinical & Clinical Experience with Tapentadol 
Tapentadol has been shown effective in models of acute, osteoarthritic, neuropathic and cancer-induced bone pain.(1) 
There is now an increasing use of tapentadol in postoperative pain treatment in Norwegian hospitals. However, there is a 
lack of broad-based evidence for the use of tapentadol in the post-surgical setting. So far, to our knowledge, there are 
only published studies on postoperative pain treatment after orthopedic and dental surgery, but none related to visceral 
pain. Most studies have so far been initiated by the industry. The standard treatment today, oxycodone, on the other 
hand is shown in several studies to have a preferable analgesic effect on pain of visceral origin compared to 
morphine.(4)  
The synergistic effect of µ-opioid receptor agonism and NRI translates clinically into less adverse effects than with pure 
opioid agonists. Tapentadol is shown in several studies on chronic pain patients to have comparable analgesic effects to 

 
Tapentadol-study Version no. 3 – 26.06.17 
Page 12 of 51 
traditional opioid pain medications like oxycodone and morphine, but with a more tolerable side effect profile. In the 
postoperative setting after dental or orthopedic surgery, studies have shown less nausea and constipation. (5-7) It has 
also been suggested a lower frequency of pruritus compared with oxycodone, but no difference in central nervous 
system symptoms such as somnolence or dizziness.(8) The most dangerous side-effect from opioids is respiratory 
depression with the potential of fatal outcome.(9) Intravenous oxycodone is shown to have dose dependent effect on 
respiratory depression decreasing the mean minute volume with a more rapid onset than morphine.(10) One study has 
attempted to study respiratory depression after tapentadol administration, but failed due to technical failure of the pulse 
oximetry device.(5) We have not found any other publications from short-term postoperative pain management 
comparing any respiratory effect of tapentadol to the traditional opioids.(11)  
1.4 
Rationale for the Study and Purpose 
Patients scheduled for elective hysterectomy are chosen as our study population, as this is a group of patients with 
significant visceral pain after surgery. The comparator, oxycodone, is the standard opioid used for treatment of acute 
postoperative pain in these patients today. Oxycodone, as all other opioids, has known side-effects such as nausea, 
vomiting, constipation, pruritus, somnolence and respiratory depression which pose potential risks or discomfort to the 
patients. From previous clinical studies in orthopedic and dental patients we know that tapentadol probably has an equal 
analgesic potential to oxycodone, but with less side-effects (best evidence for gastrointestinal side-effects).(5-7) 
However, there are no studies done on respiratory depression from tapentadol which may be the most dangerous risk to 
the patients.(5,11) Showing less respiratory depression from tapentadol, but equal analgesic effect to comparable 
opioids, would be of immense benefit to the patient population as this would eliminate or reduce the most dangerous and 
potentially fatal side-effect from opioids. Overall, less side-effects from opioids may result in less complications and 
shorter in-hospital admissions. In terms of patient comfort (both physically and mentally), less side-effects are of 
significance as previous studies have shown that patients will accept some level of pain if opioid side-effects such as 
nausea, vomiting, constipation and pruritus are reduced. 
For the individual patient in the study receiving tapentadol there is a possible benefit in experiencing better analgesic 
effect and less side-effects, and on the other hand the individual patient receiving oxycodone may experience an inferior 
analgesic treatment and more side-effects. It is however also possible that tapentadol may result in an inferior pain 
treatment and/or increase in less common opioid related side-effects such as headache. A general benefit to the study 
population may be closer follow-up in terms of postoperative pain treatment.  
We will perform a randomized, double-blind, prospective, parallel-group, single-center study on patients scheduled for 
laparoscopic sub-/total hysterectomy, as this is a classic study comparing effects from two different medications on two 
groups in a population. 
Dosing is based on the previous clinical studies done on orthopedic and dental surgery patients, showing an 
approximate 1:5 correlation between oral oxycodone and tapentadol. (11,12) In standard postoperative pain treatment 
today, OxyContin 10 mg has an extended-release effect and is used as part of premedication. It is further administered 
twice daily. OxyNorm 10 mg has an immediate-release effect and is commonly used as rescue medicine in the 
postoperative period. We have therefore chosen Palexia depot 50 mg as part of premedication and to be administered 
once more during the study period. Palexia 50 mg will be used as rescue medicine as the equivalent to OxyNorm. 
2 
STUDY OBJECTIVES AND RELATED ENDPOINTS 
The primary goal of our study is to examine the analgesic effect in patients receiving either tapentadol or oxycodone 
during the first 24 hours postoperatively after hysterectomy. As a secondary goal, we want to examine the respiratory 
depressive effect from tapentadol compared to oxycodone. Further, we will also examine other common opioid related 
side-effects: sedation, nausea, vomiting, pruritus, dizziness and headache. 
2.1 
Primary Endpoint  
Difference in scoring of pain using the numerical rating scale (NRS) between the two groups 1 hour postoperatively. 

 
Tapentadol-study Version no. 3 – 26.06.17 
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The patient will be asked to score their pain intensity by a standardized question for the NRS: “Hvor sterk er smerten din 
nå på en skala fra 0 til 10, når 0 er ingen smerte og 10 er verst tenkelig smerte?” 
2.2 
Secondary Endpoints 
• 
Pain:  
Baseline pain measured with NRS is done 15 minutes after extubation. 
Pain at rest and while coughing, measured with NRS, is registered at 30 minutes, 1, 2, 3 and 24 hours 
postoperatively. Pain intensity difference (PID) at rest at 30 minutes, 1, 2, 3 and 24 hours will be 
calculated from these values. Sum of pain intensity difference (SPID) at 24 hours is calculated as the 
time-weighted sum of the PID scores (SPID t = ΣPID x (time t - time t-1)). 
Pain relief, measured with categorical scale “none, slight, moderate, good or complete”, at 30 minutes, 
1, 2, 3 and 24 hours postoperatively. Total pain relief (TOTPAR) over 24 hours will be calculated from 
these values. 
Worst pain during 24 hours is measured with NRS. 
Global medication performance (GMP) after 24 hours: “poor, fair, good, very good, excellent”. 
Time to first rescue medicine (IV and/or PO) and total rescue analgesic consumption IV and PO over 
24 hours is also registered. 
• 
Respiratory depression:  
In the postoperative ward: continuous measurement of ETCO2 with Smart CapnoLine® Plus 
(Microstream®), data are collected at 30, 60, 120, 180 minutes postoperatively. Respiratory rate at rest 
is measured at 30, 60, 120, 180 minutes postoperatively. Any episodes of ETCO2 > 7.0 or respiratory 
rate < 10 are also recorded. 
In the gynecological ward: oxygen saturation measured by pulse oximetry and respiratory rate 
measured at rest at 24 hours postoperatively.  
• 
Sedation:  
Sedation is evaluated at 30 minutes and 1, 2, 3 and 24 hours postoperatively, using the Pasero opioid-
induced sedation scale.  

 
Tapentadol-study Version no. 3 – 26.06.17 
Page 14 of 51 
• 
Nausea: yes/no at 30 minutes and 1, 2, 3 and 24 hours postoperatively. 
• 
Vomiting: yes/no at 30 minutes and 1, 2, 3 and 24 hours postoperatively. 
• 
Pruritus: yes/no at 30 minutes and 1, 2, 3 and 24 hours postoperatively. 
• 
Dizziness: yes/no at 30 minutes and 1, 2, 3 and 24 hours postoperatively. 
• 
Headache: yes/no at 30 minutes and 1, 2, 3 and 24 hours postoperatively. 
3 
OVERALL STUDY DESIGN 
The study is a phase IV study.   
This is a randomized, double-blind, prospective, parallel-group, single-center study on patients scheduled for 
laparoscopic sub-/total hysterectomy. 
Study Period 
 
Estimated date of first patient enrolled: 01.09.17. 
Anticipated recruitment period: 1 year 6 months. 
Estimated date of last patient completed: 01.03.19. 
Treatment Duration: 
24 - 32 hours (depending on last administration of PRN). 
Follow-up: 
End of treatment visit in person at 24 hours. Last contact is made by telephone at 32 
hours. No further follow-ups. 
4 
STUDY POPULATION 
4.1 
Selection of Study Population 
The study will be conducted at Oslo University Hospital in Oslo, Norway.  
4.2 
Number of Patients 
90 patients will be included in this trial. 
4.3 
Inclusion Criteria 
• 
Women diagnosed with a benign gynecological condition, undergoing laparoscopic, supra-cervical or total 
hysterectomy in general anesthesia. 
• 
Age 18-64 years.  
• 
ASA classification I-III.  
• 
Signed informed consent and expected cooperation of the patients for the treatment and follow up must be 
obtained and documented according to ICH GCP, and national/local regulations.  
• 
The patients will be recruited from the patient population at the Department of Gynaecology. 

 
Tapentadol-study Version no. 3 – 26.06.17 
Page 15 of 51 
4.4 
Exclusion Criteria 
• 
Age under 18 or over 65.  
• 
BMI > 31 and/or weight <55 kg, >85 kg.  
• 
Chronic pain syndromes related to organ systems other than the female reproductive system.  
• 
Chronic opioid therapy (codeine medication allowed up to 60 mg/day) or enteral steroid therapy.  
• 
Alcohol or medical abuse/addiction.  
• 
Chronic obstructive pulmonary disease (spirometry with postbronchodilator FEV1/FVC ratio less than 0.7), 
untreated asthma (FEV1/FVC is reduced to less than 0.70), obstructive sleep apnea or other conditions known 
to predispose for respiratory depression.  
• 
Neurological diagnosis with affection of respiratory system or prone to seizures. 
• 
Previously diagnosed kidney (glomerular filtration rate <60 mL/min/1.73 m2 over 3 months) or liver impairment 
(ALAT > 45 U/L; ASAT > 35 U/L; ALP > 105 U/L; GT > 45 U/L age 18-39 or GT > 75 U/L age over 39; LD > 205 
U/L).  
• 
Biliary tract disease.  
• 
Paralytic ileus.  
• 
Heart failure (NYHA III-IV).  
• 
Malignancy of any kind under treatment. Malignancy during last 5 years. 
• 
HIV infection. Infections of any kind affecting the patient’s clinical status, i.e. upper or lower airway infection, 
urinary tract infection, deep wound infection. Infections not affecting the patient’s clinical status, i.e. 
conjunctivitis, is not an exclusion criteria. 
• 
Untreated depression, severe anxiety or other psychiatric disorders independent of treatment.  
• 
Nursing mothers. 
• 
Cognitive failure, language barriers, hearing/visual disability or other factors which make follow-up difficult.   
• 
Allergy or contraindication to any of the medications used in the study.  
• 
Lactose intolerance.  
• 
Monoamine oxidase inhibitors or SNRI (serotonin norepinephrine reuptake inhibitors) within 14 days prior to 
randomization. SSRI (selective serotonin reuptake inhibitors) use is not an exclusion criterion if stable dose for 
at least 30 days before screening.  
• 
H1-antihistamine is not an exclusion criterion unless the patient experiences somnolence as a side-effect.  
• 
The concurrent use of benzodiazepines, barbiturates, neuroleptics, phenytoin tricyclic antidepressants, 
gabapentanoids, tramadol, clonidine, cimetidine, rifampicin, protease inhibitors, St John’s wort (Hypericum 
perforatum), macrolides and antimycotics such as ketoconazole and fluconazole are not allowed. 
• 
Known complications to anesthesia or difficult airway (Definition of difficult airway: "The clinical situation in 
which a conventionally trained anesthesiologist experiences difficulty with mask ventilation, difficulty with 
tracheal intubation, or both."). 
• 
Patients who have participated in other clinical trials during the last 6 months are excluded to avoid confounders 
to the current study and for patient safety reasons. 
 
5 
TREATMENT 
For this study tapentadol (Palexia®, Palexia depot®) and the active comparator oxycodone (OxyContin®, OxyNorm®) 
are defined as Investigational Medicinal Products (IMP).  
5.1 
Drug Identity, Supply and Storage 
• 
Palexia 50 mg® (Tapentadol 50 mg): Tablet, immediate-release, ATC-nr N02A X06. (Grünenthal Norway AS) 
• 
Palexia depot 50 mg® (Tapentadol depot 50 mg): Tablet, extended-release, ATC-nr N02A X06. (Grünenthal 
Norway AS) 
• 
OxyNorm 10 mg® (Oxycodone immediate-release 10 mg): Capsule, immediate-release, ATC-nr N02A A05. 
(Mundipharma AS, Norway) 

 
Tapentadol-study Version no. 3 – 26.06.17 
Page 16 of 51 
• 
OxyContin 10 mg® (Oxycodone extended-release 10 mg): Tablet, extended-release, ATC-nr N02 A05. 
(Mundipharma AS, Norway) 
All four drugs can be stored in room temperature and are not light or temperature sensitive.  
The drugs will be distributed to the patients in pill box organizers. The pill box organizers will be packed by one of the 
study investigators, Harald Lenz, who will not otherwise participate in the handling of the patients. The packing and 
labeling will be double-checked by another nurse or doctor not involved in the study to ensure hospital standards for drug 
dispensing. See appendix A for instruction on how to pack and label the study medicine. 
The pill box organizer will be stored according to Oslo University Hospital guidelines for narcotics before distribution 
(locked storage room for medicines, nurse-only access). The pill box organizer must follow the patient to the 
postoperative ward for access to PRN medication.  While in the postoperative ward and the gynecological ward the 
patient is expected to administer her own pain medication from the pill box organizer, but for safety reasons the pill box 
organizer will be stored by the ward nurse. The nurse will provide the pill box organizer upon the patients request and 
the patient will administer the medication from the pill box organizer herself. This ensures the recording of all medication 
in the patient’s medicinal chart at all times. 
5.2 
Dosage and Drug Administration  
The drugs will be distributed to the patients in pill box organizers in sealed, opaque envelopes by a ward nurse at the 
time of premedication. A detailed written instruction and form for self-administration of the study medication is provided 
(see appendix B). Verbal instruction will also be given by the investigator and a sham pill box organizer will be shown to 
the patient to help illustrate which medication to use when. The patient is required to note times of administration of 
study medicine in the form for safety and study purposes. The instruction/form and pill box must follow the patient at all 
times during the first day of surgery.  
• 
Palexia depot 50 mg® (tapentadol depot 50 mg): Administered by the patient as oral premedication 1 hour 
before scheduled start of surgery. The ward nurse will administer the rest of the premedication simultaneously. 
Palexia depot is repeated once after 12 hours. 
• 
Palexia 50 mg® (tapentadol 50 mg): Administered as oral PRN. First possible administration in postoperative 
ward when the patient is awake and available for oral medication. Maximum 4 tablets/24-hour study period. 
Minimum 1 hour 15 minutes between tablets. The patient is instructed to take 1 tablet if pain is increasing and 
the minimum period since last tablet is exceeded. 
or 
• 
OxyContin 10 mg® (oxycodone extended-release 10 mg): Administered by the patient as oral premedication 1 
hour before scheduled start of surgery. The ward nurse will administer the rest of the premedication 
simultaneously. OxyContin is repeated once after 12 hours. 
• 
OxyNorm 10 mg® (oxycodone immediate-release 10 mg): Administered as oral PRN. First possible 
administration in postoperative ward when the patient is awake and available for oral medication. Maximum 4 
capsules/24-hour study period. Minimum 1 hour 15 minutes between capsules. The patient is instructed to take 
1 tablet if pain is increasing and the minimum period since last tablet is exceeded. 
 
Concerning PRN medication: 
In the postoperative ward rescue analgesic will be available according to type of study medicine: 
PRN: tapentadol 50 mg PO or oxycodone IR 10 mg PO according to randomization. Maximum total dose 
tapentadol (including PRN medication)/24 hours: 300 mg. Maximum total dose oxycodone (including PRN 
medication)/24 hours: 60 mg. 

 
Tapentadol-study Version no. 3 – 26.06.17 
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If urgent pain relief is needed oral medication is not always sufficient or feasible, fentanyl 1 microgram/kg IV will 
therefore be available as rescue analgesic medication the first postoperative hours. Fentanyl is also the drug of choice if 
postoperative shivering occurs. Fentanyl is standard postoperative pain treatment and not considered part of study 
medicine. 
 
In the gynecological ward the patients will have the opportunity to administer additional doses of study medicine as 
rescue medicine during the 24-hour study period:  
PRN: tapentadol 50 mg PO or oxycodone IR 10 mg PO according to randomization. Maximum total dose 
tapentadol (including PRN medication)/24 hours: 300 mg. Maximum total dose oxycodone (including PRN 
medication)/24 hours: 60 mg.  
 
In addition to Arcoxia® (etorikoksib) 120/90 mg PO and Paracet® (paracetamol) premedication 2.0/1.5 g, the patients 
will also receive paracetamol 1 g x 3 PO during the 24-hour study period. This is part of standard postoperative pain 
treatment and is administered by the ward nurses. 
The study treatment will be dispensed to the subject by authorized site personnel only.  
The choice of PRN oxycodone dose, OxyNorm 10 mg PO, is based on previous studies done by our study group.(13, 
14) In a similar patient group (laparoscopic hysterectomy in women) the postoperative opioid consumption of intravenous 
oxycodone versus morphine was examined. A mean need of 13.3 ± 10.4 mg oxycodone IV was accumulated over 24 
hours. Converted to PO oxycodone (conversion rate of 2.2) this is approximately 29.3 ± 22.9 mg oxycodone PO/24 
h.(13) In the second study with a similar patient group the postoperative consumption of oxycodone versus 
oxycodone+naloxone was examined. A mean need of 20 mg PO oxycodone + 19 mg IV oxycodone PRN was found over 
24 hours. Converted to PO oxycodone this amounts to 61.8 mg/24 h.(14) We have therefore chosen the dosage of 
OxyNorm 10 mg PO up to 4 times a day in addition to OxyContin 10 mg x 2 to ensure the need of up to 61.8 mg 
oxycodone during 24 hours.  
In accordance to standard pain treatment procedures the PRN medication will be administered with an interval of 
minimum 1,25 h. 
5.3 
Duration of Therapy 
• 
Palexia depot 50 mg® (Tapentadol depot 50 mg): t1/2 5-6 hours, last time of administration at 12 hours after 
study start. Expected duration of therapy 24 hours.  
• 
Palexia 50 mg® (Tapentadol 50 mg): t1/2 4 hours, last possible time of administration at 24 hours after study 
start. Expected duration of therapy 8 hours after last time of administration.  
• 
OxyContin 10 mg® (Oxycodone extended-release 10 mg): t1/2 4,5 hours, estimated effect time 12 hours 
according to SmPC, last time of administration 12 hours after study start. Expected duration of therapy 24 
hours.  
• 
OxyNorm 10 mg® (Oxycodone immediate-release 10 mg): t1/2 3 hours, estimated effect time 6 hours according 
to SmPC, last possible time of administration at 24 hours after study start. Expected duration of therapy 6 hours 
after last time of administration.  
In summary, expected therapy duration is minimum 24 hours. If immediate-release medication (Palexia® or 
OxyNorm®) is administered at 24 hours after study start, the duration of treatment is expected to extend for a 
further 6-8 hours. End of treatment is therefore set to 32 hours after first dose at premedication. 
 

 
Tapentadol-study Version no. 3 – 26.06.17 
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5.4 
Premedication and Monitoring 
Premedication:  
Administered 1 hour before surgery: Paracet® (paracetamol) 2/1.5 g PO and Arcoxia® (etorikoksib) 120/90 mg PO 
(according to weight limit 60 kg and age limit 60 years). This is part of standard pain treatment and will be administered 
by the ward nurses. Study medication according to randomization: tapentadol depot 50 mg PO or oxycodone ER 10 mg 
PO. The study medication will be self-administered by the patient. 
The patient is allowed to take any regular medication, but with restrictions according to anesthesia standards. 
The patient must be fasting prior to general anesthesia according to anesthesia standards (6 hours for food and 2 hours 
for clear liquids or smoking).  
Monitoring: 
Pre- and perioperative data:  
Vital sign assessment (blood pressure and pulse) is registered preoperatively. 
Continuous ECG, BIS, heart rate, ETCO2 and SpO2 measurement throughout the perioperative period. 
Minimum/maximum blood pressures are registered. 
Target measures and interventions: 
Blood pressure: systolic 80-120 mmHg. Intervention low pressures: Efedrin® (efedrin) 5-10 mg IV. 
Intervention high pressures: increase propofol and/or remifentanil at the discretion of the anesthetist. 
Heart rate: 45-90. Intervention if bradycardia: Atropin® (atropin) 0.4-1 mg IV or efedrin® 5-10 mg IV at 
the discretion of the anesthetist. Intervention if tachycardia: at the discretion of the anesthetist. 
 
SpO2: > 94%. Intervention at the discretion of the anesthetist. 
BIS: 40-55. Intervention at the discretion of the anesthetist. 
Postoperative data:  
Time is defined from time of emergence from anesthesia (time zero), and the time intervals are referred to as 
“postoperatively”. 
In the postoperative ward: Continuous monitoring with 3-lead ECG and oxygen saturation by pulse oximetry. 
Intermittent monitoring of blood pressure at 30, 60, 120 and 180 minutes postoperatively. Recording of all 
values in CRF at 30, 60, 120 and 180 minutes postoperatively. Continuous measurement of ETCO2 with Smart 
CapnoLine® Plus (Microstream®), data are collected at 30, 60, 120, 180 minutes postoperatively. Respiratory 
rate at rest is measured at 30, 60, 120, 180 minutes postoperatively. Any episodes of ETCO2 > 7.0 or 
respiratory rate < 10 are also recorded. 
In the gynecological ward: oxygen saturation measured by pulse oximetry and respiratory rate measured at rest 
at 24 hours postoperatively. Blood pressure and pulse are measured according to standard ward procedures. 
 
5.5 
Concomitant Medication 
All concomitant medication (incl. vitamins, herbal preparation and other “over-the-counter” drugs) used by the patient 
and the following medications as part of general anesthesia, pre- and postoperative treatment will be recorded in the 
patient’s file and CRF.  

 
Tapentadol-study Version no. 3 – 26.06.17 
Page 19 of 51 
Premedication:  
• 
Paracet® (paracetamol) 2/1.5 g PO (according to weight limit 60 kg and age limit 60 years). 
• 
Arcoxia® (etorikoksib) 120/90 mg PO (according to weight limit 60 kg and age limit 60 years).  
 
General anesthesia: 
• Propolipid® (propofol) target controlled infusion for both induction and maintenance of anesthesia. 
• Ultiva® (remifentanil) target controlled infusion for both induction and maintenance of anesthesia.  
• If a muscle relaxant is needed for intubation Nimbex® (cisatrakurium) 0.1-0.15 mg/kg IV is administered. 
• Dexamethason® (deksametason) 8 mg IV is administered at the beginning of anesthesia.  
• Zofran® (ondansetron) 4 mg IV is administered towards end of anesthesia.  
• Fentanyl® (fentanyl) 1 microgram/kg IV is administered 10 minutes prior to end of general anesthesia.  
• By the end of surgery the incision sites will be injected with a total of 20 ml Marcain® (bupivakain) 2.5 mg/ml. 
• Intervention if low blood pressures: Efedrin® (efedrin) 5-10 mg IV.  
• Intervention if bradycardia: Atropin®(atropin) 0.4-1 mg IV or efedrin® 5-10 mg IV at the discretion of the 
anesthetist.  
 
Postoperative ward: 
If urgent pain relief is needed, fentanyl 1 microgram/kg IV will be available as rescue analgesic medication the first 
postoperative hours. Fentanyl is also the drug of choice if postoperative shivering occurs. 
 
Postoperatively (postoperative and/or gynecological ward): 
In addition to paracetamol premedication 2.0/1.5 g the patients will also receive paracetamol 1 g x 3 PO during the 24-
hour study period.  
If nausea and/or vomiting:  
• 
Afipran® (metoklopramid) 10 mg IV, maximum dose 30 mg/24 hours.  
• 
If no effect within 10 minutes from afipran 10 mg IV, zofran 4 mg IV may be administered if more than 4 hours 
since previous zofran dose.  
• 
Dridol® (droperidol) 0.625 mg IV may be administered at the tending physician’s discretion if no effect from the 
previous medications. 
 
 
 

 
Tapentadol-study Version no. 3 – 26.06.17 
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Prohibited medication: 
• 
Monoamine oxidase inhibitors or SNRI (serotonin norepinephrine reuptake inhibitors) within 14 days prior to 
randomization. (SSRI (selective serotonin reuptake inhibitors) use is not prohibited if stable dose for at least 30 
days before screening.) 
• 
H1-antihistamine is prohibited if the patient experiences somnolence as a side-effect.  
• 
The concurrent use of benzodiazepines, barbiturates, neuroleptics, phenytoin tricyclic antidepressants, 
gabapentanoids, tramadol, clonidine, cimetidine, rifampicin, protease inhibitors, St John’s wort (Hypericum 
perforatum), macrolides and antimycotics such as ketoconazole and fluconazole is not allowed. 
• 
Opioids, non-steroidal anti-inflammatory drugs or steroids other than those mentioned in this protocol. 
5.6 
Subject Compliance 
A detailed written instruction and form for self-administration of the study medication is provided along with the pill box 
organizers (see appendix B). Verbal instruction on how to take the study medicine will also be given by the investigator 
at the time of inclusion. A sham pill box organizer will be shown to the patient to help illustrate which medication to use 
when. (The envelopes with pill box organizers and instructions for use will be given to the patients at the time of 
premedication by a ward nurse not participating in the study, thus blinding the researchers to the patients’ allocation.) 
The patient is required to note times of administration of study medicine in the form for safety and study purposes. The 
instruction/form and pill box must follow the patient at all times during the first day of surgery. The instruction will also 
ensure that the ward nurses know the patient is part of a study and the nurse may assist the patient accordingly if 
needed. Investigators will be at hand for questions from both the patient and the staff. 
The times for study medicine taken, including PRN medication, must also be noted in the patient’s medication chart as 
part of standard hospital procedures. This will be done by the ward nurses. 
The pill box organizers are collected at the 24-hour visit and are available for pill count by Harald Lenz before disposing. 
5.7 
Drug Accountability 
The responsible site personnel will confirm receipt of study drug and will use the study drug only within the framework of 
this clinical study and in accordance with this protocol. Receipt, distribution, return, and destruction (if any) of the study 
drug must be properly documented according to the sponsor’s agreed and specified procedures.  
Identical pill box organizers will be filled with the respective study medicines, either tapentadol depot 50 mg (Palexia 
depot®) or oxycodone extended release(OxyContin®) 10 mg and rescue medicine which is either tapentadol 50 mg 
(Palexia®) or oxycodone immediate release(OxyNorm®) 10 mg. This will be done by one of the investigators, Harald 
Lenz, and a nurse anesthetist not participating in the study. Harald Lenz will not participate in the inclusion or other 
handling of patients to ensure blinding. The nurse anesthetist has experience with drug dispensing as part of his daily 
tasks. This procedure ensures hospital standards of double checking medication before administration. The personnel 
packing and labeling the pill box dispenser will both sign a log (a batch manufacturing record) for each of the individual 
pill box dispenser assigned to a patient. The pill box organizers will have unique serial numbers to connect them to the 
accompanying self-administration log. 
The study drugs, will be distributed in the pill box organizers which are pre-packed in identical, opaque envelopes. The 
envelopes are not to be broken until randomization of the patient is done. These envelopes with instructions for use will 
be given to the patients at the time of premedication by a ward nurse not participating in the study, thus blinding the 
researchers to the patients’ allocation. While in the postoperative ward and the gynecological ward the patient is 
expected to administer her own pain medication from the pill box organizer, but for safety reasons the pill box organizer 
will be stored by the ward nurse. The nurse will provide the pill box organizer upon the patients request and the patient 
will administer the medication from the pill box organizer herself. This also maintains blinding of the study investigators 
doing pain assessments.  

 
Tapentadol-study Version no. 3 – 26.06.17 
Page 21 of 51 
The pill box organizer will be stored according to Oslo University Hospital guidelines for narcotics before distribution 
(locked storage room for medicines, nurse-only access). The pill box organizer must follow the patient to the 
postoperative ward for access to PRN medication. In the gynecological ward the nurse will provide the pill box organizer 
upon the patients request and the patient will administer the medication from the pill box organizer herself.  
The pill box organizers are collected at the 24-hours visit and put in sealed, opaque bags. Any remaining study medicine 
will be logged in the CRF by Harald Lenz before being disposed of according to hospital standards.  
5.8 
Drug Labeling 
 
The investigational product will have a label permanently affixed to the outside and will be labeled according with ICH 
GCP and national regulations, stating that the material is for clinical trial / investigational use only and should be kept out 
of reach of children.  
 
Labeling of the IMPs will be done by one of the investigators, Harald Lenz, and a nurse anesthetist not participating in 
the study. 
The labeling will be in Norwegian. One label is attached to the pill box organizer with the most critical information: pill box 
organizer serial number; “Til klinisk utprøving”; Oppbevares utilgjengelig for barn; Se vedlagt bruksanvisning. See 
pictures: 
 
Due to space limitations further labeling is included in the instructions/form accompanying the pill box organizer. The 
instructions/form and pill box organizer will have identical identifying numbers. 
The instructions/form will include the following labeling (see also appendix B): 
 
• 
Patient’s enrolment code 
• 
Patient’s initials 
• 
Date dispensed 
• 
Instructions/form unique identity number (same as number on pill box organizer) 
• 
Protocol code 
• 
Batch number 
• 
Date for packing and labeling of study medicine with signatures  
• 
Expiration date 
• 
Name of prescribing doctor 
• 
Name of Principal Investigator 
• 
Contact information to three of the investigators. 

 
Tapentadol-study Version no. 3 – 26.06.17 
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5.9 
Subject Numbering 
Each subject is identified in the study by a unique subject number (nr XX) that is assigned when subject signs the 
Informed Consent Form. A record in the clinical study file will keep track of the next number to assign. Once assigned 
the subject number cannot be reused for any other subject.  

 
Tapentadol-study Version no. 3 – 26.06.17 
Page 23 of 51 
 
6 
STUDY PROCEDURES 
6.1 
Flow Chart 
 
Screening 
Period 
 
Treatment Period 
End 
of 
treat-
ment 
visit  
Time 
 1-14 days prior to treatment 
Premedication 
Anesthesia/Surgery 
15 min postopr 
30 min postopr 
60 min postopr 
120 min postopr 
180 min postopr 
 
 
6 hours after premedication 
 
12 hours after premedication 
 
18 hours after premedication 
 
 
24 hours after premedication 
Inclusion/ 
exclusion 
evaluation 
X 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Questionnaire 
X 
 
 
 
 
 
 
 
 
 
 
 
Treatment 
administration 
 
X 
 
 
 
 
 
 
 
X 
 
 
PRN medication 
(possible times of 
administration, 
but not limited to) 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant 
medication 
 
X 
X 
 
 
 
 
 
X 
X 
X 
 
Vital signs 
 
 
X 
 
X 
X 
X 
X 
 
 
 
X 
Pain assessment 
 
 
 
X 
X 
X 
X 
X 
 
 
 
X 
Respiratory 
assessment 
 
 
 
 
X 
X 
X 
X 
 
 
 
X 
Adverse 
event 
(possible times of 
events, but not 
limited to) 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: 
PRN: pro re nata (when necessary) 
Postopr: postoperatively 

 
Tapentadol-study Version no. 3 – 26.06.17 
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6.2 
By Visit 
Informed consent 
Informed consent must have been given voluntarily by each subject before any study specific procedures are initiated. 
The following tests will be done at screening: 
Clinical status 
Medical history, physical examination (cor/pulm/gynecological examination), vital signs (weight, height, blood pressure 
and pulse) is collected by the gynecologist in the outpatient clinic upon decision for surgery. Physical examination and 
vital sign may be collected on the day of surgery for patients if they have not been to the outpatient clinic beforehand. 
Concomitant medication 
All concomitant medication (incl. vitamins, herbal preparation and other “over-the-counter” drugs) used by the subject 
within 28 days of treatment start and the following medications as part of general anesthesia, pre- and postoperative 
treatment will be recorded in the patient’s file and CRF.  
Premedication:  
• 
Paracet® (paracetamol) 2/1.5 g PO (according to weight limit 60 kg and age limit 60 years). 
• 
Arcoxia® (etorikoksib) 120/90 mg PO (according to weight limit 60 kg and age limit 60 years).  
 
General anesthesia: 
•  Propolipid® (propofol) target controlled infusion for both induction and maintenance of anesthesia. 
• Ultiva® (remifentanil) target controlled infusion for both induction and maintenance of anesthesia.  
• If a muscle relaxant is needed for intubation Nimbex® (cisatrakurium) 0.1-0.15 mg/kg IV is administered. 
•  Dexamethason® (deksametason) 8 mg IV is administered at the beginning of anesthesia.  
• Zofran® (ondansetron) 4 mg IV is administered towards end of anesthesia.  
• Fentanyl® (fentanyl) 1 microgram/kg IV is administered 10 minutes prior to end of general anesthesia.  
• By the end of surgery the incision sites will be injected with a total of 20 ml Marcain® (bupivakain) 2.5 mg/ml. 
• Intervention if low blood pressures: Efedrin® (efedrin) 5-10 mg IV.  
• Intervention if bradycardia: Atropin®(atropin) 0.4-1 mg IV or efedrin® 5-10 mg IV at the discretion of the 
anesthetist.  
 
Postoperative ward: 
If urgent pain relief is needed, fentanyl 1 microgram/kg IV will be available as rescue analgesic medication the first 
postoperative hours. Fentanyl is also the drug of choice if postoperative shivering occurs. 
 

 
Tapentadol-study Version no. 3 – 26.06.17 
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Postoperatively (postoperative and/or gynecological ward): 
In addition to paracetamol premedication 2.0/1.5 g the patients will also receive paracetamol 1 g x 3 PO during the 24-
hour study period.  
If nausea and/or vomiting:  
• 
Afipran® (metoklopramid) 10 mg IV, maximum dose 30 mg/24 hours.  
• 
If no effect within 10 minutes from afipran 10 mg IV, zofran 4 mg IV may be administered if more than 4 hours 
since previous zofran dose.  
• 
Dridol® (droperidol) 0.625 mg IV may be administered at the tending physician’s discretion if no effect from the 
previous medications. 
6.2.1 
Before Treatment Starts  
The patients will be selected from the scheduled operation program. They have by then been to a consultation with a 
gynecologist in the outpatient clinic. Medical history, list of concomitant medications, allergies, smoking, physical 
examination and vital signs are collected by the gynecologist as part of standard procedure before surgery. Some 
patients travelling from other parts of Norway may have this consultation done the same day as surgery. 
If the patient is found eligible for inclusion in the study based on the information available in the patient journal system, 
an investigator (Marlin Comelon) will assess the patient according to the ASA-classification system. If the patient is ASA 
I-III and suitable for general anesthesia the patient will be contacted by letter, phone or in person (if already admitted to 
the hospital) depending on time until surgery. Patient information about the study and a questionnaire concerning 
predisposing factors for postoperative pain (Appendix C) are distributed to the patient in paper form. The patient signs an 
informed consent form if she decides to participate in the study. Study investigators Marlin Comelon, Johan Ræder or 
Tomas Drægni will see the patient in person on the day of surgery for questions about the study and to collect the 
informed consent form. Information about previous anesthesia such as postoperative nausea and vomiting or 
complications will be then registered. An anesthesiologist not connected to the study will also perform a regular pre-
anesthesia visit. 
6.2.2 
During Treatment 
Time is defined from time of emergence from anesthesia (time zero), and the time intervals are referred to as 
“postoperatively”. 
Perioperatively/Anesthesia procedure and monitoring:  
Premedication according to standard treatment is administered 1 hour before surgery: Paracet® (paracetamol) 2/1.5 g 
PO and Arcoxia® (etorikoksib) 120/90 mg PO (according to weight limit 60 kg and age limit 60 years). Study medication 
according to randomization is administered at time of premedication: tapentadol depot 50 mg PO or oxycodone ER 10 
mg PO.  
The surgery will be conducted in general anesthesia using target controlled infusion of Propolipid® (propofol) and 
Ultiva® (remifentanil) for both induction and maintenance of anesthesia. The patients have assisted normoventilation via 
a tracheal tube or laryngeal mask airway. If a muscle relaxant is needed for intubation Nimbex® (cisatrakurium) 0.1-0.15 
mg/kg IV is administered. Dexamethason® (deksametason) 8 mg IV is administered at the beginning of anesthesia. 
Zofran® (ondansetron) 4 mg IV is administered towards end of anesthesia. Fentanyl® (fentanyl) 1 microgram/kg IV is 
administered 10 minutes prior to end of general anesthesia. By the end of surgery the incision sites will be injected with a 
total of 20 ml Marcain® (bupivakain) 2.5 mg/ml.  
Data registered for surveillance of general anesthesia and study purposes (safety; not study end-points): 
Vital sign assessment (blood pressure and pulse) is registered preoperatively. 

 
Tapentadol-study Version no. 3 – 26.06.17 
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Continuous ECG, BIS, heart rate, ETCO2 and SpO2 measurement throughout the perioperative period. 
Minimum/maximum blood pressures are registered. 
Type of surgery, surgery time, anesthesia time. Propofol dose, remifentanil dose, dexamethasone, 
ondansetron, metoclopramide, other medications. 
Target measures: 
Blood pressure: systolic 80-120 mmHg. Intervention low pressures: Efedrin® (efedrin) 5-10 mg IV. Intervention 
high pressures: increase propofol and/or remifentanil at the discretion of the anesthetist. 
Heart rate: 45-90. Intervention if bradycardia: Atropin®(atropin) 0.4-1 mg IV or efedrin® 5-10 mg IV at the 
discretion of the anesthetist. Intervention if tachycardia: at the discretion of the anesthetist. 
SpO2: > 94%. Intervention at the discretion of the anesthetist. 
BIS: 40-55. Intervention at the discretion of the anesthetist. 
 
Postoperative procedure and monitoring: 
In the postoperative ward rescue analgesic will be available according to type of study medicine: 
PRN: tapentadol 50 mg PO or oxycodone IR 10 mg PO according to randomization. Maximum total dose 
tapentadol (including PRN medication)/24 hours: 300 mg. Maximum total dose oxycodone (including PRN 
medication)/24 hours: 60 mg. 
If urgent pain relief is needed, fentanyl 1 microgram/kg IV will be available as rescue analgesic medication the first 
postoperative hours. Fentanyl is also the drug of choice if postoperative shivering occurs. 
 
In the gynecological ward the patients will have the opportunity to administer additional doses of study medicine as 
rescue medicine during the 24-hour study period:  
PRN: tapentadol 50 mg PO or oxycodone IR 10 mg PO according to randomization. Maximum total dose 
tapentadol (including PRN medication)/24 hours: 300 mg. Maximum total dose oxycodone (including PRN 
medication)/24 hours: 60 mg.  
In addition to paracetamol premedication 2.0/1.5 g the patients will also receive paracetamol 1 g x 3 PO during the 24-
hour study period. This is part of standard postoperative pain treatment. 
Continuous monitoring with 3-lead ECG and oxygen saturation by pulse oximetry while in postoperative ward. 
Intermittent monitoring of blood pressure at 30, 60, 120 and 180 minutes postoperatively. Recording of all values in CRF 
at 30, 60, 120 and 180 minutes postoperatively.  
 
Data registered: 
 
Pain:  
 
Baseline pain measured with NRS is done 15 minutes after extubation. 
Pain at rest and while coughing, measured with NRS, is registered at 30 minutes, 1, 2, 3 and 24 hours 
postoperatively. Pain intensity difference (PID) at rest at 30 minutes, 1, 2, 3 and 24 hours will be calculated from 

 
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these values. Sum of pain intensity difference (SPID) at 24 hours is calculated as the time-weighted sum of the PID 
scores (SPID t = ΣPID x (time t - time t-1)). 
Pain relief, measured with categorical scale “none, slight, moderate, good or complete”, at 30 minutes, 1, 2, 3 and 
24 hours postoperatively. Total pain relief (TOTPAR) over 24 hours will be calculated from these values. 
 
Worst pain during 24 hours is measured with NRS. 
 
Global medication performance (GMP) after 24 hours: “poor, fair, good, very good, excellent”. 
Time to first rescue medicine (IV and/or PO) and total rescue analgesic consumption IV and PO over 24 hours is 
also registered. 
 
Respiratory depression:  
In the postoperative ward: continuous measurement of ETCO2 with Smart CapnoLine® Plus (Microstream®), data 
are collected at 30, 60, 120, 180 minutes postoperatively. Respiratory rate at rest is measured at 30, 60, 120, 180 
minutes postoperatively. Any episodes of ETCO2 > 7.0 or respiratory rate < 10 are also recorded. 
In the gynecological ward: oxygen saturation measured by pulse oximetry and respiratory rate measured at rest at 
24 hours postoperatively.  
 
Sedation:  
Sedation is evaluated at 30 minutes and 1, 2, 3 and 24 hours postoperatively, using the Pasero opioid-induced 
sedation scale.  
 
 
 
Nausea: yes/no at 30 minutes and 1, 2, 3 and 24 hours postoperatively. 
 
Vomiting: yes/no at 30 minutes and 1, 2, 3 and 24 hours postoperatively. 
 
Pruritus: yes/no at 30 minutes and 1, 2, 3 and 24 hours postoperatively. 
 
Dizziness: yes/no at 30 minutes and 1, 2, 3 and 24 hours postoperatively. 
 
Headache: yes/no at 30 minutes and 1, 2, 3 and 24 hours postoperatively. 
6.2.3 
End of Treatment Visit 
End of treatment is defined as 32 hours after first dose of study medicine taken as premedication, but the final visit in 
person is performed at 24 hours after first dose of study medicine as most patients leave the hospital the morning after 
surgery.  

 
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Data registered: 
Blood pressure and heart rate are registered as part of ward routines. 
 
Pain: 
Pain at rest and while coughing, measured with NRS, is registered at 30 minutes, 1, 2, 3 and 24 hours 
postoperatively. Pain intensity difference (PID) at rest at 24 hours will be calculated from these values. Sum of pain 
intensity difference (SPID) at 24 hours is calculated as the time-weighted sum of the PID scores (SPID t = ΣPID x 
(time t - time t-1)). 
Pain relief, measured with categorical scale “none, slight, moderate, good or complete”, at 30 minutes, 1, 2, 3 and 
24 hours postoperatively. Total pain relief (TOTPAR) over 24 hours will be calculated from these values. 
 
Worst pain during 24 hours is measured with NRS. 
 
Global medication performance (GMP) after 24 hours: “poor, fair, good, very good, excellent”. 
Time to first rescue medicine (IV and/or PO) and total rescue analgesic consumption IV and PO over 24 hours is 
also registered. 
 
Respiratory depression: 
Oxygen saturation measured by pulse oximetry and respiratory rate measured at rest at 24 hours postoperatively.  
 
Sedation:  
Sedation is evaluated at 24 hours postoperatively using the Pasero opioid-induced sedation scale.  
 
 
 
Nausea: yes/no at 24 hours postoperatively. 
 
Vomiting: yes/no at 24 hours postoperatively. 
 
Pruritus: yes/no at 24 hours postoperatively. 
 
Dizziness: yes/no at 24 hours postoperatively. 
 
Headache: yes/no at 24 hours postoperatively. 
To ensure patient safety the patient will be contacted at 32 hours, either in person or by phone if she is discharged from 
the hospital, with regards to adverse events (see paragraph 8.4). 
End of trail will be at last point of contact made in person or by telephone at 32 hours. 

 
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6.2.4 
Withdrawal Visit 
The patient may withdraw from the study at any time without stating a cause for withdrawal.  
6.2.5 
After End of Treatment (Follow-up) 
Not applicable. 
6.3 
Criteria for Patient Discontinuation  
Patients may be discontinued from study treatment and assessments at any time. Specific reasons for discontinuing a 
patient for this study are: 
• 
Voluntary discontinuation by the patient who is at any time free to discontinue her participation in the study, 
without prejudice to further treatment. 
• 
Safety reason as judged by the Principal Investigator. 
• 
Major protocol deviation (e.g. change of type of surgery after randomization; other analgesic or sedative 
medication administered; other factor as judged by Principal investigator). 
• 
Incorrect enrolment i.e., the patient does not meet the required inclusion/exclusion criteria for the study. 
• 
Deterioration in the patient’s condition which in the opinion of the Principal Investigator warrants study 
medication discontinuation (to be recorded as an AE or under Investigator Discretion). 
• 
Patient’s non-compliance to study treatment and/or procedures. 
6.4 
Procedures for Discontinuation 
6.4.1 
Patient Discontinuation 
Patients who withdraw or are withdrawn from the study will stop further treatment. Patients who withdraw or are 
withdrawn from study treatment will be followed up if any study medication has been administered in case of adverse 
events.   
If possible, a final assessment shall be made (end of study visit). This to ensure that the patient receives information 
about reason for withdrawal and why she is not included in the study. The reason for discontinuation shall be recorded.  
 
The investigator is obliged to follow up any significant adverse events until the outcome either is recovered or resolved, 
recovering/resolving, not recovered/not resolved, recovered/resolved with sequelae, fatal or unknown. 
 
All patients randomized will be included in the study population.  
Patients who withdraw or are withdrawn from the study after randomization may be replaced. 
6.4.2 
Trial Discontinuation 
The whole trial may be discontinued at the discretion of the Principal investigator or the sponsor in the event of any of 
the following: 
• 
Occurrence of AEs unknown to date in respect of their nature, severity and duration. 
• 
Medical or ethical reasons affecting the continued performance of the trial. 
• 
Difficulties in the recruitment of patients. 

 
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• 
Cancellation of drug development.  
• 
Changes in funding to research team. 
 
The sponsor and principal investigator(s) will inform all investigators, the relevant Competent Authorities and Ethics 
Committees of the termination of the trial along with the reasons for such action. If the study is terminated early on 
grounds of safety, the Competent Authorities and Ethics Committees will be informed within 15 days. 
6.5 
Laboratory Tests 
Not applicable. 
7 
ASSESSMENTS  
7.1 
Assessment of Efficacy Response 
The following parameters of response will be recorded: 
Procedure for the primary efficacy parameter – Analgesic effect 
Pain: 
Baseline pain measured with NRS is done 15 minutes after extubation. 
Pain at rest and while coughing, measured with NRS, is registered at 30 minutes, 1, 2, 3 and 24 hours 
postoperatively. Pain intensity difference (PID) at rest at 30 minutes, 1, 2, 3 and 24 hours will be 
calculated from these values. Sum of pain intensity difference (SPID) at 24 hours is calculated as the 
time-weighted sum of the PID scores (SPID t = ΣPID x (time t - time t-1)). 
Pain relief, measured with categorical scale “none, slight, moderate, good or complete”, at 30 minutes, 
1, 2, 3 and 24 hours postoperatively. Total pain relief (TOTPAR) over 24 hours will be calculated from 
these values. 
Worst pain during 24 hours is measured with NRS. 
Global medication performance (GMP) after 24 hours: “poor, fair, good, very good, excellent”. 
Time to first rescue medicine (IV and/or PO) and total rescue analgesic consumption IV and PO over 
24 hours is also registered. 
Procedure for the secondary efficacy parameters – Respiration 
Respiratory depression: In the postoperative ward: continuous measurement of ETCO2 with Smart 
CapnoLine® Plus (Microstream®), data are collected at 30, 60, 120, 180 minutes postoperatively. 
Respiratory rate at rest is measured at 30, 60, 120, 180 minutes postoperatively. Any episodes of 
ETCO2 > 7.0 or respiratory rate < 10 are also recorded. 
In the gynecological ward: oxygen saturation measured by pulse oximetry and respiratory rate 
measured at rest at 24 hours postoperatively.  
Sedation: Sedation is associated with respiratory depression and evaluated at 30 minutes and 1, 2, 3 
and 24 hours postoperatively, using the Pasero opioid-induced sedation scale.  

 
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7.2 
Safety and Tolerability Assessments  
Safety will be monitored by the assessments described below as well as the collection of AEs at every visit. Significant 
findings that are present prior to the signing of informed consent must be included in the relevant medical history/ current 
medical condition page of the CRF. For details on AE collection and reporting, refer to Section 8.  
For the assessment schedule refer to Flow chart in Section 6.  
Physical examination as part of standard preoperative examination by the gynecologist will include an examination of 
heart, lung, gynecological status, height and weight.  
Vital signs include: 
 
Preoperatively: blood pressure, pulse. 
Perioperatively: Continuous 5-lead ECG, heart rate, BIS, ETCO2 and SpO2 measurement throughout the 
perioperative period. Minimum/maximum blood pressures are registered. Patients are monitored at all times during 
anesthesia by a nurse anesthetist. 
Postoperatively: Continuous monitoring with 3-lead ECG, heart rate, ETCO2, SpO2 and intermittent monitoring of 
blood pressure and respiratory rate while in postoperative ward. Patients are monitored by nurses according to 
hospital standards during the stay in the postoperative ward. In the gynecological ward: SpO2 and respiratory rate 
measured at rest at 24 hours postoperatively. Patients are monitored by nurses according to hospital standards 
during the stay in the gynecological ward. 
Pain at rest and while coughing, measured with NRS, is registered at 30 minutes, 1, 2, 3 and 24 hours postoperatively. 
Sedation is evaluated at 30 minutes and 1, 2, 3 and 24 hours postoperatively, using the Pasero opioid-induced sedation 
scale.  
Other safety assessments are done according to standard procedure for in-hospital surgical patients. 
 
 
 

 
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7.3 
Other Assessments 
Assessment of predictive factors for postoperative pain will be done by questionnaire distributed to the patients 
1-14 days before surgery. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Questionnaire 
Preoperative pain:  
Have you had pain related to the condition you are about to undergo surgery for during the last 7 days? 
Yes/No. 
If yes, how much of the time has the pain been present?  
 
 
 
 
Sporadic/about half the time/more than half the time/continuously. 
If yes, how painful is it on average?  
 
 
 
 
NRS score 0 – 10.  
Have you had pain not related to the condition you are about to undergo surgery for during the last 7 days? 
Yes/No. 
Is this pain diagnosed and/or related to a condition? If so, which condition? 
If yes, how much of the time has the pain been present?  
 
 
 
 
Sporadic/about half the time/more than half the time/continuously. 
If yes, how painful is it on average?  
 
 
 
 
NRS score 0 – 10.  
 
Anxiety:  
Have you been diagnosed with and/or treated for anxiety by a physician or another health care professional (i.e. psychologist, 
other)?  
 
 
 
 
No/Yes, once/Yes, several occasions/Yes, on-going treatment. 
Depression: 
Have you been diagnosed with and/or treated for depression by a physician or another health care professional (i.e. psychologist, 
other)?  
 
 
 
 
No/Yes, once/Yes, several occasions/Yes, on-going treatment. 
 
Catastrophizing: 
 
How would you best describe your attitude towards difficulties and problems in general:  
I’m an optimist by nature/I’m neither an optimist nor a pessimist/ I tend to think about what can go 
wrong in a situation. 
 

 
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8 
SAFETY MONITORING AND REPORTING 
The investigator is responsible for the detection and documentation of events meeting the criteria and definition of an 
adverse event (AE) or serious adverse event (SAE). Each patient will be instructed to contact the investigator/study team 
immediately should they manifest any signs or symptoms they perceive as serious. 
Personnel involved in the handling of the patient during the hospital stay will be informed about the study. The nurse 
anesthetists and nursing staff in the postoperative and the gynecological wards will receive information about the 
intervention and possible adverse effects. The expected adverse effects from the study drug should also be well known 
to nursing staff as they are the same as from standard treatment with opioids. The observation and description of side-
effects/adverse events are part of standard nursing observations of the surgical patient receiving opioids. 
The methods for collection of safety data are described below. The CRF will have a separate AE/SAE/SUSAR section 
for documentation. Any events after the end of study that the investigators are made aware of will be recorded as AE, 
SAE or SUSAR and reported to sponsor accordingly.  
8.1 
Definitions 
8.1.1 
Adverse Event (AE) 
An AE is any untoward medical occurrence in a patient administered a pharmaceutical product and which does not 
necessarily have a causal relationship with this treatment.  
An adverse event (AE) can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related 
to the medicinal (investigational) product.  
The term AE is used to include both serious and non-serious AEs. 
The following side-effects/adverse events: respiratory depression, sedation, nausea, vomiting, pruritus, dizziness and 
headache will be registered as part of end-points of interest. Further adverse events listed in the SmPCs for the study 
drugs will not be registered routinely. 
If an abnormal vital sign is associated with clinical signs and symptoms, the sign/symptom should be reported as an AE 
and the associated vital sign should be considered additional information that must be collected on the relevant CRF. 
8.1.2 
Serious Adverse Event (SAE) 
Any untoward medical occurrence that at any dose:  
 
• 
Results in death 
• 
Is immediately life-threatening 
• 
Requires in-patient hospitalization or prolongation of existing hospitalization  
• 
Results in persistent or significant disability or incapacity 
• 
Is an important medical event that may jeopardize the subject or may require medical intervention to prevent 
one of the outcomes listed above. 
Examples of possible SAE in our study: 

 
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•  Respiratory depression which may be life-threatening and/or require prolonged hospitalization and/or result in 
persistent disability. 
•  Cardiovascular collapse secondary to respiratory depression or due to anaphylactic reactions or vasodilatation 
by other mechanisms. 
• Anaphylactoid or anaphylactic reactions. 
Prolonged hospitalization due to unmanaged pain at the end of the study is not recorded as SAE as this is a common 
reason for extended stay after surgery and according to hospital standards.   
Medical and scientific judgment is to be exercised in deciding on the seriousness of a case. Important medical events 
may not be immediately life-threatening or result in death or hospitalization, but may jeopardize the subject or may 
require intervention to prevent one of the listed outcomes in the definitions above. In such situations, or in doubtful 
cases, the case should be considered as serious. Hospitalization for administrative reason (for observation or social 
reasons) is allowed at the investigator’s discretion and will not qualify as serious unless there is an associated adverse 
event warranting hospitalization. 
8.1.3 
Suspected Unexpected Serious Adverse Reaction (SUSAR)  
 
Suspected Unexpected Serious Adverse Reaction: SAE (see section 8.1.2) that is unexpected as defined in section 8.2 
and possibly related to the investigational medicinal product(s). 
 
This protocol has included a range of symptoms and vital signs which are well-known side-effects/adverse events to all 
opioids, including the study medicines. Any such event mentioned in the protocol will be considered as SAE. Any event 
other than those mentioned in the SmPCs of the study medicines may be classified as SUSAR. 
 
8.2 
Expected Adverse Events 
The following side-effects/adverse events: respiratory depression, sedation, nausea, vomiting, pruritus, dizziness and 
headache will be registered in the CRF as part of end-points of interest.  
Examples of possible SAE in our study: 
•  Respiratory depression which may be life-threatening and/or require prolonged hospitalization and/or result in 
persistent disability. 
•  Cardiovascular collapse secondary to respiratory depression or due to anaphylactic reactions or vasodilatation 
by other mechanisms. 
• Anaphylactoid or anaphylactic reactions. 
Such AEs will be registered in the AE/SAE section of the CRF. Further adverse events listed in the SmPCs for the study 
drugs will also be registered as AE/SAE if they occur. 
Investigational medicinal products SmPCs; section: 
1) Palexia 50-100 mg, Grünenthal GmbH, Norwegian version section 4.8 “Bivirkninger“. 
2) Palexia depot 25-250 mg, Grünenthal GmbH, Norwegian version section 4.8 “Bivirkninger“. 
3) OxyNorm 5-20 mg, Mundipharma AS, Norwegian version section 4.8 “Bivirkninger”. 
4) OxyContin 5-120 mg, Mundipharma AS, Norwegian version 4.8 “Bivirkninger”. 

 
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8.3 
Disease Progression/Recurrence  
Not applicable. 
8.4 
Time Period for Reporting AE and SAE  
For each patient the standard time period for collecting and recording AE and SAEs will begin at start of study medicine and will 
continue until end of treatment as defined in paragraph 5.3. All patients will be screened for AEs/SAEs at 32 hours, contact will be 
made either in person or by phone if the patient is discharged from the hospital. 
During the course of the study all AEs and SAEs will be proactively followed up for each patient; events should be followed up to 
resolution, unless the event is considered by the investigator to be unlikely to resolve due to the underlying disease. Every effort 
should be made to obtain a resolution for all events, even if the events continue after discontinuation/study completion. 
8.5 
Recording of Adverse Events 
If the patient has experienced adverse event(s), the investigator will record the following information in the CRF: 
• 
The nature of the event(s) will be described by the investigator in precise standard medical terminology (i.e. not 
necessarily the exact words used by the patient). 
• 
The duration of the event will be described in terms of event onset date and event ended data. 
• 
The intensity of the adverse event will be described by the investigator in precise standard medical terminology. The 
event will later be classified according to the International Conference on Harmonisation of Technical Requirements of 
Pharmaceutical for Human Use system MedDRA. 
• 
The Causal relationship of the event to the study medication will be assessed as one of the following (15): 
 

 
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• 
Action taken. 
• 
The outcome of the adverse event – whether the event is resolved or still ongoing. 
It is important to distinguish between serious and severe AEs. Severity is a measure of intensity whereas seriousness is 
defined by the criteria in Section 8.1. An AE of severe intensity need not necessarily be considered serious. For 
example, nausea that persists for several hours may be considered severe nausea, but is not an SAE. On the other 
hand, a stroke that results in only a limited degree of disability may be considered a mild stroke, but would be an SAE. 
8.6 
Reporting Procedure 
8.6.1 
AEs and SAEs 
All adverse events and serious adverse events that should be reported as defined in section 8.1.1 and 8.1.2 will be 
recorded in the patient's CRF. 
SAEs must be reported by the investigator to sponsor within 24 hours after the site has gained knowledge of the SAE. 
Every SAE must be documented by the investigator on the SAE pages (to be found in the investigator site file). The 
Serious Adverse Event Report Form must be completed, signed and sent to sponsor (see page 2 for contact details). 
The initial report shall promptly be followed by detailed, written reports if necessary. The initial and follow-up reports shall 
identify the trial subjects by unique code numbers assigned to the latter.  
The sponsor keeps detailed records of all SAEs reported by the investigators and performs an evaluation with respect to 
causality and expectedness. Based on, among other, SAE reports the sponsor will evaluate whether the risk/benefit ratio 
associated with study is changed.  
The sponsor will further report the event/s to The Norwegian Medicinal Agency. 
In case of a serious adverse event resulting in death the regional ethics committee (REK sør-øst C) should also be 
informed. 
8.6.2 
SUSARs 
SUSARs will be reported to the Competent Authority (The Norwegian Medicines Agency and REK sør-øst C) according 
to national regulation. The following timelines should be followed: 
The sponsor will ensure that all relevant information about suspected serious unexpected adverse reactions that are fatal 
or life-threatening is recorded and reported as soon as possible to the Competent Authority in any case no later than 
seven (7) days after knowledge by the sponsor of such a case, and that relevant follow-up information is subsequently 
communicated within an additional eight (8) days. 
All other suspected serious unexpected adverse reactions will be reported to the Competent Authority concerned as 
soon as possible but within a maximum of fifteen (15) days of first knowledge by the sponsor. 
SUSARs will be reported to The Norwegian Medicines Agency (post@legemiddelverket.no) using the CIOMS form no 
later than 7 days after the incident. 
Sponsor will also report SUSAR to the EMEAs EudraVigilance database. This may be done with assistance from 
Grünenthal or Mundipharma. 

 
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8.6.3 
Annual Safety Report 
Once a year throughout the clinical trial, the sponsor will provide the Competent Authority (The Norwegian Medicines 
Agency) with an annual safety report. The format will comply with national requirements (i.e. “Årsrapport for ikke-
kommersielle klinisk legemiddelutprøving”).  
8.6.4 
Clinical Study Report 
The adverse events and serious adverse events occurring during the study will be discussed in the safety evaluation part 
of the Clinical Study Report. 
8.7 
Procedures in Case of Emergency  
The investigator is responsible for assuring that there are procedures and expertise available to cope with emergencies 
during the study.  
• 
The randomization code will be stored in Harald Lenz’s private office, Department of Anesthesiology, Oslo 
University Hospital, building 7, Ullevål. For safety reasons a sealed copy of the randomization code will also be 
available in the gynecological postoperative ward during the study. This will be accessible 24/7. In case of an 
unexpected medical incident the code will be broken to ensure proper treatment. Each pill box organizer will 
have a corresponding sealed envelope with the randomization code for that pill box organizer. This will enable 
us to identify the study medication given to one single patient without breaking the full randomization code. 
• 
All medical staff involved in handling of patients should be trained in management of respiratory depression as 
part of professional training, but specific instructions in case of respiratory depression will be provided. These 
instructions will follow the patient at gynecological and postoperative ward (foiled version kept along with the pill 
box organizer and instructions): 
 
Interventions if SpO2 < 90% for more than 3 minutes or immediately if SpO2 < 85% or respiratory rate < 10: 
1) Stimulate patient to achieve respiratory rate > 10 and/or deeper respiratory action. 
2) Supplemental oxygen increased to 5 l/min. 
3) Reversal agent: Naloxon® (nalokson) 0.1 mg IV. Repeated every 2-5 minutes until response. 
4) Bag-mask ventilation and consider other reasons for hypoxemia than opioid effect. 
Other safety measures in case of unexpected incidents are according to standard procedures in the surgical, 
postoperative and gynecological wards. 
9 
DATA MANAGEMENT AND MONITORING   
9.1 
Case Report Forms 
Case Report Forms (paper CRF/pCRF) 
The CRF for this study will be designed and produced by research nurse Tomas Drægni and investigator Marlin 
Comelon, Oslo University Hospital, Ullevål. 
The designated investigator staff will enter the data required by the protocol into the paper Case Report Forms 
(pCRF/CRF). The Investigator is responsible for assuring that data entered into the CRF is complete, accurate, and that 

 
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entry is performed in a timely manner. The signature of the investigator will attest the accuracy of the data on each CRF. 
If any assessments are omitted, the reason for such omissions will be noted on the pCRFs. Corrections, with the reason 
for the corrections will also be recorded.  
The data will be entered into a database and double-checked for erroneous entries. The system used in this study is 
Filemaker Pro 14. The setup of the database system will be performed by research nurse Tomas Drægni, Oslo 
University Hospital, Ullevål.  
After database lock, the investigator will receive a digital copy of the subject data for archiving at the investigational site. 
9.2 
Source Data  
Source data are all information in original records and certified copies of original records of clinical findings, 
observations, or other activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Source data 
are contained in source documents (original records or certified copies). 
For studies involving patients: The medical records for each patient should contain information which is important for the 
patient’s safety and continued care, and to fulfill the requirement that critical study data should be verifiable.  
To achieve this, the medical records of each patient should clearly describe at least ((CRF) = source data recorded 
directly into the Case Report Form; (HR) source data recorded in hospital records):  
• 
That the patient is participating in the study, e.g. by including the enrollment number and the study code or 
other study identification (HR); 
• 
Date when Informed Consent was obtained from the patient and statement that patient received a copy of 
the signed and dated Informed Consent (CRF); 
• 
Results of all assessments confirming a patient’s eligibility for the study (CRF); 
• 
Diseases (past and current; both the disease studied and others, as relevant) (CRF, HR); 
• 
Surgical history, as relevant (CRF, HR); 
• 
Treatments given (CRF, HR);  
• 
Visits to the clinic / telephone contacts during the study, including those for study purposes only (CRF, HR); 
• 
Non-Serious Adverse Events and Serious Adverse Events (if any) including causality assessments (CRF, 
HR);  
• 
Date of, and reason for, discontinuation from study treatment (CRF);  
• 
Date of, and reason for, withdrawal from study (CRF); 
• 
Date of death and cause of death, if available (HR); 
• 
Additional information according to local regulations and practice (HR). 
9.3 
Study Monitoring  
The investigator will be visited on a regular basis by the Clinical Study Monitor (Department of Clinical Research Support 
at Oslo University Hospital), who will check the following: 
• 
Informed consent process 

 
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• 
Reporting of adverse events and all other safety data 
• 
Adherence to protocol 
• 
Maintenance of required regulatory documents 
• 
Study Supply accountability 
• 
Facilities and equipment (Storage of study medicine in the gynecological ward. Monitoring equipment such as 
Smart CapnoLine® Plus (Microstream®))  
• 
Data completion on the CRFs including source data verification (SDV). 
The monitor will review the relevant CRFs for accuracy and completeness and will ask the site staff to adjust any 
discrepancies as required.  
Sponsor’s representatives (e.g. monitors, auditors) and/or competent authorities will be allowed access to source data 
for source data verification in which case a review of those parts of the hospital records relevant to the study will be 
required.  
9.4 
Confidentiality 
The investigator shall arrange for the secure retention of the patient identification and the code list. Patient files shall be 
kept for the maximum period of time permitted by each hospital. The study documentation (CRFs, Site File etc.) shall be 
retained and stored during the study and for 15 years after study closure. This will be kept in the research archive at the 
Department of Anesthesiology, Oslo University Hospital, Ullevål. All information concerning the study will be stored in a 
safe place inaccessible to unauthorized personnel. 
The sponsor has the right to share de-identified individual-patient data (IPD) underlying the results presented in the final 
published article (including tables, figures, and appendices or supplementary material) should any journal or editor 
require this. The data underlying the results are defined as the IPD required to reproduce the article's findings, including 
necessary metadata. The confidentiality guidelines of Oslo University Hospital and REK sør-øst will be followed. 
9.5 
Database management 
The data will be stored in a dedicated and secured area at: 
• pCRF: in a locked filing cabinet in the office of investigator Marlin Comelon at the Department of 
Anesthesiology, Oslo University Hospital, building 7, Ullevål. 
Data will be stored in a de-identified manner, where each study participant is recognisable by his/her 
unique trial subject number. The code list to link pCRF to patient in case of need for identifying data 
will be stored in a locked filing cabinet in the private office of research nurse Tomas Drægni at the 
Department of Anesthesiology, Oslo University Hospital, building 7, Ullevål. 
After transferal of data from pCRF to the database (Filemaker Pro 14) the pCRF will be stored in in the 
research archive at the Department of Anesthesiology, Oslo University Hospital, building 36, Ullevål. 
• The database will be stored in the designated space in the secure research server for Oslo University 
Hospital (Domain “Felles”-”Sensitivt”; File “Forskning03”).   
The data will be stored until 31.12.2035. 
Data management will be performed by research nurse Tomas Drægni and investigator Marlin Comelon, Oslo University 
Hospital, Ullevål. The Data management procedures will be performed in accordance with the department’s SOPs and 
ICH guidelines. 

 
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Data entered into the database will be validated by double-checking for erroneous entries against the CRF and hospital 
records.  
Once the database has been completed and locked, the Sponsor will authorize database lock and all electronic data will 
be sent to the designated statistician for analysis. Subsequent changes to the database will then be made only by written 
agreement. 
10 
STATISTICAL METHODS AND DATA ANALYSIS 
10.1 
Determination of Sample Size 
 
A previous study done by our research group on the treatment efficacy of oxycodone on acute pain after hysterectomy 
showed that patients had a mean numerical rating scale (NRS) score of 4 1 hour postoperatively, SD 1.5.(14) A non-
inferiority margin of 10% of the total endpoint range (0-10) has been used previously, translating to an NRS score of 
1.(7)  If there is truly no difference between the treatments, then 72 completed patients are required to be 80% sure that 
the lower limit of a one-sided 97.5% confidence interval (or equivalently a 95% two-sided confidence interval) will 
exclude the non-inferiority margin of 1 in favor of the control treatment. To allow for 20% exclusions from the per-protocol 
population, we plan to randomize 90 patients.  
10.2 
Randomization  
10.2.1 
Allocation- sequence generation 
• 
Method of generating the allocation sequence: computer-generated random sequential allocation. Harald Lenz 
will generate the allocation sequence. 
• 
Allocation ratio: 1:1. 
• 
Type of randomization: blocked randomization. Details of blocked randomization are provided in a separate 
document that is unavailable to those who enroll patients or assign treatment.  
10.2.2 
Allocation- procedure to randomize a patient 
The study investigators will enroll the patients. After the informed consent form is collected, the patients will be allocated 
by choosing the next available treatment stored in sequentially numbered, opaque, sealed envelopes. The envelope will 
be opened a nurse or doctor not participating in the study. The study medication is dispensed in pill box organizers 
handed out by the ward nurse. This will ensure the blinding of the study investigators. 
 
10.2.3 
Blinding and emergency unblinding 
The investigators and potentially the patient will be blinded for the randomization and the study medication. The patient 
may theoretically identify the study medication from drug characteristics, but we consider this unlikely. At the 24-hour 
visit we will ask the patient if she identified the medication or attempted to do so. However, to avoid any 
misunderstanding about patient blinding in a publication, we will describe the situation as is. 
Harald Lenz and the colleague helping pack and label the study medicine will not be blinded, but will also not participate 
in the handling of the patients. The nurse breaking the envelopes for randomization will not be blinded, but he/she will 
not participate in the study otherwise.  

 
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Emergency unblinding should generally only be done if the safety and well-being of the patient is being compromised. 
The decision to reveal the treatment allocation during the study should be done exclusively by the principal investigator.  
Un-blinding of the treatment allocation is permissible only if the safety and well-being of the patient is being 
compromised. The decision to reveal the treatment allocation during the study may only be done by the principal 
investigator. The date and time of un-blinding must be documented in the CRF and in the patient’s hospital records. 
In the event of an SAE, the Investigator may only break the treatment code if the appropriate future management of the 
patient necessitates knowledge of the current treatment. Although it is advantageous to retain the blind for all patients 
prior to final trial analysis, when an SAE may be a serious adverse reaction unexpected or otherwise judged reportable 
on an expedited basis, it is recommended that the blind should be broken only for that specific patient, by the sponsor or 
its designee, even if the Investigator has not broken the blinding. 
10.3 
Population for Analysis 
 The following populations will be considered for the analyses:  
- 
The full analysis population: All randomized patients having received at least one dose of study medication and 
were a minimum of data is collected.  
- 
The per-protocol population: All randomized patients completing the study without major protocol violations. 
Definition of major protocol violations will be specified in the statistical analysis plan, and the final criteria will be 
defined prior to database lock. Data concerning the primary endpoint should be collected. 
- 
Safety population: Includes all randomized subjects who have received at least one dose of study medication. 
Subjects who withdraw from the study will be included in the safety analysis. A list of withdrawn subjects, 
preferably with the reasons for withdrawal, will be made. 
- 
The primary statistical analysis will be based on the patients meeting the definition of the protocol population 
according to inclusion and exclusion criteria and with no major protocol violations. Since this is a non-inferiority 
study the per-protocol polulation is of major interest. 
- 
The secondary analysis will include all patients receiving study treatment. Since this is a non-inferiority study 
the per-protocol polulation is of major interest. 
10.4 
Planned analyses 
The main statistical analysis is planned when the planned number of patients have been included and have finalized 
data collection. Furthermore all data has to be entered, verified and validated according to the data management plan. 
Prior to the main statistical analysis, the data base will be locked for further entering or altering of data. A separate 
statistical analysis plan (SAP) will provide further details on the planned statistical analyses. The SAP will be finalized, 
signed and dated prior to database lock. The treatment allocation will be revealed after the database lock and used in 
the statistical analysis. There will be no interim analysis.  
Deviation from the original statistical plan will be described and justified in the Clinical Study Report. Amendments to 
plan can be done until day of DB lock. 
10.5 
Statistical Analysis 
Statistical analysis will be done in SPSS (SPSS Inc., Chicago, IL). Parametric data will be analyzed with two-sided 
independent sample t-test or a linear mixed model where applicable. For non-parametric data the Mann Whitney U test 
will be used and for categorical data the Chi-squared test.  

 
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10.5.1 
Primary analysis 
The primary endpoint (pain score 1 hour postoperatively) will be assessed in the primary analysis set (the per-protocol 
population) using an independent two-sample t-distribution analysis.  
 
Statistical hypothesis test: 
• 
Null hypothesis: The difference in pain between the treatments is at least 1 point on the 0-10 NRS scale in 
favor of the control treatment.  
• 
Alternative hypothesis: The difference in pain between the treatments is less than 1 point on the 0-10 NRS 
scale in favor of the control treatment.  
The primary variable will be evaluated by the 95% confidence limits. A conclusion of non-inferiority will be made if the 
95% confidence limits of the estimated treatment difference fully lie within the non-inferiority margin of 1 point on the 0-
10 NRS scale. The non-inferiority margin was regarded as appropriate based on publications and discussions within the 
study committee. (7) 
Mean values with 95% confidence limits will be used. 
10.5.2 
Secondary analyses 
The following data will also be analyzed: 
Between-group comparisons will be performed for the primary endpoint on secondary populations in addition to 
secondary efficacy endpoints on all populations.  
Hypotheses testing 
The between-group comparisons for secondary variables will be tested as for the primary variable where applicable 
and additional analyses will be performed based on the following methods (but not limited to): 
- Continuous secondary variables will be subject to two-sample t-distribution analyses, repeated measures mixed 
models or appropriate non-parametric alternatives.        
- Binary response variables will be analyzed using logistic regression (possibly adjusting for within-subject 
dependencies by generalized estimating equations) or chi-square/Mantel-Haenszel test. 
- Time-to-event variables will be analyzed using the Kaplan-Meier method and comparisons between the two groups 
will be performed using the log rank test or Cox regression analyses. 
Unless otherwise specified, all statistical hypotheses will be tested as the primary variable, i.e. with an assessment of 
non-inferiority based on the 95% confidence limits of the estimated difference between the groups. Non-inferiority 
margins of the secondary endpoints will be specified in the SAP prior to analysis. If the data indicate that one of the 
groups is superior to the other, a superiority test on the 5% significance level will be performed as for the primary 
variable on the ITT population. Thus, the non-inferiority analyses will be done in the PP population and the superiority 
analyses in the ITT population as appropriate. 
Efficacy analyses 
All patients included in the PP population will form the primary analysis population of the study. All efficacy analyses 
will be presented with estimates and 95% confidence limits of the treatment effect. For the primary variable specifically, 
this will be the estimated pain difference with corresponding 95% confidence limits. 
Safety analyses 

 
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The safety analyses population will include all patients who completed the last point of contact at 32 hours 
postoperatively. Safety analyses will be descriptive and presented as summary tables by treatment group and (if 
applicable) by visit. 
11 
STUDY MANAGEMENT 
11.1 
Investigator Delegation Procedure 
The principal investigator is responsible for making and updating a “delegation of tasks” listing all the involved co-
workers and their role in the project. She will ensure that appropriate training relevant to the study is given to all staff, 
and that any new information of relevance to the performance of this study is forwarded to the staff involved. 
11.2 
Protocol Adherence 
Investigators ascertain they will apply due diligence to avoid protocol deviations.  
All significant protocol deviations will be recorded and reported in the Clinical Study Report (CSR). 
11.3 
Study Amendments 
If it is necessary for the study protocol to be amended, the amendment and/or a new version of the study protocol 
(Amended Protocol) must be notified to and approved by the Competent Authority and the Ethics Committee according 
to EU and national regulations. 
11.4 
Audit and Inspections 
Authorized representatives of a Competent Authority and Ethics Committee may visit the center to perform inspections, 
including source data verification. Likewise, the representatives from sponsor may visit the center to perform an audit. 
The purpose of an audit or inspection is to systematically and independently examine all study-related activities and 
documents to determine whether these activities were conducted, and data were recorded, analyzed, and accurately 
reported according to the protocol, Good Clinical Practice (ICH GCP), and any applicable regulatory requirements. The 
principal investigator will ensure that the inspectors and auditors will be provided with access to source data/documents. 
12 
ETHICAL AND REGULATORY REQUIREMENTS 
The study will be conducted in accordance with ethical principles that have their origin in the Declaration of Helsinki and 
are consistent with ICH/Good Clinical Practice and applicable regulatory requirements. Registration of patient data will 
be carried out in accordance with national personal data laws. 
12.1 
Ethics Committee Approval 
The study protocol, including the patient information and informed consent form to be used, must be approved by the 
regional ethics committee before enrolment of any patients into the study. The study was approved in the REK sør-øst C 
31.05.17, reference number 2017/776/REK sør-øst C. The revised protocol sent to The Norwegian Medicines Agency 
12.06.17 will also be submitted to REK sør-øst C. 
The investigator is responsible for informing the ethics committee of any serious and unexpected adverse events and/or 
major amendments to the protocol as per national requirements. 

 
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12.2 
Other Regulatory Approvals 
The protocol will be submitted and approved by the applicable competent authorities before commencement of the 
study. 
The protocol will also be registered in www.clinicaltrials.gov before inclusion of the first patient. 
12.3 
Informed Consent Procedure 
The investigator is responsible for giving the patients full and adequate verbal and written information about the nature, 
purpose, possible risk and benefit of the study. They will be informed as to the strict confidentiality of their patient data, 
but that their medical records may be reviewed for trial purposes by authorized individuals other than their treating 
physician.  
It will be emphasized that the participation is voluntary and that the patient can refuse further participation in the protocol 
whenever she/he wants. This will not prejudice the patient’s subsequent care. Documented informed consent must be 
obtained for all patients included in the study before they are registered in the study. This will be done in accordance with 
the national and local regulatory requirements. The investigator is responsible for obtaining signed informed consent. 
As the patients may be scheduled for surgery anytime between 1-14 days ahead the patients will primarily be contacted 
by mail with study information. This ensures information about the study a head of time and the patients are given ample 
time to reflect over their wish to participate. The patient will be contacted by phone the day before surgery to make time 
for questions and to let the investigators prepare for the inclusion the following day. If the patient is scheduled for surgery 
in only a few days’ time, personal contact by telephone is made directly to inform about the study, but written study 
information will also be handed out on the day of surgery. The informed consent is collected by the study investigator on 
the day of surgery.  
A copy of the patient information and consent will be given to the patients. The signed and dated patient consent forms 
will be filed in the Investigator Site File binder and also scanned to be part of the patient’s electronic medical record at 
the hospital. 
12.4 
Subject Identification 
The investigator is responsible for keeping a list of all patients (who have received study treatment or undergone any 
study specific procedure) including patient’s date of birth and personal number, full names and last known addresses.  
The patients will be identified in the CRFs by patient number, initials and date of birth. 
13 
TRIAL SPONSORSHIP AND FINANCING 
The study is sponsored by funds from the Department of Anesthesiology, Oslo University Hospital.   
14 
TRIAL INSURANCE 
For studies conducted in Norway: The Principal investigator has insurance coverage for the participants in this study 
through membership of the Drug Liability Association for the appropriate numbers included each year.  
15 
PUBLICATION POLICY 
Upon study completion and finalization of the study report the results of this study will either be submitted for publication 
and/or posted in a publicly assessable database of clinical study results.  

 
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The results of this study will also be submitted to the Competent Authority and the Ethics Committee according to EU 
and national regulations. 
All personnel who have contributed significantly with the planning and performance of the study (Vancouver convention 
1988) may be included in the list of authors. 
16 
CONFLICT OF INTEREST 
The investigators declare no conflicts of interest. 
17 
REFERENCES 
1. 
Langford RM, Knaggs R, Farquhar-Smith P, Dickenson AH. Is tapentadol different from classical 
opioids? A review of the evidence. Br J Pain. 2016;10(4):217-21. 
2. 
Raeder J. Opioids in the treatment of postoperative pain: old drugs with new options? Expert Opin 
Pharmacother. 2014;15(4):449-52. 
3. 
Schröder W, Vry JD, Tzschentke TM, Jahnel U, Christoph T. Differential contribution of opioid and 
noradrenergic mechanisms of tapentadol in rat models of nociceptive and neuropathic pain. Eur J Pain. 
2010;14(8):814-21. 
4. 
Riley J, Eisenberg E, Müller-Schwefe G, Drewes AM, Arendt-Nielsen L. Oxycodone: a review of its 
use in the management of pain. Curr Med Res Opin. 2008;24(1):175-92. 
5. 
Kleinert R, Lange C, Steup A, Black P, Goldberg J, Desjardins P. Single dose analgesic efficacy of 
tapentadol in postsurgical dental pain: the results of a randomized, double-blind, placebo-controlled study. 
Anesth Analg. 2008;107(6):2048-55. 
6. 
Stegmann JU, Weber H, Steup A, Okamoto A, Upmalis D, Daniels S. The efficacy and tolerability of 
multiple-dose tapentadol immediate release for the relief of acute pain following orthopedic 
(bunionectomy) surgery. Curr Med Res Opin. 2008;24(11):3185-96. 
7. 
Daniels SE, Upmalis D, Okamoto A, Lange C, Haeussler J. A randomized, double-blind, phase III study 
comparing multiple doses of tapentadol IR, oxycodone IR, and placebo for postoperative (bunionectomy) 
pain. Curr Med Res Opin. 2009;25(3):765-76. 
8. 
Hale M, Upmalis D, Okamoto A, Lange C, Rauschkolb C. Tolerability of tapentadol immediate 
release in patients with lower back pain or osteoarthritis of the hip or knee over 90 days: a randomized, 
double-blind study. Curr Med Res Opin. 2009;25(5):1095-104. 
9. 
Lee L, Caplan RA, Stephens LS, Posner KL, Terman GW, Voepel-Lewis T, Domino KB. Postoperative 
Opioid-induced Respiratory Depression. A closed claims analysis. Anesthesiology. 2015;122(3):659-65. 
10. 
Chang SH, Maney KM, Phillips JP, Langford RM, Mehta V. A comparison of the respiratory effects of 
oxycodone versus morphine: a randomised, double-blind, placebo-controlled investigation. Anaesthesia. 
2010;65(10):1007-12. 
11. 
Ramaswamy S, Chang S, Mehta V. Tapentadol-the evidence so far. Anaesthesia. 2015;70(5):511-27. 
12. 
Daniels SE. Clinical efficay and safety of tapentadol immediate release in the postoperative setting. 
J Am Podiatr Med Assoc. 2012;102(2):139-48. 
13. 
Lenz H, Sandvik L, Qvigstad E, Bjerkelund CE, Raeder J. A comparison of intravenous oxycodone and 
intravenous morphine in patient-controlled postoperative analgesia after laparoscopic hysterectomy. 
Anesth Analg. 2009; 109(4): 1279-83.  
14. 
Comelon M, Wisloeff-Aase K, Raeder J, Draegni T, Undersrud H, Qvigstad E, Bjerkelund CE, Lenz H. A 
comparison of oxycodone prolonged-release vs. oxycodone + naloxone prolonged-release after 
laparoscopic hysterectomy. Acta Anaesthesiol Scand. 2013;57(4):509-17. 
15.  
 Uppsala Monitoring Centre. The use of the WHO-UMC system for standardised case causality 
assessment [cited 2017 08th June]. Available from: http://www.webcitation.org/6kYn8ezcY 
 
 

 
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18 
LIST OF APPENDICES 
A  
Instructions on how to pack and label study medicine. 
B  
Labeling, information and log form for self-administration of study drug. 
C  
Questionnaire on predisposing factors for postoperative pain. 
 
 

 
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APPENDIX A 
Instruksjoner for pakking og merking av studiemedisiner til Tapentadolstudien 
Medikamentene skal pakkes og merkes av Harald Lenz med dobbeltkontroll fra sykepleier eller lege. 
Det skal føres logg for pakking og merking som inneholder: 
• 
Dosettnummer 
• 
Batchnummere 
• 
Dato for pakking og merking 
• 
Signatur fra begge tilvirkere 
 
Studiemedikamenter: 
 
A: Palexia Depot (tapentadol depot) 50 mg tablett og Palexia (tapentadol) 50 mg tablett. 
B: OxyContin (oxycodone extended-release) 10 mg tablett og OxyNorm 10 mg (oxycodone 
immediate-release) 10 mg kapsel. 
 
Studiemedikamentene pakkes i identiske, nummererte dosetter. Dosettene plasseres i ugjennomsiktige, 
forseglede konvolutter med nummer som korresponderer med dosettene. I konvoluttene skal det også 
ligge et ark med instruksjoner for hvordan pasienten skal ta medisinene og der pasienten loggfører når 
medisinene tas. Instruksjonsarket skal ha nummerering i samsvar med dosetten. Dette arket inneholder 
også all påkrevet informasjon for merking av studiemedikamenter til bruk i klinisk studie (erstatter etikett). 
Dosettene vil allikevel ha en etikett som inneholder den viktigste informasjonen: «Til klinisk utprøving; 
Oppbevares utilgjengelig for barn; Se vedlagt bruksanvisning».  
 
Pakking i dosett: 
I dosettene skal det enten være Palexia Depot + Palexia ELLER OxyContin + OxyNorm. 
Studiemedisin med langtidsvirkende effekt (enten Palexia Depot 50 mg eller OxyContin 10 mg) plasseres i 
lukene merket «Morgen» (1 tablett) og «Kveld» (1 tablett). 
Studiemedisin med hurtigvirkende effekt (enten Palexia 50 mg eller OxyNorm 10 mg) plasseres i luken 
merket «Ved behov». I denne luken skal det ligger 4 tabletter/kapsler. 

 
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APPENDIX B  
Instruksjoner og loggføring for Tapentadol-studien 
Pasientens studienummer: ____________ 
Pasientens initialer: ____________ 
Dato for utlevering av medisin til pasient: ____________ 
 
Bruksanvisning for medisindosett til klinisk utprøving av studiemedisin: 
Luke Morgen:  
Medisinen tas med maks et 1/2 glass vann 1 time før operasjon. Du vil få vite av sykepleier 
akkurat når du skal ta medisinen. Gi sykepleier beskjed om at du har tatt medisinen og 
noter tidspunktet du tok medisinen her:  
kl ________  
Luke Kveld:  
Medisinen tas med ønsket mengde væske ca 12 timer etter første dose. Gi sykepleier 
beskjed om at du har tatt medisinen og noter tidspunktet du tok medisinen her:  
kl________ 
Luke Ved behov:  
Her finner du 4 tabletter/kapsler med sterke smertestillende. Du kan ta 1 tablett/kapsel når 
du har økende smerter. Det må ha gått minst 75 minutter (1 t og 15 min) mellom hver 
gang du tar en tablett/kapsel. Gi sykepleier beskjed om at du tar medisinen og noter 
eventuelle tidspunkter du tok behovsmedisinen her:  
kl ________ 
kl ________ 
kl ________ 
kl ________ 
Du kan ta total 4 tabletter/kapsler ved behov i løpet av de 24 timene studien pågår. Dersom 
dette ikke er tilstrekkelig eller det skulle oppstå andre behov tar du kontakt med 
sykepleieren din på sengeposten. Dersom du er godt smertelindret med medisinene du tar 
1 time før operasjonen og 12 timer etter første dose, så trenger du ikke ta behovsmedisin. 
 
Medisinene er kun til bruk i klinisk studie. Medisinene skal oppbevares i dosetten ved romtemperatur. 
Oppbevares utilgjengelig for barn. Ikke anvendte medikamenter returneres ved studiens avslutning. 
Kontaktinformasjon til studiepersonell finner du på baksiden av dette arket. 
Vedlegg i konvolutt nummer (= dosett id-nummer): ________ 
Sponsor: Avdelingsleder, Avdeling for anestesiologi, Oslo Universitetssykehus, Ullevål. 
Utprøvingssted: Gynekologisk avdeling, Oslo Universitetssykehus, Ullevål.                

 
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Informasjon og merking av studiemedikamentet som er delt ut. 
Protokollkode: EudraCT nummer 2017-001285-23. 
Batch nummer: ____________ 
Produksjonsdato: ____________ pakket av________________(sign) /________________(sign) 
Utløpsdato: ____________ 
Ansvarlig og forskrivende lege: Marlin Comelon, Avdeling for anestesiologi, Oslo 
Universitetssykehus, telefon 957 05 758. 
 
Studiemedisin inneholder enten Palexia 50 mg® (tapentadol 50 mg) og Palexia depot 50 mg® 
(tapentadol depot 50 mg) ELLER OxyNorm 10 mg® (oxycodone immediate-release 10 mg) og 
OxyContin 10 mg® (oxycodone extended-release 10 mg) 
 
 
Utprøvere og kontaktpersoner for informasjon om legemiddelene, studien eller ved behov for 
avblinding (akutte medisinske tilfeller der man må avbryte studien og avsløre type medikament): 
Marlin Comelon. Mobil: 957 05 758. Overlege ved anestesiavdelingen, Ullevål.  
Johan Ræder. Mobil: 922 49 669. Overlege ved anestesiavdelingen, Ullevål. 
Harald Lenz. Mobil: 905 49 545. Overlege ved anestesiavdelingen, Ullevål. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vedlegg i konvolutt nummer (= dosett id-nummer): ________ 
Sponsor: Avdelingsleder, Avdeling for anestesiologi, Oslo Universitetssykehus, Ullevål. 
Utprøvingssted: Gynekologisk avdeling, Oslo Universitetssykehus, Ullevål.    

 
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APPENDIX C 
 

 
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