Pain Response to Open Label Placebo in Induced Acute Pain in Healthy Male Adults - A Randomized Single Blinded Clinical Trail
Phase: NA
Conditions: Acute Pain
Sponsor: University Hospital, Basel, Switzerland

 
 
 
1 
 
Pain response to open label placebo in induced acute pain in healthy 
male adults 
Study protocol  
Study type:  prospective, randomized, assessor blinded crossover study  
Categorisation: Risk category B 
Study registration:  
 
clinicaltrials.gov (intended) 
Study identifier:  
 
None 
Principal investigators:  
Tobias Schneider, MD 
 
 
 
 
Senior Physician  
 
 
 
 
Department of Anaesthesiology University of Basel (USB) 
 
 
 
 
Spitalstrasse 22 
 
 
 
 
 
4031 Basel CH  
 
 
 
 
Tel.: +41613285165 
Fax: +41612655720 
 
 
 
 
E-mail: tobias.schneider@usb.ch 
 
 
 
 
 
Eckhard Mauermann, MD, MSc 
 
 
 
 
Research Fellow, 
 
 
 
 
Department of Anaesthesiology University of Basel (USB) 
Spitalstrasse 22 
 
 
 
 
 
4031 Basel CH  
 
 
 
 
Tel.: +41787200189 
Fax: +41612655720 
 
 
 
 
E-mail: eckhard.mauermann@usb.ch 
 
 
 
 
 
 
 
 
 
Oliver Bandschapp, PD 
 
 
 
 
Senior Physician 
 
 
 
 
Department of Anaesthesiology University of Basel (USB) 
Spitalstrasse 22 
 
 
 
 
 
4031 Basel CH  
 
 
 
 
Tel.: +41613286513 
Fax: +41612655720 
 
 
 
 
E-mail: oliver.bandschapp@usb.ch 
 
 
 
 
 
Julian Lüthi 
 
 
 
 
Scientific assistant, doctoral candidate 
 
 
 
 
Department of Anaesthesiology University of Basel (USB) 
Spitalstrasse 22 
 
 
 
 
 
4031 Basel CH  
 
 
 
 
Tel.: +41613285165 
Fax: +41612655720 
 
 
 
 
E-mail: julian.luethi@stud.unibas.ch 
 
 
 
 
 
Wolfgang Koppert, Prof. 
 
 
 
 
Carl-Neuberg-Straße 1 
 
 
 
 
30625 Hannover 
 
 
 
 
Tel: +49 511 - 532 – 2489 
Fax: +49511 - 532 - 3642  
 
 
 
 
E-mail: koppert.wolfgang@mh-hannover.de 
 
 
 
 
 
 
 
 

 
 
 
2 
 
 
Wilhelm Ruppen, PD 
 
 
 
 
Head of the Pain Unit 
 
 
 
 
Department of Anaesthesiology University of Basel (USB) 
Spitalstrasse 22 
 
 
 
 
 
4031 Basel CH  
 
 
 
 
Tel.: +41613286496 
 
 
 
 
Fax: +41612655720 
 
 
 
 
E-mail: wilhelm.ruppen@usb.ch  
 
 
 
 
 
 
 
 
Investigational product/ medication: 
open label placebo 
 
Protocol version and Date:  
 
Version 1.5 27.10.2017 
 
 

 
 
 
3 
 
Table of contents 
Abbreviations: ....................................................................................................................... 6 
Signature Page ................................................................ Fehler! Textmarke nicht definiert. 
Study Synopsis:..................................................................................................................... 8 
Study aims: ........................................................................................................................ 9 
Inclusion criteria: ...............................................................................................................10 
Study summary in local language: ........................................................................................13 
Studienziele: .....................................................................................................................13 
Relevanz der Studie:.........................................................................................................13 
Study schedule: ....................................................................................................................14 
1. 
Administrative structure: ................................................................................................15 
1.1 
Sponsor: .................................................................................................................15 
1.2 
Sponsor investigators: ............................................................................................15 
1.3 
Principal Investigators: ...............................................................................................15 
1.4 
Statistician (Biostatistician) .....................................................................................16 
1.5 
Pharmacy: ..............................................................................................................16 
1.6 
Monitoring Institution: .............................................................................................16 
1.7. Data Safety Monitoring committee: ............................................................................16 
1.8 Any other relevant Committee, Person, Organization, Institution: ................................16 
2. Ethical and Regulatory aspects: .......................................................................................16 
2.1 Study registration: .......................................................................................................16 
2.2 Categorization of the study: ........................................................................................16 
2.3 Competent Ethics Committee (CEC): ..........................................................................17 
2.4 Competent Authorities (CA) ........................................................................................17 
2.5 Ethical Conduct of the Study .......................................................................................17 
2.6 Declaration of interest .................................................................................................17 
2.7 Patient Information and Informed Consent ..................................................................17 
2.8 Participant privacy and confidentiality .........................................................................18 
2.9 Early termination of the study ......................................................................................18 
2.10 Protocol amendments ...............................................................................................18 
3. Background and rationale .................................................................................................19 
3.1 Importance of the study...............................................................................................20 
4. Study objectives ...............................................................................................................20 
4.1 Primary objective ........................................................................................................20 
4.2 
Secondary objectives .............................................................................................20 
5. Study outcomes ................................................................................................................20 

 
 
 
4 
 
5.1 Primary outcome .........................................................................................................20 
5.2 
Secondary outcomes ..............................................................................................21 
5.3 Safety outcomes .........................................................................................................21 
5.4 Safety and Tolerability Assessment ............................................................................21 
6. Investigational medical product ........................................................................................21 
7. Study design ....................................................................................................................21 
7.2 General study design and justification of design .........................................................21 
7.3 General participant information ...................................................................................22 
7.4 Participant education in in the placebo education group..............................................22 
7.5 Experimental design ...................................................................................................22 
7.6 Experimental setup .....................................................................................................23 
7.7 General setup of intradermal electrical stimulation (cp. Figure 3) ................................24 
7.8 Procedures/ Recordings/ Interventions before and during electrical stimulation ..........24 
7.9 Application of study medication ...................................................................................25 
7.10 Open label placebo application .................................................................................25 
7.11 Achievement of blinded medication application .........................................................25 
7.12 Collection and processing of biomarkers ...................................................................26 
8. Medical products and Medications used during the study .................................................27 
8.1 Medication used: .........................................................................................................27 
8.2 Medical products used for the pain model: ..................................................................27 
8.3 Medical products used for the infusion application/ patient monitoring: .......................27 
9.Study population ................................................................................................................28 
9.1 Recruitment of volunteers ...........................................................................................28 
9.2 Inclusion criteria ..........................................................................................................28 
9.3 Exclusion criteria .........................................................................................................28 
9.4 Subject Withdrawal .....................................................................................................28 
9.5 Expense allowance for participants .............................................................................28 
10. SAFETY .........................................................................................................................28 
10.1 Drug studies ..............................................................................................................29 
10.2 Definition and assessment of (serious) adverse events and other safety related 
events ...............................................................................................................................29 
10.3 Assessment of Causality ...........................................................................................29 
10.4 Unexpected Adverse Drug Reaction .........................................................................30 
10.5 Suspected Unexpected Serious Adverse Reactions (SUSARs) ................................30 
10.6 Assessment of Severity .............................................................................................30 
10.7 Reporting of serious adverse events (SAE) and other safety related events .............30 

 
 
 
5 
 
10.8 Reporting of SUSARs: ..............................................................................................30 
10.9 Reporting of Safety Signals: ......................................................................................30 
10.10 Follow up of (Serious) Adverse Events:...................................................................30 
11. Statistical Methods .........................................................................................................31 
11.1 Hypothesis ................................................................................................................31 
11.2 Determination of sample size ....................................................................................31 
11.3 Statistical criteria of termination of the trail: ...............................................................31 
11.4 Planned Analyses, Datasets, and Analysis Populations: ...........................................31 
11.8 Interim analysis: ........................................................................................................32 
11.9 Safety analysis: .........................................................................................................32 
11.10 Deviation(s) from the original statistical plan: ..........................................................32 
11.11 Handling of missing data and drop outs: .................................................................32 
12. Quality Assurance and Control .......................................................................................32 
12.1 Data handling and record keeping / archiving: ..........................................................32 
12.2 Case Report Forms (CRF) ........................................................................................32 
12.3 Specification of source documents ............................................................................32 
12.4 Record keeping / archiving ........................................................................................32 
13. Data management: .........................................................................................................33 
13.1 Data Management System ........................................................................................33 
13.2 Analysis and archiving ..............................................................................................33 
13.3 Electronic and central data validation ........................................................................33 
13.4 Monitoring .................................................................................................................33 
13.5 Audits and Inspections ..............................................................................................33 
13.6 Confidentiality, Data Protection .................................................................................33 
13.7 Storage of biological material and related health data: ..............................................34 
14. Publication and Dissemination Policy .............................................................................34 
15. Funding and Support ......................................................................................................34 
15.1 Funding: ....................................................................................................................34 
15.2 Other Support: ..........................................................................................................34 
16. Cited literature: ...............................................................................................................34 
Appendix: .............................................................................................................................36 
Text of the assessor direct before placebo application ......................................................36 
Slides of the Presentation for the “Placebo education group” with oral given information in 
text form: ...........................................................................................................................37 
 
 
 

 
 
 
6 
 
Abbreviations: 
 
DLPC  
 
dorsolateral prefrontal cortex 
NEG  
 
non-educated group 
nPEG  
 
non Placebo educated group 
NRS  
 
numeric rating scale 
OLP  
 
open label placebo 
OMT  
 
oral mucosal tissue 
PA 
 
 
placebo analgesia 
PEG  
 
placebo educated group 
PR 
 
 
placebo reactions 
i.v. 
 
 
Intravenous  
sTNFaRII 
 
soluble tumour necrosis factor alpha Receptor II 
 
 

 
 
 
7 
 
 
 

 
 
 
8 
 
Study Synopsis:  
 
Sponsor/ Sponsor 
Investigaor: 
 
Wilhelm Ruppen, PD 
Head of  the Pain Unit 
Department of Anaesthesiology/ Pain Relief Unit 
Spitalstrasse 22 
 
4031 Basel CH  
Phone:  +41613286496 
E-mail: Wilhelm.ruppen@usb.ch 
 
Study Title: 
Pain response to open label placebo in induced acute pain in healthy 
male adults 
Short Title/ Study 
ID: 
POLAP-Study 
Protocol Version 
and Date: 
Version 1.4 21.09.2017 
Trail registration: 
Clinicaltrails.gov (intended) 
Study category and 
Rationale: 
Category B: This study involves the use of an established pain model, a 
placebo (NaCl), and a carrier solution (Ringer Lactate). No other drugs 
will be applied. However, it is our understanding that even NaCl 0.9% 
used within the guidelines of suggested use (1 ml injection) mandate 
pro forma a category B, since volunteers have no indication for NaCl 
0.9%. In our study NaCl 0.9% is not the investigational product. Any 
other carrier solution without an analgesic potential (placebo) could 
have been used. We are not performing a classical medical drug trail, 
therefore catogory B has to be applied. 
Background and 
Rationale: 
Open label placebo treatment studies have reached great interest in 
research in the recent past. Current studies suggest that placebos have 
a clinically significant effect, even if patients and treating physicians 
know they are using a placebo. This is true for chronic pain states like 
chonic low back pain [1] and chronic disease like the irritable bowel 
syndrome [2]. However, data regarding the response of acute pain to 
open label placebo are lacking. 
The neuro-biologic basis of placebo analgesia (PA) has been studied 
for over 40 years, since Levine at al. showed that the opiate antagonist 
naloxone could annul placebo analgesia after wisdom tooth extraction 
[3]. We know today that the mediation of PA is complex and involves 
several pain modulation systems like the opioidergic descending pain 
control [4], the endogenous cannabinoid system [5], the dorsolateral 
prefrontal cortex [6] and takes even place at spinal cord level [7]. 
To activate and maximize the cascade of PA, psychologic mechanisms 
play the key role. Three key points can determine the placebo reaction 

 
 
 
9 
 
(PR): 
1) 
patient 
expectations 
[8-11] 
2) physician 
– 
patient 
communication [12, 13] 3) conditioning [14, 15].  
These interactions are mainly investigated in the context of chronic pain 
conditions. 
Study aims: 
To investigate pain response to an open label placebo application in 
healthy male adults in a well-established acute pain model [16].  
Importance of the study: 
Until today there are no studies investigating open label placebo effects 
in acute pain. Additionally, a potential effect should be examined in a 
clinical setting (e.g. a model mimicking surgical wound pain). 
This is however of great clinical value because:  
Firstly, open label placebo administration releases the treating 
physician from the ethical dilemma to deceive the patient with a 
placebo treatment.  
Secondly, beside possible cost effectiveness, reduced dosages of 
active pain medication (as well as the possible avoidance of opioids) 
due to placebo application could result in a better safety profile 
especially in older patients or patients otherwise at high risk of side-
effects. The dose extending potential of placebos has been shown in 
clinical studies, but was never proved in an open-label placebo 
intervention in an acute pain model.   
Objective(s): 
Primary: 
To investigate the effect of open label placebo application on acute pain 
in an experimental model of acute pain. 
Secondary:  
 
To investigate the effect of education prior to an open label 
placebo application.  
 
To investigate the effect of open label placebo application on 
biomarkers of stress (saliva cortisol) 
Outcome(s): 
Primary outcome:  
Pain response measured by the Area under the Pain Curve (AUPC) 
using the numeric rating scale (NRS) from minute 30 to 100 after 
inducing definded pain in an experimental setting. Main comparison: 
The effect of open label placebo v.s. no treatment intervention. 
Secondary outcomes: 
1. The pain response measured by the AUPC (NRS every 10 
minutes during electrical stimulation) will be used for further 
comparison of the two different treatment interventions every 
participant recieves during the study. 

 
 
 
10 
 
2. Hyperalgesia and allodynia will be measured analogously to the 
NRS as above. 
3.  Saliva concentration of cortisol, measured at baseline, 30, 60 
and 100 minutes after pain induction.  
Study design: 
A prospective randomized, assessor-blinded trial.  In order to address 
our aims, participants will receive each of the two treatments listed 
below. Patients will furthermore be randomized to receive an open-label 
placebo education denoted with a 1 in the treatment set (A, B1) or to 
receive no open-label placebo education denoted with a 2 in the 
treatment set (A, B2).   
 
TREATMENT 
General (visible) 
Open drug application 
A No treatment 
intervention 
 
Infusion RL  
Infusion rate: 100ml/h 
No 
B1,2 Open-label 
Placebo alone 
Infusion RL  
Infusion rate: 100ml/h 
OLP 
 
Each patient will receive exactly one of the two treatments sets (e.g. A, 
B1 or A, B2) in a randomized oder. 
Inclusion/ 
Esxclusion criteria: 
Inclusion criteria: 
 
Healthy 
male 
volunteers 
(American 
Society 
of  
Anaesthesiologist’s Class I or II) 
 
Body mass index between 18 and 25kg/m2 
 
Able to understand the study and the NRS scale 
 
Able to give informed consent 
 
 Exclusion criteria:  
 
Recreational drug abuse 

 
 
 
11 
 
 
Regularly taking medication potentially interfere with pain 
sensitation (analgesics, antihistamines and calcium and 
potassium channel blockers) 
 
Neuropathy 
 
Chronic pain 
 
Neuromuscular or psychiatric disease 
 
Known or suspected kidney or liver disease 
 
Measurements and 
procedures: 
Healthy male adults are recruted via an advertisment on the homepage 
of the University of Basel. After informed consent, but before any 
intervention, the participiants are randomized to a placebo educated 
and a non-educated group. The education group will receive an 
education about placebos and their effects prior to study intervention 
during the placebo will be applied. Every participiant will pass trough 
two interventions with electrical induced pain, defined at a NRS of six 
for 100 minutes each. Between the sessions a minimal two weeks 
washout period will be hold. During the two interventions participiants 
receive the following treatments delineated above in a randomized 
manner. 
Study medication/ 
Study product:  
Intravenous application of: open label placebo (  2ml saline 0.9%). 
 
Control 
intervention 
During one intervention (A) we do not apply any treatment at all during 
the intervention time. This to control for habitation effects during current 
application and create a comparison.  
Number of 
Participants with 
Rationale: 
Based on our sample size calculation, we will require 22 participants. 
Recent estimates state that some 20-30% of patients are placebo-non-
responders. Consequently, we will include 29 patients. However, with 
an estimated drop-out of 10% we plan to recruit 32 paitents. Patients 
dropping out will be replaced. 
Study duration: 
The duration of the study from the first participant in to the last 
participant out is 14 weeks. 
Duration of an individual participant: minimum 2 weeks (time from 
primary assessment with 1st intervention until 2nd intervention). 
Study Schedule: 
First inclusion: December 2017  
Last intervention in April 2018. 
Investigator(s): 
                          
 
 
Tobias Schneider, MD 
 
             Senior Physician  
                          Department of Anaesthesiology University of Basel (USB) 
 
 
Spitalstrasse 22 
 
 
 
4031 Basel CH  
 
 
Tel.: +41613285165 
                          Fax: +41612655720 
 
 
 E-mail: tobias.schneider@usb.ch 
 

 
 
 
12 
 
 
 
Eckhard Mauermann, MD, MSc 
 
 
Research Fellow, 
 
 
Department of Anaesthesiology University of Basel (USB) 
 
 
Spitalstrasse 22 
 
 
 
4031 Basel CH  
 
 
Tel.: +41787200189 
 
 
Fax: +41612655720 
 
 
E-mail: eckhard.mauermann@usb.ch 
 
 
 
 
 
 
 
Oliver Bandschapp, PD 
 
 
Senior Physician 
 
 
Department of Anaesthesiology University of Basel (USB) 
 
 
Spitalstrasse 22 
 
 
 
4031 Basel CH  
 
 
Tel.: +41613286513 
 
 
Fax: +41612655720 
 
 
E-mail: oliver.bandschapp@usb.ch 
 
 
 
Julian Lüthi 
 
 
Scientific assistant, doctoral candidate 
 
 
Department of Anaesthesiology University of Basel (USB) 
 
 
Spitalstrasse 22 
 
 
 
4031 Basel CH  
 
 
Tel.: +41613285165 
 
 
Fax: +41612655720 
 
 
E-mail: julian.luethi@stud.unibas.ch 
 
 
 
Wolfgang Koppert, Prof. 
 
 
Carl-Neuberg-Straße 1 
 
 
30625 Hannover 
 
 
Tel: +49 511532 2489 
 
 
Fax: +495115323642  
 
 
E-mail: koppert.wolfgang@mh-hannover.de 
 
 
 
 
Wilhelm Ruppen, PD 
 
 
Head of the Pain Unit 
 
 
Department of Anaesthesiology University of Basel (USB) 
 
 
Spitalstrasse 22 
 
 
 
4031 Basel CH  
 
 
Tel.: +41613286496 
 
 
Fax: +41612655720 
 
 
E-mail: wilhelm.ruppen@usb.ch 
 
 
Study Center(s): 
Monocentric study: Basel University Hospital 
Statistical 
Considerations:  
We will conduct a number of analyses as delineated in the statistics 
section. Briefly put, for each of the hypotheses a simpler, generally 
paired nonparametric test will be conducted. Additionally, a mixed-
effects model will be employed to attain further information and account 
for the order of treatments, and the effect of time. 
GCP Statement: 
This study will be conducted in compliance with the protocol, the 
current version of the Declaration of Helsinki, the ICH-G, as well as all 

 
 
 
13 
 
national legal und regulatory requirements. 
Study summary in local language:  
 
In der jüngeren Vergangenheit haben unverblindete Placebo Behandlungen bei der 
Behandlung von Schmerzen das Interesse der Wissenschaft auf sich gezogen. Aktuelle 
Studien geben Hinweise darauf, dass eine Placebo Behandlung effektiv sein kann, obwohl 
Patient und behandelnder Arzt wissen, dass mit einem Placebo behandelt wird. Dies konnte 
bisher vor allem für chronische Schmerzen und das Reizdarmsyndrom und bei chron. 
Rückenschmerzen gezeigt werden. Daten über die mögliche Effektivität einer offenen 
Placebo Behandlung bei akuten Schmerzen fehlen bis zum heutigen Tag.  
Studienziele: 
Wir wollen das Ansprechen von Schmerzen auf eine offene Placebo-Applikation bei 32 
gesunden männlichen Probenden anhand eines gut etablierten Akut-Schmerzmodels 
(Koppert et al.) untersuchen. Dies um einen Beitrag zur Fragestellung zu leisten, ob eine 
offene Placebo Behandlung bei akuten Schmerzen sinnvoll und unterstützend eingesetzt 
werden kann.  
Relevanz der Studie:  
Zum heutigen Zeitpunkt gibt es in der Literatur keine Studien, welche die Anwendung von 
offener Placebo-Applikation bei akuten Schmerzen untersuchen. 
Aus Autorensicht ist dies jedoch von grossem klinischem Interesse, da:  
A) Die offene Placebo Applikation befreit den Behandler vom ethischen Dilemma, den 
Patienten mit einer Placebo Behandlung zu täuschen. 
B) Neben einer möglichen Kosten-Ersparnis durch die Placebo Applikation können 
durch Dosisreduktionen der üblichen Schmerzmedikamente gerade Hochrisiko 
Patienten für mögliche Medikamenten Nebenwirkungen von einer offenen Placebo 
Applikation profitieren. 
Dieser Dosis reduzierende Effekt konnte bei Studien bezüglich chronischer 
Schmerzen bereits gezeigt werden, wurde aber nicht für akute Schmerzen 
untersucht.  
Primärziele: 
Untersuchung der Effekte einer offenen Placebo-Applikation  auf akute Schmerzen induziert 
in gesunden Probanden in einem experimentellen Akutschmerzmodel.  
 
Sekundärziele: 
 
Untersuchung des Einflusses von Probanen-Edukation bezüglich Placebo-Analgesie vor 
einer Placebo Applikation.  
 
Untersuchung des Effektes der offenen Placebo Applikation auf Stress assoziierter 
Biomarker (Speichel Kortisol)  
 

 
 
 
14 
 
Study schedule: 
 
We plan to include the first patient in December 2017 and to finish with the last intervention 
in April 2018. 
The duration of the study from the first participant in to the last participant out is 5 months. 
Duration of an individual participant from T0-T2 (cp. figure 1) will be approximately 2-3 weeks 
weeks (time from primary assessment with 1st intervention until 2nd intervention). 
 
 
 
 
 
Visit 
Description 
Involved stuff 
Duration 
Inclusion/ 
Randomization/ 
Education 
 Check of inclusion/ exclusion criteria  
 Discussion of open questions prior to 
study inclusion 
 Obtain written consent 
 Randomization to PEG or nPEG 
 Placebo education depending on 
randomization 
 
Study nurse 
 
 
Investigator not 
involved in 
treatment 
interventions 
 
Administrative 
tasks: 30min 
Placebo education 
10-15min 
1st intervention 
 Treatment A-B depending on 
randomization 
 Application of open label placebo in 
treatment B (study nurse; 
investigator not present) 
 Assessment of outcomes 
(investigator) 
 
 
Study nurse 
 
 
Investigator 
 
Preparation time: 
30 min 
Intervention time: 
          100 min 
2nd intervention 
 Second treatment (i.e. treatment B if 
treatment A applied in 1st 
intervention). 
 Application of open label placebo in 
treatment B (study nurse; 
investigator not present) 
 Assessment of outcomes 
(investigator) 
 
 
Study nurse 
 
 
Investigator 
  
Preparation time:  
30 min 
Intervention time:  
100 min 
Table1: Overview of interventions, involved study stuff and time course 
Figure 1: Study time course for a participant. T= time point 
T0 
Study enrolment/ 
study information 
T1 
2 weeks washout 
1
st Intervention 
2
nd Intervention  
T2 

 
 
 
15 
 
1. Administrative structure:  
1.1 
Sponsor:  
Department of Anaesthesia, Surgical Intensive Care, Prehospital Emergency Medicine and 
Pain Therapy of the University Hospital Basel 
1.2 
Sponsor investigators:  
 
Wilhelm Ruppen, PD 
Head of Pain Unit 
Department of Anaesthesiology/ Chronic pain Unit 
Spitalstrasse 22 
 
4031 Basel CH 
 
Phone:  +41613286496 
E-mail: Wilhelm.ruppen@usb.ch 
1.3 
Principal Investigators:  
 
Tobias Schneider, MD 
Senior physician 
Department of Anaesthesiology/ Chronic pain Unit 
Spitalstrasse 22 
 
4031 Basel CH 
 
Phone: +41613285165 
E-mail: tobias.schneider@usb.ch 
 
Eckhard Mauermann, MD, MSc 
Research Fellow, 
Department of Anaesthesiology University of Basel (USB) 
Spitalstrasse 22 
 
4031 Basel CH 
 
Tel.: +41787200189Fax: +41612655720 
E-mail: eckhard.mauermann@usb.ch 
 
Oliver Bandschapp, PD 
Senior Physician 
Department of Anaesthesiology University of Basel (USB 
Spitalstrasse 22 
 
4031 Basel CH  
Tel.: +41613286513 
Fax: +41612655720 
E-mail: oliver.bandschapp@usb.ch 
 
Julian Lüthi 
Scientific assistant, doctoral candidate 
Department of Anaesthesiology University of Basel (USB) 
Spitalstrasse 22 
 
4031 Basel CH  
Tel.: +41613285165 
Fax: +41612655720 
E-mail: julian.luethi@stud.unibas.ch 
 

 
 
 
16 
 
 
Wolfgang Koppert, Prof. 
Carl-Neuberg-Straße 1 
30625 Hannover 
Tel: +49 511 - 532 – 2489 
Fax: +49511 - 532 - 3642  
E-mail: koppert.wolfgang@mh-hannover.de 
 
1.4 
Statistician (Biostatistician) 
When required, assistance will be obtained by the Clinical Trails Unit of the University of 
Basel. 
1.5 
Pharmacy: 
Not required. Placebo (NaCl 0.9%) given as a market-batch. 
1.6 
Monitoring Institution: 
The monitoring of our study will be performed by  
Esther Seeberger 
Study Manager/ Study nurse 
Dep. of clinical research/ Dep. of Anaesthesiology University Hospital Basel 
Spitalsstrasse 22 
4031 Basel 
Tel: +41613287424 
Fax: +41612655720 
E-mail: esther.seeberger@usb.ch 
 
For further information c.p. separate monitoring plan.  
  
1.7. Data Safety Monitoring committee:  
c.p. 1.6 
1.8 Any other relevant Committee, Person, Organization, Institution:  
n/a 
2. Ethical and Regulatory aspects:  
2.1 Study registration:  
This study will be registered with www.clinicaltrails.gov upon approval. 
2.2 Categorization of the study: 
Category B: This study involves the use of an established pain model, a placebo (NaCl), 
and a carrier solution (Ringer Lactate). No other drugs will be applied. However, it is our 
understanding that even NaCl 0.9% used within the guidelines of suggested use (1 ml 
injection) mandate pro forma a category B, since volunteers have no indication for NaCl 
0.9%. In our study NaCl 0.9% is not the investigational product. Any other carrier solution 
without an analgesic potential (placebo) could have been used. We are not performing a 
classical medical drug trail, therefore catogory B has to be applied.   

 
 
 
17 
 
2.3 Competent Ethics Committee (CEC): 
The responsible investigator will ensure that approval from an appropriately constituted CEC 
is sought for the clinical study, in this case the EKNZ. 
Reporting duties will be conducted within standard times. No relevant changes will be made 
to the protocol without prior Sponsor and CEC approval, except where necessary to 
eliminate apparent immediate hazards to study participants. 
Premature study end or interruption of the study will be reported within 15 days. The regular 
end of the study is reported to the CEC within 90 days, the final study report shall be 
submitted within one year after study end. Amendments are reported like explained in the 
corresponding chapter. No secondary analyses are planned at this point. In the event that 
these should be desired at some point, permission will be sought from the CEC. 
2.4 Competent Authorities (CA)  
n/a 
2.5 Ethical Conduct of the Study  
The study will be carried out in accordance to the protocol and with principles enunciated in 
the current version of the Declaration of Helsinki, the guidelines of Good Clinical Practice 
(GCP) issued by ICH, in case of medical device: the European Directive on medical devices 
93/42/EEC and the ISO Norm 14155, the Swiss Law and Swiss regulatory authority’s 
requirements. The CEC and regulatory authorities will receive annual safety and interim 
reports if required and be informed about study stop/end in agreement with local 
requirements.  
2.6 Declaration of interest 
No conflict of interest. 
2.7 Patient Information and Informed Consent 
The investigator team (physician or study nurse) will explain to each participant the nature of 
the study, its purpose, the procedures involved, the expected duration, the potential risks and 
benefits and any discomfort participation may entail. Each participant will be informed that 
the participation in the study is voluntary and that he may withdraw from the study at any 
time and that withdrawal of consent will not affect his/her subsequent medical assistance and 
treatment.  
All participants for the study will be provided a participant information sheet and a consent 
form describing the study and providing sufficient information for participant to make an 
informed decision about their participation in the study. Participants will confirm that 
adequate time for reaching a decision was allocated. 
The participant information sheet and the consent form will be submitted to the CEC/EKNZ to 
be reviewed and approved. The formal consent of a participant, using the approved consent 
form, must be obtained before the participant is submitted to any study procedure. 
The participant will read and consider the statement before signing and dating the informed 
consent form, and will be given a copy of the signed document. The consent form must also 
be signed and dated by the investigator (or designee) and it will be retained as part of the 
study records. 

 
 
 
18 
 
2.8 Participant privacy and confidentiality  
The investigator affirms and upholds the principle of the participant's right to privacy and shall 
comply with applicable privacy laws. Especially, anonymity of the participants shall be 
guaranteed when presenting the data at scientific meetings or publishing them in scientific 
journals.  
Individual subject medical information obtained as a result of this study is considered 
confidential and disclosure to third parties is prohibited. Subject confidentiality will be further 
ensured by utilizing subject identification code numbers. 
For data verification purposes, authorized representatives of the Sponsor (-Investigator) or 
an ethics committee may require direct access to parts of the medical records relevant to the 
study, including participants’ medical history. 
2.9 Early termination of the study  
The Sponsor-Investigator may terminate the study prematurely according to certain 
circumstances, for example:  
 
ethical concerns 
 
insufficient participant recruitment 
 
when the safety of the participants is doubtful or at risk 
 
alterations in accepted clinical practice that make the continuation of a clinical trial 
unwise 
As a study with no active medication the only risk for the participants is infection or allergic 
local skin reaction by the insertion/ material of the microdialysis membrane. We don’t expect 
any infection during the study period. But if there occurs more than one we stop using 
membranes from the same charge. If another infection manifests the study is terminated. 
Participants are monitored for skin infections during the second study date and are told to 
contact the study team in case of suspected infection. (24 hours contact hotline is listed in 
the participant information)  
For study reasons vital signs of participants are recorded during every intervention. We don’t 
expect safety issues during the investigation, but in case of development of health threat 
during an intervention, the experiment is directly stopped. If this occurs more than once study 
is stopped until a clear reason is identified and terminated if it cannot be eliminated.    
2.10 Protocol amendments 
The PI or persons delegated by the PI may make amendments to the protocol. The 
submission of amendments as well as their approval will be communicated internally as 
needed. 
Substantial amendments are only implemented after approval of the CEC/EKNZ. 
Under emergency circumstances, deviations from the protocol to protect the rights, safety 
and well-being of human subjects may proceed without prior approval of the sponsor, the 
CEC, and Swiss medic. Such deviations shall be documented and reported to the sponsor, 
the CEC, and Swiss medic as soon as possible. 
All non-substantial amendments are communicated to the CEC and Swiss medic within the 
Annual Safety Report (ASR).  

 
 
 
19 
 
3. Background and rationale 
Open label placebo treatment studies have reached great interest in research in the recent 
past. Current studies suggest that placebos have a clinical significant effect, even if patients 
and treating physicians know they are using a placebo [1, 2]. This is true for chronic pain 
states and chronic disease like the irritable bowel syndrome.  
Placebo reactions (PR) describe positive physiologic and psychologic changes after the 
administration of pharmacologic effect-free substances, shine operations or interventions, or 
after therapeutic symbols or rituals. 
PR are based on multiple psycho-social components influencing the treatment context [17] 
as well as through activation of different neuro-psychopharmacologic systems. It has been 
shown that there are different kinds of placebo reactions depending on the involved 
physiologic system, the diseases or specific therapy [17, 18]. 
PR have been proven to be effective in numerous clinical and experimental studies in adults 
[19] and children [20]. These reactions have been identified as complex psycho-neuro-
biologic reactions. 
The neuro-biologic basis of placebo analgesia (PA) has been studied for over 40 years, since 
Levine at al. showed that the opiate antagonist naloxone could annul placebo analgesia after 
wisdom tooth extraction [3].  
Petrovic et al. detected common mechanisms in opioid analgesia and PA, with similar 
activation of the opioidergic descending pain control system through placebo application [4]. 
The dorsolateral prefrontal cortex (DLPC) plays a central role as neuronal context mediator 
in this system. Trans-cranial magnet stimulation over the DLPC [6] or application of naloxone 
[4] can stop the processing of expectation-induced PA completely. Functional imaging 
indicates that inhibition of nociceptive afferents takes place even at spinal cord level in PA 
[7]. Beside endogenous opioids other neuropharmacologic mediators are involved in 
processing and transmitting PA. Benedetti at al. could detect the neuropeptide 
Cholecystokinine as an antagonist of PA [21]. Furthermore the dopaminergic system [22] and 
in the non-opioid mediated PA the endogenous cannabinoid system [5] play an important 
role. An intensifying effect of PA is also known for the neuropeptide oxytocin for both sexes 
[23] and for vasopressin in women [24].  
To activate and maximise the cascade of PA, psychologic mechanisms play the key role. 
Three key points can determine the PR: 1) patient expectations 2) physician – patient 
communication 3) conditioning.  
Ad 1): PA can be induced through suggestion, associative learning and social observing 
learning. So enchant self-efficacy expectations and positive expectations of treatment can 
reduce anxiety and stress [8, 9]. For example, promoting positive expectations before 
application of an opioid or a NSAID analgesic is about 30% to 100% more effective than a 
blinded application [10, 11]. 
Ad 2): A resent published meta-analysis showed that trust in the treating health care 
professional is associated with subjective improvement of symptoms, satisfaction and life 
quality of patients [12]. Egbert et al showed that an instructive and encouraging preoperative 

 
 
 
20 
 
informative conservation has significant impact on postoperative morphine consumption and 
hospital stay [13]. 
Ad 3) Due to conditioning processes during verum treatment it is possible transfer the verum 
treatment effects to a placebo treatment [14]. Benedetti at al. showed that for morphine 
imitation. This conditioning works for days and weeks [15]. As mentioned before, after 
conditioning, placebos have been used successfully as dose extenders [25] with the potential 
to reduce side effects, addiction potential and last but not least have the potential to be cost 
effective. 
Study aims: 
We want to investigate pain response to an open-label placebo application in healthy male 
adults in a well-established pain model first described by Koppert et al. [16]. This as a 
contribution to the ongoing discussion, if the use of open label placebo in acute pain 
management can be useful and supportive. 
3.1 Importance of the study 
Until today there are no studies investigating open label placebo effects in acute pain. This is 
however of great clinical value because:  
Firstly, open label placebo administration releases the treating physician from the ethical 
dilemma to deceive the patient with a placebo treatment.  
Secondly, beside possible cost effectiveness, reduced dosages of active pain killers due to 
placebo application could result in a better safety profile especially in older patients or 
patients otherwise at high risk of side-effects. The dose extending potential of placebos has 
been shown in clinical studies [25], but was never proved in an open label placebo 
intervention in an acute pain model.   
4. Study objectives 
4.1 Primary objective 
To investigate the effect of open label placebo application on acute pain in an experimental 
model of acute pain (simulating wound pain). 
 
4.2 Secondary objectives 
 
To investigate the effect of education prior to an open label placebo application.  
 
To investigate the effect of open label placebo application on biomarkers of stress 
(saliva cortisol, OMT sTNFII-R) 
5. Study outcomes 
5.1 Primary outcome 
Pain response measured by the Area under the Pain Curve (AUPC) using the numeric 
rating scale (NRS) from minute 40 to100 after inducing definded pain in an experimental 
setting. Main comparison: The effect of open label placebo v.s. no treatment intervention. 

 
 
 
21 
 
5.2 Secondary outcomes 
1. The pain response measured by the AUPC (NRS every 10 minutes during electrical 
stimulation) will be used for further comparison of the two different treatment 
interventions every participant recieves during the study. We compare the 
participants received a education about placebo to the non prior educated 
participants.  
2. Hyperalgesia and allodynia will be measured analogously to the NRS as above. 
3. Saliva concentration of cortisol, measured at baseline, 30, 60 and 100 minutes after 
pain induction. 
5.3 Safety outcomes 
General patient well-being will be assessed by a consultant anaesthesiologist. 
5.4 Safety and Tolerability Assessment 
The participant will be under constant supervision during the course of stay by anaesthetist 
staff.  
6. Investigational medical product 
 
 
Placebo: 
The placebo will be applied via a 5ml syringe containing 5ml of saline 0.9%. Application is 
done via a venous access inserted at the beginning of the experiment. 
7. Study design 
 
7. 1 Subjects and Study Center:  
Type and number of study participants: 32 healthy male volunteers. 
Number and location of participating centers: monocenter study, University Hospital Basel, 
Switzerland 
 
7.2 General study design and justification of design 
An assessor-blinded, randomized crossover study design will be applied.  Each patient will 
undergo each of the two treatments (A-B) listed below. Furthermore, patients will be 
randomized to either receive placebo education or to not receive placebo education (e.g. B1 
= placebo education; B2= no placebo education). In other words, each patient will receive 
one of the two following treatment sets: either (A, B1) or (A, B2); the individual components of 
these sets will be randomized. 
 
TREATMENT 
General (visible) 
Open drug application 
A No treatment 
intervention 
 
Infusion RL  
Infusion rate: 100ml/h 
No 

 
 
 
22 
 
B1,2 Open-label 
Placebo alone 
Infusion RL  
Infusion rate: 100ml/h 
OLP 
 
Table 1: Overview study interventions 
In each treatment the patient will receive a standard infusion containing only Ringer lactate 
(RL) infused at a rate of 100ml/h. The purpose of this infusion is simply to keep venous 
access.  
To avoid any systematic bias the assignment of the study groups will be performed in a 
balanced randomized manner. To control for excitement and habituation effects we operate 
the interventions in a randomized order in every participant. 
The participants are recruited by an advertisement on the University of Basel homepage and 
eligible volunteers will be included on a “first come, first served” basis.    
Study participants are orally and written informed about study aims and interventions before 
the first assessment.  
7.3 General participant information 
Every participant is informed that he will receive an open label placebo during one of the two 
interventions and no treatment in the other intervention. In addition, every participant 
receives the explanation that a placebo is an inactive substance therefore contains no active 
ingredient. A general explanation of the term “placebo effect” is also given to every volunteer.  
7.4 Participant education in in the placebo education group 
The participants randomized to the PEG will receive additionally an education about 
placebos prior to the first intervention with following content (adopted from prior open label 
placebo studies [1, 2] and adapted to the current study design):   
A) Showing data about the possible strength of a placebo effect. Abstracts of prior 
placebo investigations are presented [1, 2]. 
B) The possible automatically response of the body to placebo application is discussed. 
Pavlov dogs experiments and effects of prior studies are presented to the volunteer. 
C) Education that a positive attitude towards placebos can be helpful but is not 
necessary for the placebo effect [8-10].  
D) A television news report of an open label placebo education is shown to the 
participant at the end of the education session. (excerpted from: http:// 
www.nbcnews.com/video/nightly-news/40787382#40787382). 
To 
ensure 
proper 
understanding we add a German subtitle to the original report (English). 
The education is done via a slide show, performed exactly the same in every volunteer. The 
duration of the presentation is about 10 minutes. (Slides are attached at the appendix of this 
protocol.) The investigator of the treatment interventions is not involved in placebo education 
prior to intervention.  
7.5 Experimental design 
Acute pain will be induced through electrical stimulation in an established model first 
described by Koppert et al.[16]. (For detailed experimental setup cp. Chapter 7.6-7.7) 
Before the first intervention participants will be randomized to: 

 
 
 
23 
 
1) A placebo education group 
2) A non-placebo education group 
Participants in both groups will undergo the pain model two times. Every participant will 
receive treatment as follows in a sequential cross-over design (cp fig. 1). 
 
 
During every experiment levels of saliva cortisol levels are collected at baseline, 30min, 
60min and 100min after pain induction (cp. Fig. 4). 
A washout period of two weeks well be instituted to prevent contamination (cp. Fig 1). 
Randomization as well as preparation and application of the hidden and not hidden study 
medication will be executed by study stuff not involved in assessments during the 
intervention. During the individual experiment pain scores, hyperalgesia and allodynia will be 
assessed and documented by an investigator blinded to the treatment group.  
7.6 Experimental setup 
Every participant will be intensive familiarized with the pain scale, the intradermal electrical 
stimulation model evoking pain, hyperalgesia and allodynia examination. A training session 
would be rather invasive and includes the risk of habituation and is therefore not applied. 
Previous studies conducted by our research group using this model have also shown that 
this is not required. 
The model we use in this study was first described by Koppert at al.[16]. It has been used in 
numerous studies investigating pain, pain medications, hyperalgesia and allodynia [26-31]. 
Our utilized pain model has been shown to provoke stable  areas of secondary hyperalgesia 
Figure 1: Experimental design 

 
 
 
24 
 
to pinprick and touch caused by an activation of mechanoinsensitive C-nociceptors [32] (a 
class of nociceptors shown to be activated electrically, preferentially at high current densities, 
as used in this model [33, 34]). 
7.7 General setup of intradermal electrical stimulation (cp. Figure 3) 
Two microdialysis catheters with internal stainless steel wires are inserted in parallel into the 
intradermal, volar surface of the contralateral forearm for a length of approximately 10mm 
and are separated 5mm from each other. The catheters are filled with 0.9% saline and a 
continuous flow of 0.2µl/min ensured by a syringe pump (Perfusor®) to facilitate conduction. 
The stainless steel wires are attached to a constant current stimulator (manufactured by 
Koppert et al.) and monophasic, rectangular electrical pulses of 0.5ms duration are applied 
with alternating polarity at 2 Hz. The current will be increased to target a pain rating of 6 of 10 
on a numeric rating scale (NRS) (0= no pain and 10 maximum tolerable pain). Three further 
increases in current will be made every 5 min for the next 15min to compensate for 
habituation. This final current will be kept constant until the end of the particular experiment 
(100min cp. figure 4). After calibration to NRS 6 there is no further increase of the current. 
7.8 Procedures/ Recordings/ Interventions before and during electrical stimulation 
 
Measurement of pain: 
After adjusting for habituation as delineated above, pain, hyperalgesia, and allodynia will be 
assessed every ten minutes after time-point for possible OLP-application, using the NRS 
until the end of the individual session after 100 minutes (cp.Figure 4). 
Measurement of hyperalgesia and allodynia:  
Immediately after every pain rating the area of pinprick hyperalgesia is determined using a 
256 mN von Frey filament and allodynia is determined using a dry cotton swab. 
Measurements are conducted from a more distant to a more central site along four 
orthogonal lines (distal, proximal, lateral, and medial) that will be drawn onto the skin with tick 
marks indicating each centimetre (cp. picture 1). Distal and proximal measurements will 
begin 12cm from the site of electronical stimulation; whereas the lateral and medial 
measurements were begin 6cm from this site. In both cases the used filament will be moved 
towards the site of stimulation in 0.5 cm increments until the subject reports either increased 
pain sensations from the von Frey filament (hyperalgesia) or an unpleasant “rougher” 
sensation from the cotton swab (allodynia). To create an area from these linear 
measurements, the assumption is made, that this field has the shape of an ellipse. The area 
is calculated using the formula 1/4πD·d.  
Pain, hyperalgesia and allodynia measurement are exactly the same in both experimental 
interventions.  
 

 
 
 
25 
 
 
Picture 1: A: microdialys catheter inserted intra-cutaneous at the forearm; B: testing 
hyperalgesiawith 256 mN von Frey filament; C: testing allodynia with a cotton swap.; adopted with 
permission from Mauermann et al.,  Anesthesiology, 2016. 124(2): p. 453-63. 
 
7.9 Application of study medication 
As mentioned before a venous access is installed at the forearm not used for experimental 
measurements.  
There are two different treatment options every volunteer receives during the two 
experimental interventions. 
A) No medical or open label placebo (OLP) treatment during the intervention. 
B) Application of OLP 30 min after calibration for NRS 6. 
7.10 Open label placebo application 
Open-label placebo is given during Treatment B. A pain expert of the study stuff (the same 
person for one participant during the two interventions) applies placebo in treatment B. For 
an open-label placebo application the volunteer is orally informed that he will receive an 
intravenous placebo (“medical” not active substance) now. To strengthen positive 
expectations the study nurse assures the patient that placebos can have a strong effect on 
pain before application of the syringe content. The placebo is then injected intravenous while 
the investigator ensures that the volunteer watches the injection. The oral information text is 
standardized is exactly the same in every participant. (For the orginal text in german 
language cp. appendix)   
7.11 Achievement of blinded medication application 
A venous access is placed before every intervention session starts. An infusion of Ringer 
lactate with an infusion speed of 100ml/h (controlled via infusion pump) will be attached. The 
investigator performing the testing during the intervention leaves the test-room before 
possible placebo application. He is blinded if treatment A or B is applied. This, to ensure 
objective data collection. 
The randomisation code is kept in a locked up folder in the office of  the principle investigator 
Tobias Schneider with restricted access only to the in intervention planning involved study 
personal, namely: Monika Kirsch and Tobias Schneider 
Unblinding is done after the last last experimental intervention. The Randomization is than 
open to the study stuff taking part in the analysis of obtained data.  
 

 
 
 
26 
 
7.12 Collection and processing of biomarkers 
 
Saliva collection and processing 
Oral fluids are collected to measure cortisol levels in response to induced pain. To control for 
diurnal variations of neuroendocrine parameters all experiments will be carried out between 
4pm and 7pm. 
Consistent with the procedures incorporated be Dickerson et al. [35] we decided to obtain the 
biological parameters in this study from oral fluids. Saliva levels of cortisol [36] are reliable 
and highly correlated with plasma levels. Therefore it is a less reactive, less invasive but 
reliable method to measure neuroendocrine immune activity. 
To ensure a non-contaminated measurement participants are asked: 
- 
Not to use non-prescription medications or alcohol within 24 hours before 
measurement 
- 
To refrain from exercise and caffeine at least 2 hours to testing session 
- 
Not to eat foods that may cause bleeding of the gums (e.g. potato chips) or brush 
their teeth for at least 2 hours prior to testing session.   
Collection of saliva for cortisol determinations 
A collection device (Salivette®) is placed into the mouth on the top of the tongue for 2.5min 
per sampling time point. Cortisol in saliva is in its unbound biologically active form and its 
concentration is independent of saliva flow rate [37]. 
Time points of measurements 
Basic value: 
After arrival of the participant for the intervention a 15 min rest must be hold before the first 
collection. The first collection during the first experimental intervention is to make the 
participant familiar with the procedure and will not be used for later analyses. A second 
collection will be performed directly after the test collection. 
Further collections: 
Saliva will be further collected as follows during the experimental intervention (cp. figure 4): 
1. 30 min after constant electrical stimulation before application of study medication 
2. 30 min after completed application of the study medication 
3. 60 min after completed application of the study medication 
After collection the oral fluids samples are immediately refrigerated before being transferred 
and will be stored at -80°C until further analysis, if analysis cannot be performed within 6 
hours after collection. 

 
 
 
27 
 
 
8. Medical products and Medications used during the study 
8.1 Medication used: 
Carrier solution: Ringer Lactat Fresenius 1000ml Infusion solution. License number: 42692 
(Swissmedic); license holders: Fresenius Kabi (Schweiz) AG, Oberdorf NW 
NaCl 0.9%: NACL Bichsel Inj. Lös 0.9% 10ml ampulle; license number: 29800 (Swissmedic); 
license holder: Dr. Bichsel AG, Interlaken 
All medication will exclusively be used as an unaltered medical batch. 
8.2 Medical products used for the pain model:  
Current stimulator: Digitimer S7; Digitimer, Hertfordshire, United Kingdom 
Microdialysis catheter: self-manufactured at the laboratory of Koppert et al. University 
Hopsital Hannover 
8.3 Medical products used for the infusion application/ patient monitoring: 
Controlled Infusion application: Injectomat Agilia, Producer: Fresenius Kabi; PZN: 
4377569 
Infusion application: Original B. Braun Perfusor® Syringe 50 ml PZN: 00570097; Original 
B. Braun Perfusor® Line IV Standard, Luer Lock PZN: 06100642;  
Venous catheterization: B. Braun Vasofix® Safety 20G or 18G, CE-number: 0123 Producer 
of all products: B. Braun Melsungen AG 
Storage conditions: 
Study medications are stored with the medications for regular pain treatment in the chronic 
pain unit, according to the manufactures specification at room temperature and protected 
from light. 
Figure 4: Schedule for measurement of pain, hyperalgesia, allodynia, biomarker collection and application 
of study medication during an individual study intervention session.  

 
 
 
28 
 
 
9.Study population 
9.1 Recruitment of volunteers  
Volunteer recruitment will occur by an advertisement on the University Basel homepage, an 
occlusion will occur on a “first come, first served” basis. 
9.2 Inclusion criteria  
- 
Healthy male volunteers (American Society of Anaesthesiologist’s Class I or II) 
- 
Body mass index between 18 and 25kg/m2 
- 
Able to understand the study and the NRS scale 
- 
Able to give informed consent 
 
9.3 Exclusion criteria 
- 
Recreational drug abuse 
- 
Regularly taking medication potentially interfere with pain sensitation (analgesics, 
antihistamines and calcium and potassium channel blockers) 
- 
Neuropathy 
- 
Chronic pain 
- 
Neuromuscular or psychiatric disease 
Inclusion and exclusion criteria will be checked prior to inclusion into the study.  
Informed written consent is obtained from every participant after detailed oral and written 
information by the study stuff.   
9.4 Subject Withdrawal 
Subjects may withdraw from the study at any time and for any reason (stating reason is not 
required). If patients elect to do so, data will be anonymized and no further analyses 
conducted. To replace this study drop-out, an additional patient will be recruited. Drop outs 
will be reported in the final publication.  
The following reasons result in withdrawal: 
 
AE challenging the health of the subject if continuing the study 
 
Severe protocol violations 
 
Administrative troubles 
9.5 Expense allowance for participants 
Participants will receive a financial compensation for their expenditure of time and possible 
travel expenses. This compensation is standardized and will be graded with respect to 
attended interventions.   
A one-time financial compensation will be awarded to patients completing the study (250 
CHF). The compensation is graduated. Compensation for the first interverntion is 100 CHF, 
for the second 150 CHF. In the event of early termination (before/ during first intervention), 
patients will be compensated with 20 CHF/h. 
10. SAFETY 

 
 
 
29 
 
10.1 Drug studies 
During the entire duration of the study, all adverse events (AE) and all serious adverse 
events (SAEs) are collected, fully investigated and documented in source documents and 
case report forms (CRF). 
Study duration encompassed the time from when the participant signs the informed consent 
until the last protocol-specific procedure has been completed, including a safety follow-up 
period. 
 
10.2 Definition and assessment of (serious) adverse events and other safety related 
events 
An AE is any untoward medical occurrence in a patient or a clinical investigation participant 
administered a pharmaceutical product and which does not necessarily have a causal 
relationship with the study procedure. An AE can therefore be any unfavourable 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. 
[From ICH E2A and E6, “investigational” term only in E6] 
 
A Serious Adverse Event (SAE) is classified as any untoward medical occurrence that: 
- 
results in death 
- 
is life-threatening, 
- 
requires in-patient hospitalization or prolongation of existing hospitalisation, 
- 
results in persistent or significant disability/incapacity, or 
- 
is a congenital anomaly/birth defect. 
 
In addition, important medical events that may not be immediately life-threatening or result in 
death, or require hospitalisation, but may jeopardise the patient or may require intervention to 
prevent one of the other outcomes listed above should also usually be considered serious. 
[ICH E2A]  
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalisation, 
or development of drug dependency or drug abuse. 
SAEs should be followed until resolution or stabilisation. Participants with ongoing SAEs at 
study termination (including safety visit) will be further followed up until recovery or until 
stabilisation of the disease after termination. 
 
10.3 Assessment of Causality 
Both Investigator and Sponsor-investigator make a causality assessment of the event to the 
study drug, based on the criteria listed in the ICH E2A guidelines: 
 
Relationship 
Description 
Definitely 
Temporal relationship 
Improvement after dechallange* 
Recurrence after rechallenge 
(or other proof of drug cause) 
Probably 
Temporal relationship 

 
 
 
30 
 
Improvement after dechallenge 
No other cause evident 
Possibly 
Temporal relationship 
Other cause possible 
Unlikely 
Any assessable reaction that does not fulfil 
the above conditions 
Not related 
Causal relationship can be ruled out 
*Improvement after dechallenge only taken into consideration, if applicable to reaction 
 
10.4 Unexpected Adverse Drug Reaction 
An “unexpected” adverse drug reaction is an adverse reaction, the nature or severity of 
which is not consistent with the applicable product information. [ICH E2A] 
 
10.5 Suspected Unexpected Serious Adverse Reactions (SUSARs) 
The Sponsor-Investigator evaluates any SAE that has been reported regarding seriousness, 
causality and expectedness. If the event is related to the investigational product and is both 
serious and unexpected, it is classified as a SUSAR. 
 
10.6 Assessment of Severity 
The Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 of the National 
Cancer Institute (published may 2009) are used to classify severity of possible adverse 
events.  
 
 
10.7 Reporting of serious adverse events (SAE) and other safety related events 
All SAEs will be reported immediately and within a maximum of 24 hours to the Sponsor-
Investigator of the study. The Sponsor-Investigator will re-evaluate the SAE and return the 
form to the site. SAEs resulting in death are reported to the local Ethics Committee (via local 
Investigator) within 7 days. 
 
10.8 Reporting of SUSARs: 
A SUSAR will to be reported to the local Ethics Committee (local event via local Investigator) 
within 7 days, if the event is fatal, or within 15 days (all other events). 
 
10.9 Reporting of Safety Signals: 
All suspected new risks and relevant new aspects of known adverse reactions that require 
safety related measures, i.e. so called safety signals, must be reported to the Sponsor-
Investigator within 24 hours. The Sponsor-Investigator must report the safety signals within 7 
days to the local Ethics committee. 
 
10.10 Follow up of (Serious) Adverse Events: 
The participant will be told which test substance he had taken to avoid future complications. 
In case of an acute allergic reaction, the participant is referred to our emergency department 

 
 
 
31 
 
and the study is discontinued. The participant is informed about the applied test substance 
and will eventually be referred to an allergologist to verify allergic reaction in order to avoid 
future exposure. 
 
11. Statistical Methods 
11.1 Hypothesis 
 
Main hypotheses 
We first hypothesize that open label placebo administration leads to a significant reduction in 
the area under the pain curve (AUPC) from minute 40 to minute100 compared to no open-
label placebo in induced acute pain in healthy male adults (i.e. B1/2 vs. A)  
Secondary Hypotheses 
Secondly, we hypothesize that education and conditioning further reduce the AUPC in the 
same period of time compared to those patients receiving open-label placebo without 
education in induced acute pain in healthy male adults (i.e. B2 vs. B1). 
Finally, we hypothesize that the observed differences in the AUPC will be reflected in both 
hyperalgesia and allodynia as well as by biomarkers. 
11.2 Determination of sample size 
Sample size has been determined by a Wilcoxon signed-rank test for the AUPC for 
Treatments A and B. The AUPC is the product of the NRS x Time. 7 measurements of NRS 
will be made in total, one every ten minutes. We expect the area under the curve to be 50 
NRSxminutes based on a general difference of 1 NRS point and some time for the effect to 
fully develop. We expect the standard deviations in both groups to be 1 NRS or 60 NRS*min. 
Using a t-test with a 20% mark-up for non-parametric data we have arrived at a required 
number of patients of 22. However since 20-30% of participants can be expected to be non-
responders to placebo [38] and expecting 10% drop out we have arrived at a total number of 
patients to be recruited of 32. 
11.3 Statistical criteria of termination of the trail: 
Upon completion. With such a small sample size, no interim analysis will be conducted. 
 
11.4 Planned Analyses, Datasets, and Analysis Populations: 
For the first hypothesis (AUPC for B1/2 vs. A) we will conduct a Wilcoxon signed-rank test. 
Additionally, we conduct a mixed effects model using the AUPC as the dependent outcome 
and the treatment, the session order (e.g. Treatment B before Treatment A) time during 
electrical stimulation (in minutes), and finally the individual. This will allow for a more 
differentiated analysis accounting for temporal and sessional habituation in explaining the 
treatment effect. 
 
For the effect of education, we will compare the AUPC of: Treatment B1 vs Treatment B2, 
again by a Wilcoxon signed-rank test. 
 
 
The outcomes hyperalgesia and allodynia, as well as biomarkers will be examined 
analogously to the respective comparisons with the AUPC. 

 
 
 
32 
 
11.8 Interim analysis:  
Given the small sample size and limited time, no interim analysis will be conducted. 
 
11.9 Safety analysis: 
None. However, patients will be under the continuous surveillance of anesthesiology staff. 
 
11.10 Deviation(s) from the original statistical plan:  
The statistical plan will be published prior to commencement on clinicaltrials.gov. Any 
deviations from the statistical plan will be reported and justified in the final report. 
 
11.11 Handling of missing data and drop outs: 
All available data will be used, as far as possible considering the paired nature most of the 
tests. As long as the participant completes both treatments and data is complete for the 
primary analysis, the data will count as sufficiently complete. Participants electing to drop-out 
of the study will be replaced by another participant. However, whatever data is available at 
the time of drop-out will be analysed. Data completeness will be reported in the final 
publication and a consort diagram will be made. If a participant withdraws his agreement 
from the study all obtained data will be immediately deleted. Only anonymized data will be 
used for publication. Obtained cortisol probes will be destroyed after analyzation and will not 
be used for further research.     
 
12. Quality Assurance and Control 
 
12.1 Data handling and record keeping / archiving: 
Personal data is kept in a computer database, and all CRFs and informed consents are kept 
in a folder and archived for a minimum of 10 years. 
 
12.2 Case Report Forms (CRF) 
Study data is recorded with paper CRFs. For each enrolled study participant CRFs are 
maintained. 
Participants are not identified in the CRF by name or initials and birth date; instead the 
participant number is used. The nursing personnel and the PIs are authorized for all CRF. As 
paper CRFs are used, the data is entered into an electronic database for analysis during the 
trial (by the study nurse and/or PhD student). 
 
12.3 Specification of source documents 
Demographic data, visit dates, participation in study and Informed Consent Forms, 
randomisation number, SAEs, AEs and concomitant medication, results of relevant 
examinations and all CRFs are considered the source documents in the study. Source 
documents are archived in folders at the study site with restricted access (Pain Relief Unit 
USB). 
 
12.4 Record keeping / archiving 
All study data will be archived for a minimum of 10 years after study termination or premature 

 
 
 
33 
 
termination of the clinical trial. All data is archived in folders at the study site with restricted 
access (Pain unit USB). 
 
 
13. Data management: 
 
13.1 Data Management System 
The data collection is based on paper source. This data will then be transferred from paper 
source documentation to a secure database. This database is based on Microsoft Access 
and will be operated with individual user log in, time stamp, and logging of changes. For 
security purposes, remote log in will not be allowed. The database will be backed up 
periodically on the Department for Anaesthesia, Surgical Intensive Care, Prehospital 
Emergency Medicine and Pain Therapy’s server. 
 
13.2 Analysis and archiving 
Upon conclusion, the database is secured and cannot be changed anymore 
13.3 Electronic and central data validation 
All data will be validated when entering them into the database and a quality check will be 
conducted before analyses. 
 
13.4 Monitoring 
The aim of monitoring is to evaluate the progress of the study, to verify the accuracy and 
completeness of CRFs, to ensure that all protocol requirements, applicable local authority 
regulations and investigator’s obligations are being fulfilled, and to resolve any 
inconsistencies in the study records. Regular monitoring visits at the investigator’s site prior 
to the start and during the course of the study will be performed by independent monitors not 
included in the research group. The monitoring is performed by Esther Seeberger c.p. 1.6 
and separate monitoring plan. The source data/documents are accessible to monitors and 
questions are answered during monitoring. 
 
13.5 Audits and Inspections 
Audits by the sponsor or inspections by regulatory authorities (IEC) during study or after 
study closure may be performed to ensure proper study conduct and data handling 
procedures according to ICHGCP guidelines and regulatory requirements. Audits and 
inspections may include verification of all source documents, check of CRFs and site files 
and a visual inspection of the study site. All involved parties must keep the participant data 
strictly confidential. 
 
13.6 Confidentiality, Data Protection 
Participant’s confidentiality will be maintained at all times. The investigator affirms and 
upholds the principle of the participant's right to privacy and those they shall comply with 
applicable privacy laws. 
Individual subject medical information obtained as a result of this study is considered 
confidential and disclosure to third parties is prohibited. Subject confidentiality will be further 
ensured by utilising subject identification code numbers to correspond to treatment data in 
the computer files. Personnel from the sponsor, the Pain Unit USB and members of IEC are 
obliged to respect medical secrecy and to refrain from divulging the participant’s identity or 
any other personal information they might fortuitously be aware of. 

 
 
 
34 
 
Direct access to source documents will be permitted for purposes of monitoring, audits and 
inspections. All study personnel involved in this trial (Tobias Schneider, Wilhelm Ruppen, 
Eckhard Mauermann, Oliver Bandschapp, Julian Lüthi, Wolfgang Koppert, Silvia Wuchner, 
Manuela Semeraro and Monika Kirsch) will have access to protocol, dataset during and after 
the study (publication, dissemination). 
Demographic data and personal data will be kept in the electronic database. Subjects will 
receive a study number upon inclusion, and in the data base only the study number will 
appear. Only the principal investigators will have the key. Data generation, transmission, 
storage and analysis of health related personal data and the storage of biological samples 
within this project will follow strictly the current Swiss legal requirements for data protection 
and will be performed according to the Ordinance HRO Art. 5. Health related personal data 
captured during this project and biological samples from participants are strictly confidential 
and disclosure to third parties is prohibited; coding will safeguard participants' confidentiality. 
Project data will be handled with uttermost discretion and only be accessible to authorised 
personnel. 
 
13.7 Storage of biological material and related health data: 
NaCl 0.9% and Ringer’s Lactate will be stored according to the manufacture specification at 
room temperature and protected from light. The infusion is prepared max. 1 hour before 
application. Saliva samples will be processed into different aliquots and kept frozen at -80°C 
until analysis, if analysis within 6 hours after probe drawing is not possible. 
 
 
14. Publication and Dissemination Policy 
 
We plan to publish the results in a peer-reviewed scientific journal. Upon request, we will 
provide the full study protocol and data (as required by some journals). The trial results might 
be presented at scientific congresses. The main publication will be created by Tobias 
Schneider, Eckhard Mauermann, OliverBandschapp, Wolfgang Koppert, Julian Lüthi and 
Wilhelm Ruppen. Subsequent publications of subgroups can follow thereafter and will have 
to be approved by the PI’s. No unpublished data may be transmitted to a third party without 
prior written approval by sponsors and PI’s. No publication or communication involving the 
results of the study is authorized without prior written consent from the PIs. In view of patent 
and confidentiality issues, however, the PIs must accept requirements on the timing of early 
publication.  
No use of professional writers is intended. The PIs will have ultimate authority over any of the 
activities. 
 
15. Funding and Support 
 
15.1 Funding: 
The study is funded by the Dep. of Anaesthesiology of the USB. There is no conflict of 
interest and the financing party has no influence on the protocol, analysis or publication. 
 
15.2 Other Support: 
No other financial support is expected. 
 
16. Cited literature:  
 
1. 
Carvalho, C., et al., Open-label placebo treatment in chronic low back pain: a randomized 
controlled trial. Pain, 2016. 157(12): p. 2766-2772. 

 
 
 
35 
 
2. 
Kaptchuk, T.J., et al., Placebos without deception: a randomized controlled trial in irritable 
bowel syndrome. PloS one, 2010. 5(12): p. e15591. 
3. 
Levine, J.D., N.C. Gordon, and H.L. Fields, The mechanism of placebo analgesia. Lancet 
(London, England), 1978. 2(8091): p. 654-7. 
4. 
Eippert, F., et al., Activation of the opioidergic descending pain control system underlies 
placebo analgesia. Neuron, 2009. 63(4): p. 533-43. 
5. 
Benedetti, F., et al., Nonopioid placebo analgesia is mediated by CB1 cannabinoid receptors. 
Nature medicine, 2011. 17(10): p. 1228-30. 
6. 
Krummenacher, P., et al., Prefrontal cortex modulates placebo analgesia. Pain, 2010. 148(3): 
p. 368-74. 
7. 
Eippert, F., et al., Direct evidence for spinal cord involvement in placebo analgesia. Science 
(New York, N Y ), 2009. 326(5951): p. 404. 
8. 
Klinger, R. and H. Flor, Clinical and ethical implications of placebo effects: enhancing patients' 
benefits from pain treatment. Handbook of experimental pharmacology, 2014. 225: p. 217-
35. 
9. 
Klinger, R., et al., Placebo analgesia: clinical applications. Pain, 2014. 155(6): p. 1055-8. 
10. 
Colloca, L., et al., Overt versus covert treatment for pain, anxiety, and Parkinson's disease. 
The Lancet Neurology, 2004. 3(11): p. 679-84. 
11. 
Bingel, U., et al., The effect of treatment expectation on drug efficacy: imaging the analgesic 
benefit of the opioid remifentanil. Science translational medicine, 2011. 3(70): p. 70ra14. 
12. 
Birkhauer, J., et al., Trust in the health care professional and health outcome: A meta-
analysis. PloS one, 2017. 12(2): p. e0170988. 
13. 
Egbert, L.D., et al., REDUCTION OF POSTOPERATIVE PAIN BY ENCOURAGEMENT AND 
INSTRUCTION OF PATIENTS. A STUDY OF DOCTOR-PATIENT RAPPORT. The New England 
journal of medicine, 1964. 270: p. 825-7. 
14. 
Amanzio, M. and F. Benedetti, Neuropharmacological dissection of placebo analgesia: 
expectation-activated opioid systems versus conditioning-activated specific subsystems. The 
Journal of neuroscience : the official journal of the Society for Neuroscience, 1999. 19(1): p. 
484-94. 
15. 
Benedetti, F., A. Pollo, and L. Colloca, Opioid-mediated placebo responses boost pain 
endurance and physical performance: is it doping in sport competitions? The Journal of 
neuroscience : the official journal of the Society for Neuroscience, 2007. 27(44): p. 11934-9. 
16. 
Koppert, W., et al., A new model of electrically evoked pain and hyperalgesia in human skin: 
the effects of intravenous alfentanil, S(+)-ketamine, and lidocaine. Anesthesiology, 2001. 
95(2): p. 395-402. 
17. 
Wager, T.D. and L.Y. Atlas, The neuroscience of placebo effects: connecting context, learning 
and health. Nature reviews Neuroscience, 2015. 16(7): p. 403-18. 
18. 
Schedlowski, M., et al., Neuro-Bio-Behavioral Mechanisms of Placebo and Nocebo Responses: 
Implications for Clinical Trials and Clinical Practice. Pharmacological reviews, 2015. 67(3): p. 
697-730. 
19. 
Schedlowski, M., et al., Neuro-Bio-Behavioral Mechanisms of Placebo and Nocebo Responses: 
Implications for Clinical Trials and Clinical Practice. Pharmacol Rev, 2015. 67(3): p. 697-730. 
20. 
Krummenacher, P., et al., Expectancy-induced placebo analgesia in children and the role of 
magical thinking. J Pain, 2014. 15(12): p. 1282-93. 
21. 
Benedetti, F., The opposite effects of the opiate antagonist naloxone and the cholecystokinin 
antagonist proglumide on placebo analgesia. Pain, 1996. 64(3): p. 535-43. 
22. 
Scott, D.J., et al., Placebo and nocebo effects are defined by opposite opioid and 
dopaminergic responses. Archives of general psychiatry, 2008. 65(2): p. 220-31. 
23. 
Kessner, S., et al., Effect of oxytocin on placebo analgesia: a randomized study. Jama, 2013. 
310(16): p. 1733-5. 
24. 
Colloca, L., et al., Vasopressin Boosts Placebo Analgesic Effects in Women: A Randomized 
Trial. Biological psychiatry, 2016. 79(10): p. 794-802. 

 
 
 
36 
 
25. 
Colloca, L., P. Enck, and D. DeGrazia, Relieving pain using dose-extending placebos: a scoping 
review. Pain, 2016. 157(8): p. 1590-8. 
26. 
Koppert, W., et al., Naloxone provokes similar pain facilitation as observed after short-term 
infusion of remifentanil in humans. Pain, 2003. 106(1-2): p. 91-9. 
27. 
Bandschapp, O., et al., Analgesic and antihyperalgesic properties of propofol in a human pain 
model. Anesthesiology, 2010. 113(2): p. 421-8. 
28. 
Bandschapp, O., et al., Tropisetron blocks analgesic action of acetaminophen: a human pain 
model study. Pain, 2011. 152(6): p. 1304-10. 
29. 
Koppert, W., et al., Differential modulation of remifentanil-induced analgesia and 
postinfusion hyperalgesia by S-ketamine and clonidine in humans. Anesthesiology, 2003. 
99(1): p. 152-9. 
30. 
Troster, A., et al., Interaction of fentanyl and buprenorphine in an experimental model of pain 
and central sensitization in human volunteers. Clin J Pain, 2012. 28(8): p. 705-11. 
31. 
Mauermann, E., et al., Does Fentanyl Lead to Opioid-induced Hyperalgesia in Healthy 
Volunteers?: A Double-blind, Randomized, Crossover Trial. Anesthesiology, 2016. 124(2): p. 
453-63. 
32. 
Orstavik, K., et al., Pathological C-fibres in patients with a chronic painful condition. Brain : a 
journal of neurology, 2003. 126(Pt 3): p. 567-78. 
33. 
Schmelz, M., et al., Sensitization of insensitive branches of C nociceptors in human skin. The 
Journal of physiology, 1994. 480 ( Pt 2): p. 389-94. 
34. 
Weidner, C., et al., Functional attributes discriminating mechano-insensitive and mechano-
responsive C nociceptors in human skin. J Neurosci, 1999. 19(22): p. 10184-90. 
35. 
Dickerson, S.S. and M.E. Kemeny, Acute stressors and cortisol responses: a theoretical 
integration and synthesis of laboratory research. Psychological bulletin, 2004. 130(3): p. 355-
91. 
36. 
Kirschbaum, C. and D.H. Hellhammer, Salivary cortisol in psychoneuroendocrine research: 
recent developments and applications. Psychoneuroendocrinology, 1994. 19(4): p. 313-33. 
37. 
Goodin, B.R., et al., Salivary cortisol and soluble tumor necrosis factor-alpha receptor II 
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38. 
Colagiuri, B., et al., The placebo effect: From concepts to genes. Neuroscience, 2015. 307: p. 
171-90. 
 
Appendix: 
Text of the assessor direct before placebo application  
 
The text will be recited and is exactly the same in every participant (German language): 
“ Ich werde ihnen nun ein Placebo in die Vene verabreichen. Wie sie bereits aus den 
Studieninformationen wissen, enthält ein Placebo keine medizinisch aktive Wirksubstanz. 
Wir wissen aus der aktuellen wissenschaftlichen Forschung, dass die Gabe eines Placebos 
einen starken positiven Effekt auf Schmerzen hat. Ich bin daher sehr zuversichtlich, dass 
dies auch bei ihnen zu einer deutlichen Reduktion der Schmerzen führen wird.“ 
During this announcement the assessor is facing the participant and speaks with a calm, 
friendly voice. It is always the same person, who makes this speech. 

 
 
 
37 
 
The subsequent application is good visible for the participant and the saline is injected slow 
over at least 30 seconds via two ml syringe, clearly recognisable for the participant.   
Slides of the Presentation for the “Placebo education group” with oral given 
information in text form: 
 
 
Starting slide 
 
 
 
 
 
 
 
 
 
 
 
 
Oral information: 83 patients with chronic low back pain were enrolled in this study. The first group 
received a treatment as usual (consisting of physical therapy and NSAID) and the second received an 
open label placebo in addition to the treatment concept in group one. The result was a statistical and 
clinical relevant better pain relief and disability improvement in the placebo group compared to the 
treatment as usual group.    

 
 
 
38 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Oral information: 80 patients with IBS diagnosed by Rome III criteria were randomized to either open 
label placebo or no treatment control. The primary was the global improvement score. Secondary 
outcomes were symptom severity score, percent of adequate pain relief, and improvement of quality 
of life.  For all outcomes significant better results in the open placebo group were obtained. 
Oral information: Learning processes of our brain and body run off partially subconscious. For 
clarification of this processes Pawlows dogs experiment is explained to the participant. Like in 
Pawlows dog learning processes activate body`s own analgesic systems in response to a conditioned
impulse (injection of a fluid into a vein). Benedetti et al. showed that it is possible to transfer 
analgesic effects of an opioid treatment to a following treatment with placebo in parts. 

 
 
 
39 
 
 
Oral information: To clarify that a positive attitude towards a given medication can be helpful, 
but is not mandatory, data from Colloca et al are shown. Hidden application of an opioid 
(shown in the graph on the slide) is also effective in pain treatment. But an open application 
works faster and even stronger.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Oral information: The slide from Benedetti et al. shows the strong placebo and nocebo 
effects.  Exemplary shown for proglumide and remifentanil. New drugs have to show a 
significant superiority compared to placebo. Especially for pain medication this can be 
hard to achieve because of the strong placebo effect.    

 
 
 
40 
 
 
 
 
 
 
 
 
 
Oral information: For closure and as a summary of the presentation this 2min 19sec 
news report is presented to the participant.