Understanding Opioid Use Before and After Surgery in Norway: A Prospective Multicenter Study and Randomized Double-blind Controlled Study
Phase: PHASE4
Conditions: Opioid Use, Affective Symptoms
Sponsor: Oslo University Hospital

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Affective effects of pre-surgery opioids (AFFECT2): a randomized 
double-blind placebo-controlled trial  
 
A randomized, double-blind placebo-controlled Phase IV study with three drug arms (three doses 
each) in healthy adult surgery patients, to investigate the affective short-term effects of 
morphine, oxycodone, and fentanyl, administered intravenously to the participants before the 
induction of general anesthesia. 
Protocol Number: AFFECT2 
Amendment Number: 0 
Compound: morphine «Orion», oxycodone  «Hameln», fentanyl «Hameln» 
Brief Title: Affective effects of pre-surgery opioids 
Study Phase: IV 
Acronym: Affect2 
Sponsor Name:  
Gernot Ernst, Head of the Research department, Kongsberg Hospital 
Legal Registered Address: Vestre Viken Health Trust, Postboks 800, 3004 Kongsberg 
Regulatory Agency Identifier Number(s) 
EudraCT:  2022-002938-13 
 
Approval Date:  
 
 

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Sponsor Signatory: 
 
 
 
 
 
Gernot Ernst 
Head of Research Department, Associate Professor, 
Dr.med. 
 
Date 
 
 
 
 
 
 
 
 
Medical Monitor Name and Contact Information will be provided separately. 
 
 
 

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Protocol Amendment Summary of Changes Table 

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Contact Details:  
Sponsor 
Gernot Ernst, Head of the Research 
Department, Kongsberg Hospital 
Vestre Viken HF 
Postboks 800 
3004 Drammen 
Tel: 32725454 
E-mail: bserng@vestreviken.no 
Study Chair 
Gernot Ernst, Dr. med, Associate Professor 
Address: Vestre Viken HF, Postboks 800, 
3004 Drammen 
Tel: 32725454 
E-mail: bserng@vestreviken.no 
Principal Investigator 
Gernot Ernst, Dr. med, Associate Professor 
Address: Vestre Viken HF, Postboks 800, 
3004 Drammen 
Tel: 32725454 
E-mail: bserng@vestreviken.no 
Coordinating monitoring unit 
Department of Research, Vestre Viken Trust 
Address: Postboks 800, 3004 Drammen 
Steering Committee  
 
Gernot Ernst (Chair) (Kongsberg hospital) 
Siri Leknes (co-Chair) (UiO) 
Marie Eikemo (UiO) 
Participating Site 
Kongsberg hospital 
Drammensvei 2, 3612 Kongsberg 
Tel: 03525 
E-mail: postmottak@vestreviken.no 
Oslo University Hospital 
Address: Postboks 4956 Nydalen, 0424 Oslo 
Tel: 91 50 27 70 
E-mail: post@oslo-universitetssykehus.no  
 
 
 

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Innhold 
Affective effects of pre-surgery opioids (AFFECT2): a randomized 
double-blind placebo-controlled trial............................................................................1 
Protocol Amendment Summary of Changes Table .........................................................................3 
Contact Details: ..............................................................................................................................4 
1. 
Protocol Summary ..........................................................................................................8 
1.1. 
Synopsis ............................................................................................................................8 
1.2. 
Schema ............................................................................................................................12 
1.3. 
Schedule of Activities .....................................................................................................15 
2. 
Introduction ...................................................................................................................16 
2.1. 
Study Rationale ...............................................................................................................18 
2.2. 
Background .....................................................................................................................18 
2.3. 
Benefit/Risk Assessment ................................................................................................19 
2.3.1. 
Risk Assessment .............................................................................................................20 
2.3.2. 
Benefit Assessment .........................................................................................................21 
2.3.3. 
Overall Benefit: Risk Conclusion ...................................................................................21 
3. 
Objectives and [Endpoints and/or Estimands] ..........................................................22 
4. 
Study Design ..................................................................................................................24 
4.1. 
Overall Design ................................................................................................................24 
4.2. 
Scientific Rationale for Study Design ............................................................................24 
4.2.1. 
Participant Input into Design ..........................................................................................25 
4.3. 
Justification for Dose ......................................................................................................25 
4.4. 
End of Study Definition ..................................................................................................25 
5. 
Study Population ...........................................................................................................26 
5.1. 
Inclusion Criteria ............................................................................................................26 
5.2. 
Exclusion Criteria ...........................................................................................................27 
5.3. 
Lifestyle Considerations .................................................................................................28 
5.3.1. 
Meals and Dietary Restrictions .......................................................................................28 
5.3.2. 
Caffeine, Alcohol, and Tobacco .....................................................................................28 
5.3.3. 
Activity ...........................................................................................................................28 
5.4. 
Screen Failures ................................................................................................................28 
5.5. 
Criteria for Temporarily Delaying ..................................................................................28 
6. 
Study Intervention(s) and Concomitant Therapy......................................................29 
6.1. 
Study Intervention(s) Administered................................................................................29 
6.1.1. 
Medical Devices..............................................................................................................30 
6.2. 
Preparation/Handling/Storage/Accountability ................................................................30 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ............................................31 
6.4. 
Study Intervention Compliance ......................................................................................32 
6.5. 
Dose Modification ..........................................................................................................32 
6.5.1. 
Retreatment Criteria ........................................................................................................32 
6.6. 
Continued Access to Study Intervention after the End of the 
Study ...............................................................................................................................32 
6.7. 
Treatment of Overdose ...................................................................................................33 

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6.8. 
Concomitant Therapy .....................................................................................................33 
6.8.1. 
Rescue Medicine .............................................................................................................33 
7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal........................................................................................34 
7.1. 
Discontinuation of Study Intervention ............................................................................34 
7.1.1. 
Liver Chemistry Stopping Criteria..................................................................................34 
7.1.2. 
QTc Stopping Criteria .....................................................................................................34 
7.1.3. 
Temporary Discontinuation ............................................................................................34 
7.1.4. 
Rechallenge .....................................................................................................................34 
7.2. 
Participant Discontinuation/Withdrawal from the Study................................................34 
7.3. 
Lost to Follow up ............................................................................................................34 
7.4. 
Other safety procedures ..................................................................................................34 
8. 
Study Assessments and Procedures.............................................................................36 
8.1. 
Efficacy Assessments .....................................................................................................36 
8.2. 
Safety Assessments .........................................................................................................36 
8.3. 
Adverse Events (AEs), Serious Adverse Events (SAEs), and 
Other Safety Reporting ...................................................................................................37 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE 
Information .....................................................................................................................37 
8.3.2. 
Method of Detecting SAEs .............................................................................................37 
8.3.3. 
Follow-up of SAEs .........................................................................................................37 
8.3.4. 
Regulatory Reporting Requirements for SAEs and SUSARs.........................................37 
8.3.5. 
Pregnancy ........................................................................................................................38 
8.3.6. 
Medical Device Deficiencies ..........................................................................................38 
9. 
Statistical Considerations .............................................................................................39 
9.1. 
Statistical Hypotheses .....................................................................................................39 
9.2. 
Primary Analyses ..........................................................................................................39 
9.2.1. 
Descriptions of Subjective and Physiological Effects ....................................................39 
9.2.2. 
Determining the Preferred Treatment .............................................................................39 
9.2.3. 
Replicating Predictors of Mood Improvements ..............................................................40 
9.3. 
Demographic and Baseline Variables .............................................................................41 
9.4. 
Missing Data ...................................................................................................................41 
9.5. 
Sample Size Determination ............................................................................................41 
9.6. 
Multiple Testing ..............................................................................................................42 
9.7. 
Analysis Sets ...................................................................................................................42 
10. 
Supporting Documentation and Operational Considerations ..................................44 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations ................................................................................................................44 
10.1.1. Regulatory and Ethical Considerations ...........................................................................44 
10.1.2. Financial Disclosure........................................................................................................44 
10.1.3. Informed Consent Process ..............................................................................................44 
10.1.4. Data Protection................................................................................................................45 
10.1.5. Committees Structure......................................................................................................45 
10.1.6. Dissemination of Clinical Study Data.............................................................................45 

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10.1.7. Data Quality Assurance ..................................................................................................45 
10.1.8. Source Documents ..........................................................................................................46 
10.1.9. Study and Site Start and Closure ....................................................................................46 
10.1.10. Publication Policy ...........................................................................................................47 
10.2. 
Appendix 2: Clinical Laboratory Tests ...........................................................................48 
10.3. 
Appendix 3: AEs and SAEs: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .........................................................48 
10.3.1. Definition of AE .............................................................................................................48 
10.3.2. Definition of SAE ...........................................................................................................49 
10.3.3. Definition of SUSAR (suspected unexpected serious adverse 
reaction) ..........................................................................................................................50 
10.3.4. Recording and Follow-UP of SAE and SUSAR .............................................................51 
10.3.5. Reporting of SAEs ..........................................................................................................52 
10.3.6. Reporting of SUSARs .....................................................................................................53 
11. 
References ......................................................................................................................55 
 
 

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1. 
Protocol Summary 
1.1. 
Synopsis 
Protocol Title: Affective effects of opioids on pre-surgery opioids (AFFECT2): a randomized 
double-blind placebo-controlled trial  
A randomized, double-blind placebo-controlled Phase IV study with three drug arms (three doses 
each) in healthy adult surgery patients, to investigate the affective short-term effects of 
morphine, oxycodone, and fentanyl, administered intravenously to the participants before the 
induction of general anesthesia.  
 
Brief Title: Affective effects of pre-surgery opioids 
Rationale: 
Opioid medications are commonly used in many fields and aspects of medicine, in particular for 
the management of surgical and postsurgical pain. In Norwegian hospitals, as a standard 
procedure for anesthesia, an opioid is usually administered to the patients before the hypnotic 
used to induce general anesthesia.  
While opioid analgesics are known to elicit certain side effects as well as pain relief (Angst et al., 
2012), their effects on the patients’ subjective emotional (affective) state are less well described. 
Besides their analgesic effects, opioids are often considered to have beneficial effects on mood 
(such as relieving anxiety or having anti-depressive effects) (Colasanti, Rabiner, Lingford-
Hughes, & Nutt, 2011; Schaffer, Nordahl, Schaffer, & Howe, 2007). 
However, results from a quality control study conducted by our team in surgery patients on the 
operating table, show that the opioid analgesic remifentanil induced only a weak reduction of 
anxiety, and the majority of patients reported feeling worse or equally good, but not better, after 
the infusion. 
On the basis of these open-label findings, we will now conduct a more comprehensive, 
randomised, double-blind placebo-controlled study comparing the affective effects (mood and 
drug specific effects on a verbal numeric rating scale 0-10, see Table 1) induced by three 
commonly used opioid analgesics (morphine, oxycodone and fentanyl) or placebo administered 
before surgery in a clinical setting associated with physiological and psychological acute stress. 
To the best of our knowledge, no study has compared the short-term effects of opioids analgesics 
on emotions, stress response and the sedation level in a clinical (operating theatre) setting. 
As a consequence, contributing to the knowledge on the affective reactions to distinct opioid 
analgesics will provide important information to the clinicians who wish to optimize both pre-
and post-surgery treatments and pain management plans. 
 
 

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Table 1 - Objectives and Endpoints: 
Objectives 
Endpoints 
Assessments 
Primary 
 
 
Describe the subjective 
effects of morphine “Orion”, 
oxycodone “Hameln”, and 
fentanyl “Hameln” (each at 
three different doses: small, 
medium, and large), and 
placebo when administered 
pre-surgery. 
Mean ratings and 
corresponding 95% 
confidence intervals for each 
of the 10 treatment arms for 
the following 10 self-report 
items: 
Subjective state and acute 
subjective drug effects rated 
by the participants on 
numeric rating scales (0 “not 
at all” to 10 “very much”) pre 
and post treatment 
administration. 
Pre and post 
treatment: 
 
Anxious 
 
Relaxed 
 
Pain 
level 
 
Good 
Post treatment 
only: 
 
Dizzy 
 
Sedated 
 
High 
 
Euphoric 
 
Drug liking 
 
Drug 
disliking 
Secondary 
 
 
Determine the preferred 
treatment among the three 
opioids (each at three 
different doses), and placebo 
in terms of beneficial effects 
pre-surgery. 
P-scores (ranking metric) 
based on pairwise differences 
between all 10 treatments 
arms in mean ratings post 
treatment on the following 4 
self-report items: 
 Anxious 
 Relaxed 
 Pain level 
 Good 
Subjective state rated by the 
participants on numeric rating 
scales (0 “not at all” to 10 
“very much”) post treatment 
administration. 
Replicate previous findings 
that prior opioid experience 
and negative affect prior to 
surgery predict improvements 
in mood following 
administration of opioids pre-
surgery. 
 
Changes in ratings of feeling 
good and anxious from pre to 
post treatment, recoded to an 
ordinal scale with the three 
levels “feeling worse” (≥ 1 
point decrease), “feeling the 
same” (no change), and 
“feeling better” (≥ 1 point 
increase). 
Subjective state rated by the 
participants on numeric rating 
scales (0 “not at all” to 10 
“very much”) pre and post 
treatment administration. 

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Exploratory 
 
 
Describe the physiological 
effects of the three opioids 
(each at three different doses) 
when administered pre-
surgery. 
Mean and corresponding 95% 
confidence intervals for each 
of the 10 treatment arms for 
the following 2 physiological 
measures collected pre and 
post treatment: 
 Heart rate 
 Heart rate variability 
ECG collected from the 
participants pre and post 
treatment administration. 
Explore whether changes in 
subjective state from pre to 
post treatment coincide with 
changes in physiological state 
from pre to post treatment 
when the treatment is 
administered pre-surgery. 
Correlations between numeric 
changes in physiological 
measures (heart rate, and 
heart rate variability) from 
pre to post treatment and 
numeric changes in subjective 
state measures (anxious, 
relaxed, pain level, and good) 
from pre to post treatment. 
Subjective state rated by the 
participants on numeric rating 
scales (0 “not at all” to 10 
“very much”) pre and post 
treatment administration. 
 
ECG collected from the 
participants pre and post 
treatment administration. 
 
Brief Summary: 
Patients in this study will undergo surgery according to standard procedure for anaesthesia, in 
which an opioid is given before the hypnotic used to induce general anaesthesia. Specific to this 
study, patients are asked standardized questions about their well-being and affective state before 
and after the administration of the opioid. Participants will be randomized to receive placebo or 
one of three opioids commonly used in surgery settings before the induction of general 
anaesthesia, at one of three equianalgesic doses. The drugs and the placebo will be administered 
intravenously: 
 
 
 
Morphine 
Oxycodone 
Fentanyl 
0.9% NaCl (saline) 
2.5 mg 
2.5 mg 
0.025 mg 
5 mg 
5 mg 
0.05 mg 

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10 mg 
10 mg 
0.1 mg 
 
The scope of the RCT is limited to the pre-operative analgesic administered on the operating 
table, and baseline measures recorded on the operating table immediately before. All other 
anaesthesia and surgery-related procedures will remain unaltered. Administration of medications 
at any other time, e.g. on the morning of the surgery, during the surgery and after the surgery, 
will be unaltered. The use of a placebo for one subgroup of the RCT does not represent a 
deviation from standard clinical care, since many anaesthetists choose not to administer an 
opioid before anaesthesia. Both outpatients and inpatients will be included in the study. 
Based on pilot data and experience from a recent quality control study (Eikemo et al., 2022), we 
expect to enroll 800-1000 participants in total. See analysis plan. 
Note: “Enrolled” means a participant’s agreement to participate in a clinical study following 
completion of the informed consent process. Potential participants who are screened for the 
purpose of determining eligibility for the study, but do not participate in the study, are not 
considered enrolled, unless otherwise specified by the protocol.  
Intervention Groups and Duration: 
Participants will be randomized and allocated to ten different groups, receiving either placebo or 
one of the three study drugs before the start of the induction of general anaesthesia (Figure 1). 
The study starts when the participant enters the day surgery unit or the ward and signs the 
informed consent and ends when the general anaesthesia induction has been conducted. The 
duration of the study following the administration of the randomized drug is no more than 10 
minutes.  
Discontinuation from the study: 
• 
Voluntary withdrawal by the participant (withdrawal of written consent). 
• 
Occurrence of a serious event judged by the investigator. 
Data Monitoring/Other Committee:  
Yes, via Forskningsenheten at Vestre Viken Trust.  

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1.2. 
Schema 
 
Figure 1 – Flow Chart RCT AFFECT2. 
 
 

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Study Timeline 
 
Figure 2. RCT AFFECT timeline.  
 
Baseline before surgery:  
After informed consent, the patients fill in a questionnaire with general demographic and health 
data relevant to surgery (e.g. age, gender, BMI, type of surgery, smoking status).  
In addition, we will collect data on pre-operative pain, depression, anxiety (Hospital Anxiety and 
Depression Scale) and mood. 
 Subjective: a brief questionnaire on their current affective state, pain (items from Brief 
Pain Inventory (BPI) and prior opioid use. Affective state items include feeling “good”,  
“safe”, “anxious”, “upset” and “nervous”. 
 Physiological: After filling in the questionnaire, baseline heart rate variability will be 
recorded during a 10min resting period in the waiting room before drug administration. 
The heart rate equipment will stay in place until the patient is asleep. 
On the operating table pre-surgery:  
 Pre: During the first minutes immediately preceding surgery, we first ask the patient a 
short series of questions about their affective state, e.g. how “good”, “anxious”, “pain”, 
and “relaxed” they feel on a numerical rating scale NRS 0-10. We also record heart rate 
and blood pressure. 

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 Drug administration: Following this, the pre-surgery opioid is administered. In this 
study, we will use a dose of intravenously morphine (2.5 – 5 – 10 mg), oxycodone (2.5 – 
5 – 10 mg) and fentanyl (0.025 – 0.05 – 0.1 mg). In addition, one group receive placebo 
(saline) 
 Post: After drug administration, the patient is asked to indicate when they first feel a drug 
effect, and the time (seconds post-administration) is recorded along with the patient’s 
description of this effect. Next, after a standardized waiting time (2 minutes after the end 
of drug injection, based on a trade-off of minimum discomfort for the patient and the best 
opioid analgesic drug effects of morphine, oxycodone and fentanyl), the study personnel 
ask further questions about the patients’ affective state. In the case that no effect has been 
indicated within the first two minutes, patients are asked if they feel an effect and if so, to 
describe it. The patient is then asked to report on an NRS 0-10, again how “good”, 
“anxious”, “pain”, and “relaxed” they feel on a numerical rating scale NRS 0-10. We also 
measure acute drug effects such as “high”, “liking the effect”, “disliking the effect”, 
“euphoric”, “dizzy”, and “sedated”; partially selected from the Drug Effects 
Questionnaire (DEQ27) commonly used to assess abuse liability of drugs. During the 
RCT data collection we will also record heart rate and heart rate variability (HRV). 
A few patients might experience intense anxiety or distress on the operating table; the 
anaesthesiologist/nurse can make the decision to proceed with the induction of the general 
anesthesia in such cases, skipping the pre/post drug data collection. 

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1.3. 
Schedule of Activities  
 
Procedure 
Intervention Period 
Baseline  
On the operating table ~10 
minutes before anaesthesia 
induction 
On the operating table ~  
immediately before 
anaesthesia induction 
Informed consent 
X 
 
 
Inclusion and exclusion 
criteria 
X 
 
 
Demography 
X 
 
 
Medical history (includes 
substance usage) 
X 
 
 
Past and current medical 
conditions   
X 
 
 
Questionnaires 
X 
 
 
Heart rate variability (10 
minutes) 
X 
 
 
Heart Rate Variability (~ 5 
minutes) 
 
X 
X 
Vital signs 
X 
X 
X 
Randomization (Allocation) 
X 
 
 
Study intervention 
(questionnaire before 
drug/placebo administration) 
 
X 
 
Study intervention 
(questionnaire two minutes 
after drug/placebo 
administration) 
 
 
X 
SAE review 
 
 
X 
 
 

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2. 
Introduction 
Despite having fallen under scrutiny for the enormous consequences of the opioid epidemic, 
opioids medications are still commonly used in many fields and aspects of medicine, in 
particular for surgical and post-surgical pain. While opioid analgesics are known to elicit 
variable degrees of side effects and large variability in individual responses (Angst et al., 2012), 
their effects on the patients’ subjective emotional (affective) state are less well described. As a 
consequence, contributing to the knowledge on the affective reactions to different classes of 
opioid medications in a real clinical setting, such as surgery, will provide important information 
to the clinicians to optimize both pre-and post-surgery treatments and pain management plans, 
and at the same time reducing risks for the patients. 
In Norway, about 60% of planned surgery is a day surgery, totalling 216 395 procedures in 2017 
(Helsedirektoratet, 2018). The most common outpatient procedures in Norwegian hospitals 
include minor orthopedic, abdominal, colorectal, gynecological and otorhinolaryngological 
surgery. The patient group thus spans most of the population, encompassing men and women, 
young and old, people of low and high socioeconomic status (SES), with and without pain, a 
history of trauma or other psychosocial vulnerability risk factors. For many patients, these 
procedures represent their first introduction to opioid drugs, and an unknown proportion of these 
patients go on to develop opioid misuse. 
Opioids analgesics are typically given, before, throughout and after surgery, and patients are 
often discharged with a prescription for opioids to manage their post-surgical pain at home. 
Many commonly prescribed opioids are associated with substantial misuse potential, e.g. 
oxycodone and fentanyl. New clinical data show that the misuse of prescription opioids in 
chronic pain is driven more by a desire for stress relief than by pain itself (McHugh et al., 2016). 
These findings fit with epidemiological studies highlighting stress as a vulnerability factor 
(Stone, Becker, Huber, & Catalano, 2012b). Surgery represents a major stressor at both the 
physiological and psychological level, and pre-surgery stress relief is cited as one benefit of pre-
anaesthesia opioid administration (Doleman et al., 2018).  
Besides analgesic effects, opioids are often considered to have beneficial effects on mood (such 
as relieving anxiety or having anti-depressive effects) (Colasanti et al., 2011; Schaffer et al., 
2007). However, preliminary results from a pilot study conducted by our team on the operating 
table in surgery patients, show that opioid analgesic remifentanil induced only a weak reduction 
of anxiety, and the majority of patients reported feeling worse or equally good, but not better, 
after the infusion. On the basis of these intriguing, preliminary findings, we will now conduct a 
more comprehensive randomized double-blind placebo-controlled study comparing different 
classes of opioid analgesic and their effect on affective states. 
Opioids analgesics can be administered through a variety of drug formulations. Although most of 
the opioids commonly used in analgesia have the common feature of acting on the mu-opioid 
receptor as primary target, large difference between classes of opioids are often seen in clinical 
practice. Indeed, opioids differ markedly in their side effects (Drewes et al., 2013). Some 
patients, for example, appear to respond to certain opioids but are intolerant to others, and 
switching from one class of opioid to another often results in an improvement of symptoms 

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(Dale, Moksnes, & Kaasa, 2011). These clinical observations have led the pain research on 
focusing in particular on physical side effects, and less attention has been given to the affective 
reactions to different classes of opioid medications. 
Morphine, oxycodone and fentanyl are three commonly used opioid compounds which differ in 
chemical structure and pharmacokinetics but share the common mechanism of acting on the mu-
opioid system and are all commonly used in clinical practice in Norway. To the best of our 
knowledge, ours will be the first randomized placebo-controlled study to investigate the affective 
reactions to opioids medications given in an ecological situation of acute stress such as surgery. 
Much of the current knowledge on opioid drug effects – including opioid abuse liability – 
derives from laboratory studies where healthy people are told they can get an active drug or 
placebo and that the (experimental) pain stimuli are temporary and unlikely to cause harm. The 
experimental setting lacks ecological validity and may not generalise to patients undergoing 
complex surgical treatment with take-home opioid drugs. For instance, acute experimental pain 
differs from clinical pain mechanisms (Tracey, Woolf, & Andrews, 2019), where there is real 
tissue damage and uncertainty about when the pain will subside. Moreover, surgery represents a 
major stressor that deeply impacts the systemic stress response at both physiological and 
psychological level. 
It has been shown that opioid analgesics reduce stress responses such as cortisol release 
(Bershad, Miller, Norman, & de Wit, 2018), and reducing pre-surgery stress is considered to be 
one benefit of pre-anaesthesia opioid administration      (Doleman et al., 2018). Although there is 
little research to support such a benefit, administering an opioid a few minutes before anaesthesia 
in order to manage the patient’s stress and to improve postoperative pain is common practice in 
many hospitals in Norway and internationally (Doleman et al., 2018). 
New clinical data examining the contribution of pain and psychological factors in opioid misuse 
behaviour shows that prescription opioid misuse in pain patients is driven more by a desire for 
stress relief than by pain itself (Martel, Dolman, Edwards, Jamison, & Wasan, 2014; McHugh et 
al., 2016). Similarly, high-stress conditions (low socioeconomic status, a history of trauma, 
symptoms of depression or anxiety and poor social support) are all reported to increase the 
vulnerability to adverse post-surgery outcomes (Stone, Becker, Huber, & Catalano, 2012a) and 
risk of opioids misuse. Stress typically increases inflammatory and immune responses, which are 
heightened in people with anxiety (Stone et al., 2012b), depression (Bjerkeset, Romild, Smith, & 
Hveem, 2011; Naude, Roest, Stein, de Jonge, & Doornbos, 2018) and a history of trauma 
(Deighton, Neville, Pusch, & Dobson, 2018). High stress reactivity and reduced ability to 
regulate negative emotional states could thus be key predisposing risk factors of postoperative 
adverse events. The biological mechanisms that link psychosocial factors with these health 
vulnerabilities are still unclear (Garland, Froeliger, Zeidan, Partin, & Howard, 2013). Indeed, 
stress-related measures such as autonomic markers (e.g. heart rate variability; (Sgoifo, Carnevali, 
Alfonso Mde, & Amore, 2015; Thomas & Garland, 2017) are emerging as potential predictors 
and could provide the missing link between psychosocial vulnerability and physical health. 
In this study, we will assess and compare the affective effects of three commonly used opioid 
analgesics (morphine, oxycodone, and fentanyl) administered before surgery in a clinical setting 
associated with physiological and psychological stress. 
 

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2.1. 
Study Rationale 
The aim of the present study is to assess and compare, with a randomized, double-blind placebo-
controlled trial, the affective effects of three commonly used opioid analgesics (Morphine 
«Orion», oxycodone  «Hameln» and fentanyl «Hameln») administered in three different doses 
before surgery in a clinical setting associated with physiological and psychological stress. 
 
2.2. 
Background 
As a starting point, we have conducted an observational quality control study on peri-operative 
opioid pain management in day surgery patients. 
Quality control study – a pilot study 
In this observational quality control study, we measured acute effects of the opioid agonist 
Remifentanil (effect site concentration 5ng/ml, Minto model) in day surgery patients on the 
operating table at Kongsberg hospital. Patients rated their levels of “feeling good” and “anxious” 
on an 0-10 numerical rating scale (NRS) immediately before and 1 minute after receiving 
remifentanil infusion. They also rated drug-specific effects such as “feeling high”, “liking the 
drug effects” and their “level of drug-related discomfort”. Moreover, we collected data on 
postoperative opioid use and pain during recovery through a telephone interview on the day 
following the surgery. The study was conducted with the usual standard hospital treatment and as 
such, did not interfere with the patients’ medical procedures. All the procedures were approved 
by the data protection officer at Kongsberg Hospital, and all included patients signed informed 
consent on the day of surgery. 
Figure 3 gives an overview of the study procedure and Table 3 of the study sample 
characteristics. 
Figure 3. Study timeline of the pilot quality control study. In the weeks prior to surgery (T1) participants received a 
questionnaire to assess their pain levels, nervousness and demographics as part of the hospital’s standard procedure. 
On the day of surgery, approximately 30 min before surgery (T2) patients were asked to fill in questionnaires to 
assess mood, pain and prior opioid use. One minute before and one minute after opioid ( administration (T3), the 
patient was asked to rate mood, anxiety, drug liking and drug related discomfort. On the day following surgery 
patients were contacted by phone to assess their mood, pain and pain interference, as well as their pain relief 
strategies in the last 24h (e.g. use of provided analgesics). 
 

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Table 3. Overview of the sample characteristics of the first 160 patients included in the pilot quality control study. 
Unless otherwise noted, we list mean and standard deviation (SD).  
N 
160 (96 women) 
Age 
46.5 years (14.2) 
Height 
173m (0.1) 
Weight 
80.3kg (15.5) 
Tobacco use 
34 (21.3%) 
Prior opioid use 
103 (64.4%) 
Prior pain (weeks before surgery) 
73 (45.6%) 
Procedure (N) 
Surgical 
74 
 
Orthopedic 
25 
 
Gynecological 
52 
 
Otorhinolaryngological 
4 
 
The results of the pilot study show that patients report a clear feeling of ‘drug high’ after 
remifentanil infusion. Surprisingly, however, the opioid analgesic induced only a weak reduction 
of anxiety, and the majority of patients reported feeling worse or equally good, but not better, 
after the infusion. In the postoperative phone interview, many patients tell us they have not used 
any of the opioid drugs prescribed for at-home pain relief during the first 24 hours are recovering 
at home. Stated reasons include a fear of addiction, as well as a wish to keep the analgesics in 
case of breakthrough/peak pain at a later stage. These preliminary results do not support the 
opioid pre-induction procedure as an effective manner to produce pre-surgery stress relief. It 
might be possible that the subjective perception of stress relief does not match the physiological 
relief reaction to stress. 
On the basis of these intriguing, preliminary findings, we will now conduct a more 
comprehensive randomized double-blind controlled study comparing different classes of pre-
surgical opioid analgesics on the subjective and physiological affective reactions in an acute 
stress clinical situation in Norway. 
Possible participants of the AFFECT2 RCT will also be asked if they wish to join a parallel 
longitudinal study conducted in collaboration with the University of Oslo (UiO) in which we will 
collect and analyse data on relevant pre-surgery risk factors for problematic opioid use, and to 
quantify opioid-induced analgesia before and after surgery using prescription registry data.  
 
2.3. 
Benefit/Risk Assessment 
The induction of anaesthesia is defined as the transition from an awake state to an anaesthetized 
state (Astuto & Lauretta, 2009). In most circumstances, the airway has to be secured with eg. a 
laryngeal mask or by intubation. Induction of anaesthesia is usually achieved with an intravenous 
anaesthetic agent of choice, in our clinic mostly propofol, combined with an opioid and (in case 
of intubation) a nondepolarizing muscle relaxant. While propofol is used to get the patient 
asleep, the role of the opioid is to prevent the hypertensive response to laryngoscopy or the 

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handling of the airway and to block the nociceptive response when surgery is initiated. In case of 
a rather short day surgery operations, a long-acting opioid also contributes to postoperative 
analgesia. All the drugs used for this randomized clinical trial (oxycodone, morphine, fentanyl) 
are strong opioids which are used daily in operating theatres. Fentanyl is frequently used before 
induction, whereas oxycodone and morphine are more frequently used to relieve postoperative 
pain. The relative (analgesic) potency of opioids can be estimated based on the scientific 
literature and is described in dose equivalents of morphine (Natusch, 2012). In this study, we will 
use an equianalgesic dose of intravenously morphine (2.5 – 5 – 10 mg), oxycodone (2.5 – 5 – 10 
mg) and fentanyl (0.025 – 0.05 – 0.1 mg). In addition, one group receive placebo (saline). The 
largest dose is a standard dosage for opioids given prior before anaesthesia inductions. 
2.3.1. 
Risk Assessment 
The participant could have received an opioid in a similar equianalgesic dosage prior to the 
induction of anaesthesia independently of the randomized clinical trial, depending on the 
preferences of the individual anaesthetist. Compared to the standard pre-surgery procedure, the 
main difference in the present trial is represented by the administration of three different class of 
opioids analgesic, all of which have been largely used in clinical setting for several decades. 
Morphine has been on the market since 1827 (Courtwright, 2001; Inglis, 2018), fentanyl was 
approved in 1968 (Stanley, 1992), and oxycodone, although already introduced in 1916 
(Sneader, 2005), was then reintroduced in 1996 (Inglis, 2018). Opioid analgesics generally have 
similar adverse effects. Individual differences may exist due to individual genetic and epigenetic 
differences, e.g. in the composition of opioid receptors, their expression and intracellular 
signaling mechanisms. In clinical practice, it is not possible to predict exactly how a patient will 
respond to a given dose of an opioid drug (Angst et al., 2012), and dose titration is usually based 
on observation of the patient’s response. Common adverse effects can include respiratory 
depression, nausea, low blood pressure, and sedation, beyond others, and the incidence rate of 
the adverse effects of the three compounds is comparable. Patients are routinely monitored 
(blood pressure, ECG, oxygen saturation in the blood) and an anaesthetist and an anaesthetist 
nurse, experienced to handle adverse effects or any airway, respiratory or circulatory problems 
are on stand-by. At the study sites (Kongsberg, Oslo University Hospital) the responsible 
anaesthetists are specialists with more than 10 years’ experience. Postoperatively, as all hospitals 
in Norway, the study sites have an established routine to follow-up patients, to identify early 
potential adverse effects and to handle them, following the Norwegian Standard for 
Anaesthesia1.  
The only major risk is an anaphylactic reaction or shock due to the specific opioid. These 
allergies are rare and possible participants with known allergies to any opioid will be excluded. 
The application of the opioids occurs in an operation theatre with three health professionals (the 
anaesthetist, the anaesthetist nurse, and the study nurse or study physician) experienced in 
                                                 
 
 
 
1 https://www.nafweb.com/dokumenter/norsk-standard-for-anestesi-2016.pdf 

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managing any potential life-threatening events. All necessary equipment is available in the 
surgery setting. In addition, an extra emergency team consisting of two physicians, two specialist 
nurses, and additional staff is available within three minutes. The participants are in overall good 
health and they are fasting. All local and national standard operating procedures regarding 
anaesthesia are followed. At Kongsberg hospital, according to the safety records, no serious 
anaphylactic shock based on opioids has occurred in the last 20 years. In case of very rare 
adverse effects (e.g. allergies, which occur in less than 2% of patients (Li, Ue, Wagner, 
Rutkowski, & Rutkowski, 2017), the clinical staff can unblind the drug at once. Most, if not all, 
adverse effects of opioids receive the same treatment independently of the class of opioid. We 
regard therefore, the risk for serious adverse effects as extremely low and the risk of adverse 
effects which can occur due to the trial (compared to standard treatment) also as extremely low. 
Regarding the use of placebo in one treatment arm, the practice of administering intravenous 
opioid before induction of anaesthesia is highly variable in Norway. The rationale for 
administering before sleep is preparing for intubation/surgery which is painful and/or make the 
patient more relaxed before sleep. On the other hand, some patients will feel dizziness and/or 
itching after intravenous opioid before anaesthesia induction. These side effects are often 
experienced as unpleasant. Therefore, some anaesthesiologists prefer not to administer opioid 
before sleep (as in our placebo group). There is no clear evidence of what practice is best. Our 
study will give a clearer picture of what practice is best: low or high dose of opioid? Or no 
opioid at all before induction of anaesthesia. All patients in the study will receive an opioid at 
latest after sleep induction. 
2.3.2. 
Benefit Assessment 
The individual participant will not have direct benefits from being enrolled in the investigation, 
beyond contributing to the knowledge of opioids which might be relevant for the individual at a 
later time point. This project will help determine which opioid has a relevant impact on how 
patients feel, especially regarding anxiety and physiological stress, and thus should be preferred 
to manage stress and anxiety in clinical settings such as pre and post-surgery treatment and 
palliative care. This knowledge will enable a benefit for future patients.  
 
2.3.3. 
Overall Benefit: Risk Conclusion 
Summarized, opioid administration before anaesthesia induction is part of the standard surgical 
procedure in many hospitals in Norway. Patients participating in the study will receive a 
commonly used opioid in similar doses; however, both the patient and the anaesthetic staff will 
be blinded to the specific type of the opioid drug. A high safety standard, established knowledge 
of the drugs, highly skilled personnel with more than 10 years of expertise, as well as, and the 
immediate possibility to unblind the treatment and to implement established methods to treat 
possible complications, make it highly unlikely that any fatal outcomes or even disadvantages for 
the participants will occur. 

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3. 
Objectives and [Endpoints and/or Estimands] 
 
Objectives 
Endpoints 
Assessments 
Primary 
 
 
Describe the subjective 
effects of morphine “Orion”, 
oxycodone “Hameln”, and 
fentanyl “Hameln” (each at 
three different doses: small, 
medium, and large), and 
placebo when administered 
pre-surgery. 
Mean ratings and 
corresponding 95% 
confidence intervals for each 
of the 10 treatment arms for 
the following 10 self-report 
items: 
Subjective state and acute 
subjective drug effects rated 
by the participants on 
numeric rating scales (0 “not 
at all” to 10 “very much”) pre 
and post treatment 
administration. 
Pre and post 
treatment: 
 
Anxious 
 
Relaxed 
 
Pain 
level 
 
Good 
Post treatment 
only: 
 
Dizzy 
 
Sedated 
 
High 
 
Euphoric 
 
Drug liking 
 
Drug 
disliking 
Secondary 
 
 
Determine the preferred 
treatment among the three 
opioids (each at three 
different doses), and placebo 
in terms of beneficial effects 
pre-surgery. 
P-scores (ranking metric) 
based on pairwise differences 
between all 10 treatments 
arms in mean ratings post 
treatment on the following 4 
self-report items: 
 Anxious 
 Relaxed 
 Pain level 
 Good 
Subjective state rated by the 
participants on numeric rating 
scales (0 “not at all” to 10 
“very much”) post treatment 
administration. 
Replicate previous findings 
that prior opioid experience 
and negative affect prior to 
surgery predict improvements 
in mood following 
administration of opioids pre-
surgery. 
Changes in ratings of feeling 
good and anxious from pre to 
post treatment, recoded to an 
ordinal scale with the three 
levels “feeling worse” (≥ 1 
point decrease), “feeling the 
same” (no change), and 
Subjective state rated by the 
participants on numeric rating 
scales (0 “not at all” to 10 
“very much”) pre and post 
treatment administration. 

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“feeling better” (≥ 1 point 
increase). 
Exploratory 
 
 
Describe the physiological 
effects of the three opioids 
(each at three different doses) 
when administered pre-
surgery. 
Mean and corresponding 95% 
confidence intervals for each 
of the 10 treatment arms for 
the following 2 physiological 
measures collected pre and 
post treatment: 
 Heart rate 
 Heart rate variability 
ECG collected from the 
participants pre and post 
treatment administration. 
Explore whether changes in 
subjective state from pre to 
post treatment coincide with 
changes in physiological state 
from pre to post treatment 
when the treatment is 
administered pre-surgery. 
Correlations between numeric 
changes in physiological 
measures (heart rate, and 
heart rate variability) from 
pre to post treatment and 
numeric changes in subjective 
state measures (anxious, 
relaxed, pain level, and good) 
from pre to post treatment. 
Subjective state rated by the 
participants on numeric rating 
scales (0 “not at all” to 10 
“very much”) pre and post 
treatment administration. 
 
ECG collected from the 
participants pre and post 
treatment administration. 
 

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4. 
Study Design 
 
4.1. 
Overall Design 
Patient enrolment is planned for end of 2022, and the study will be conducted until 1000 
participants are included or until December 2025. The main study centre is Kongsberg 
Hospital, with additional sites at Oslo University Hospital. 
• 
Randomized double-blind study with ten arms 
• 
Placebo-controlled 
• 
Patients scheduled for surgery will be recruited at the outpatient clinic at Kongsberg and 
Oslo University Hospital. Patient groups with severe disease burden or other risks will 
not be enrolled. Consequently, the patients included in this sample are relatively healthy 
individuals. 
• 
Randomization sequences will be generated prior to the first enrolment by a statistician 
not affiliated with the present study at UiO (Kongsberg) and by the Clinical Trials Unit at 
Oslo University Hospital (OUS sites). 
• 
The assignment will be performed by study personnel after the participant has signed the 
consent form, on the day of the surgery 
• 
Participants will be asked to fill in questionnaires before and on the day of surgery. The 
total duration of the study after the administration of the randomized drug is 
approximately 10 minutes. 
• 
Participant will be invited to take part in an observational long-term follow-up study 
independently of the participation in the AFFECT2 RCT. 
 
4.2. 
Scientific Rationale for Study Design 
The main endpoints of this study are the affective effects of three different opioids administered 
pre-surgery.  
 
The study will be conducted as a double-blind placebo-controlled randomized design since it is 
essential that the anaesthesia staff remains blinded to the drug type until completion of the study.  
Effects of the opioids on patients’ affective state are highly relevant in clinical practice. To our 
knowledge, no study has investigated the effects of opioids medications on emotions, stress 
response and the sedation level in pre-surgery setting. We have chosen endpoints to yield 
maximally useful information in the shortest amount of time so that participants will not wait 
long on the operating table before anaesthesia. Questions on mood are primarily asked pre- and 
post-drug administration, to assess how each opioid may shape how “good”, “relaxed”, 
“anxious”, and “pain” participants feel. In addition, 2-4 minutes after drug administration we 
include key questions on drug effects from the Drug Effects Questionnaire (DEQ), commonly 
used to assess abuse liability of drugs (Evans, Foltin, Levin, & Fischman, 1995; Morean et al., 
2013), such as “drug high”, “liking of drug effects” and “disliking of drug effects”. We also 
specifically measure drug-induced euphoria, dizziness and sedation. 

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In combination, these items will allow us to establish a distinct affective effect profile for 
morphine, oxycodone and fentanyl in the pre-surgery setting. We hope that these results will help 
determine future treatments, e.g.: which opioid should a clinician preferably use in patients with 
high anxiety; or which opioid should be used if a patient would benefit from a sedating effect? 
 
This investigation will include a representative group of adult day-surgery and inpatients, which 
enables us to generalize to a broader population.  
4.2.1. 
Participant Input into Design 
The research group at Kongsberg hospital has established a user panel for research questions. 
The panel members contribute to developing relevant research questions, establishing study 
designs, give advice for participant recruitments, discuss results and give advice for the 
implementation of results and information to the public. For the current project, one member of 
the panel has agreed to participate also in the project group. We also collaborate with the user 
council of the Vestre Viken health trust. The current proposal was created based on our 
experiences from conducting a quality control study, including post-surgery phone interviews 
with day surgery patients at Kongsberg hospital (160 patients). The knowledge arising from 
these semi-structured conversations with patients, as well as our clinical interactions in the 
hospital, has informed several aspects of the study design, such as the importance of prior beliefs 
and attitudes about opioid medications and addiction. 
4.3. 
Justification for Dose 
The dosage of opioids given prior to anaesthesia induction varies between 10 mg and 30 mg 
morphine equivalent (Choudhary et al., 2019; Dutta et al., 2018), or even higher (Wang, 
Hermann, & Westrin, 1996). The chosen opioid doses for this study represents a normal dose 
used in these patients´ groups, as well as two lower doses per drug to produce a dose-response 
function. The main function of the pre-induction opioid, when used, is to avoid stress reactions 
by maintaining the airway with intubation or laryngeal mask. All surgeries conducted in the 
study group will provoke little to moderate nociception during operation, higher doses would not 
be used normally to induce anaesthesia. After the induction, the anaesthesia will be continued 
with a steady-state dose of propofol and remifentanil, which will be continually adapted 
according to the observed physiological parameters of the patient. After the induction, when the 
anaesthesia team will be unblinded, they will be aware whether the patient has received a rather 
long-acting opioid (Oxycodone «Hameln» or morphine «Orion»), short-acting one (fentanyl 
«Hameln») or placebo, so that they can adapt the anaesthesia accordingly. The highest dose is 
estimated as effective in patients with an BMI between 18 and 35.  
4.4. 
End of Study Definition 
The end of the study is defined as the end of the anaesthesia induction on the same day.  
A participant is considered to have completed the study if he/she has completed all phases of the 
study, including the interview at pre and post drug just before falling asleep. 

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5. 
Study Population 
5.1. 
Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
Age: 
1. Participants must be 18 years of age or above at the time of signing the informed 
consent. 
Type of Participant and Disease Characteristics: 
2. Health status ASA1 or ASA2 as categorised by a medical doctor at the hospital based 
on medical history, physical examination, laboratory test etc. unrelated to the current 
study. The American Society of Anesthesiologists physical status (ASA-PS) ASA1 and 
ASA2 (ASA1 is defined as “Healthy, non-smoking, no or minimal alcohol use” and 
ASA2 is defined as “Mild diseases only without substantive functional limitations). 
Being eligible for day surgery means participants are overtly healthy as determined by 
clinical staff. 
3. The participant is considered as eligible for the use of fentanyl, morphine and 
oxycodone by a medical doctor at the hospital, based on an overall assessment of the 
psychiatric and somatic condition, used medical drugs, regarding possible interactions 
and contraindications for the use of the study medicaments. 
Weight: 
4. Body weight and body mass index (BMI) within the range 18-35 kg/m2 (inclusive). 
Informed Consent: 
5. Capable of giving signed informed consent as described in Appendix 1 which includes 
compliance with the requirements and restrictions listed in the informed consent form 
(ICF) and in this protocol. 
Other criteria: 
6. Having good verbal communication skills in Norwegian. 
7. Patients undergoing surgery in general anaesthesia: 
a. Planned day surgery: Orthopedic, minor gastrointestinal surgery, gynecological, hand 
and foot surgery, and minor vascular procedures. 
OR 
Inpatients undergoing planned gynecological, minor gastrointestinal, orthopedic surgery 
or other related procedures. 
 
 

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5.2. 
Exclusion Criteria  
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions 
1. Known allergic reactions to morphine, oxycodone,or fentanyl. Known allergic 
reactions to any of the incredients described in the SPC, pt 6.1. 
2. Severe chronic obstructive lung disease,  
3. Cor pulmonale,  
4. Severe bronchial asthma,  
5. Severe respiratory failure with hypoxemia and hypercapnia 
6. Moderate to severe hepatic impairment,  
7. Moderate to severe kidney failure 
8. Acute abdomen 
9. Increased brain pressure 
10. Head trauma 
11. Use of MAO blockers in the last two weeks 
12. Hypovolemia 
13. Hypotension 
14. Myastenia gravis 
15. Any other health status not corresponding to ASA1 or ASA2. This includes patients 
with severe disease burden, major psychiatric disorders that could interefere with the 
procedures and communication.  
16. Pregnancy. Women of childbearing potential defined as all premenopausal female (a 
postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause) will be asked if they are pregnant. 
17. Breastfeeding women. 
18. Prior or ongoing use of illicit drugs like opioids, cocaine and amphetamine. 
 

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5.3. 
Lifestyle Considerations 
5.3.1. 
Meals and Dietary Restrictions 
All the patients included in the AFFECT2 RCT will follow the Standard Operating Procedures 
already in place for at Kongsberg Hospital for all the surgery. Which include: 
1. Refrain from consumption of food six hours before the induction of anaesthesia.  
2. Refrain from beverages two hours before the induction of anaesthesia  
5.3.2. 
Caffeine, Alcohol, and Tobacco 
1. No restrictions beyond 5.3.1 
5.3.3. 
Activity 
1. No restrictions beyond the usual preoperative recommendations. 
5.4. 
Screen Failures 
Not applicable 
5.5. 
Criteria for Temporarily Delaying  
Not applicable 
 

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6. 
Study Intervention(s) and Concomitant Therapy 
Study intervention is defined as any investigational intervention intended to be administered to a 
study participant according to the study protocol. 
6.1. 
Study Intervention(s) Administered 
 
ARM Name 
[1] 
[2] 
[3] 
Intervention 
Name 
Morphine «Orion» 
 
Oxycodone  «Hameln» 
 
Fentanyl «Hameln» 
 
Type  
Drug 
Drug 
Drug 
Dose 
Formulation 
Ampule 
Ampule 
Ampule 
Unit Dose 
Strength(s) 
Placebo 0.9% saline 
2.5 mg 
2.5 mg 
0.025 mg 
5 mg 
5 mg 
0.05 mg 
10 mg 
10 mg 
0.1 mg 
Dosage 
Level(s) 
1 single dose 
1 single dose 
1 single dose 
Route of 
Administratio
n 
IV injection  
IV injection  
IV injection  
Use 
experimental and 
active comparator 
experimental and active 
comparator 
experimental and active 
comparator 
Investigation 
Medicinal 
Product 
IMP  
IMP  
IMP  
Sourcing 
Provided locally by 
the trial site 
Provided locally by the 
trial site 
Provided locally by the 
trial site 
Packaging and 
Labeling 
Study Intervention 
will be provided in a 
syringe labeled with 
Study Intervention will 
be provided in a syringe 
Study Intervention will 
be provided in a syringe 

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the participant 
number 
labeled with the 
participant number 
labeled with the 
participant number 
6.1.1. 
Medical Devices 
 
ECG monitoring (HRV monitoring pre and post opioid administration) 
6.2. 
Preparation/Handling/Storage/Accountability 
 
1. Only participants enrolled in the study will receive study intervention, and only 
authorized site staff will supply or administer study intervention. All study intervention 
must be stored in a secure, environmentally controlled, and monitored (manual or 
automated) area in accordance with the labelled storage conditions with access limited to 
the investigator and authorized site staff. 
2. The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(i.e., receipt, reconciliation, and final disposition records). 
3. Study drugs will be prepared by qualified medical personnel according to the 
randomization protocol at day of the inclusion of the individual participant. The different 
study drugs will be matched visually (e.g. colour) during preparation to ensure full 
blinding. The study drug will be handed out in a syringe labeled with the participant 
number and date in a syringe: 
a) Morphine «Orion» will be diluted to 1 mg/ml  
= 2.5 mg = 2.5 ml + 7.5 ml saline = 10 ml in a 10 ml syringe 
= 5 mg = 5 ml + 5 ml saline = 10 ml in a 10ml syringe 
= 10 mg = 10 ml = 10 ml in a 10 ml syringe 
b) Oxycodone «Hameln» will be diluted to 1 mg/ml 
= 2.5 mg = 2.5 ml + 7.5 ml saline = 10 ml in a 10 ml syringe 
= 5 mg = 5 ml + 5 ml saline = 10 ml in a 10 ml syringe 
= 10 mg = 10 ml = 10 ml in a 10 ml syringe 
c) Fentanyl «Hameln» will be diluted to 0.05mg/ml 
= 0.025 mg = 0.5 ml + 9.5 ml saline = 10 ml in a 10 ml syringe 
= 0.05 mg = 1 ml + 9 ml saline = 10 ml in a 10 ml syringe 
= 0.1 mg = 2 ml + 8 ml saline = 10 ml in a 10 ml syringe 
d) Natriumklorid 9 mg/ml (saline-placebo) = 10 ml syringe 
 
 
 

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6.3. 
Measures to Minimize Bias: Randomization and Blinding 
Table 3. – Randomization plan 
Generation of the 
Randomization 
list  
The randomization list for Kongsberg will be generated by an independent 
statistician of the University of Oslo, not affiliated with this study, and stored on 
TSD.  
Other researchers at UiO who are not involved in the RCT data collection will 
note the results of the allocation sequence and will use opaque, sealed, and 
sequentially numbered envelopes for its concealment. 
Participant´s assignment in sealed, opaque envelopes will be only opened for 
each participant after the study staff obtained consent form and confirmed 
eligibility on the day of the surgery at Kongsberg Hospital. 
At Oslo University Hospital (OUS) an independent unit (CTU, clinical trials unit) 
will perform the randomization and oversee the storage of the code list. CTU 
uses an independent printing house which prints and prepares envelopes with 
drug randomization inside. These opaque envelopes are then delivered to the 
study personnel at OUS.  
Study using Pre-
Coded 
Randomization 
provided to site 
On the inclusion day (day of the surgery), after signing the informed consent, the 
participants will be assigned to one of the interventions accordingly to the 
randomization list, by study personnel. 
Each participant will be assigned a unique number (randomization number) in 
ascending numerical order, which encodes the participant’s assignment to one 
of the arms of the study. 
A nurse or physician who is not part of the study team will open the sealed 
envelope and prepare the pre-surgery intervention.  
Each participant will be dispensed blinded study intervention, labelled with 
his/her unique randomization number, throughout the study. 
The medical staff involved in the administration of the intervention, and the pre 
and post-surgery questions (at baseline, pre- and post drug, see figure 2) will be 
blinded to the treatment assignment. 
Blind Break 
(Envelopes) 
A sealed envelope that contains the study intervention assignment for each 
participant will be provided to the investigator. The sealed envelope will be 
retained by the anaesthesia team. In case of an emergency, the anaesthetist 
has the sole responsibility for determining if unblinding of a participants’ 
intervention assignment is warranted. Participant safety must always be the first 
consideration in making such a determination. If a participant’s intervention 
assignment is unblinded, the sponsor must be notified within 24 hours after 
breaking the blind. Once the study is complete, all envelopes (sealed and 
opened) must be inventoried and returned to the sponsor. 

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Blinded study 
with unblinded 
site study 
personnel who is 
dispensing 
intervention 
Participants will be randomly assigned in a 1:1:1 ratio to receive study 
intervention. Investigators will remain blinded to each participant’s assigned 
study intervention throughout the course of the study. To maintain this blinding, 
an otherwise uninvolved 3rd party will be responsible for the reconstitution and 
dispensation of all study intervention and will endeavor to ensure that there are 
no differences in time taken to dispense following randomization. The study 
personnel will further ensure that all study medication is visually matched during 
the preparation. Only the participants number and no drug-specific code will be 
visible on the vial to the investigators to ensure allocation concealment across 
sessions. 
In the event of a Quality Assurance audit, the auditor(s) will be allowed access to 
unblinded study intervention records at the site(s) to verify that 
randomization/dispensing has been done accurately. 
Sponsor safety staff may unblind the intervention assignment for any participant with an SAE. If 
the SAE requires that an expedited regulatory report be sent to one or more regulatory agencies, 
a copy of the report, identifying the participant’s intervention assignment, may be sent to 
investigators in accordance with local regulations and/or sponsor policy. 
6.4. 
Study Intervention Compliance 
The participants are dosed at the site, they will receive study intervention directly from the 
investigator (anaesthetist or study personnel), under medical supervision. The date and time of 
each dose administered in the clinic will be recorded in the source documents and recorded. The 
dose of study intervention and study participant identification will be confirmed at the time of 
dosing by a member of the study site staff other than the person administering the study 
intervention.  
 
6.5. 
Dose Modification 
Not applicable 
 
6.5.1. 
Retreatment Criteria 
Not applicable 
6.6. 
Continued Access to Study Intervention after the End of the Study 
Not applicable 
 

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6.7. 
Treatment of Overdose 
Interventions if SpO2 < 90% for more than 3 minutes or immediately if SpO2 < 85% or 
respiratory rate < 8: 
1) 
Stimulate patient to achieve respiratory rate > 8 and/or deeper respiratory action. 
2) 
Supplemental oxygen to 2 l/min. 
3) 
Reversal agent: Naloxone® (naloxone) 0.1 mg IV. Repeated every 2-5 minutes until 
response. 
4) 
Bag-mask ventilation and consider other reasons for hypoxemia than opioid effect. 
6.8. 
Concomitant Therapy 
Concomitant therapies would be treated according to the standard surgical procedures at 
Kongsberg Hospital and Oslo University Hospital. Analgesics, anti-inflammatory and anti-
rheumatic drugs, antiepileptics and psychotropic medication (antipsychotic drugs, anxiolytics, 
sedatives and hypnotics, anti-depressants) must be recorded along with: 
1) Reason for use 
2) Dates of administration  
3) Dosage information including dose and frequency 
The Medical Monitor will be contacted if there are any questions regarding concomitant or prior 
therapy. 
 
6.8.1. 
Rescue Medicine 
The study site will not supply rescue medication to patients. Possible rescue medicine (additional 
opioids, others) will be applied by the anaesthetic team immediately. After the anaesthesia 
induction, all patients will receive normal treatments according to the standard operation 
procedures of Kongsberg Hospital or Oslo University Hospital and the individual assessment. 

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7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal 
 
7.1. 
Discontinuation of Study Intervention 
7.1.1. 
Liver Chemistry Stopping Criteria 
Not applicable. 
7.1.2. 
QTc Stopping Criteria 
Not applicable. 
7.1.3. 
Temporary Discontinuation 
Not applicable. 
 
7.1.4. 
Rechallenge 
7.2. 
Participant Discontinuation/Withdrawal from the Study 
 
1. A participant may withdraw from the study at any time at his/her own request or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioral, or 
compliance reasons. This is expected to be uncommon. 
2. The participant will be permanently discontinued both from the study intervention and from 
the study at that time. 
3. If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent. 
 
7.3. 
Lost to Follow up 
Not applicable. 
 
7.4. 
Other safety procedures 
The study is conducted in operation theatres. All the national and local standard operation 
procedures are followed. In detail, during application of the drug, an anaesthetist specialist and 
an anaesthetist nurse is conducting the anaesthesia procedure. In addition, an anaesthetist 
specialist or an anaesthetist nurse is conducting the study. In addition, an emergency team 
consisting of an additional anaesthetist specialist, an intensive nurse, an anaesthetist nurse, and 
an internal medicine specialist is available and on place within 5 minutes. Kongsberg hospital 

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and Oslo University Hospital have fully equipped intensive care units with possibilities for 
respiratory treatment and circulatory resuscitation.  
All three medicaments are use daily in the hospitals and are registered several decades. Serious 
adverse effects (usually in higher dosages) include respiratory depression, and circulatory 
adverse effects, which are under control in this setting. As part of postoperative care, a 
standardized postoperative surveillance is used. An extremely rare serious adverse effect is an 
anaphylactic reaction. In this case, both the anaesthesia team, the study team and the emergency 
team are highly experienced to manage anaphylactic shock. In addition are patients excluded 
who have a relevant history of anaphylactic reactions.  
Minor adverse effects include dizziness, nausea, itch, and urine retention. These are typical 
adverse effects with a moderate incidence and would happen independent of the study. The 
standard operation procedures from Vestre Viken HF and Kongsberg hospital will be followed in 
this case, or similar standard procedures from Oslo University Hospital (OUS) for OUS sites. 
Summarized will the study be conducted in a high security setting. It is highly unlikely that up to 
now unknown serious adverse effects will occur. Known possible serious adverse effects will be 
managed on specialist level and deleterious outcomes are highly unlikely. Minor adverse effects 
will be managed according to the standard operation procedures. All patients would in any case 
receive one of the three opioids, independent of the study. 

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8. 
Study Assessments and Procedures 
4. Study procedures and their timing are summarized in the SoA. Protocol waivers or 
exemptions are not allowed. 
5. Immediate safety concerns will be discussed with the sponsor immediately upon occurrence 
or awareness to determine if the participant should continue or discontinue study 
intervention. 
6. Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct. 
7. All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
8. Procedures conducted as part of the participant’s routine clinical management (e.g., blood 
count) and obtained before signing of the ICF may be utilized for screening or baseline 
purposes provided the procedures met the protocol-specified criteria and were performed 
within the time frame defined in the SoA. 
8.1. 
 Efficacy Assessments 
Not applicable. 
8.2. 
Safety Assessments 
Planned time points for all safety assessments are provided in the SoA. 
● Each patient is in the study period (after admission to the hospital day surgery unit until 
the anaesthesia conduction) under close observation of intensive care nurses, the study 
personnel and the anaesthesia team consisting of a senior anaesthetist and an anaesthetist 
nurse. 
● Each patient will be monitored before the study drugs are applied with ECG, oxygen 
saturation and intermittent blood pressure (every 3rd minute) according to the standard 
operation procedure of Kongsberg hospital or Oslo University Hospital based on the 
Norwegian standard for anaesthesia. 
● Postoperatively, patients will be monitored with ECG, oxygen saturation and intermittent 
blood pressure (every 5th to 10th minute) according to the standard operation procedure 
for postoperative treatment of Kongsberg hospital or Oslo University Hospital, again 
based on the Norwegian standard for anaesthesia. 
● In addition, all Serious Adverse Events (SAEs) will be continuously monitored by the 
anaesthetists and the study personnel. The sponsors medical officer will review all SAEs 
and evaluate whether the event is expected according to the reference safety information 
(RSI). The Summary of Product Characteristics will be used as RSI in this trial. All 
SUSARs will be reported to the Norwegian Medical Agency within 7/15 days by the 
medical officer. 
 

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8.3. 
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other 
Safety Reporting 
The investigator is responsible for the detection and documentation of events meeting the criteria 
and definition of a serious adverse event (SAE). Each patient will be instructed to contact the 
investigator immediately should they manifest any signs or symptoms they perceive as serious. 
The definitions of adverse events (AEs) and serious adverse events (SAEs) can be found in 
Appendix 3. 
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. 
Since all drugs are being used in several decades, and based on the advice of the Norwegian 
Medicines Agency, AEs will not be reported.  
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an SAE and remain responsible for following up. 
The method of recording, evaluating, and assessing causality of SAEs and the procedures for 
completing and transmitting SAE reports are provided in Appendix 3. 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE Information 
All SAEs will be collected from the start of intervention until the end of the study (when 
anaesthesia induction begins. 
Medical occurrences that begin before the start of study intervention but after obtaining informed 
consent will be recorded as Medical History/Current Medical Conditions, not as AEs. 
All SAEs will be recorded and reported to the sponsor or designee immediately and under no 
circumstance should this exceed 24 hours, as indicated in Appendix 3. The investigator will 
submit any updated SAE data to the sponsor within 24 hours of it being available. 
8.3.2. 
Method of Detecting SAEs 
Care will be taken not to introduce bias when detecting SAEs. Open-ended and non-leading 
verbal questioning of the participant is the preferred method to inquire about SAE occurrences. 
8.3.3. 
Follow-up of SAEs 
After the initial SAE report, the investigator is required to proactively follow each participant at 
subsequent visits/contacts. All SAEs, will be followed until resolution, stabilization, or the event 
is otherwise explained. Further information on follow-up procedures is provided in Appendix 3. 
8.3.4. 
Regulatory Reporting Requirements for SAEs and SUSARs 
9. Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a 
study intervention under clinical investigation are met. 

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10. The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, Institutional Review Boards (IRB)/Independent Ethics 
Committees (IEC), and investigators. 
11. An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (e.g., summary or listing of SAEs) from the sponsor will review 
and then file it along with the Investigator’s Brochure and will notify the IRB. 
12. Suspected unexpected serious adverse reactions (SUSAR) will be reported through the 
EudraVigilance (EVCTM) system according to directive 2001/20/EC or regulation 
536/2014 (https://www.ema.europa.eu/en/human-regulatory/research-
development/pharmacovigilance/eudravigilance) 
13. In addition, the sponsor will send every year a report according to the requirements of the 
Norwegian Medicines Agency 2 
8.3.5. 
Pregnancy 
Not relevant 
 
8.3.6. 
Medical Device Deficiencies 
Not applicable 
                                                 
 
 
 
2Rapportering for kliniske studier - Legemiddelverket 

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9. 
Statistical Considerations 
9.1. 
Statistical Hypotheses 
This RCT explores the subjective effects profiles of opioids commonly administered pre-surgery. 
Acute administration of opioids pre-surgery can produce positive and negative subjective effects 
that may or may not be beneficial. The quality and intensity of these subjective effects could 
depend on the opioid type and dose, as well as certain participant characteristics. The aim of the 
analysis plan for this RCT is therefore threefold: 
1) To describe the subjective effects of morphine, oxycodone and fentanyl (each at three 
different doses: small, medium, and large) when administered pre-surgery. 
2) To determine the preferred treatment among morphine, oxycodone and fentanyl (each at 
three different doses: small, medium, and large), and placebo in terms of beneficial 
effects pre-surgery (i.e., feeling more relaxed, feeling less anxious, experiencing less 
pain, and feeling better). 
3) To replicate previous findings that prior opioid experience and negative affect prior to 
surgery predict improvements in mood (e.g., feeling better or less anxious) following 
administration of opioids pre-surgery. 
 
9.2. 
Primary Analyses 
9.2.1. 
Descriptions of Subjective and Physiological Effects 
To describe the subjective and physiological effects of morphine, oxycodone, and fentanyl, we 
will plot dose-response curves for each of the 10 subjective effect measures (good, anxious, 
relaxed, pain, dizzy, sedated, high, euphoric, drug liking, drug disliking) and two physiological 
measures (heart rate and heart rate variability) collected post treatment. The dose levels will be 
(in increasing order) placebo, small (2.5 mg morphine or oxycodone; 0.025 mg fentanyl), 
medium (5 mg morphine or oxycodone; 0.05 mg fentanyl), and large (10 mg morphine or 
oxycodone; 0.1 mg fentanyl). For measures that are collected both pre and post treatment 
administration (i.e., good, anxious, relaxed, pain level), scores observed pre treatment will be 
included in the plots for reference. The dose-response curves will display the mean subjective 
rating or physiological level and corresponding 95% confidence interval at each dose level.  
To explore whether changes in subjective state coincide with changes in physiological state, we 
will also compute correlation coefficients between numeric changes in physiological measures 
from pre to post treatment and numeric changes in subjective effects measures from pre to post 
treatment.  
 
9.2.2. 
Determining the Preferred Treatment 
A common analytic approach to multi-arm RCTs is to conduct pairwise comparisons between 
treatment arms (Baron, Perrodeau, Boutron, & Ravaud, 2013). However, ranking treatments 

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based on pairwise comparisons becomes increasingly complex as more treatment arms and 
outcome measures are added to the study design (Juszczak, Altman, Hopewell, & Schulz, 2019). 
Fortunately, methods for ranking treatments have been developed in the context of network 
meta-analysis (Rücker & Schwarzer, 2015). These methods can generate treatment hierarchies 
based on a single or multiple outcome measures (Mavridis, Porcher, Nikolakopoulou, Salanti, & 
Ravaud, 2020) and can easily be applied to multi-arm RCTs. 
Network meta-analysis is a statistical method for combining data from individual studies into a 
connected network of multiple treatments of interest. This enables ranking of each treatment 
according to its estimated effect relative to all other treatments in the network. The 10 parallel 
treatment arms in this RCT form a network with 45 possible direct pairwise comparisons 
between treatment arms. To rank these treatments in terms of beneficial effects on subjective 
well-being, we will use an adaptation of network meta-analysis ranking methods. The analysis 
yields a ranking metric (P-score) per treatment, which can range from 0 (worst) to 1 (best) and 
reflects the average certainty that a particular treatment is superior to any of the other treatments 
in the network (Rücker & Schwarzer, 2015; Salanti et al., 2022). The treatment with the highest 
P-score is therefore considered the preferred treatment among the treatments in the network. P-
scores account for both the magnitude and certainty of the difference in outcome between 
treatments. They can also be adjusted to account for numeric thresholds for clinical significance. 
Importantly, P-scores can be calculated to represent rankings on a single outcome measure or on 
multiple outcome measures (Mavridis et al., 2020). We will calculate a single P-score for each 
treatment arm based on the following four subjective effects measures: Anxious, relaxed, level of 
pain, and good. 
 
9.2.3. 
Replicating Predictors of Mood Improvements 
Results from a recent observational study conducted at Kongsberg Hospital indicate that prior 
opioid exposure and negative affect prior to surgery significantly predict mood improvements 
(i.e., feeling good) following administration of the opioids remifentanil and oxycodone pre-
surgery (Eikemo et al., 2022). To determine whether these findings replicate with the opioids 
used in this RCT, we will conduct ordinal logistic regressions similar to those reported in 
Eikemo et al. (2022). The outcome variables in these analyses will be changes in ratings of 
feeling good and anxious from pre to post treatment, recoded to an ordinal scale with the three 
levels “feeling worse” (≥ 1 point decrease), “feeling the same” (no change), and “feeling better” 
(≥ 1 point increase).  
Main predictors of interest (i.e., prior opioid experience and negative affect prior to surgery) will 
be evaluated individually in separate analyses. Negative affect prior to surgery will be entered as 
a continuous predictor with a possible range of 0-10. Prior opioid experience will be entered as a 
categorical predictor with the three levels “opioid naïve” (i.e., no prior opioid use), “some 
experience” (i.e., prior opioid use lasting ≤ 2 weeks), and “prolonged use” (i.e., prior opioid use 
lasting > 2 weeks). The models will include treatment, sex, and age as covariates. The replication 
analyses will only include the opioid arms of the RCT. 

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We will also conduct various sensitivity analyses and exploratory analyses. Because the doses 
used in this RCT are fixed, we will run models with weight as an additional predictor to assess 
whether participants’ weight contributes to variation in mood improvements with opioids. We 
will also run models that allow for interaction between treatment and the main predictor of 
interest. These models will include the placebo arm and will address whether the effect of prior 
opioid use or negative affect on mood improvement following treatment administration differs 
between treatment drugs. 
The statistical significance of marginal main and interaction effects in these models will be 
assessed with likelihood ratio chi-squared (LR χ2) tests. 
 
9.3. 
Demographic and Baseline Variables 
Summary statistics for a range of demographic and baseline variables (e.g., health status, surgical 
procedures, resting heart rate, prior and concomitant medications, age, gender, and pain 
measures) will be produced. Continuous variables will be summarized using the following 
descriptive statistics: n (non-missing sample size), mean, standard deviation, median, maximum, 
and minimum where relevant. The frequency and percentages (based on the non-missing sample 
size) of observed levels will be reported for all categorical measures. 
 
9.4. 
Missing Data 
For the primary outcomes, a table or graph showing the percentage of missing data will be 
produced. We assume little drop-out and missing data based on implementing a similar 
procedure in more than 200 participants in a quality assurance study (Eikemo et al., 2022). 
Missing data will be handled by means of listwise deletion on an analysis-by-analysis basis to 
minimize data loss across analyses. 
 
9.5. 
Sample Size Determination 
The expected sample size for this RCT was determined primarily by logistical factors. The 
sample in this RCT is a convenience sample and the final sample size depends on the recruitment 
and testing capacity at each of the two study sites throughout the duration of the RCT. Based on 
pilot data and experience from a recent quality control study (Eikemo et al., 2022), we expect to 
enroll 800-1000 participants in total. 
We conducted power analyses to assess the minimum effect size we would likely be able to 
detect with the planned analyses and expected sample size. These calculations were done in R (R 
Core Team, 2021) and used an unadjusted alpha level of 0.05. With approximately 80 
participants in each treatment arm, power analysis with the function pwr.t2n.test from the pwr 
package (Champely, 2020) indicates that we would have 90% power to detect a Cohen’s d of 
0.52 in pairwise comparisons (t-tests) between treatment arms. Power analysis for ordinal 

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logistic regressions were implemented using the function popower from the Hmisc package 
(Harrell Jr, 2021). These calculations were based on frequencies of opioid use and anxiety as 
well as estimated marginal probabilities of mood improvements in a previous observational study 
(Eikemo et al., 2022). With approximately 720 participants receiving an opioid drug, we would 
have 90% power to detect 1.59-2.03 times greater odds of ≥ 1 point mood improvement (i.e., 
increase in feeling good or decrease in feeling anxious) for participants with more relative to less 
prior opioid experience or negative affect. 
 
9.6. 
Multiple Testing  
This RCT is primarily exploratory. Corrections for multiple testing will only be applied in 
analyses evaluating the replicability of results from exploratory analyses in a previous 
observational study (Eikemo et al., 2022). This set of analyses consists of three LR χ2 tests of 
interest. These tests assess the statistical significance of the marginal main effects of 1) prior 
opioid experience on change in feeling good, 2) prior negative affect on change in feeling good, 
and 3) prior negative affect on change in feeling anxious. The tests will be grouped into families 
according to the outcome variable (i.e., change in feeling good and change in feeling anxious) 
and Bonferroni correction will be applied within each family. As such, the adjusted alpha levels 
for significant predictors in analyses of change in feeling good and change in feeling anxious 
will be 0.025 (k = 2) and 0.05 (k = 1), respectively. 
 
9.7. 
Analysis Sets 
For the purposes of analysis, the following analysis sets are defined: 
Participant Analysis Set 
Description 
Randomized 
All participants allocated to the randomization list after informed 
consent 
Evaluable 
All participants with at least one item on baseline and pre/post drug 
Safety 
All randomized participants who are exposed to study intervention. 
Participants will be analyzed according to the intervention they actually 
received. The statistician conducting the analysis will be blinded to the 
study manipulation. 
 
Defined Analysis Data Sets 
Description 
Analysis set for primary 
estimand 
All randomized participants. Participants who discontinue study 
intervention are included up to the point of discontinuation, unless they 
withdraw their consent for already collected data points. 

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Analysis for secondary 
parameters 
All randomized participants. Participants who discontinue study 
intervention are included up to the point of discontinuation, unless they 
withdraw their consent for already collected data points. 

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10. 
Supporting Documentation and Operational Considerations 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations 
10.1.1. 
Regulatory and Ethical Considerations 
14. This study will be conducted in accordance with the protocol and with the following: 
 Consensus ethical principles derived from international guidelines including the Declaration of Helsinki 
and Council for International Organizations of Medical Sciences (CIOMS) International Ethical 
Guidelines 
 Applicable ICH Good Clinical Practice (GCP) Guidelines 
 Applicable laws and regulations 
15. The protocol, protocol amendments, ICF, SmPC, questionnaires and other relevant 
documents are submitted to an IRB/IEC by the investigator and reviewed and will be 
approved by the IRB/IEC before the study is initiated. 
16. Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants.  
17. Protocols and any substantial amendments to the protocol will require health authority 
approval prior to initiation except for changes necessary to eliminate an immediate hazard 
to study participants. 
18. The investigator will be responsible for the following: 
 Providing written summaries of the status of the study to the IRB/IEC annually or more frequently in 
accordance with the requirements, policies, and procedures established by the IRB/IEC 
 Notifying the IRB/IEC of SAEs or other significant safety findings as required by IRB/IEC procedures 
 Providing oversight of the conduct of the study at the site and adherence to requirements of 21 CFR, ICH 
guidelines, the IRB/IEC, European regulation 536/2014 for clinical studies, and all other applicable local 
regulations. 
10.1.2. 
Financial Disclosure 
Not applicable. 
10.1.3. 
Informed Consent Process 
 
19. The investigator or his/her representative will explain the nature of the study to the 
participant and answer all questions regarding the study. 
20. Participants must be informed that their participation is voluntary. Participants will be 
required to sign a statement of informed consent that meets the requirements of 21 CFR 50, 
local regulations, ICH guidelines, Health Insurance Portability and Accountability Act 
(HIPAA) requirements, where applicable, and the IRB/IEC or study center. 

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21. The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF. 
22. Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study. 
23. A copy of the ICF(s) must be provided to the participant. 
10.1.4. 
Data Protection 
 
24. Participants will be assigned a unique identifier by the sponsor. Any participant records or 
datasets that are transferred to the sponsor will contain the identifier only; participant names 
or any information which would make the participant identifiable will not be transferred. 
25. The participant must be informed that his/her personal study-related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant who will be required to give consent for their data to be used as 
described in the informed consent  
26. The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
10.1.5. 
Committees Structure 
Study monitoring will be based on the risk assessment and will be performed by 
Forskningsenheten at Vestre Viken Trust for Kongsberg and Oslo University Hospital sites.  
10.1.6. 
Dissemination of Clinical Study Data 
10.1.7. 
Data Quality Assurance 
 
27. All participant data relating to the study will be recorded on printed or electronic CRF 
unless transmitted to the sponsor or designee electronically (e.g., laboratory data). The 
investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF. 
28. Guidance on completion of CRFs will be provided in an standard operation procedure 
provided to the study personnel. 
29. The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
30. Quality tolerance limits (QTLs) will be pre-defined in the monitoring plan to identify 
systematic issues that can impact participant safety and/or reliability of study results. These 
pre-defined parameters will be monitored during the study and important deviations from 
the QTLs and remedial actions taken will be summarized in the clinical study report. 

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31. Monitoring details describing strategy (e.g., risk-based initiatives in operations and quality 
such as Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site monitoring) 
are provided in the monitoring plan. 
32. The sponsor is responsible for the data management of this study including quality checking 
of the data. 
33. Records and documents, including signed ICFs, pertaining to the conduct of this study must 
be retained by the investigator for five years after study completion unless local regulations 
or institutional policies require a longer retention period. No records may be destroyed 
during the retention period without the written approval of the sponsor. No records may be 
transferred to another location or party without written notification to the sponsor. 
10.1.8. 
Source Documents 
 
34. Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site. 
35. Data reported on the CRF that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained. The investigator may 
need to request previous medical records or transfer records, depending on the study. Also, 
current medical records must be available. 
36. The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
37. Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study 
is being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements. 
10.1.9. 
Study and Site Start and Closure 
First Act of Recruitment 
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
Study Termination 
The sponsor reserves the right to terminate the study at any time for any reason at the sole 
discretion of the sponsor.  
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any contract research organization(s) 
used in the study of the reason for termination or suspension, as specified by the applicable 
regulatory requirements.  

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10.1.10. 
Publication Policy 
 
38. The results of this study may be published or presented at scientific meetings 
39. The sponsor will comply with the requirements for publication of study results.  
40. Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 
 
 

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10.2. 
Appendix 2: Clinical Laboratory Tests 
 Not applicable. 
 
10.3. 
Appendix 3: AEs and SAEs: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting 
10.3.1. 
Definition of AE 
Note that AEs will not be registered in this study. The definition of AE is added to make the 
distinction to SAEs and SUSAR clear. 
AE Definition 
41. An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention. 
42. NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of study intervention. 
Definition of Unsolicited and Solicited AE 
43. An unsolicited adverse event is an adverse event that was not solicited using a Participant 
Diary and that is communicated by a participant who has signed the informed consent. 
Unsolicited AEs include serious and non-serious AEs. 
44. Potential unsolicited AEs may be medically attended (i.e., symptoms or illnesses 
requiring a hospitalisation, or emergency room visit, or visit to/by a health care provider). 
The participant will be instructed to contact the site as soon as possible to report 
medically attended event(s), as well as any events that, though not medically attended, are 
of participants concern. Detailed information about reported unsolicited AEs will be 
collected by qualified site personnel and documented in the participant’s records.. 
 
 
Events Meeting the AE Definition 
45. Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (e.g., ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the investigator (i.e., not related to progression of underlying 
disease). 
46. Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 

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47. New conditions detected or diagnosed after study intervention administration even though 
it may have been present before the start of the study. 
48. Signs, symptoms, or the clinical sequelae of a suspected intervention- intervention 
interaction. 
49. Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-harming 
intent. Such overdoses should be reported regardless of sequelae. 
50. The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be 
reported as AE or SAE if they fulfill the definition of an AE or SAE. “Lack of efficacy” 
or “failure of expected pharmacological action” also constitutes an AE or SAE. 
 
Events NOT Meeting the AE Definition 
51. Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition. 
52. The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition. 
53. Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that leads 
to the procedure is the AE. 
54. Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
55. Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
10.3.2. 
Definition of SAE 
A SAE is defined as any serious adverse event that, at any dose: 
a. Results in death 
b. Is life-threatening 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, which 
hypothetically might have caused death, if it were more severe. 
c. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
56. In general, hospitalization signifies that the participant has been admitted (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 

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outpatient setting. Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious. 
57. Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE. 
d. Results in persistent or significant disability/incapacity 
58. The term disability means a substantial disruption of a person’s ability to conduct normal 
life functions. 
59. This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and 
accidental trauma (e.g., sprained ankle) which may interfere with or prevent everyday life 
functions but do not constitute a substantial disruption. 
e. 
Is a congenital anomaly/birth defect 
f. 
Is a suspected transmission of any infectious agent via an authorised medicinal product] 
g. Other situations: 
60. Medical or scientific judgment should be exercised by the investigator in deciding 
whether SAE reporting is appropriate in other situations such as significant medical 
events that may jeopardize the participant or may require medical or surgical intervention 
to prevent one of the other outcomes listed in the above definition. These events should 
usually be considered serious. 
es of such events include invasive or malignant cancers, intensive treatment for allergic 
spasm, blood dyscrasias, convulsions or development of intervention dependency or 
tion abuse. 
 
10.3.3. 
Definition of SUSAR (suspected unexpected serious adverse reaction) 
 
A SUSAR is defined as any serious adverse event that, at any dose: 
a. Results in death 
b. Is life-threatening 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, which 
hypothetically might have caused death, if it were more severe. 

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c. Requires inpatient hospitalization or prolongation of existing 
hospitalization 
61. In general, hospitalization signifies that the participant has been admitted (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious. 
62. Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE. 
d. Results in persistent or significant disability/incapacity 
63. The term disability means a substantial disruption of a person’s ability to conduct normal 
life functions. 
64. This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and 
accidental trauma (e.g., sprained ankle) which may interfere with or prevent everyday life 
functions but do not constitute a substantial disruption. 
e. Is a congenital anomaly/birth defect 
f. Is a suspected transmission of any infectious agent via an authorised medicinal 
product] 
g. Other situations: 
65. Medical or scientific judgment should be exercised by the investigator in deciding 
whether SAE reporting is appropriate in other situations such as significant medical 
events that may jeopardize the participant or may require medical or surgical intervention 
to prevent one of the other outcomes listed in the above definition. These events should 
usually be considered serious. 
es of such events include invasive or malignant cancers, intensive treatment for allergic 
spasm, blood dyscrasias, convulsions or development of intervention dependency or 
tion abuse. 
10.3.4. 
Recording and Follow-UP of SAE and SUSAR  
 
SAE and SUSAR Recording 
1. When a SAE or SUSAR occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory reports, and diagnostics 
reports) related to the event. 

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2. The investigator will then record all relevant SAE or SUSAR information. 
3. The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the SAE or SUSAR. 
Assessment of Causality 
1. The investigator is obligated to assess the relationship between study intervention and 
each occurrence of each SAE/SUSAR. 
2. A “reasonable possibility” of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot be 
ruled out. 
3. The investigator will use clinical judgment to determine the relationship. 
4. Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated. 
5. The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment. 
6. For each SAE or SUSAR, the investigator must document in the medical notes that 
he/she has reviewed the SAE and has provided an assessment of causality. 
7. The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE or SUSAR follow-up report with the updated causality 
assessment. 
8. The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
Follow-up of SAEs and SUSARs 
1. The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated to elucidate the nature and/or 
causality of the SAE or SUSAR as fully as possible. This may include additional 
laboratory tests or investigations, histopathological examinations, or consultation with 
other health care professionals. 
2. New or updated information will be recorded in the originally submitted documents. 
 
10.3.5. 
Reporting of SAEs 
 
SAE Reporting to the sponsor and study monitor via Paper Data Collection Tool 
3. Facsimile transmission of the SAE paper data collection tool is the preferred method to 
transmit this information to the sponsor and study monitor 

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10.3.6. 
Reporting of SUSARs 
 
SUSAR Reporting to the sponsor and study monitor via Paper Data Collection Tool 
The initial SUSAR report must contain at least the following information: 
4. Valid EudraCT number 
5. Sponsor study number, (e.g. REK reference number) 
6. One identifiable coded subject  
7. One identifiable reporter 
8. One SUSAR 
9. One suspect IMP 
The initial SUSAR report should contain in addition: 
 A full description of the event (or if all the information is not available at the 
time of the initial report, this could be included in the follow-up), including 
the event start date, whether or not it is resolved and, if resolved, the date of 
resolution 
 Any relevant medical history or relevant concurrent conditions that are not 
already listed as part of the  
 event 
 An assessment of seriousness and expectedness 
 Dates that the suspected drug was administered to the subject, and whether 
any changes to  
 administration have been made as a result of the event (such as ceasing the 
medication, or changing the dose) 
 Details of any concomitant medications 
 In the case of death, the date and cause of death 
 Receipt date of the information from the investigator 
 Whether the report is an initial report or a follow-up report 
10. The first report has to be submitted within 7 days 
11. The Follow-Up report has to be issued within 15 days. 
12. Facsimile transmission of the SAE/SUSAR paper data collection tool is the preferred 
method to transmit this information to the sponsor, study monitor, and authorities. 

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13. The authorities to be reported are the Norwegian Board of Health Supervision (Statens 
helsetilsyn) and the Norwegian Medicines Agency (Statens legemiddelverk). 
  
 
 
Appendix 10: Protocol Amendment History 
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC). 
Amendment [amendment number]:  
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
Overall Rationale for the Amendment 
 
Section # and Name 
Description of Change 
Brief Rationale 
 
 
 
 
 
 
 
 
 

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11. 
References 
 
Angst, M. S., Lazzeroni, L. C., Phillips, N. G., Drover, D. R., Tingle, M., Ray, A., . . . Clark, J. 
D. (2012). Aversive and reinforcing opioid effects: a pharmacogenomic twin study. 
Anesthesiology, 117(1), 22-37. doi:10.1097/ALN.0b013e31825a2a4e 
Astuto, M., & Lauretta, D. (2009). Anesthesia Induction. In M. Astuto (Ed.), Basics (pp. 85-99). 
Milano: Springer Milan. 
Baron, G., Perrodeau, E., Boutron, I., & Ravaud, P. (2013). Reporting of analyses from 
randomized controlled trials with multiple arms: a systematic review. BMC Medicine, 
11(1), 84. doi:10.1186/1741-7015-11-84 
Bershad, A. K., Miller, M. A., Norman, G. J., & de Wit, H. (2018). Effects of opioid- and non-
opioid analgesics on responses to psychosocial stress in humans. Horm Behav, 102, 41-
47. doi:10.1016/j.yhbeh.2018.04.009 
Bjerkeset, O., Romild, U., Smith, G. D., & Hveem, K. (2011). The associations of high levels of 
C-reactive protein with depression and myocardial infarction in 9258 women and men 
from the HUNT population study. Psychol Med, 41(2), 345-352. 
doi:10.1017/s0033291710000887 
Champely, S. (2020). pwr: Basic Functions for Power Analysis (Version 1.3-0).  
Choudhary, P., Dutta, A., Sethi, N., Sood, J., Rai, D., & Gupta, M. (2019). Pre-induction 
fentanyl dose-finding study for controlled hypotension during functional endoscopic 
sinus surgery. Indian J Anaesth, 63(8), 653-659. doi:10.4103/ija.IJA_866_18 
Colasanti, A., Rabiner, E. A., Lingford-Hughes, A., & Nutt, D. J. (2011). Opioids and anxiety. J 
Psychopharmacol, 25(11), 1415-1433. doi:10.1177/0269881110367726 
Courtwright, D. T. (2001). Dark Paradise: A History of Opiate Addiction in America. Cambridge 
MA: Harvard University Press. 
Dale, O., Moksnes, K., & Kaasa, S. (2011). European Palliative Care Research Collaborative 
pain guidelines: Opioid switching to improve analgesia or reduce side effects. A 
systematic review. Palliat Med, 25(5), 494-503. doi:10.1177/0269216310384902 
Deighton, S., Neville, A., Pusch, D., & Dobson, K. (2018). Biomarkers of adverse childhood 
experiences: A scoping review. Psychiatry Res, 269, 719-732. 
doi:10.1016/j.psychres.2018.08.097 
Doleman, B., Leonardi-Bee, J., Heinink, T. P., Bhattacharjee, D., Lund, J. N., & Williams, J. P. 
(2018). Pre-emptive and preventive opioids for postoperative pain in adults undergoing 
all types of surgery. Cochrane Database Syst Rev, 12, Cd012624. 
doi:10.1002/14651858.CD012624.pub2 
Drewes, A. M., Jensen, R. D., Nielsen, L. M., Droney, J., Christrup, L. L., Arendt‐Nielsen, L., . . 
. Dahan, A. (2013). Differences between opioids: pharmacological, experimental, clinical 
and economical perspectives. Br J Clin Pharmacol, 75(1), 60-78. doi:10.1111/j.1365-
2125.2012.04317.x 

CONFIDENTIAL 
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Dutta, A., Sethi, N., Choudhary, P., Sood, J., Panday, B. C., & Chugh, P. T. (2018). The impact 
of preinduction fentanyl dosing strategy on postoperative nausea and vomiting in patients 
undergoing laparoscopic cholecystectomy. J Opioid Manag, 14(4), 283-293. 
doi:10.5055/jom.2018.0460 
Eikemo, M., Meier, I. M., Løseth, G. E., Trøstheim, M., Ørstavik, N., Jensen, E. N., . . . Leknes, 
S. (2022). Do opioid analgesics improve subjective well-being? A prospective 
observational study of acute opioid effects before surgery. PsyArXiv Preprints. 
doi:10.31234/osf.io/pq7dh 
Evans, S. M., Foltin, R. W., Levin, F. R., & Fischman, M. W. (1995). Behavioral and subjective 
effects of DN-2327 (pazinaclone) and aiprazolam in normal volunteers. Behav 
Pharmacol, 6(2), 176-186. doi:10.1097/00008877-199503000-00010 
Garland, E. L., Froeliger, B., Zeidan, F., Partin, K., & Howard, M. O. (2013). The downward 
spiral of chronic pain, prescription opioid misuse, and addiction: cognitive, affective, and 
neuropsychopharmacologic pathways. Neurosci Biobehav Rev, 37(10 Pt 2), 2597-2607. 
doi:10.1016/j.neubiorev.2013.08.006 
Harrell Jr, F. E. (2021). Hmisc: Harrell Miscellaneous (Version 4.5-0).  
Helsedirektoratet. (2018). Utvikling og variasjon i kirurgisk behandling 2013-2017. Retrieved 
from Oslo:  
Inglis, L. (2018). Milk of paradise : a history of opium. London: Macmillan. 
Juszczak, E., Altman, D. G., Hopewell, S., & Schulz, K. (2019). Reporting of Multi-Arm 
Parallel-Group Randomized Trials: Extension of the CONSORT 2010 Statement. JAMA, 
321(16), 1610-1620. doi:10.1001/jama.2019.3087 
Li, P. H., Ue, K. L., Wagner, A., Rutkowski, R., & Rutkowski, K. (2017). Opioid 
Hypersensitivity: Predictors of Allergy and Role of Drug Provocation Testing. J Allergy 
Clin Immunol Pract, 5(6), 1601-1606. doi:10.1016/j.jaip.2017.03.035 
Martel, M. O., Dolman, A. J., Edwards, R. R., Jamison, R. N., & Wasan, A. D. (2014). The 
association between negative affect and prescription opioid misuse in patients with 
chronic pain: the mediating role of opioid craving. J Pain, 15(1), 90-100. 
doi:10.1016/j.jpain.2013.09.014 
Mavridis, D., Porcher, R., Nikolakopoulou, A., Salanti, G., & Ravaud, P. (2020). Extensions of 
the probabilistic ranking metrics of competing treatments in network meta-analysis to 
reflect clinically important relative differences on many outcomes. Biometrical Journal, 
62(2), 375-385. doi:10.1002/bimj.201900026 
McHugh, R. K., Weiss, R. D., Cornelius, M., Martel, M. O., Jamison, R. N., & Edwards, R. R. 
(2016). Distress Intolerance and Prescription Opioid Misuse Among Patients With 
Chronic Pain. J Pain, 17(7), 806-814. doi:10.1016/j.jpain.2016.03.004 
Morean, M. E., de Wit, H., King, A. C., Sofuoglu, M., Rueger, S. Y., & O'Malley, S. S. (2013). 
The drug effects questionnaire: psychometric support across three drug types. 
Psychopharmacology (Berl), 227(1), 177-192. doi:10.1007/s00213-012-2954-z 

CONFIDENTIAL 
Protocol [AFFECT2 Version 2, 04.11.2022] 
 
Doc. No. 2.01.1. Valid from March 2020.  
Only the electronic version is valid. 
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Natusch, D. (2012). Equianalgesic doses of opioids - their use in clinical practice. Br J Pain, 
6(1), 43-46. doi:10.1177/2049463712437628 
Naude, P. J. W., Roest, A. M., Stein, D. J., de Jonge, P., & Doornbos, B. (2018). Anxiety 
disorders and CRP in a population cohort study with 54,326 participants: The LifeLines 
study. World J Biol Psychiatry, 19(6), 461-470. doi:10.1080/15622975.2018.1433325 
R Core Team. (2021). R: A language and environment for statistical computing. (Version 4.1.1). 
Vienna, Austria: R Foundation for Statistical Computing.  
Rücker, G., & Schwarzer, G. (2015). Ranking treatments in frequentist network meta-analysis 
works without resampling methods. BMC Medical Research Methodology, 15(1), 58. 
doi:10.1186/s12874-015-0060-8 
Salanti, G., Nikolakopoulou, A., Efthimiou, O., Mavridis, D., Egger, M., & White, I. R. (2022). 
Introducing the Treatment Hierarchy Question in Network Meta-Analysis. American 
Journal of Epidemiology, 191(5), 930-938. doi:10.1093/aje/kwab278 
Schaffer, C. B., Nordahl, T. E., Schaffer, L. C., & Howe, J. (2007). Mood-Elevating Effects of 
Opioid Analgesics in Patients With Bipolar Disorder. J Neuropsychiatry Clin Neurosci, 
19(4), 449-452. doi:10.1176/jnp.2007.19.4.449 
Sgoifo, A., Carnevali, L., Alfonso Mde, L., & Amore, M. (2015). Autonomic dysfunction and 
heart rate variability in depression. Stress, 18(3), 343-352. 
doi:10.3109/10253890.2015.1045868 
Sneader, W. (2005). Drug discovery : a history. Chichester: Wiley. 
Stanley, T. H. (1992). The history and development of the fentanyl series. J Pain Symptom 
Manage, 7(3 Suppl), S3-7. doi:10.1016/0885-3924(92)90047-l 
Stone, A. L., Becker, L. G., Huber, A. M., & Catalano, R. F. (2012a). Review of risk and 
protective factors of substance use and problem use in emerging adulthood. Addictive 
Behaviors. doi:S0306-4603(12)00081-0 [pii] 
10.1016/j.addbeh.2012.02.014 
Stone, A. L., Becker, L. G., Huber, A. M., & Catalano, R. F. (2012b). Review of risk and 
protective factors of substance use and problem use in emerging adulthood. Addict 
Behav, 37(7), 747-775. doi:10.1016/j.addbeh.2012.02.014 
Thomas, E. A., & Garland, E. L. (2017). Mindfulness is Associated With Increased Hedonic 
Capacity Among Chronic Pain Patients Receiving Extended Opioid Pharmacotherapy. 
Clin J Pain, 33(2), 166-173. doi:10.1097/ajp.0000000000000379 
Tracey, I., Woolf, C. J., & Andrews, N. A. (2019). Composite Pain Biomarker Signatures for 
Objective Assessment and Effective Treatment. Neuron, 101(5), 783-800. 
doi:10.1016/j.neuron.2019.02.019 
Wang, L. P., Hermann, C., & Westrin, P. (1996). Thiopentone requirements in adults after 
varying pre-induction doses of fentanyl. Anaesthesia, 51(9), 831-835. 
doi:10.1111/j.1365-2044.1996.tb12611.x