Affective Effects of Pre-surgery Opioids: a Randomized, Doubleblind Placebo-controlled Trial (AFFECT2)

Understanding Opioid Use Before and After Surgery in Norway: A Prospective Multicenter Study and Randomized Double-blind Controlled Study

1. To investigate and compare the affective short-term effects of opioid drugs: morphine, oxycodone and fentanyl, administered to the patients before the induction of general anesthesia.
2. Charting opioid use after surgery in patients treated at hospitals in Norway
3. Identify predictors for postoperative opioid use and persistent pain

Study Overview

• Status: Recruiting
• Conditions: Opioid Use; Affective Symptoms
• Intervention / Treatment: Drug: Placebo; Drug: Morphine 2.5 mg i.v.; Drug: Morphine 5 mg i.v.; Drug: Morphine 10 mg i.v.; Drug: Oxycodone 2.5 mg i.v.; Drug: Oxycodone 5 mg i.v.; Drug: Oxycodone 10 mg i.v.; Drug: Fentanyl 0.025 mg i.v.; Drug: Fentanyl 0.05 mg i.v.; Drug: Fentanyl 0.1 mg i.v.

Detailed Description

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, oxycodone and fentanyl) administered in three different doses before surgery in a clinical setting associated with physiological and psychological stress.

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 a 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.

In the weeks prior to surgery 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).

160 patients were included in the pilot quality control study. 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 (randomized controlled trial) 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.

• Study Type: Interventional
• Enrollment (Estimated): 1000
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Gernot Ernst, MD, PhD; Phone Number: +4748072777; Email: bserng@vestreviken.no
• Study Contact Backup: Name: Harald Lenz, MD, PhD; Phone Number: +4790549545; Email: harald.lenz@medisin.uio.no

Study Locations

• Norway
  • Oslo, Norway
    • Recruiting
    • Harald Lenz
    • Contact: Harald Lenz, PhD; Phone Number: 004790549545; Email: harald.lenz@medisin.uio.no
    • Contact: Leiv Arne Rosseland, PhD; Phone Number: 004792204274; Email: l.a.rosseland@medisin.uio.no

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

- Health status ASA1 (American Society of Anesthesiologists physical status) 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.

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.

• 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.
• Body weight and body mass index (BMI) within the range 18-35 kg/m2 (inclusive).
• Capable of giving signed informed consent as which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
• Having good verbal communication skills in Norwegian.
• Patients undergoing planned day surgery with general anesthesia (outpatient sample).
• Orthopedic, rectal, gynecological, hand and foot surgery, and minor vascular procedures.
• Inpatients undergoing planned gynecological and orthopedic surgery.
• Hysterectomy, laparoscopic ovariectomy, lumbal herniotomy and other related procedures.
• Minor gastrointestinal surgery

Exclusion Criteria:

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. Myasthenia gravis
15. Any other health status not corresponding to ASA1 or ASA2. This includes patients with severe disease burden, major psychiatric disorders that could interfere 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. Illegal drugs use like opioids, cocaine and amphetamine

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

10

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; The patient is given standardized questions about their well-being and affective state before and after the administration of placebo (0.9% NaCl intravenously). This is carried out on the operating table right before anesthesia	Drug: Placebo; The patient is given standardized questions about their well-being and affective state before and after the administration of placebo intravenously. This is carried out on the operating table right before anesthesia; Other Names: 0.9% NaCl , Natriumklorid 9 mg/ml, Hameln (ATC code: B05B B01)
Active Comparator: Morphine 2.5 mg; The patient is given standardized questions about their well-being and affective state before and after the administration of morphine 2.5 mg intravenously. This is carried out on the operating table right before anesthesia	Drug: Morphine 2.5 mg i.v.; The patient is given standardized questions about their well-being and affective state before and after the administration of 2.5 mg morphine intravenously. This is carried out on the operating table right before anesthesia; Other Names: Morphine, Orion (ATC code: N02A A01)
Active Comparator: Morphine 5 mg; The patient is given standardized questions about their well-being and affective state before and after the administration of morphine 5 mg intravenously. This is carried out on the operating table right before anesthesia	Drug: Morphine 5 mg i.v.; The patient is given standardized questions about their well-being and affective state before and after the administration of morphine 5 mg intravenously . This is carried out on the operating table right before anesthesia; Other Names: Morphine, Orion (ATC code: N02A A01)
Active Comparator: Morphine 10 mg; The patient is given standardized questions about their well-being and affective state before and after the administration of morphine 10 mg intravenously. This is carried out on the operating table right before anesthesia	Drug: Morphine 10 mg i.v.; The patient is given standardized questions about their well-being and affective state before and after the administration of morphine 10 mg intravenously . This is carried out on the operating table right before anesthesia; Other Names: Morphine, Orion (ATC code: N02A A01)
Active Comparator: Oxycodone 2.5 mg; The patient is given standardized questions about their well-being and affective state before and after the administration of oxycodone 2.5 mg intravenously. This is carried out on the operating table right before anesthesia	Drug: Oxycodone 2.5 mg i.v.; The patient is given standardized questions about their well-being and affective state before and after the administration of oxycodone 2.5 mg intravenously . This is carried out on the operating table right before anesthesia; Other Names: Oxycodone, Hameln (ATC code: N02A A05)
Active Comparator: Oxycodone 5 mg; The patient is given standardized questions about their well-being and affective state before and after the administration of oxycodone 5 mg intravenously. This is carried out on the operating table right before anesthesia	Drug: Oxycodone 5 mg i.v.; The patient is given standardized questions about their well-being and affective state before and after the administration of oxycodone 5 mg intravenously . This is carried out on the operating table right before anesthesia; Other Names: Oxycodone, Hameln (ATC code: N02A A05)
Active Comparator: Oxycodone 10 mg; The patient is given standardized questions about their well-being and affective state before and after the administration of oxycodone 10 mg intravenously. This is carried out on the operating table right before anesthesia	Drug: Oxycodone 10 mg i.v.; The patient is given standardized questions about their well-being and affective state before and after the administration of oxycodone 10 mg intravenously . This is carried out on the operating table right before anesthesia; Other Names: Oxycodone, Hameln (ATC code: N02A A05)
Active Comparator: Fentanyl 0.025 mg; The patient is given standardized questions about their well-being and affective state before and after the administration of fentanyl 0.025 mg intravenously. This is carried out on the operating table right before anesthesia	Drug: Fentanyl 0.025 mg i.v.; The patient is given standardized questions about their well-being and affective state before and after the administration of fentanyl 0.025 mg intravenously . This is carried out on the operating table right before anesthesia; Other Names: Fentanyl, Hameln (ATC code: N01A H01)
Active Comparator: Fentanyl 0.05 mg; The patient is given standardized questions about their well-being and affective state before and after the administration of fentanyl 0.05 mg intravenously. This is carried out on the operating table right before anesthesia	Drug: Fentanyl 0.05 mg i.v.; The patient is given standardized questions about their well-being and affective state before and after the administration of fentanyl 0.05 mg intravenously . This is carried out on the operating table right before anesthesia; Other Names: Fentanyl, Hameln (ATC code: N01A H01)
Active Comparator: Fentanyl 0.1 mg; The patient is given standardized questions about their well-being and affective state before and after the administration of fentanyl 0.1 mg intravenously. This is carried out on the operating table right before anesthesia	Drug: Fentanyl 0.1 mg i.v.; The patient is given standardized questions about their well-being and affective state before and after the administration of fentanyl 0.1 mg intravenously . This is carried out on the operating table right before anesthesia; Other Names: Fentanyl, Hameln (ATC code: N01A H01)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Anxious	Asking the patient of feeling anxious; Numeric rating scale 0 -10 prior opioid and post opioid intravenously (or placebo). 0=not anxious and 10=feeling extremely anxious	8-10 minutes
Relaxed	Asking the patient of feeling relaxed. Numeric rating scale 0 -10 prior opioid and post opioid intravenously (or placebo). 0=not relaxed and 10=very relaxed.	8-10 minutes
Pain level	Asking the patient of pain level. Numeric rating scale 0 -10 prior opioid and post opioid intravenously (or placebo). 0=no pain and 10= worst pain imaginable	8-10 minutes
Good	Asking the patient of feeling good. Numeric rating scale 0 -10 prior opioid and post opioid intravenously (or placebo). 0=feeling no good and 10= feeling very good.	8-10 minutes
Dizzy	Asking the patient of feeling dizzy. Numeric rating scale 0-10 post opioid intravenously (or placebo). 0=feeling not dizzy and 10=feeling very dizzy.	2-4 minutes
Sedated	Asking the patient of feeling sedated. Numeric rating scale 0-10 post opioid intravenously (or placebo). 0=feeling not sedated and 10=feeling very sedated.	2-4 minutes
Feeling high, Numeric rating scale 0 -10	Asking the patient of feeling high. Numeric rating scale 0-10 post opioid intravenously (or placebo). 0=feeling not high and 10=feeling very high.	2-4 minutes
Euphoric	Asking the patient of feeling high. Numeric rating scale 0-10 post opioid intravenously (or placebo). 0=feeling not euphoric and 10=feeling very euphoric.	2-4 minutes
Drug liking	Asking the patient of drug liking. Numeric rating scale 0-10 post opioid intravenously (or placebo). 0=feeling not drug liking and 10=feeling very drug liking.	2-4 minutes
Drug disliking	Asking the patient of drug disliking. Numeric rating scale 0-10 post opioid intravenously (or placebo). 0=feeling not drug disliking and 10=feeling very drug disliking.	2-4 minutes

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Heart rate	beats/min prior opioid and post opioid intravenously	10 min
Heart rate variability	Heart rate variability (HRV) prior opioid and post opioid intravenously	10 min

Collaborators and Investigators

• Sponsor: Oslo University Hospital
• Collaborators: Vestre VikenHF Kongsberg Sykehus
• Investigators: Principal Investigator: Gernot Ernst, MD,PhD, Kongsberg Hospital, Vestre Viken Health Trust Norway

Publications and helpful links

General Publications

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Study record dates

Study Major Dates

• Study Start (Actual): December 13, 2022
• Primary Completion (Estimated): December 1, 2025
• Study Completion (Estimated): December 1, 2025

Study Registration Dates

• First Submitted: November 17, 2022
• First Submitted That Met QC Criteria: November 28, 2022
• First Posted (Actual): December 6, 2022

Study Record Updates

• Last Update Posted (Actual): September 18, 2023
• Last Update Submitted That Met QC Criteria: September 14, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Behavioral Symptoms; Affective Symptoms; Physiological Effects of Drugs; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Analgesics, Opioid; Narcotics; Adjuvants, Anesthesia; Fentanyl; Morphine; Oxycodone
• Other Study ID Numbers: AFFECT2 Version 2, 04.11.2022; 2022-002938-13 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No