Remifentanil and Hyperalgesia: Gradual Withdrawal Versus Immediate Discontinuation
Primary Purpose
Anesthesia, Pain
Status
Completed
Phase
Not Applicable
Locations
Belgium
Study Type
Interventional
Intervention
Remifentanil
NaCl 0.9%
Sponsored by
About this trial
This is an interventional treatment trial for Anesthesia
Eligibility Criteria
Inclusion Criteria:
- All patients undergoing a thyroid surgery
- male/female
- from the age of 18 until 65
- ASA physical status of I-III
- Knowledge of French, English or Dutch is required in order to be enrolled in this study.
Exclusion Criteria:
- Pregnancy
- hypo-/hyperthyroidism
- gastro-duodenal ulcer
- allergy or contraindications to one of the study drugs
- renal insufficiency
- liver insufficiency
- neuropsychiatric disturbance
- BMI >30
- history of drug and alcohol abuse
- preoperative analgesic drug use
Sites / Locations
- Erasme Hospital
Arms of the Study
Arm 1
Arm 2
Arm Type
Active Comparator
Placebo Comparator
Arm Label
Remifentanil
NaCl 0.9%
Arm Description
Remifentanil TCI: gradual withdrawal: reduction of 30% / 15 mins (2 -> 1.4 -> 1 -> 0.7-> 0.5 -> 0.35 -> 0.25 -> 0 ng/ml)
Remifentanil abrupt discontinuation / NaCl 0.9% (control group with a reduction of 30% /15 mins) (2 -> 1.4 -> 1 -> 0.7-> 0.5 -> 0.35 -> 0.25 -> 0 ng/ml)
Outcomes
Primary Outcome Measures
First demand of postoperative analgesic
the first demand of post-operative analgesic will be compared in both groups.
Secondary Outcome Measures
Pain evaluation
Numeric Rating Scale (NRS) will be collected multiple times in both groups ( 0,15, 30, 45, 60, 75, 90, 105, 120 minutes, 4 hours and 24 hours postoperatively)
Patient satisfaction
A questionnaire (QoR-40) will be given to each patient pre- and post-operatively.
Full Information
NCT ID
NCT03110653
First Posted
March 31, 2017
Last Updated
October 16, 2017
Sponsor
Université Libre de Bruxelles
1. Study Identification
Unique Protocol Identification Number
NCT03110653
Brief Title
Remifentanil and Hyperalgesia: Gradual Withdrawal Versus Immediate Discontinuation
Official Title
Remifentanil and Hyperalgesia: Gradual Withdrawal Versus Immediate Discontinuation
Study Type
Interventional
2. Study Status
Record Verification Date
October 2017
Overall Recruitment Status
Completed
Study Start Date
April 15, 2017 (Actual)
Primary Completion Date
August 30, 2017 (Actual)
Study Completion Date
August 30, 2017 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Université Libre de Bruxelles
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
Modern anesthesia has made a lot of progress, however, postoperative pain remains one of the major problems associated with patient discomfort, prolonged hospital stay and increased health care costs.
Remifentanil is an ultra-short-acting phenylpiperidine opioid analgesic with high lipid solubility and a rapid onset of effect.
Recently, opioid use has also been associated with postoperative opioid-induced hyperalgesia or acute opioid tolerance. An immediate discontinuation of remifentanil has been associated to increased postoperative pain levels.
We would like to investigate whether a gradual post-operative withdrawal of remifentanil is indeed associated with less immediate pain compared to after an abrupt withdrawal in surgical patients undergoing minor surgery.
Detailed Description
Modern anesthesia has made a lot of progress, however, postoperative pain remains one of the major problems associated with patient discomfort, prolonged hospital stay and increased health care costs.
Remifentanil is an ultra-short-acting phenylpiperidine opioid analgesic with high lipid solubility and a rapid onset of effect.
It is rapidly metabolized by non-specific blood and tissue esterases, which also ensures rapid recovery. Remifentanil can be given in high doses and is easily titratable. Due to its rapid elimination, a bridge to post-operative analgesia is a necessity when using this drug.
Recently, opioid use has also been associated with postoperative opioid-induced hyperalgesia or acute opioid tolerance. An immediate discontinuation of remifentanil after digestive surgery has been associated to increased postoperative pain levels.
Studies have been done to investigate this phenomenon. Gradual withdrawal of remifentanil seems to be associated with less pain in a rodent population. (4) A recent study by Norwegian colleagues in a human population evaluating two types of pain stimuli seems to confirm this in healthy volunteers. (5) The investigators would like to investigate whether a gradual post-operative withdrawal of remifentanil is indeed associated with less immediate pain compared to after an abrupt withdrawal in surgical patients undergoing minor surgery.
Methods and materials Sample size The primary outcome of the study is to compare the first post-operative demand of analgesic drugs (mins).
Between both groups, we considered a difference of first demand of post-operative analgesia at 35 minutes or more to be of clinical relevance.
Thus, at a two-sided alpha level of 0.05 and power of 90% (Standard deviation 27), the study needs to be conducted on 26 patients, each group consisting of 13 patients.
As data is always lost, the study will be conducted on 30 patients (15 in each group).
Statistical analysis will be done using Mann-Whitney U test.
Blinding procedure and data collection The study is 'double' blinded. Patients, the anesthesiologist and an external observer will be blinded.
A neutral observer will collect data pre-operatively and post-operatively (first 24 hours post-operation).
Concretely, the observer will pre-operatively collect an informed consent form of the patient and, at the same time, asses the patient's state via QoR-40. Both groups will have a remifentanil infusion upon arrival in the PACU. A nurse, independent to the study, will prepare the adequate post-operative syringe (remifentanil diluted at 20 µg/ml or NaCl 0.9%) and will change the syringe according to pre-operative randomization.
Post-operatively, in the PACU, the quantity of morphine used as well as NRS at several times post-operative will be written down.
Once the patient is at the ward, the observer verifies NRS 24 hours post-operatively and, at the same time, patient comfort at 24 hours post-operative will be evaluated through QoR-40 scores.
Study design Protocol Premedication: each group receives alprazolam (0.5 mg) one hour pre-operatively.
Monitoring In both groups, hemodynamic stability will be evaluated by monitoring ECG, heart rhythm, pulse oximetry and (noninvasive) blood pressure, BIS levels, NMT (TOF ratio).
In case blood pressure drops 20% or more from initial measurement, a bolus of ephedrine will be given in both groups.
The total quantity of each drug used will be written down. All drugs are administered intravenously. Different timings will be written down (induction time, incision time, end of surgery time, extubation time).
Group 1 Induction Remifentanil TCI (Minto model) 5 ng/ml Propofol TCI (Schnider model) closed loop (via Toolbox) adjusted to BIS levels between 40-60 Rocuronium 0.6 mg/kg Maintenance Remifentanil TCI (minto model) 5 ng/ml Propofol TCI (Schnider model) closed loop (via Toolbox) adjusted to BIS levels between 40-60 Upon the incision Acetaminophen 1g Diclofenac 1mg/kg Dexamethasone 10 mg Morphine 0.15 mg/kg Rocuronium 0.3 mg/kg
End of the surgery Ondansetron 4mg Discontinuation of propofol TCI Extubation based on TOFF ratio > 90% Remifentanil TCI 2ng/ml Post-operative analgesia (PACU) Remifentanil TCI: gradual withdrawal: reduction of 30% / 15 mins (2 -> 1.4 -> 1 -> 0.7-> 0.5 -> 0.35 -> 0.25 -> 0 ng/ml) Acetaminophen 1g/6h Diclofenac 1mg/kg /12h Morphine (two mg /5 min if NRS > 3/10) (As all patients are monitored and under immediate medical surveillance, no limit will be imposed to morphine consumption.)
Group 2 Induction Remifentanil TCI (Minto model) 5 ng/ml Propofol TCI (Schnider model) closed loop (via Toolbox) adjusted to BIS levels between 40-60 Rocuronium 0.6 mg/kg Maintenance Remifentanil TCI (Minto model) 5 ng/ml Propofol TCI (Schneider model) closed loop (via Toolbox) adjusted to BIS levels between 40-60 Upon the incision Acetaminophen 1g Diclofenac 1mg/kg Dexamethasone 10 mg Morphine 0.15 mg/kg Rocuronium 0.3 mg/kg
End of the surgery Ondansetron 4mg Discontinuation of propofol TCI Remifentanil TCI 2 ng/ml Extubation based on TOFF ratio > 0.9 Post-operative analgesia (PACU) Remifentanil abrupt discontinuation / NaCl 0.9% (control group with a reduction of 30% /15 mins) (2 -> 1.4 -> 1 -> 0.7-> 0.5 -> 0.35 -> 0.25 -> 0 ng/ml) Acetaminophen 1g/6h Diclofenac 1mg/kg /12h Morphine (two mg / 5 min if NRS > 3/10) (As all patients are monitored and under immediate medical surveillance, no limit will be imposed to morphine consumption.)
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Anesthesia, Pain
7. Study Design
Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigatorOutcomes Assessor
Masking Description
Patients, the anesthesiologist and an external observer will be blinded.
Allocation
Randomized
Enrollment
30 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Remifentanil
Arm Type
Active Comparator
Arm Description
Remifentanil TCI: gradual withdrawal: reduction of 30% / 15 mins (2 -> 1.4 -> 1 -> 0.7-> 0.5 -> 0.35 -> 0.25 -> 0 ng/ml)
Arm Title
NaCl 0.9%
Arm Type
Placebo Comparator
Arm Description
Remifentanil abrupt discontinuation / NaCl 0.9% (control group with a reduction of 30% /15 mins) (2 -> 1.4 -> 1 -> 0.7-> 0.5 -> 0.35 -> 0.25 -> 0 ng/ml)
Intervention Type
Drug
Intervention Name(s)
Remifentanil
Other Intervention Name(s)
ultiva
Intervention Description
Remifentanil will be continued postoperatively, while being decreased (gradually by 30% every 15 mins)
Intervention Type
Drug
Intervention Name(s)
NaCl 0.9%
Other Intervention Name(s)
physiological serum
Intervention Description
NaCl 0.9% will be administered postoperatively, while being decreased by 30% every 15 mins.
Primary Outcome Measure Information:
Title
First demand of postoperative analgesic
Description
the first demand of post-operative analgesic will be compared in both groups.
Time Frame
24 hours postoperative
Secondary Outcome Measure Information:
Title
Pain evaluation
Description
Numeric Rating Scale (NRS) will be collected multiple times in both groups ( 0,15, 30, 45, 60, 75, 90, 105, 120 minutes, 4 hours and 24 hours postoperatively)
Time Frame
24 hours postoperative
Title
Patient satisfaction
Description
A questionnaire (QoR-40) will be given to each patient pre- and post-operatively.
Time Frame
24 hours postoperative
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
All patients undergoing a thyroid surgery
male/female
from the age of 18 until 65
ASA physical status of I-III
Knowledge of French, English or Dutch is required in order to be enrolled in this study.
Exclusion Criteria:
Pregnancy
hypo-/hyperthyroidism
gastro-duodenal ulcer
allergy or contraindications to one of the study drugs
renal insufficiency
liver insufficiency
neuropsychiatric disturbance
BMI >30
history of drug and alcohol abuse
preoperative analgesic drug use
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Luc Barvais
Organizational Affiliation
Erasme Hospital, Brussels
Official's Role
Principal Investigator
Facility Information:
Facility Name
Erasme Hospital
City
Brussels
ZIP/Postal Code
1070
Country
Belgium
12. IPD Sharing Statement
Plan to Share IPD
Undecided
Citations:
PubMed Identifier
31027480
Citation
Saxena S, Gonsette K, Terram W, Huybrechts I, Nahrwold DA, Cappello M, Barvais L, Engelman E. Gradual withdrawal of remifentanil delays initial post-operative analgesic demand after thyroid surgery; double-blinded, randomized controlled trial. BMC Anesthesiol. 2019 Apr 25;19(1):60. doi: 10.1186/s12871-019-0731-9.
Results Reference
derived
Learn more about this trial
Remifentanil and Hyperalgesia: Gradual Withdrawal Versus Immediate Discontinuation
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