Remifentanil and Hyperalgesia: Gradual Withdrawal Versus Immediate Discontinuation

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.

Study Overview

• Status: Completed
• Conditions: Pain; Anesthesia
• Intervention / Treatment: Drug: Remifentanil; Drug: NaCl 0.9%

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.)

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Belgium
  • Brussels, Belgium, 1070
    • Erasme hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 63 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Remifentanil; Remifentanil TCI: gradual withdrawal: reduction of 30% / 15 mins (2 -> 1.4 -> 1 -> 0.7-> 0.5 -> 0.35 -> 0.25 -> 0 ng/ml)	Drug: Remifentanil; Remifentanil will be continued postoperatively, while being decreased (gradually by 30% every 15 mins); Other Names: ultiva
Placebo Comparator: NaCl 0.9%; 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)	Drug: NaCl 0.9%; NaCl 0.9% will be administered postoperatively, while being decreased by 30% every 15 mins.; Other Names: physiological serum

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
First demand of postoperative analgesic	the first demand of post-operative analgesic will be compared in both groups.	24 hours postoperative

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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)	24 hours postoperative
Patient satisfaction	A questionnaire (QoR-40) will be given to each patient pre- and post-operatively.	24 hours postoperative

Collaborators and Investigators

• Sponsor: Université Libre de Bruxelles
• Investigators: Principal Investigator: Luc Barvais, Erasme Hospital, Brussels

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): April 15, 2017
• Primary Completion (Actual): August 30, 2017
• Study Completion (Actual): August 30, 2017

Study Registration Dates

• First Submitted: March 31, 2017
• First Submitted That Met QC Criteria: April 5, 2017
• First Posted (Actual): April 12, 2017

Study Record Updates

• Last Update Posted (Actual): October 18, 2017
• Last Update Submitted That Met QC Criteria: October 16, 2017
• Last Verified: October 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Nervous System Diseases; Neurologic Manifestations; Sensation Disorders; Somatosensory Disorders; Hyperalgesia; Physiological Effects of Drugs; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Analgesics, Opioid; Narcotics; Remifentanil
• Other Study ID Numbers: remi074

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No