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.

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.)