QUALITY OF RECOVERY AFTER INTRAOPERATIVE MORPHINE OR METHADONE
Condition: Pain, Postoperative; Nausea and Vomiting, Postoperative
MeSH terms: Nausea; Vomiting; Pain, Postoperative; Postoperative Nausea and Vomiting
Study type: Interventional
Phase: Phase 4

Summary: 
      Introduction. Despite the advantages associated with the use of remifentanil during total
      intravenous anesthesia (TIVA), it has been observed a frequent difficulty in the control of
      postoperative pain due to the risk of developing hyperalgesia and acute tolerance associated
      with the administration of this opioid. There is evidence that NMDA receptors are involved in
      the development of these changes. Methadone is an opioid that exhibits analgesic potency
      similar to that of morphine but has NMDA antagonist activity and longer duration of action as
      additional features. The objective of the study was to evaluate the quality of recovery
      (QoR40) of patients undergoing TIVA for laparoscopic cholecystectomy and who received
      morphine or methadone to control postoperative pain. Methods. Patients aged 18 to 65 years,
      physical status ASA I and II, submitted to total venous anesthesia (propofol and
      remifentanil) for laparoscopic cholecystectomy and eligible to participate in this
      prospective and randomized clinical study will be evaluated. After induction of anesthesia,
      patients will receive a solution containing 0.1 mg.kg-1 morphine (MF group) or 0.1 mg.kg-1
      methadone (MT group). Data on the presence of pain, nausea, vomiting, tremor, drowsiness,
      presence of SpO2 <92%, even with O2 face mask (5 L.min-1) and length of stay will be recorded
      at PACU. The pain will be evaluated every 15 minutes on a verbal numerical scale (ENV) from 0
      to 10. E.v. morphine 0.1 mg.kg-1 (MF group) or methadone 0.1 mg.kg-1 (MT group) will be
      administered every 15 minutes to obtain the score below 3. After discharge from the PACU, all
      patients will receive intravenous ketoprofen every 12 hours and dipyrone every 6 hours. For
      cases where the patient considers the analgesic regimen insufficient, tramadol (100 mg) will
      be administered intravenously at 8-hour intervals. The consumption of analgesics, the
      intensity of pain, the occurrence of nausea, vomiting and other complications in the ward
      will be recorded. The application of the questionnaire (QoR40) will be performed in the ward
      the morning after the surgery by a medical student.
    

Detailed description: 
      We hypothesized that methadone treatment would beneficially affect patient-perceived quality
      of recovery after laparoscopic cholecystectomy under total intravenous anesthesia. The
      primary outcome was assessed using the Quality of Recovery Questionnaire (QoR-40), a 40-item
      quality of recovery scoring system, on postoperative day (POD) 1. In addition, the effects of
      both opioids on early clinical recovery variables, such as the time to eye opening, the
      occurrence of nausea and vomiting, pain score, use of analgesics, and length of PACU stay,
      were determined.

      Methods. This randomised trial was approved by the Research Ethics Committee of the School of
      Medical and Health Sciences, Pontifical Catholic University of São Paulo.

      Study sequence No premedication will be applied to the patients. Patients´ preoperative data
      including age, gender, physical status and, BMI will be collected. Subjects will be
      randomized using a computer-generated (www.random.org) table of random numbers into 2 groups:
      MT (methadone 0.1 mg.kg-1) or MF (morphine 0.1 mg.kg-1). Group assignments were sealed in
      sequentially numbered opaque envelopes that were opened after patient inclusion in the study.
      All care providers, researchers, and patients were blinded to group assignments. Two study
      10-mL syringes will be prepared by an anesthesiologist independent of the study. Syringe 1 to
      be used during intraoperative phase and syringe 2 as a rescue for postoperative pain.
      Methadone 0.1 mg.kg-1 (made up to 10 mL with normal saline) or morphine 0.1 mg.kg-1 (made up
      to 10 mL with normal saline) will be drawn into each syringe which will be offered to the
      anesthesia provider after the opaque envelope is opened.

      Anesthetic and Surgical Management After arrival in the operating room, standard ASA monitors
      will be applied. Lidocaine (30 mg) will be administered intravenously immediately after
      venoclysis. After anesthesia induction, capnographic monitoring will be added. Anesthesia
      will be induced with remifentanil 0.5 µg.kg-1.min-1 over three minutes followed by propofol
      2.0 mg. kg-1. Rocuronium 0.6 mg.kg-1 will be administered to facilitate tracheal intubation.
      Anesthetic maintenance will be achieved with a continuous infusion of remifentanil 0.3
      µg.kg-1.min-1 and propofol 4 to 6 mg. kg-1. h-1. Ventilation will be controlled mechanically
      to maintain an end-tidal carbon dioxide concentration of 30-40 mmHg using a 50% oxygen-air
      gas mixture. Immediately after the induction of anesthesia, patients will receive
      intravenously: MT group - Methadone 0.1 mg/kg or MF group - morphine 0.1 mg/kg. Patients who
      exhibit reductions in systolic arterial pressure (SAP) greater than 30% or heart rate (HR)
      reductions to less than 50 bpm will be given ephedrine (10 mg) and atropine (0.5 mg),
      respectively. Normal saline will be used for fluid replacement therapy at a rate of 500 ml
      throughout the first 30 minutes, and, then, 2 ml/kg/h until the end of the surgical
      procedure. All of the participants will receive dexamethasone (8 mg) and ketoprofen (100 mg)
      at the onset of surgery and ondansetron (4 mg) and dipyrone (1 g). Residual neuromuscular
      blockade will be antagonized by atropine (0.01 mg/ kg) and neostigmine (0.015 mg/kg).
      Extubation will be performed after awakening. The time elapsed from discontinuation of the
      anesthetics until the eye opening will be registered.

      When stable vital signs and respiration are confirmed, all patients will be transferred to
      the post-anesthesia care unit (PACU). Early recovery times includes time to eye opening (time
      from the discontinuation of anaesthetics to eye opening) and time to Aldrete score ≥ 9. Data
      related to the occurrence of pain, nausea and vomiting at the PACU will be recorded. Pain
      will be assessed while at rest and after asking the subjects to cough, every 15 minutes using
      a 0-10 numeric pain rating scale (NRS), where zero meant no pain and 10 the worst imaginable
      pain. When stable vital signs and respiration are confirmed, all patients will be transferred
      to the post-anesthesia care unit (PACU). Early recovery times includes time to eye opening
      (time from the discontinuation of anaesthetics to eye opening) and time to Aldrete score ≥ 9.
      Data related to the occurrence of pain, nausea and vomiting at the PACU will be recorded.
      Pain will be assessed while at rest and after asking the subjects to cough, every 15 minutes
      using a 0-10 numeric pain rating scale (NRS), where zero meant no pain and 10 the worst
      imaginable pain. One or two mL from the solution previously prepared (Syringe 2) will be
      administered intravenously every 15 minutes to maintain the pain score below 3 (1 mg when the
      pain score is <7 and 2 mg when it is ≥7). Following discharge from the PACU (minimum stay 60
      minutes and Aldrete score ≥ 9), all of the participants will receive ketoprofen (100 mg)
      every 12 hours and dipyrone (30 mg.kg-1, maximum 1 g) every six hours intravenously. Whenever
      patients judge that their analgesia is insufficient, tramadol (100 mg) will be administered
      intravenously at eight-hour minimum intervals. Postoperative nausea and vomiting (PONV) will
      be treated with ondansetron (4 mg) intravenously. An investigator who will be blinded to
      group assignment will collect all postoperative outcome data 24 hours after surgical
      procedure. Subjects will rate the higher score of pain (NRS) during the hospital ward stay.
      Tramadol consumption and the number of nausea and vomiting episodes will also be recorded.
      These findings will be confirmed with the ward nursing staff. All subjects will stay at
      hospital for at least 24 hours.

      Data Collection The baseline QoR-40 questionnaire will be provided to subjects after informed
      consent is obtained in the preoperative holding area and 24 hours after surgery by a blinded
      investigator. The QoR-40 questionnaire assesses five dimensions of recovery (physical comfort
      - 12 items; emotional state - 7 items; physical independence - 5 items; physiological support
      - 7 items; and pain - 7 items). Each item is rated on a five-point Likert scale: none of the
      time, some of the time, usually, most of the time, and all the time. The total score on the
      QoR-40 ranges from 40 (poorest quality of recovery) to 200 (best quality of recovery). The
      primary outcome of interest will be the QoR-40 score, however the following data will also be
      recorded: age, gender, physical status, BMI, and length of PACU stay.

      Statistical Analysis The sample size was calculated considering 90% power to detect a
      10-point difference in QoR-40, which indicated the need to include 31 participants in each
      group. Taking possible losses into consideration, the final sample included 70 patients.
    

Intervention name(s): Methadone; Morphine
Intervention type(s): Drug; Drug
Intervention description(s): Immediately after the induction of anesthesia, patients will receive intravenously methadone 0.1 mg/kg; Immediately after the induction of anesthesia, patients will receive intravenously morphine 0.1 mg/kg
Intervention MeSH terms: Morphine; Methadone
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Prospective, randomized, double-blinded trial
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Prevention
Keywords: Postoperative pain; Postoperative nausea and vomiting; Quality of recovery; QoR-40; Total intravenous anesthesia