This study will be carried out at the Pontifical Catholic University of Chile Hospital with
prior approval by the ethics committee. Study staff will assess the inclusion criteria,
obtain informed consent, withdraw the blood samples, and record and manage the data.
Patients will be recruited before surgery. At the time the patient agrees to participate in
the study, the functioning and adequate use of an intravenous patient-controlled analgesia
(IV-PCA) pump will be explained by one of the members of the research team. The anesthetic,
surgical, or postoperative care will not be affected by this research study.
Once the patient is in the theatre, standard intraoperative monitoring will be applied,
including pulse oximetry, electrocardiography, automatic blood pressure cuff, capnography,
and bispectral index monitoring (BIS system). The induction of anesthesia will be performed
by the administration of remifentanil in a target-controlled infusion (TCI) using the MINTO
model, propofol 1-2mg/kg and atracurium 0.5mg/kg or rocuronium 0.6mg/kg.
After induction, a second intravenous line will be installed in the contralateral arm
exclusively to obtain blood samples. Subsequently, based on the ideal body weight, patients
will receive a bolus of 0.1mg/kg of methadone at the beginning of surgery with a maximum dose
of 20mg.
The maintenance of general anesthesia will be through the administration of sevoflurane to
achieve BIS values between 40-60. Atracurium or rocuronium in doses of 5-10mg will be
administered according to the neuromuscular block monitor and the infusion of remifentanil
will be at the discretion of the anesthesiologist in charge to achieve mean arterial pressure
within 20% of the baseline measure (previous induction of anesthesia). Episodes of
hypotension will be treated with phenylephrine 50-100 mcg, ephedrine 6-12mg, or fluid bolus,
as indicated.
Once the surgery is finished, the neuromuscular block will be reversed with neostigmine 30-70
mcg/kg or sugammadex 2-4mg/kg, as indicated and the patient will be extubated. Then, the
patient will be transferred to the postoperative acute care unit (PACU) and assessed for pain
by a nurse at the admission and every 15 minutes thereafter. If the patient reports a pain
intensity greater than 3/10 at rest as measured by the numeric rating scale (NRS, being 0, no
pain; 10, worst pain imaginable), methadone boluses of 3 mg will be administered every 15
minutes until the pain intensity is less than or equal to 3/10 or the patient has a
respiratory rate less than 10/minute. Then, the IV-PCA device will be installed and its
correct use will be explained again. The following IV-PCA program will be used: no background
infusion, boluses of 1 milligram, and 8-minute lockout interval. Once the patient meets the
discharge criteria from PACU using the Aldrete Scoring System (greater than or equal to 8 out
of 10), the patient will be transferred to the ward.
In addition to the use of an IV-PCA device, the multimodal postoperative analgesia will
consist of intravenous or oral paracetamol of 1gr every 8 hours as tolerated, rescue
methadone boluses of 3 mg administered by the nurse in case the patient experiences pain
intensity at rest greater than 3/10 despite an adequate use of the PCA pump. Also, no patient
will receive non-steroidal anti-inflammatory drugs due to possible greater impairment of the
baseline renal function. The pain team will remove the IV-PCA pump after 48 hours from the
initial methadone bolus unless the surgical team determines earlier removal of the pump since
the patient meets the discharge criteria from the hospital.
Number of blood samples: After the administration of methadone, a total of 12 venous blood
samples will be obtained for each patient to investigate the potential accumulation of this
opioid in the postoperative period. The samples will be collected at 5, 15, 30 and 60 minutes
and 2, 4, 6, 9, 12, 24, 36, and/or 72 hours after the intraoperative bolus of methadone. The
blood sample at 72 hours will be conditioned to the early removal of the IV-PCA pump in case
the patient is ready to be discharged from the hospital. Blood samples will be collected in
heparin tubes and centrifuged. The extracted serum will be placed in cryotubes which will be
stored at -80°C until analysis. Methadone samples will be analyzed using a high-performance
liquid chromatography (HPLC) spectrofluorometric method in the environmental and food
analytical chemistry laboratory, Faculty of Chemistry and Pharmacy, Pontificia Universidad
Católica de Chile. The lower limits of quantification (LLOQ) will be determined. Samples
below the LLOQ will not be included in the analysis.
At the time of subsequent methadone plasma measurements, the following data will be recorded:
IV-PCA boluses administered and demanded, pain intensity using the numeric rating scale, the
degree of sedation using a 5-point scale, presence of pruritus/nausea/vomiting will also be
recorded, and episodes of respiratory depression (respiratory rate <8/min) or oxygen
saturation <90% measured by the pulse oximetry.
The nursing chart will also be reviewed to evaluate the additional administration of
intravenous methadone.