Methadone Pharmacokinetics in End-stage Renal Disease

The goal of this observational study is to describe the influence of renal function on the pharmacokinetics of methadone used through an intravenous patient-controlled analgesia (IV-PCA) pump for the management of acute postoperative pain. After surgery the participants will use an IV-PCA of methadone and blood samples will be withdrawn to measure the plasmatic levels of it.

The main question the study aims to answer is:

• Is the pharmacokinetic of methadone used in an IV-PCA pump impaired in patients with chronic kidney disease?

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.

Eligibility Criteria:
Inclusion Criteria:

* Patients with chronic kidney disease (CrCl 15-60 ml/min)
* Patients over 18 years old undergoing surgery requiring general anesthesia with subsequent use of intravenous methadone patient-controlled analgesia
* Hospital stay ≥ 48 hours
* Body mass index 18-35 kg/m2

Exclusion Criteria:

* History of liver disease
* Need for dialysis (hemo or peritoneal dialysis)
* Use of home oxygen therapy
* American Society of Anesthesiologists (ASA) physical status IV-V
* Pregnancy
* Chronic opioid use
* Methadone allergy
* Prolonged QT interval
* Use of antiarrhythmics that prolong the QT interval
* Inability to understand the proper use of PCA