Methadone Pharmacokinetics in End-stage Renal Disease

Study Overview
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Brief Summary
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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. The main question it aims to answer is: • Is the pharmacokinetic of methadone used in an IV-PCA pump impaired in patients with chronic kidney disease? After surgery the participants will use an IV-PCA of methadone and blood samples will be withdrawn to measure the plasmatic levels of it.

Detailed Description
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This study will be carried out at the UC-Christus Clinical 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 in order to achieve mean arterial pressures 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 baseline renal function. The pain team will remove the IV-PCA pump after 72 hours from the initial methadone bolus unless the surgical team determines early 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 in order 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 cryo tubes 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 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 <92% with FiO2 21%. The nursing chart will also be reviewed to evaluate the additional administration of intravenous methadone.

Official Title
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Postoperative Pharmacokinetics of Methadone in Patients With Chronic Kidney Disease

Conditions
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Chronic Kidney Diseases, Post Operative Pain, Pain, Acute

Intervention / Treatment
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* Procedure: Preoperative step
* Drug: Intraoperative
* Drug: Post-operative


Participation Criteria
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Eligibility Criteria
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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 ASA 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Study group<br>Patients with chronic kidney disease (CKD) over 18 years old undergoing surgery using general anesthesia with subsequent use of intravenous patient-controlled analgesia (IV-PCA) of methadone. | Procedure: Preoperative step<br>* Explanation of the surgery and use of the IV-PCA pump. Signed informed consent.<br>Drug: Intraoperative<br>* Bolus of methadone 0.1mg/kg based on ideal body weight (up to a maximum dose of 20 mg), at the beginning of surgery.<br>* Other names: Methadone administration during surgery;Drug: Post-operative<br>* Installation of IV-PCA of methadone. Program to be used of no background infusion, boluses of 1 mg, and the intervals between boluses of 8 minutes.<br>* Other names: Methadone boluses administered by IV-PCA pump;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma concentration | Blood samples will be taken, collected in heparin tubes, and centrifuged. The extracted serum will be placed in cryotubes that will be stored at -80 °C until analysis. Methadone samples will be analyzed using a high performance liquid chromatography (HPLC) spectrofluorometric method. Lower limits of quantification (LLOQ) will be determined and samples below the LLOQ will not be included in the analysis. | 5, 15, 30, 60 minutes and 2, 4, 6, 9, 12, 24, 48 and/or 72 hours post intraoperative methadone bolus | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total use of methadone. | The administered and demanded boluses of the IV-PCA device will be assessed along with the intravenous methadone administered by the nursing staff. | 5, 15, 30, 60 minutes and 2, 4, 6, 9, 12, 24, 48 and/or 72 hours post intraoperative methadone bolus | 
| Post-operative Pain | The numeric rating scale will be used, being 0, no pain and 10, worst pain imaginable. In the event that the pain intensity is greater than 3 at rest, 3mg methadone boluses will be administered until an intensity of less than 3 is achieved or the patient presents a respiratory rate of less than 10/minute. | 24, 48 and/or 72 hours post intraoperative methadone bolus | 
| Nausea or vomiting | Presence of nausea or vomiting in the postoperative acute care unit and the surgical ward. | In the postoperative acute care unit and at 24, 48, and/or 72 hours post intraoperative methadone bolus | 
| Respiratory depression | Presence of respiratory depression in the postoperative acute care unit and the surgical ward. The patient's clinical record will be reviewed. It will be considered as episodes of respiratory depression when the respiratory rate is less than 8/minute | 5, 15, 30, 60 minutes and 2, 4, 6, 9, 12, 24, 48 and/or 72 hours post intraoperative methadone bolus | 
| Hypoxemia | Presence of peripheral oxygen saturation less than 90% with fraction of inspired oxygen of 21%. The patient's clinical record will be reviewed. | 5, 15, 30, 60 minutes and 2, 4, 6, 9, 12, 24, 48 and/or 72 hours post intraoperative methadone bolus | 
| Sedation | The degree of sedation will be assessed using a four point sedation scale (score 1 = spontaneous eye opening; score 2 = drowsy, responsive to verbal stimuli; score 3 = drowsy, arousable to physical stimuli; score 4 = unresponsive) | In the postoperative acute care unit and at 24, 48, and/or 72 hours post intraoperative methadone bolus | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Methadone, Patient Controlled Anesthesia, Chronic Kidney Diseases, Post Operative Pain