Clinical trial NCT02300077
Conditions: Post-operative Pain Anesthesia
Keywords: fentanyl, morphine methadone
Sponsor: Washington University School of Medicine
Start date: 2014-12-01; Completion date: 2018-02-12
Enrollment: 60 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The μ-opioid receptor agonist methadone is frequently used in adult anesthesia and adult pain therapy. Methadone has an extremely long half-life, which confers therapeutic advantage by providing more stable plasma concentrations and long-lasting pain relief. Methadone perioperative pharmacokinetics and effectiveness in perioperative pain relief in inpatients is well characterized. There is, however, no information on methadone use in an ambulatory surgery setting and outpatient procedures. This pilot investigation will determine effectiveness of intraoperative methadone in reducing postoperative opioid consumption and providing improved pain relief in patients undergoing moderately painful, ambulatory surgical procedures.

Detailed description:

Arms: arm 1: Control (Intra-operative administration of opioids, other than methadone) arm 2: methadone 0.1 mg/kg arm 3: None
Interventions: intervention 1: methadone intervention 2: Control (Intra-operative administration of opioids, other than methadone)
Intervention descriptions: intervention 1: Escalating dose of methadone up to .3mg/kg. intervention 2: Intra-operative administration of opioids, other than methadone

Protocol documents:
Prot_SAP_000.pdf: 
Methadone in Ambulatory Surgery 
 
 
 
Principal Investigator 
 
Helga Komen MD, 
Instructor 
Department of Anesthesiology, BO 8054 
Tel: 314 286 2997 
komenh@wustl.edu 
 
 
Co-Investigators 
 
Evan Kharasch, MD PhD 
Russell D. and Mary B. Shelden Professor of Anesthesiology 
Director, Division of Clinical and Translational Research 
Department of Anesthesiology, Box 8054 
T 314-362-8796 
F 314-362-8571 
kharasch@wustl.edu 
 
 
L. Michael Brunt, MD 
Professor of Surgery 
Department of General Surgery 
T 314454-7194 
F 314-454-5396 
Bruntm@wustl.edu 
 
 
 
Version 1.0 
June 25, 2014 
 
Version 2.0 (includes Amendment 1) 
January 3, 2015 
 
Version 3.0 (includes Amendent 2) 
July 24, 2015 
 
Version 4.0 (includes Amendment 3) 
August 27, 2017 
 
 


2 
 
CONFIDENTIAL: This document is the intellectual property of Helga Komen, MD. Acceptance of this document 
constitutes the agreement by the recipient that no unpublished information contained herein will be published or disclosed 
without prior written approval.  
Methadone in Ambulatory Surgery 
 
Amendment 1  
 
January 3, 2015 
 
Purpose 
1.  Add a second study cohort (same-day surgery outpatients) to the original cohort (ambulatory surgery 
with overnight stay, less than 24 hr total duration) 
 
Changes 
 
A. Additions: 
 
2.  Background 
 
Add a second study cohort (same-day surgery outpatients) to the original cohort (ambulatory surgery with 
overnight stay, less than 24 hr total duration) 
 
9.  Statistical Methods 
Analysis:  Identify that each cohost is analyzed separately 
 
B. Deletions: 
 
4. Eligibility 
 
Delete overnight  
 
C. Changes: 
 
Change from 60 evaluable subjects to 60 evaluable subjects in each cohort (120 total). 
 
 


3 
 
CONFIDENTIAL: This document is the intellectual property of Helga Komen, MD. Acceptance of this document 
constitutes the agreement by the recipient that no unpublished information contained herein will be published or disclosed 
without prior written approval.  
 
Methadone in Ambulatory Surgery 
 
Amendment 2  
 
July 24, 2015 
 
Purpose 
Clarify data collection at 30 days to include questions about the subject’s remaining pain medications and 
their disposal. 
 
Changes 
 
Additions:7.  Data Collection and Monitoring. 
 
 
Follow up assessments   
A home diary will be used to assess daily drug dosing history upon discharge from the hospital until 
the patient’s postop clinic visit at approximately 30 days. Subjects will also record daily pain self-
assessments using a colored-visual analogue scale (at rest, with activity and with coughing). The 
ORSDS will be completed and recorded on approximately the 7th, 14th and 30th day. We will also ask 
subjects about remaining number of pain medications and their disposal at the 30 day time point. 
 
 
 


4 
 
CONFIDENTIAL: This document is the intellectual property of Helga Komen, MD. Acceptance of this document 
constitutes the agreement by the recipient that no unpublished information contained herein will be published or disclosed 
without prior written approval.  
Methadone in Ambulatory Surgery 
 
Amendment 3  
 
August 24, 2017 
 
Purpose 
Clarify that > 60 evaluable subjects will be enrolled in study cohorts  
 
 
Changes 
Study table clarified to state a minimum of 60 evaluable subjects will be enrolled for each cohort; up to 
200 total evaluable.  
Protocol para 6 and 9 changed to indicate ≥ 60 evaluable subjects in each cohort may be required for 
analysis. 
 
Deletions 
Protocol p. 12, deleted sentence stating analysis to include total of “120 evaluable” 
 
 


5 
 
CONFIDENTIAL: This document is the intellectual property of Helga Komen, MD. Acceptance of this document 
constitutes the agreement by the recipient that no unpublished information contained herein will be published or disclosed 
without prior written approval.  
Abstract 
 
The μ-opioid receptor agonist methadone is frequently used in adult anesthesia and adult pain 
therapy.  Methadone has an extremely long half-life, which confers therapeutic advantage by providing 
more stable plasma concentrations and long-lasting pain relief. Methadone perioperative 
pharmacokinetics and effectiveness in perioperative pain relief in inpatients is well characterized.  There 
is, however, no information on methadone use in an ambulatory surgery setting and outpatient 
procedures. This pilot investigation will determine effectiveness of intraoperative methadone in reducing 
postoperative opioid consumption and providing improved pain relief in patients undergoing moderately 
painful, ambulatory surgical procedures.  
 
 


6 
 
CONFIDENTIAL: This document is the intellectual property of Helga Komen, MD. Acceptance of this document 
constitutes the agreement by the recipient that no unpublished information contained herein will be published or disclosed 
without prior written approval.  
SYNOPSIS  
Study Title 
Methadone in Ambulatory Surgery 
Objective 
Two arm randomized controlled pilot study to evaluate the efficacy of a single dose of 
intraoperative methadone in reducing post-operative pain and opioid consumption in 
patients undergoing moderately painful, ambulatory (less than 24 hr  hospital stay) surgical 
procedures.  Our secondary goal is to assess opioid consumption and pain relief within the 
first 30 postoperative days 
Study Period 
Planned enrollment duration: Approximately 12 months. 
Planned study duration: Approximately 30 days per subject 
Number of 
Patients 
200 evaluable subjects 
Study 
Medication 
Administration 
At least 60 evaluable patients in each of two cohorts (ambulatory with less than 24 hr 
overnight stay, and same-day outpatients) will be randomized into two groups. Group I will 
receive 0.1- 0.3 mg/kg IV methadone HCl.  Group II will be the control group and not 
receive any methadone. 
Study Design 
Single-center, randomized, single blinded, positive-controlled dose escalation pilot study.  
Patients receive standard monitoring for anesthesia and postoperative care. Surgical and 
anesthesia care (except for intraoperative opioid use) are not altered for study purposes. In 
each cohort, subjects are randomized 1:2 to either control (standard intraop opioid at 
anesthesiologists’ discretion, not methadone) or methadone HCl (0.1 – 0.3 mg/kg ideal 
body weight, IBW). Subjects in Group I will receive methadone (IV bolus, at induction of 
anesthesia) as their primary intraoperative opioid.  Dose of methadone may be increased up 
to 0.3 mg/kg IBW following preliminary analysis and review of initial subjects enrolled to 
Group I. Subjects in Group II (control) will receive intraoperative opioid administration at 
the discretion of the anesthesia providers (typically fentanyl or morphine). Postoperative 
pain management for both groups will be per standard of care.   
Inclusion and 
Exclusion 
Criteria 
Inclusion Criteria 
1. Age 18-65 years 
2. Undergoing general anesthesia and moderately painful, ambulatory surgical procedures, 
with anticipated postop stay of < 24 hours 
3. Signed, written, informed consent  
Exclusion Criteria 
1. History of liver or kidney disease. 
2. Females who are pregnant or nursing. 
3. Opioid tolerant patients (e.g. preoperative methadone therapy or use of fentanyl 
transdermal patches) 
4. History of allergy to methadone 
Measurements 
Total intraoperative and postoperative opioid administration during hospitalization will be 
recorded from the patient’s electronic medical record (EMR). Pain intensity will be assessed 
using the Numeric Rating Scale (NRS) and colored-visual analogue scale. Pain relief will 
be assessed using five point scale (0-no relief, 4-complete pain relief). Postoperative 
sedation will be recorded using Modified Observer`s Assessment of Alertness/Sedation 
(MOAA/S). Assessment of opioid side effects will be performed using Opioid-Related 
Symptom Distress Scale (ORSDS). Daily opioid consumption and daily pain self-
assessments using a colored-visual analogue scale will be recorded in a home diary for 
approx 30 days following surgery (from hospital discharge until postop clinic visit). 
Additional ORSDS assessments will be recorded at various timepoints (approx 7, 14 and 30 
days postop) in the home diary.  Subjects may have their CYP2B6 genotype determined. 


7 
 
CONFIDENTIAL: This document is the intellectual property of Helga Komen, MD. Acceptance of this document 
constitutes the agreement by the recipient that no unpublished information contained herein will be published or disclosed 
without prior written approval.  
Statistical 
Methodology 
Demographic data including race, sex, and age will be analyzed using chi-square and t- test 
or ANOVA, as appropriate. Baseline characteristics of the cohort will be described. Total 
daily opioid consumption and pain scores using NRS, will be compared between the groups.  
Outcome measures will be expressed as the mean and standard deviation. Group outcomes 
will be compared across the two groups, using t-test and/or analysis of variance, ANOVA 
and MANCOVA to account for potential cofounders. 
Outcomes 
Primary: Intraoperative and postoperative opioid utilization    
Secondary:  
1) Opioid consumption and pain relief within first 30 postoperative days 
2) Pain scores and pain self-assessments 
3) Influence of CYP2B6*6 genotype on methadone clinical effectiveness for pain 
relief and opioid consumption 
 
 
 


8 
 
CONFIDENTIAL: This document is the intellectual property of Helga Komen, MD. Acceptance of this document 
constitutes the agreement by the recipient that no unpublished information contained herein will be published or disclosed 
without prior written approval.  
1. Specific Aims 
1.1.  To study the effects of a single dose of methadone on postoperative pain and opioid 
consumption in patients undergoing moderately painful, ambulatory surgical procedures. 
1.2. Determine opioid consumption and pain relief within first 30 postoperative days 
1.3. Determine cytochrome P4502B6 (CYP2B6) genotype in patients receiving methadone, and any 
relationship to postop pain relief and opioid consumption 
 
2. Background 
Inadequate pain relief has a significant psychological and physiological impact on patients. The degree to 
which  postoperative pain is controlled impacts the ability of patients to cope with the next pain episode 
(1, 2). Postoperative pain itself is a risk factor for development of chronic pain syndromes (3).  
 
Methadone is a µ opioid agonist which is highly efficacious in the treatment of acute, chronic, 
neuropathic and cancer pain.  In adults it is increasingly being used as a first-line analgesic.  Methadone is 
highly efficacious in adult anesthesia and postoperative pain (4, 5). The typical dose for adult inpatient 
anesthesia is 20 mg (nominally 0.3 mg/kg) at the beginning of anesthesia.  Methadone is advantageous 
because it has slow elimination, resulting in prolonged effect and significantly diminished need for 
postoperative analgesics.  Reducing postop opioid analgesic use also decreases the potential for opioid-
related side effects.  Methadone has a long half-life, averaging 24-36 hours in healthy adults and 
adolescent patients.  It has no active metabolites or pro-drug forms.  Methadone is metabolized in the 
liver primarily by cytochrome P450 CYP2B6 (6, 7). 
 
Perioperative analgesia remains a major challenge for physicians who care for patients undergoing any 
type of surgery, including ambulatory and 24 hour observation procedures. We propose to compare the 
standard of care intraoperative opioid administration to intraoperative methadone bolus in reducing 
postoperative opioid consumption and prescribing. 
 
Evaluating the role of methadone in ambulatory surgery patients is advantageous because 1) prolonged 
analgesia from methadone is expected to decrease the need for additional opioids in the immediate 
postoperative period, 2) opioid quantities routinely prescribed upon discharge may be reduced with 
methadone use,  3) lower overall dose of opioids administered can decrease possible side effects of 
opioids, and 4) improved immediate postoperative pain relief can decrease occurrence of chronic 
postoperative pain. 
 
Assessment of pain has become standard practice in the treatment of surgical patients. Several tools are 
often used, including the Numeric Rating Scale and colored-visual analogue scale (8, 9, 10).  
 
We propose to evaluate intraoperative and postoperative opioid consumption, pain intensity and pain 
relief in patients undergoing moderately painful, ambulatory surgical procedures (anticipated length of 
stay <24 hrs) in 2 cohorts, and 2 groups in each cohort. Cohort 1 is ambulatory patients with <24 hr 
overnight stay, cohort 2 is same-day surgery outpatients).  In each cohort, Group I will receive a single 
dose of methadone during surgery and Group II will receive a non-methadone intraoperative opioid 
(typically fentanyl or morphine).  Secondarily, we will study opioid consumption and pain self-
assessments within approximately the first 30 postoperative days, or until the initial postop clinic visit. 
 
3. Drug Information 
Methadone hydrochloride is a synthetic μ-agonist with multiple actions qualitatively similar to those of 
morphine.  Onset of effect is about 2-10 min for parenteral dosing.  Methadone is primarily metabolized 
by N-demethylation to an inactive metabolite, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidene 
(EDDP). In vivo, CYP2B6 is a major determinant of metabolism to inactive metabolites which are 
excreted mainly in the urine.  The terminal half-life (T½) in healthy adults averages 24-36 hrs (11, 12). 


9 
 
CONFIDENTIAL: This document is the intellectual property of Helga Komen, MD. Acceptance of this document 
constitutes the agreement by the recipient that no unpublished information contained herein will be published or disclosed 
without prior written approval.  
The most common side effect of methadone, like other opioids, is sedation, nausea and vomiting.  
Respiratory depression is the chief hazard associated with methadone, like all opioids.  
 
4. Eligibility 
Inclusion Criteria 
 Age 18-65 years 
 Undergoing general anesthesia and moderately painful, ambulatory surgical procedures with 
anticipated postop hospital stay of < 24 hours 
 Signed, written, informed consent  
 
Exclusion Criteria 
 History of or known liver or kidney disease. 
 Females who are pregnant or nursing. 
 Opioid tolerant patients (e.g. preoperative methadone therapy or use of fentanyl transdermal patches) 
 History of allergy to methadone 
 
5. Enrollment 
Subjects will be approached prior to surgery in the Center for Preoperative Assessment and Planning or 
preoperative holding area.  Patients will be consented for participation and enrolled in the study by trained 
study personnel. 
 
6. Methods 
Preoperative and Intraoperative Period 
Enrolled subjects will be asked to complete a questionnaire about their current pain and what they 
anticipate following surgery. Patients will receive standard physiologic monitoring for anesthesia and 
postoperative care.  Subjects within each cohort (n≥60 evaluable, depending on the number of dose levels 
in each cohort) are randomized 1:2 to receive either control (typical intraop opioid, such as fentanyl or 
morphine) or methadone HCl (0.1 – 0.3 mg/kg ideal body weight, IBW). It is anticipated that the first ten 
patients will receive 0.1 mg/kg IV methadone. If patients still have significant post-op opioid 
requirements, subsequent groups may receive 0.2 mg/kg and then 0.3 mg/kg ideal body weight. 
 
Anesthesia and surgical care will not be altered for the purposes of this investigation, except that subjects 
in methadone group will receive methadone as their intraoperative opioid, rather than leaving the choice 
of intraoperative opioid to the anesthesiologist. The control group patients will receive intraoperative 
analgesia with opioids other than methadone left at the discretion of their anesthesiologist (typically 
fentanyl or morphine). 
 
Administration of Study Medication 
Methadone is administered as an IV bolus at induction of anesthesia. Methadone hydrochloride is 
available commercially for injection (10 mg/ml). Subjects randomized to the control group will receive 
typical (non-methadone) opioids. Both groups will receive standard of care postoperative analgesia as 
determined by the treating physician.  Postoperative care is not altered for purposes of this study. 
 
Assessments 
Pain assessments at rest (when patient awake) will be conducted in the postoperative period by a trained 
member of the research team. These will occur after handoff in the Postop Anesthesia Care Unit (PACU) 
and approx every 15 minutes during first PACU hour, then approx every hour for the next 4 hours and at 
bedtime. The pain assessments will also be performed at approx 24 hrs or prior to discharge from the 
hospital, whichever occurs first. Pain intensity will be assessed using the 0-10 Numeric Rating Scale and 
a colored-visual analogue scale. Pain relief will be assessed using five point scale (0-no relief, 4-complete 


10 
 
CONFIDENTIAL: This document is the intellectual property of Helga Komen, MD. Acceptance of this document 
constitutes the agreement by the recipient that no unpublished information contained herein will be published or disclosed 
without prior written approval.  
pain relief). Observed sedation (Modified Observer’s Assessment of Alertness/Sedation, MOAA/S) and 
subject’s self-assessment of sedation are recorded at the same intervals as pain assessments. Assessment 
of opioid side effects is performed at approximately 24 hrs or prior to discharge from the hospital using 
Opioid-Related Symptom Distress Scale (ORSDS).  The total amount of other drugs administered during 
hospitalization for prophylaxis or treatment of opioid side effects will be recorded from the EMR. Daily 
home opioid usage and pain self-assessments will be recorded in a home diary. The ORSDS assessments 
will also be completed at various timepoints (approximately 7, 14 and 30 days postop). 
 
Any adverse events are described, recorded and reported according to GCP and IRB regulations. 
 
7. Data Collection and Monitoring. 
Opioid Consumption During Hospitalization 
The EMR will be used to calculate the amount of morphine or morphine equivalents administered during 
surgery and until discharge, as well as other drug administration for treatment and/or prophylaxis of 
possible opioid side effects. 
 
Follow-up Assessments 
A home diary will be used to assess daily drug dosing history upon discharge from the hospital until the 
patient’s postop clinic visit at approximately 30 days. Subjects will also record daily pain self-
assessments using a colored-visual analogue scale (at rest, with activity and with coughing). The ORSDS 
will be completed and recorded on approximately the 7th, 14th and 30th day. We will also ask subjects 
about remaining number of pain medications and their disposal at the 30 day time point. 
 
CYP Genotyping 
Approximately 5 ml of blood will be collected from an IV line for CYP2B6 genotyping.  Genotyping will 
be performed at the WUSTL Genome Technology Access Center (GTAC).  
 
Other Measurements 
Required baseline measurements that will be obtained from the EMR are age, vital signs, weight, height, 
and peripheral oxygen saturation by pulse oximetry and are all collected as standard of care. 
 
8. Data and Safety Monitoring Plan. 
In general, the Department of Anesthesiology has developed a specific set of Standard Operating 
Procedures (SOPs) for clinical research.  All individuals working on study are required to read and be 
totally familiar with and compliant with the SOPs.  The SOPs are in part developed from and are 
compliant with the Institutional guidelines, including those for a) Interactions with the Washington 
University Human Subjects Review Committee, b) Informed Consent Development and Implementation, 
c) Subject Recruitment and Screening, d)  Subject Management While on Study, e) Adverse Event 
Reporting. The specific plan for submitting Adverse Event Reports to the IRB is detailed in the SOP for 
Adverse Event Reporting. 
 
The specific monitoring plan for this investigation is commensurate with the risks, size and complexity of 
the investigations planned.  The potential risks are attributable to the use of methadone.  Based on the 
small size and relatively low risks nature of the protocol, only the PI and CoI are involved in monitoring 
plan, rather than a full DSMB.  These individuals will review the annual summary of adverse events. In 
addition, they will review all reports of a Serious Adverse Event, or an Unexpected Adverse Event.   
 
9. Statistical Methods 
Primary Assessment 
Overall opioid (morphine equivalents) consumption for each patient during hospital stay 
Absolute pain and sedation scores 


11 
 
CONFIDENTIAL: This document is the intellectual property of Helga Komen, MD. Acceptance of this document 
constitutes the agreement by the recipient that no unpublished information contained herein will be published or disclosed 
without prior written approval.  
Secondary Assessments 
Opioids (morphine equivalence) consumption within approx. first 30 postoperative days 
Postoperative pain self assessments 
CYP2B6*6 Genotype 
 
Analysis  
Sample Size: Our initial plan is to enroll ≥ 60 evaluable subjects in each of two cohorts for this pilot study  
.  More specifically, this pilot plans 20 evaluable subjects in each methadone group within each cohort, 
with requisite proportional controls.  Total number in each of the two cohorts will reflect the number of 
dose groups in each cohort (per escalation).  Anticipated total evaluable is <200. 
 
Statistical Analysis: Each cohort is analyzed separately.  Baseline characteristics of each cohort and 
groups within each cohort will be described. Demographic data including race, sex, and age at study entry 
will be analyzed using chi-square and t-test or ANOVA, as appropriate. Total daily opioid consumption 
and pain scores using NRS will be compared between the groups.  Outcome measures will be expressed 
by the mean and standard deviation. Group outcomes will be compared across the two groups, using t-test 
and/or analysis of variance, ANOVA and MANCOVA to account for potential cofounders. 
 
10. Risk Assessment 
Methadone    
The most common side effect of opioids such as methadone is mild sedation. Since patients will be 
anesthetized during this period, clinical methadone effects are expected to be no different from those of 
anesthesia and any other opioid administered during anesthesia.  The most common adverse effect of 
methadone is nausea and/or vomiting.  Patients will have only clear liquids 6 hours before anesthesia, per 
standard of care.  If nausea and/or vomiting occur, they will be treated using the standard of care for all 
post-anesthesia nausea and vomiting.  Respiratory depression is a potential concern with all opioids, but 
has not been problematic at the doses of methadone that have been used in similar previous studies.  Mild 
respiratory depression is defined as respiratory rate <8/min in adults.  Severe depression will be defined 
as the administration of naloxone to a patient with respiratory rate < 6/min.  If treatment is required, 
naloxone will be used.  Patients in the hospital are routinely periodically monitored by blood pressure 
and/or pulse oximetry, and receive supplemental oxygen if dictated, according to good clinical practice.   
 
Special Precautions 
Standard of care for all surgical patients includes an IV, pulse oximetry, ECG, blood pressure monitoring. 
 
Genotyping 
With regard to the determination of CYP2B genotype: 1) CYP2B genes are not associates with any 
disorder(s), syndrome(s), or adverse condition. 2) Samples will be kept confidentially. They will be 
coded, with a key to the code linking code numbers to names kept at a separate location, under lock and 
key. 3) The link to identifiers will be destroyed at the end of the study. 4) We have no evidence to suggest 
that testing will provide evidence of previously undiagnosed or unrecognized illness, or susceptibility to 
illness. 5) We will not use samples for any purpose other than to study genes related to the disposition and 
response to study drugs. 6) Blood samples will not be used to establish permanent cell lines. 7) Data will 
be stored under lock and key (office, file cabinet) and only the investigators will have access. If data are 
published, there will be no link to identifiers. Study data will not be revealed to any organization, 
individuals other than the subjects, or the subjects themselves. 8) We will not enter any genetic study data 
in subjects’ medical records. 9) Studies are not likely to result in findings that meet the National Bioethics 
Advisory Commission criteria for disclosure. 10) We will not have genetics counseling available to 
subjects, as they will not be informed of results and there are no know implications with respect to 
disease. 11) DNA samples will stripped of identifiers and given a separate code numbers unrelated to the 
subjects’ study identification numbers. The code key will be kept by the PI under lock and key. 


12 
 
CONFIDENTIAL: This document is the intellectual property of Helga Komen, MD. Acceptance of this document 
constitutes the agreement by the recipient that no unpublished information contained herein will be published or disclosed 
without prior written approval.  
Procedures to Maintain Confidentiality 
Any information that is obtained in connection with research that can be identified with a subject will 
remain confidential.  The consent form, medical information, flow-sheets, will be stored under lock and 
key (office, file cabinet) and only the PI, physician investigators, and research team will have access.  
Statisticians involved in the project will have access to de-identified data for the purposes of analysis.   
 
Risk/Benefit Assessment 
The dose of methadone given will be a standard analgesic dose, and it might provide longer pain relief 
than other opioids. The risk of respiratory depression is no more than that expected from standard 
morphine therapy as the patients will only receive one dose of methadone and it will be at doses less than 
treatment doses.  
 
11. Human Subjects Research 
Protection of Human Subjects 
The study will be conducted under appropriate Washington University Institutional Review Board 
protocols and consent forms approvals.  The study will be conducted under the supervision of the PI and 
Co-Investigator, who is a Board-Certified anesthesiologist with many years of experience in the conduct 
of human volunteer studies. 
 
Sources of Materials 
Information including demographic data, outpatient medications, chronic medical conditions, surgical 
procedure, length of stay, opioid and other drug administration and physiological monitoring will be 
obtained from the patient’s electronic medical record. 
 
Recruitment and Informed Consent 
Patients will be screened based on operating room schedules, and approached prior to surgery at the 
Barnes-Jewish Hospital Center for Preoperative Planning and Assessment. All study related procedures, 
risks and benefits will be described to eligible patients, and time will be provided for addressing all 
questions and concerns. 
   
Potential Benefits of the Proposed Research to the Subjects and Others 
1) Prolonged analgesia from methadone is expected to decrease the need for additional opioids in the 
immediate postoperative period, 2) opioid quantities routinely prescribed upon discharge may be reduced 
with methadone us, 3) lower overall dose of opioids administered can decrease possible side effects of 
opioids, and 4) improved immediate postoperative pain relief may decrease the occurrence of chronic 
postoperative pain 
 
Inclusion of Women 
Studies and their advertisements actively encourage the participation of women in the research. Women 
of childbearing potential are not excluded from our research protocols.  Pregnancy testing is performed as 
standard of care to protect female research subjects, and subjects are instructed when appropriate to use 
adequate contraceptive measures and avoid breastfeeding. 
 
Inclusion of Minorities 
All of our studies actively encourage the participation of minorities in the research.  Our minority 
recruiting typically matches the demographic composition of the Washington University community from 
which subjects will be recruited (78% white, 21% Black, <1 % Hispanic).  
 
Inclusion of Children 
Children <18 yr will not be studied in these investigations. 
 
 


13 
 
CONFIDENTIAL: This document is the intellectual property of Helga Komen, MD. Acceptance of this document 
constitutes the agreement by the recipient that no unpublished information contained herein will be published or disclosed 
without prior written approval.  
12. References 
 
1. 
Apfelbaum, J. L., Chen, C., Mehta, S. S., et al. Postoperative pain experience: results from a 
national survey suggest postoperative pain continues to be undermanaged. Anesth. Analg. 97:534–540, 
2003. 
2. 
Sandkühler J. Fear the pain. Lancet. 2002 Aug 10;360(9331):426.  
3. 
Perkins FM, Kehlet H. Chronic pain as an outcome of surgery. A review of predictive factors. 
Anesthesiology. 2000 Oct;93(4):1123–33. 
4. 
Gourlay GK, Wilson PR, Glynn CJ. Pharmacodynamics and pharmacokinetics of methadone 
during the perioperative period. Anesthesiology. 1982 Dec;57(6):458–67.  
5. 
Gourlay GK, Willis RJ, Wilson PR. Postoperative pain control with methadone: influence of 
supplementary methadone doses and blood concentration--response relationships. Anesthesiology. 1984 
Jul;61(1):19–26.  
6. 
Kharasch ED, Hoffer C, Whittington D, Sheffels P. Role of hepatic and intestinal cytochrome 
P450 3A and 2B6 in the metabolism, disposition, and miotic effects of methadone. Clin. Pharmacol. Ther. 
2004 Sep;76(3):250–69.  
7. 
Totah RA, Sheffels P, Roberts T, Whittington D, Thummel K, Kharasch ED. Role of CYP2B6 in 
stereoselective human methadone metabolism. Anesthesiology. 2008 Mar;108(3):363–74.  
8. 
Moore A, Moore O, McQuay H, Gavaghan D. Deriving dichotomous outcome measures from 
continuous data in randomised controlled trials of analgesics: use of pain intensity and visual analogue 
scales. Pain. 1997 Feb;69(3):311–5.  
9. 
Giordano J, Abramson K, Boswell MV. Pain assessment: subjectivity, objectivity, and the use of 
neurotechnology. Pain Physician. 2010 Jul-Aug;13(4):305-15. 
10. 
Gourlay GK, Wilson PR, Glynn CJ. Methadone produces prolonged postoperative analgesia. Br 
Med J (Clin Res Ed) 1982;284:630-1. 
11. 
Kharasch ED: Intraoperative methadone: rediscovery, reappraisal and reinvigoration? Anesth 
Analg 2011:112:13-6 
12. 
Sharma A, Tallchief D, Blood J, Kim T, London A, Kharasch ED: Perioperative 
pharmacokinetics of methadone in adolescents. Anesthesiology 2011:115:1153-61