Pharmacogenomics of Methadone in Spine Fusion Surgery - Full Text View

Purpose

The overall objective is to develop a patient oriented research program to efficiently evaluate the effects of pharmacogenetic variants on the dose-response relationships and safety of opioids and non-opioid analgesics. If an opioid regimen can be created that produces excellent opioid analgesia with minimal toxicity related to supratherapeutic opioid concentrations (i.e., ventilatory depression), other non-opioid analgesics (i.e., gabapentin/pregabalin, ketamine, lidocaine, cyclooxygenase inhibitors, etc.) that may decrease preoperative opioid requirements can be more efficiently and safely evaluated. These interventions may limit the opioid related toxicities related to effect site concentrations that are below those required when opioids are the predominant analgesic, such as opioid related ileus. Methadone's slow elimination clearance and limited pharmacokinetic drug-drug interactions make it an attractive perioperative opioid. The first step towards personalized opioid analgesia is to determine the effect of common pharmacogenetic variants that affect either methadone metabolism (CYP2B6) or opioid elimination.

This study is being done to find the optimal dose of methadone (a long acting pain medication) that decreases the amount of pain that people have after spine surgery. Five different doses of methadone will be compared to each other, while keeping the remainder of the anesthetic routine for surgery. The investigators will determine the analgesic dose-response of methadone. The investigators will also determine the effect of methadone on the incidence of opioid related side effects, the quality of outcome of recovery, and the change in the 3-month opioid use.

Condition	Intervention	Phase
Spinal Fusion	Drug: Methadone	Phase 1

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor) Primary Purpose: Treatment
Official Title:	The Influence of Pharmacogenetics on Methadone Dose, Safety, and Outcomes After Spine Fusion

Resource links provided by NLM:

MedlinePlus related topics: Depression Nausea and Vomiting

Drug Information available for: Methadone Methadone hydrochloride

U.S. FDA Resources

Further study details as provided by Northwestern University:

Primary Outcome Measures:

Time until initial request for postoperative analgesic. [ Time Frame: 60 minutes after extubation, 24, 48, and 72 hours after methadone administration ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

The determination of minimum effective analgesic concentration of methadone. [ Time Frame: 60 minutes after extubation, 24, 48, and 72 hours after methadone administration ] [ Designated as safety issue: No ]
Postoperative pain at rest and with movement (numerical rating scale, NRS) [ Time Frame: 60 minutes after extubation, 24, 48, and 72 hours after methadone administration ] [ Designated as safety issue: No ]
The number of occurrences of ventilatory depression during each evaluation interval [ Time Frame: 60 minutes after extubation, 24, 48, and 72 hours after methadone administration ] [ Designated as safety issue: Yes ]
Nausea and vomiting: number of rescue antiemetic doses and episodes of emesis [ Time Frame: 60 minutes after extubation, 24, 48, and 72 hours after methadone administration ] [ Designated as safety issue: No ]
Level of sedation (modified Observer's Assessment of Alertness and Sedation Scale, modified OAA/S scale) [ Time Frame: 60 minutes after extubation, 24, 48, and 72 hours after methadone administration ] [ Designated as safety issue: Yes ]
Occurence of pruritis [ Time Frame: 60 minutes after extubation, 24, 48, and 72 hours after methadone administration ] [ Designated as safety issue: No ]
Algometry to assess pain tolerance [ Time Frame: Pre-operatively, 60 minutes after extubation, 24, 48, and 72 hours after methadone administration ] [ Designated as safety issue: No ]
Degree of bother associated with opioid-related adverse effects: Opioid-related Symptom Distress Scale (OR-SDS) [ Time Frame: 24, 48, and 72 hours after methadone administration ] [ Designated as safety issue: No ]
Quality of Recovery: Quality of Recovery-40 score [ Time Frame: 24, 48, and 72 hours after methadone administration ] [ Designated as safety issue: No ]
Patient analgesic satisfaction [ Time Frame: 24, 48, and 72 hours after methadone administration ] [ Designated as safety issue: No ]
Assessment of back condition pre and post-operatively [ Time Frame: Pre-operatively, 6 weeks and 3 months post-operatively ] [ Designated as safety issue: No ]
Effects of common opioid related metabolic pathway polymorphisms on methadone's dose response relationships for analgesia and side effects [ Time Frame: Preoperatively ] [ Designated as safety issue: No ]
CYP2B6 Polymorphism effect on
1. Time to first request for analgesia
2. Secondary outcomes
Pupillometry for assessment of sedation [ Time Frame: Pre-operatively, 60 minutes after extubation, 24, 48, and 72 hours after methadone administration ] [ Designated as safety issue: No ]

Estimated Enrollment:	95
Study Start Date:	September 2012
Estimated Study Completion Date:	December 2014
Estimated Primary Completion Date:	December 2014 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Active Comparator: Methadone 0.5 mg/kg Methadone 0.5 mg/kg	Drug: Methadone Methadone IV Pre-Induction of Anesthesia 0.15 to 0.5 mg/kg
Experimental: Methadone 0.4 mg/kg Methadone 0.4 mg/kg	Drug: Methadone Methadone IV Pre-Induction of Anesthesia 0.15 to 0.5 mg/kg
Active Comparator: Methadone 0.3 mg/kg Methadone 0.3 mg/kg	Drug: Methadone Methadone IV Pre-Induction of Anesthesia 0.15 to 0.5 mg/kg
Active Comparator: Methadone 0.2 mg/kg Methadone 0.2 mg/kg	Drug: Methadone Methadone IV Pre-Induction of Anesthesia 0.15 to 0.5 mg/kg
Active Comparator: Methadone 0.15 mg/kg Methadone 0.15 mg/kg	Drug: Methadone Methadone IV Pre-Induction of Anesthesia 0.15 to 0.5 mg/kg

Eligibility

Ages Eligible for Study:	18 Years to 75 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

ASA physical status I, II, and III
male and non-pregnant female
English-speaking
undergoing elective < 3 vertebral level lumbar spine fusion (with and without interbody fusion)

Exclusion Criteria:

Use of more than the equivalent of 20 mg of IV morphine/24 hr in the past 2 weeks
history of substance abuse at any time in the past
known QT prolongation
Non-elective operations (i.e., cancer or trauma)
severe hepatic impairment (serum albumin <3.0 g/dL, history of liver disease)
pregnancy

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT01677650

Locations

United States, Illinois
Northwestern Memorial Hospital
Chicago, Illinois, United States, 60611

Sponsors and Collaborators

Northwestern University

Investigators

Principal Investigator:

Dhanesh K. Gupta, M.D.

Northwestern University Feinberg School of Medicine

More Information

Publications:

Rajaee SS, Bae HW, Kanim LE, Delamarter RB. Spinal fusion in the United States: analysis of trends from 1998 to 2008. Spine (Phila Pa 1976). 2012 Jan 1;37(1):67-76.

Jadad AR, Browman GP. The WHO analgesic ladder for cancer pain management. Stepping up the quality of its evaluation. JAMA. 1995 Dec 20;274(23):1870-3. Review.

Gottschalk A, Durieux ME, Nemergut EC. Intraoperative methadone improves postoperative pain control in patients undergoing complex spine surgery. Anesth Analg. 2011 Jan;112(1):218-23. Epub 2010 Apr 24.

Upton RN, Semple TJ, Macintyre PE. Pharmacokinetic optimisation of opioid treatment in acute pain therapy. Clin Pharmacokinet. 1997 Sep;33(3):225-44. Review.

Taylor S, Kirton OC, Staff I, Kozol RA. Postoperative day one: a high risk period for respiratory events. Am J Surg. 2005 Nov;190(5):752-6.

Taylor S, Voytovich AE, Kozol RA. Has the pendulum swung too far in postoperative pain control? Am J Surg. 2003 Nov;186(5):472-5.

Liu N, Kuhlman G, Dalibon N, Moutafis M, Levron JC, Fischler M. A randomized, double-blinded comparison of intrathecal morphine, sufentanil and their combination versus IV morphine patient-controlled analgesia for postthoracotomy pain. Anesth Analg. 2001 Jan;92(1):31-6.

Joris J, Kaba A, Lamy M. Transition between anesthesia and post-operative analgesia: relevance of intra-operative administration of analgesics. Acta Anaesthesiol Belg. 2001;52(3):271-9. Review.

Carroll IR, Angst MS, Clark JD. Management of perioperative pain in patients chronically consuming opioids. Reg Anesth Pain Med. 2004 Nov-Dec;29(6):576-91. Review.

Yaksh TL, Hua XY, Kalcheva I, Nozaki-Taguchi N, Marsala M. The spinal biology in humans and animals of pain states generated by persistent small afferent input. Proc Natl Acad Sci U S A. 1999 Jul 6;96(14):7680-6. Review.

Parker RK, Holtmann B, White PF. Effects of a nighttime opioid infusion with PCA therapy on patient comfort and analgesic requirements after abdominal hysterectomy. Anesthesiology. 1992 Mar;76(3):362-7.

Gourlay GK, Wilson PR, Glynn CJ. Pharmacodynamics and pharmacokinetics of methadone during the perioperative period. Anesthesiology. 1982 Dec;57(6):458-67. No abstract available.

Chui PT, Gin T. A double-blind randomised trial comparing postoperative analgesia after perioperative loading doses of methadone or morphine. Anaesth Intensive Care. 1992 Feb;20(1):46-51.

van Dorp EL, Kest B, Kowalczyk WJ, Morariu AM, Waxman AR, Arout CA, Dahan A, Sarton EY. Morphine-6beta-glucuronide rapidly increases pain sensitivity independently of opioid receptor activity in mice and humans. Anesthesiology. 2009 Jun;110(6):1356-63.

Egan TD, Huizinga B, Gupta SK, Jaarsma RL, Sperry RJ, Yee JB, Muir KT. Remifentanil pharmacokinetics in obese versus lean patients. Anesthesiology. 1998 Sep;89(3):562-73.

Lemmens HJ, Brodsky JB, Bernstein DP. Estimating ideal body weight--a new formula. Obes Surg. 2005 Aug;15(7):1082-3.

Bowdle TA, Even A, Shen DD, Swardstrom M. Methadone for the induction of anesthesia: plasma histamine concentration, arterial blood pressure, and heart rate. Anesth Analg. 2004 Jun;98(6):1692-7, table of contents.

Chernik DA, Gillings D, Laine H, Hendler J, Silver JM, Davidson AB, Schwam EM, Siegel JL. Validity and reliability of the Observer's Assessment of Alertness/Sedation Scale: study with intravenous midazolam. J Clin Psychopharmacol. 1990 Aug;10(4):244-51.

Apfelbaum JL, Gan TJ, Zhao S, Hanna DB, Chen C. Reliability and validity of the perioperative opioid-related symptom distress scale. Anesth Analg. 2004 Sep;99(3):699-709, table of contents.

Myles PS, Hunt JO, Fletcher H. Measuring health status (quality of recovery?) after anesthesia and surgery. Anesth Analg. 2001 Jan;92(1):281.

Myles PS, Hunt JO, Nightingale CE, Fletcher H, Beh T, Tanil D, Nagy A, Rubinstein A, Ponsford JL. Development and psychometric testing of a quality of recovery score after general anesthesia and surgery in adults. Anesth Analg. 1999 Jan;88(1):83-90.

Chou WY, Wang CH, Liu PH, Liu CC, Tseng CC, Jawan B. Human opioid receptor A118G polymorphism affects intravenous patient-controlled analgesia morphine consumption after total abdominal hysterectomy. Anesthesiology. 2006 Aug;105(2):334-7.

Romberg RR, Olofsen E, Bijl H, Taschner PE, Teppema LJ, Sarton EY, van Kleef JW, Dahan A. Polymorphism of mu-opioid receptor gene (OPRM1:c.118A>G) does not protect against opioid-induced respiratory depression despite reduced analgesic response. Anesthesiology. 2005 Mar;102(3):522-30.

Responsible Party:	Dhanesh Gupta, Associate Professor of Anesthesiology & Neurological Surgery, Northwestern University
ClinicalTrials.gov Identifier:	NCT01677650 History of Changes
Other Study ID Numbers:	STU00064915
Study First Received:	August 30, 2012
Last Updated:	October 24, 2012
Health Authority:	United States: Institutional Review Board

Keywords provided by Northwestern University:

Spinal Fusion
Opioid Analgesia

Additional relevant MeSH terms:

Methadone
Analgesics, Opioid
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Pharmacologic Actions

Central Nervous System Agents
Therapeutic Uses
Central Nervous System Depressants
Antitussive Agents
Respiratory System Agents
Narcotics

ClinicalTrials.gov processed this record on May 21, 2013