- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT01677650
Pharmacogenomics of Methadone in Spine Fusion Surgery
April 21, 2015 updated by: Dhanesh Gupta, Northwestern University
The Influence of Pharmacogenetics on Methadone Dose, Safety, and Outcomes After Spine Fusion
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.
Study Overview
Detailed Description
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.
Study Type
Interventional
Phase
- Phase 1
Contacts and Locations
This section provides the contact details for those conducting the study, and information on where this study is being conducted.
Study Locations
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Illinois
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Chicago, Illinois, United States, 60611
- Northwestern Memorial Hospital
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-
Participation Criteria
Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.
Eligibility Criteria
Ages Eligible for Study
18 years to 75 years (Adult, Older Adult)
Accepts Healthy Volunteers
No
Genders Eligible for Study
All
Description
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
Study Plan
This section provides details of the study plan, including how the study is designed and what the study is measuring.
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Quadruple
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Active Comparator: Methadone 0.5 mg/kg
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Methadone IV Pre-Induction of Anesthesia 0.15 to 0.5 mg/kg
Other Names:
|
Experimental: Methadone 0.4 mg/kg
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Methadone IV Pre-Induction of Anesthesia 0.15 to 0.5 mg/kg
Other Names:
|
Active Comparator: Methadone 0.3 mg/kg
|
Methadone IV Pre-Induction of Anesthesia 0.15 to 0.5 mg/kg
Other Names:
|
Active Comparator: Methadone 0.2 mg/kg
|
Methadone IV Pre-Induction of Anesthesia 0.15 to 0.5 mg/kg
Other Names:
|
Active Comparator: Methadone 0.15 mg/kg
|
Methadone IV Pre-Induction of Anesthesia 0.15 to 0.5 mg/kg
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Time Frame |
---|---|
Time until initial request for postoperative analgesic.
Time Frame: 60 minutes after extubation, 24, 48, and 72 hours after methadone administration
|
60 minutes after extubation, 24, 48, and 72 hours after methadone administration
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
The determination of minimum effective analgesic concentration of methadone.
Time Frame: 60 minutes after extubation, 24, 48, and 72 hours after methadone administration
|
60 minutes after extubation, 24, 48, and 72 hours after methadone administration
|
|
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
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60 minutes after extubation, 24, 48, and 72 hours after methadone administration
|
|
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
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60 minutes after extubation, 24, 48, and 72 hours after methadone administration
|
|
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
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60 minutes after extubation, 24, 48, and 72 hours after methadone administration
|
|
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
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60 minutes after extubation, 24, 48, and 72 hours after methadone administration
|
|
Occurence of pruritis
Time Frame: 60 minutes after extubation, 24, 48, and 72 hours after methadone administration
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60 minutes after extubation, 24, 48, and 72 hours after methadone administration
|
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Algometry to assess pain tolerance
Time Frame: Pre-operatively, 60 minutes after extubation, 24, 48, and 72 hours after methadone administration
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Pre-operatively, 60 minutes after extubation, 24, 48, and 72 hours after methadone administration
|
|
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
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24, 48, and 72 hours after methadone administration
|
|
Quality of Recovery: Quality of Recovery-40 score
Time Frame: 24, 48, and 72 hours after methadone administration
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24, 48, and 72 hours after methadone administration
|
|
Patient analgesic satisfaction
Time Frame: 24, 48, and 72 hours after methadone administration
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24, 48, and 72 hours after methadone administration
|
|
Assessment of back condition pre and post-operatively
Time Frame: Pre-operatively, 6 weeks and 3 months post-operatively
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Pre-operatively, 6 weeks and 3 months post-operatively
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Effects of common opioid related metabolic pathway polymorphisms on methadone's dose response relationships for analgesia and side effects
Time Frame: Preoperatively
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CYP2B6 Polymorphism effect on
|
Preoperatively
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Pupillometry for assessment of sedation
Time Frame: Pre-operatively, 60 minutes after extubation, 24, 48, and 72 hours after methadone administration
|
Pre-operatively, 60 minutes after extubation, 24, 48, and 72 hours after methadone administration
|
Collaborators and Investigators
This is where you will find people and organizations involved with this study.
Sponsor
Investigators
- Principal Investigator: Dhanesh K. Gupta, M.D., Northwestern University Feinberg School of Medicine
Publications and helpful links
The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.
General Publications
- 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. doi: 10.1213/01.ANE.0000133143.60584.38.
- 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. doi: 10.1097/00000542-200608000-00016.
- 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. doi: 10.1097/00000542-200503000-00008.
- 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. doi: 10.1213/ANE.0b013e3181d8a095. Epub 2010 Apr 24.
- 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. doi: 10.1097/00000539-199901000-00016.
- Gourlay GK, Wilson PR, Glynn CJ. Pharmacodynamics and pharmacokinetics of methadone during the perioperative period. Anesthesiology. 1982 Dec;57(6):458-67. doi: 10.1097/00000542-198212000-00005. 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. doi: 10.1177/0310057X9202000109.
- 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. doi: 10.1097/BRS.0b013e31820cccfb.
- Upton RN, Semple TJ, Macintyre PE. Pharmacokinetic optimisation of opioid treatment in acute pain therapy. Clin Pharmacokinet. 1997 Sep;33(3):225-44. doi: 10.2165/00003088-199733030-00005.
- 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.
- 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. doi: 10.1016/j.amjsurg.2005.07.015.
- 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. doi: 10.1016/j.amjsurg.2003.07.021.
- 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. doi: 10.1097/00000539-200101000-00007.
- 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.
- 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. doi: 10.1016/j.rapm.2004.06.009.
- 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. doi: 10.1073/pnas.96.14.7680.
- 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. doi: 10.1097/00000542-199203000-00007.
- 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. doi: 10.1097/ALN.0b013e3181a105de.
- 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. doi: 10.1097/00000542-199809000-00004.
- Lemmens HJ, Brodsky JB, Bernstein DP. Estimating ideal body weight--a new formula. Obes Surg. 2005 Aug;15(7):1082-3. doi: 10.1381/0960892054621350.
- 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):1692-1697. doi: 10.1213/01.ANE.0000114085.20751.20.
- Myles PS, Hunt JO, Fletcher H. Measuring health status (quality of recovery?) after anesthesia and surgery. Anesth Analg. 2001 Jan;92(1):281. doi: 10.1097/00000539-200101000-00062. No abstract available.
Study record dates
These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.
Study Major Dates
Study Start
March 1, 2014
Primary Completion (Anticipated)
January 1, 2015
Study Completion (Anticipated)
January 1, 2015
Study Registration Dates
First Submitted
August 30, 2012
First Submitted That Met QC Criteria
August 31, 2012
First Posted (Estimate)
September 3, 2012
Study Record Updates
Last Update Posted (Estimate)
April 22, 2015
Last Update Submitted That Met QC Criteria
April 21, 2015
Last Verified
April 1, 2015
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Musculoskeletal Diseases
- Spinal Diseases
- Bone Diseases
- Spinal Curvatures
- Scoliosis
- Kyphosis
- Physiological Effects of Drugs
- Central Nervous System Depressants
- Peripheral Nervous System Agents
- Analgesics
- Sensory System Agents
- Analgesics, Opioid
- Narcotics
- Respiratory System Agents
- Antitussive Agents
- Methadone
Other Study ID Numbers
- STU00064915
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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