Pharmacogenomics of Methadone in Spine Fusion Surgery

Scoliosis Clinical Trial

Official title:

The Influence of Pharmacogenetics on Methadone Dose, Safety, and Outcomes After Spine Fusion

Clinical Trial Details — Status: Withdrawn

Administrative data

• NCT number: NCT01677650
• Other study ID #: STU00064915
• Status: Withdrawn
• Phase: Phase 1
• First received: August 30, 2012
• Last updated: April 21, 2015
• Start date: March 2014
• Est. completion date: January 2015

Study information

• Verified date: April 2015
• Source: Northwestern University
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review Board
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Withdrawn
• Enrollment: 0
• Est. completion date: January 2015
• Est. primary completion date: January 2015
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 75 Years

Eligibility

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 Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Kyphosis
• Scoliosis

Intervention

Drug:
• Methadone
Methadone IV Pre-Induction of Anesthesia 0.15 to 0.5 mg/kg

Locations

Country	Name	City	State
United States	Northwestern Memorial Hospital	Chicago	Illinois

Sponsors (1)

Lead Sponsor	Collaborator
Northwestern University

Country where clinical trial is conducted

United States, 

References & Publications (23)

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Gourlay GK, Wilson PR, Glynn CJ. Pharmacodynamics and pharmacokinetics of methadone during the perioperative period. Anesthesiology. 1982 Dec;57(6):458-67. — View Citation

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. — View Citation

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. — View Citation

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

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. — View Citation

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

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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

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. — View Citation

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. — View Citation

* Note: There are 23 references in all — Click here to view all references

Outcome

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