NCT01677650

Brief 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.

Trial Health

30
At Risk

Trial Health Score

Automated assessment based on enrollment pace, timeline, and geographic reach

Trial has exceeded expected completion date
Timeline
Completed

Started Mar 2014

Geographic Reach
1 country

1 active site

Status
withdrawn

Health score is calculated from publicly available data and should be used for screening purposes only.

Trial Relationships

Click on a node to explore related trials.

Study Timeline

Key milestones and dates

First Submitted

Initial submission to the registry

August 30, 2012

Completed
4 days until next milestone

First Posted

Study publicly available on registry

September 3, 2012

Completed
1.5 years until next milestone

Study Start

First participant enrolled

March 1, 2014

Completed
10 months until next milestone

Primary Completion

Last participant's last visit for primary outcome

January 1, 2015

Completed
Same day until next milestone

Study Completion

Last participant's last visit for all outcomes

January 1, 2015

Completed
Last Updated

April 22, 2015

Status Verified

April 1, 2015

Enrollment Period

10 months

First QC Date

August 30, 2012

Last Update Submit

April 21, 2015

Conditions

ScoliosisKyphosis

Keywords

Spinal FusionOpioid Analgesia

Outcome Measures

Primary Outcomes (1)

  • Time until initial request for postoperative analgesic.

    60 minutes after extubation, 24, 48, and 72 hours after methadone administration

Secondary Outcomes (13)

  • The determination of minimum effective analgesic concentration of methadone.

    60 minutes after extubation, 24, 48, and 72 hours after methadone administration

  • Postoperative pain at rest and with movement (numerical rating scale, NRS)

    60 minutes after extubation, 24, 48, and 72 hours after methadone administration

  • The number of occurrences of ventilatory depression during each evaluation interval

    60 minutes after extubation, 24, 48, and 72 hours after methadone administration

  • Nausea and vomiting: number of rescue antiemetic doses and episodes of emesis

    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)

    60 minutes after extubation, 24, 48, and 72 hours after methadone administration

  • +8 more secondary outcomes

Study Arms (5)

Methadone 0.5 mg/kg

ACTIVE COMPARATOR

Methadone 0.5 mg/kg

Drug: Methadone

Methadone 0.4 mg/kg

EXPERIMENTAL

Methadone 0.4 mg/kg

Drug: Methadone

Methadone 0.3 mg/kg

ACTIVE COMPARATOR

Methadone 0.3 mg/kg

Drug: Methadone

Methadone 0.2 mg/kg

ACTIVE COMPARATOR

Methadone 0.2 mg/kg

Drug: Methadone

Methadone 0.15 mg/kg

ACTIVE COMPARATOR

Methadone 0.15 mg/kg

Drug: Methadone

Interventions

MethadoneDRUG

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

Also known as: Dolophine
Methadone 0.15 mg/kgMethadone 0.2 mg/kgMethadone 0.3 mg/kgMethadone 0.4 mg/kgMethadone 0.5 mg/kg

Eligibility Criteria

Age18 Years - 75 Years
Sexall
Healthy VolunteersNo
Age GroupsAdult (18-64), Older Adult (65+)

You may qualify if:

  • 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)

You may not qualify if:

  • 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

Contact the study team to confirm eligibility.

Sponsors & Collaborators

Study Sites (1)

Northwestern Memorial Hospital

Chicago, Illinois, 60611, United States

Location

Related Publications (23)

  • 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.

    PMID: 21311399BACKGROUND

  • 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.

    PMID: 7500538BACKGROUND

  • 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.

    PMID: 20418538BACKGROUND

  • 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.

    PMID: 9314613BACKGROUND

  • 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.

    PMID: 16226953BACKGROUND

  • 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.

    PMID: 14599609BACKGROUND

  • 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.

    PMID: 11133596BACKGROUND

  • 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.

    PMID: 11732383BACKGROUND

  • 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.

    PMID: 15635517BACKGROUND

  • 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.

    PMID: 10393880BACKGROUND

  • 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.

    PMID: 1539846BACKGROUND

  • 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.

    PMID: 6128949BACKGROUND

  • 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.

    PMID: 1609941BACKGROUND

  • 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.

    PMID: 19461298BACKGROUND

  • 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.

    PMID: 9743391BACKGROUND

  • 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.

    PMID: 16105412BACKGROUND

  • 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.

    PMID: 15155330BACKGROUND

  • 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.

    PMID: 2286697BACKGROUND

  • 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.

    PMID: 15333398BACKGROUND

  • 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.

    PMID: 11133650BACKGROUND

  • 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.

    PMID: 9895071BACKGROUND

  • 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.

    PMID: 16871067BACKGROUND

  • 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.

    PMID: 15731588BACKGROUND

MeSH Terms

Conditions

ScoliosisKyphosis

Interventions

Methadone

Condition Hierarchy (Ancestors)

Spinal CurvaturesSpinal DiseasesBone DiseasesMusculoskeletal Diseases

Intervention Hierarchy (Ancestors)

KetonesOrganic Chemicals

Study Officials

  • Dhanesh K. Gupta, M.D.

    Northwestern University Feinberg School of Medicine

    PRINCIPAL INVESTIGATOR
0

Study Design

Study Type
interventional
Phase
phase 1
Allocation
RANDOMIZED
Masking
QUADRUPLE
Who Masked
PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
Purpose
TREATMENT
Intervention Model
PARALLEL
Sponsor Type
OTHER
Responsible Party
PRINCIPAL INVESTIGATOR
PI Title
Associate Professor of Anesthesiology & Neurological Surgery

Study Record Dates

First Submitted

August 30, 2012

First Posted

September 3, 2012

Study Start

March 1, 2014

Primary Completion

January 1, 2015

Study Completion

January 1, 2015

Last Updated

April 22, 2015

Record last verified: 2015-04

Locations

US(1)