Adjunct Methadone to Decrease the Duration of Mechanical Ventilation in the Medical Intensive Care Unit

• ClinicalTrials.gov Identifier: NCT02025855
• Recruitment Status: Unknown
• First Posted: January 1, 2014
• Last Update Posted: January 17, 2014
• Sponsor: Henry Ford Health System
• Information provided by (Responsible Party): Thomas Smoot, PharmD, BCPS, Henry Ford Health System

Tracking Information

• First Submitted Date: December 30, 2013
• First Posted Date: January 1, 2014
• Last Update Posted Date: January 17, 2014
• Study Start Date: January 2014
• Estimated Primary Completion Date: March 2015 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 30, 2013)

Time to extubation [ Time Frame: Up to 14 days ]

The time to extubation will be calculated and compared for both groups.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: December 30, 2013)

• Cumulative opioid consumption [ Time Frame: Up to 14 days ]
  Cumulative doses of opioids will be collected and converted to morphine equivalents for analysis.
• Level of sedation [ Time Frame: Up to 14 days ]
  Levels of pain and sedation will be assessed per institutional policy, which utilizes the Motor Agitation Assessment Scale (MAAS). Average daily scores will be collected and compared for each group.
• Corrected QT interval [ Time Frame: Up to 14 days ]
  QTc intervals will be calculated and documented at baseline and every 24 hours after to ensure it does not become prolonged. These values will be compared between groups.
• Cumulative Antipsychotic Use [ Time Frame: Up to 14 days ]
  The number of doses of antipsychotic medications will be collected and compared as a surrogate marker for presumed delirium.
• Cumulative benzodiazepine consumption [ Time Frame: Up to 14 days ]
  Doses of all benzodiazepines will be collected and compared between groups to determine if methadone reduces consumption.

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Adjunct Methadone to Decrease the Duration of Mechanical Ventilation in the Medical Intensive Care Unit
• Official Title: Adjunct Methadone to Decrease the Duration of Mechanical Ventilation in the Medical Intensive Care Unit

Brief Summary

The purpose of this study is to determine if administering methadone to mechanically ventilated patients in the medical intensive care unit (ICU) requiring continuous infusions of sedatives and analgesics will decrease the time of mechanical ventilation, when initiated within 48 hours of their admission. Patients meeting enrollment criteria will be randomly assigned to receive methadone or placebo in addition to standard care. Methadone is a long acting pain medication that is approved by the Food and Drug Administration (FDA) to manage withdrawal from opioids and moderate to severe pain. Both of these indications are a frequent concern for critically ill patients that require mechanical ventilation. These patients often require intravenous (IV) opioids to manage the pain they experience due to their illness, procedures, and mechanical ventilation. During this time patients can develop physical dependence, which leads to withdrawal symptoms when the opioids are stopped or the dose is reduced. These symptoms can include agitation, pain, diarrhea and several others. Currently this is managed by a slow reduction in the dose of the IV opioid, but this can lead to prolonged time on mechanical ventilation, which has been associated with increased morbidity. Administering oral methadone to patients experiencing withdrawal symptoms has been shown to reduce and even eliminate these symptoms in the outpatient setting. This should also benefit patients in the ICU experiencing withdrawal from intravenous opioids required during their stay. It may allow for the other opioids to be discontinued more quickly, allowing for a shorter duration of mechanical ventilation.

The level of pain and sedation will be assessed between groups randomized to either methadone or placebo in addition to current intravenous sedative and analgesic agents. The duration of mechanical ventilation will be assessed between both groups. Opioid withdrawal symptoms may manifest or be mistaken for delirium symptoms. ICU delirium is often managed with antipsychotic medications. To assess if methadone can reduce the need for antipsychotic medication, all administered antipsychotic doses will be recorded and total consumption will be compared between the two groups. Methadone has been associated with abnormal heart rhythms in rare instances. To ensure patient safety, data from the heart monitor will be collected and compared between the two groups to assess for QT interval prolongation.

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 4
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment

Condition

• Opioid Use, Unspecified With Withdrawal
• Opioid-Induced Disorders
• Delirium

Intervention

• Drug: Methadone
• Drug: Placebo

Study Arms

• Experimental: Methadone
  Methadone will be administered at a dose calculated from the subjects total daily opioid requirements, with a maximum methadone dose of 60 mg per day. The methadone will be administered every 8 hours as 5 mg capsules that will be given via an enteral feeding tube.
  Intervention: Drug: Methadone
• Placebo Comparator: Placebo
  This will be a capsule containing only lactose and will be given every 8 hours via an enteral feeding tube. The number of placebo capsules will be calculated based on the subjects opioid requirements. This will ensure the same number of capsules will be given despite which arm the patient is enrolled in.
  Intervention: Drug: Placebo

Publications *

• Kollef MH, Levy NT, Ahrens TS, Schaiff R, Prentice D, Sherman G. The use of continuous i.v. sedation is associated with prolongation of mechanical ventilation. Chest. 1998 Aug;114(2):541-8.
• Wanzuita R, Poli-de-Figueiredo LF, Pfuetzenreiter F, Cavalcanti AB, Westphal GA. Replacement of fentanyl infusion by enteral methadone decreases the weaning time from mechanical ventilation: a randomized controlled trial. Crit Care. 2012 Dec 12;16(2):R49. doi: 10.1186/cc11250.
• Lugo RA, MacLaren R, Cash J, Pribble CG, Vernon DD. Enteral methadone to expedite fentanyl discontinuation and prevent opioid abstinence syndrome in the PICU. Pharmacotherapy. 2001 Dec;21(12):1566-73.
• Martell BA, Arnsten JH, Krantz MJ, Gourevitch MN. Impact of methadone treatment on cardiac repolarization and conduction in opioid users. Am J Cardiol. 2005 Apr 1;95(7):915-8.
• Tobias JD, Schleien CL, Haun SE. Methadone as treatment for iatrogenic narcotic dependency in pediatric intensive care unit patients. Crit Care Med. 1990 Nov;18(11):1292-3.
• Johnson PN, Boyles KA, Miller JL. Selection of the initial methadone regimen for the management of iatrogenic opioid abstinence syndrome in critically ill children. Pharmacotherapy. 2012 Feb;32(2):148-57. doi: 10.1002/PHAR.1001. Epub 2012 Jan 24. Review.
• Bowens CD, Thompson JA, Thompson MT, Breitzka RL, Thompson DG, Sheeran PW. A trial of methadone tapering schedules in pediatric intensive care unit patients exposed to prolonged sedative infusions. Pediatr Crit Care Med. 2011 Sep;12(5):504-11. doi: 10.1097/PCC.0b013e3181fe38f5.
• Hovav E, Weinstock M. Temporal factors influencing the development of acute tolerance to opiates. J Pharmacol Exp Ther. 1987 Jul;242(1):251-6.

Recruitment Information

• Recruitment Status: Unknown status
• Estimated Enrollment (submitted: December 30, 2013): 46
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: March 2015
• Estimated Primary Completion Date: March 2015 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Mechanically ventilated patients with opioid consumption greater than or equal to 1,200 mcg of fentanyl or equivalent consumption of another opioid per day during the first 48 hours of intubation.

Exclusion Criteria:

• Allergy to methadone
• Admitted for head injury
• Admitted for seizure
• Seizure during admission, prior to enrollment
• Subjects at high risk for developing a prolonged corrected QT (QTc) interval
• Gastric residual volume ≥200 mL
• Suspected obstruction or ileus
• Nausea and vomiting
• Recent abdominal surgery
• Active upper or lower gastrointestinal bleeding
• Active order for no medications by mouth or Total parenteral nutrition (TPN)
• Pregnancy
• Subjects receiving neuromuscular blocker infusions
• Subjects taking antipsychotics at baseline

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT02025855
• Other Study ID Numbers: Smoot_8503
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Thomas Smoot, PharmD, BCPS, Henry Ford Health System
• Study Sponsor: Henry Ford Health System
• Collaborators: Not Provided

Investigators

• Principal Investigator: Thomas L Smoot, PharmD; Henry Ford Health System

• PRS Account: Henry Ford Health System
• Verification Date: January 2014