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

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.

Study Overview

• Status: Unknown
• Conditions: Delirium; Opioid-Induced Disorders; Opioid Use, Unspecified With Withdrawal
• Intervention / Treatment: Drug: Placebo; Drug: Methadone

• Study Type: Interventional
• Enrollment (Anticipated): 46
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Henry Ford Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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.	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.	Drug: Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to extubation	The time to extubation will be calculated and compared for both groups.	Up to 14 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cumulative opioid consumption	Cumulative doses of opioids will be collected and converted to morphine equivalents for analysis.	Up to 14 days
Level of sedation	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.	Up to 14 days
Corrected QT interval	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.	Up to 14 days
Cumulative Antipsychotic Use	The number of doses of antipsychotic medications will be collected and compared as a surrogate marker for presumed delirium.	Up to 14 days
Cumulative benzodiazepine consumption	Doses of all benzodiazepines will be collected and compared between groups to determine if methadone reduces consumption.	Up to 14 days

Collaborators and Investigators

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

Publications and helpful links

General 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. doi: 10.1378/chest.114.2.541.
• 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. doi: 10.1592/phco.21.20.1566.34471.
• 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. doi: 10.1016/j.amjcard.2004.11.055.
• 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. doi: 10.1097/00003246-199011000-00024. No abstract available.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start: January 1, 2014
• Primary Completion (ANTICIPATED): March 1, 2015
• Study Completion (ANTICIPATED): March 1, 2015

Study Registration Dates

• First Submitted: December 30, 2013
• First Submitted That Met QC Criteria: December 30, 2013
• First Posted (ESTIMATE): January 1, 2014

Study Record Updates

• Last Update Posted (ESTIMATE): January 17, 2014
• Last Update Submitted That Met QC Criteria: January 15, 2014
• Last Verified: January 1, 2014

More Information

Terms related to this study

• Keywords: Methadone; Mechanical ventilation; ICU delirium; Iatrogenic opioid abstinence syndrome; Continuous sedation
• Additional Relevant MeSH Terms: Mental Disorders; Nervous System Diseases; Neurologic Manifestations; Confusion; Neurobehavioral Manifestations; Neurocognitive Disorders; Delirium; 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: Smoot_8503