Intraoperative Methadone vs Morphine for Postoperative Pain Control in Patients Undergoing Surgery of the Tibia

This study has been terminated.
(Shortages of study drug, difficulty enrolling patients)
Sponsor:
Information provided by (Responsible Party):
Neil S Bailard, Baylor College of Medicine
ClinicalTrials.gov Identifier:
NCT01430182
First received: September 6, 2011
Last updated: July 16, 2014
Last verified: July 2014
  Purpose

The purpose of this study is to determine whether, for surgery of the tibia, one dose of methadone provides better control of pain afterward as compared to morphine, which is the usual drug given to control pain after surgery. Immediately after the beginning of general anesthesia ("intraoperatively"), subjects will receive one dose of either methadone or morphine, in the amount of 0.2 milligrams per kilogram of body weight, intravenously.

The primary hypothesis is that, subjects who receive one dose of methadone intraoperatively will require less pain medicine than subjects who receive one dose of morphine intraoperatively.


Condition Intervention
Pain, Postoperative
Drug: Methadone
Drug: Morphine

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Intraoperative Methadone Versus Morphine for Postoperative Pain Control in Patients Undergoing Intramedullary Nailing or Open Reduction and Internal Fixation of the Tibia

Resource links provided by NLM:


Further study details as provided by Baylor College of Medicine:

Primary Outcome Measures:
  • opioid consumption [ Time Frame: First 24 hours after discharge from PACU ] [ Designated as safety issue: No ]
    Number of morphine equivalents used by subject during first 24 hours after discharge from PACU


Secondary Outcome Measures:
  • Pain scores [ Time Frame: Postoperatively, Up to 72 hours after discharge ] [ Designated as safety issue: No ]
    VAS 0-10 pain scores q 15 minutes while in PACU, then at 1, 6, 12, 24, 36, 48, and 72 hours after discharge from PACU


Enrollment: 17
Study Start Date: September 2011
Estimated Study Completion Date: July 2014
Estimated Primary Completion Date: July 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Methadone 0.2 mg/kg
0.2 mg/kg methadone by actual body weight, administered over ten minutes, initiated after induction of anesthesia and endotracheal intubation complete.
Drug: Methadone
0.2 mg*kg-1 by actual body weight, administered over 10 minutes, once induction of anesthesia and endotracheal intubation are complete.
Other Name: Bioniche Pharma, METHADONE HYDROCHLORIDE INJECTION, USP
Active Comparator: Morphine 0.2 mg/kg
0.2 mg/kg morphine by actual body weight, administered over ten minutes, initiated after induction of anesthesia and endotracheal intubation complete.
Drug: Morphine
0.2 mg*kg-1 by actual body weight, administered over 10 minutes, once induction of anesthesia and endotracheal intubation are complete.
Other Name: Morphine sulfate

Detailed Description:

Satisfactory pain control can generally be achieved after major surgery of the tibia through a combination of enteral and parenteral medications, neuraxial techniques (such as epidural analgesia), and/or regional techniques (such as sciatic and femoral nerve block). Intramedullary nailing (IMN) and open reduction/internal fixation (ORIF) of the tibia have been important exceptions, and postoperative pain control can be difficult to achieve in these cases.

Surgical repair of fractures of the tibial shaft and of the proximal tibia can be complicated by compartment syndrome, with the possibility of substantial morbidity and loss of function if not detected and treated promptly. It is not always possible to determine preoperatively which tibial fractures are at high risk, and which are low risk for this complication.

The hallmark of compartment syndrome, and often the earliest sign, is pain out of proportion to the nature of the injury. This pain is poorly relieved by morphine or other strong analgesics. In contrast, because peripheral nerve blocks, spinals, and epidurals can completely block the neural transmission of nociceptive stimuli, they can obliterate this important early warning sign. For this reason, orthopedic surgeons often request of anesthesiologists that patients who are to undergo IMN or ORIF of at-risk tibial fractures not receive neuraxial blocks or regional nerve blocks. As a result, patients who undergo IMN/ORIF of the tibia often receive poor pain relief because they are denied these treatment options, even though the vast majority do not go on to develop compartment syndrome.

A typical postoperative pain regimen for IMN/ORIF tibia patients usually begins with a parenteral opioid such as morphine, along with an oral analgesic such as acetaminophen/hydrocodone ("Vicodin"), acetaminophen/codeine ("Tylenol #3"), or tramadol. The parenteral opioid is often given by patient-controlled analgesia pump (PCA), with supplemental doses ordered for breakthrough pain. A major disadvantage of morphine is its equilibration half-time of 2-4 hours. Thus there is considerable lag between the plasma morphine concentration (which peaks immediately) and the morphine concentration at the effector sites. This hysteresis results in the slow onset of analgesia, with peak analgesia occurring some 80-90 minutes after IV administration. It can also result in excessive somnolence, when several demand doses in a row finally take effect. Morphine has an elimination half-time of 2-3 hours. These repeated bolus doses result in the classic "see-saw" graph of plasma morphine concentration over time, with its peaks and troughs. Methadone, in contrast, has a much lower equilibration half-time, on the order of 4-8 minutes. This results in quicker transfer of methadone from the plasma to its effector sites, and hence quicker onset of action, with peak analgesia occurring in just 11.3 minutes. Methadone's elimination half-life after a single dose is approximately 24-36 hours, resulting in prolonged analgesia, with less re-dosing necessary.

Most recently, for multilevel thoracolumbar spine surgery with instrumentation and fusion, intraoperative intravenous methadone was shown to have substantial opioid-sparing effects compared to intraoperative sufentanil bolus with sufentanil infusion, and similar rates of side effects such as hypotension, respiratory depression, hypoxemia, arrhythmia, nausea, and vomiting.

For these reasons, administering an intraoperative loading dose of 0.2 mg/kg methadone IV should result in better analgesia for ORIF and IMN of the tibia, compared with an intraoperative loading dose of 0.2 mg/kg morphine IV. This dose of methadone has previously been shown to yield plasma concentrations above the MEC (Minimum Effective Concentration), without excessive respiratory depression. This dose has been shown to provide long-lasting analgesia after painful procedures, often to the point that subjects needed no supplemental analgesics at all, or only non-narcotic analgesics.

  Eligibility

Ages Eligible for Study:   18 Years to 50 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Subjects scheduled for elective, non-emergent intramedullary nailing (IMN) or open reduction/internal fixation (ORIF) of the tibia at Ben Taub General Hospital
  • Able to give consent (not cognitively impaired or intoxicated)
  • Subjects must be 18-50 years of age
  • ASA physical status I-III
  • Scheduled for primary intramedullary nailing or open reduction/internal fixation of fractures of the tibial shaft or proximal tibia. This must be the first operation for this injured extremity.
  • Associated fractures of the fibula will be allowed.
  • Minor lacerations or other associated injuries like "road rash" or open wounds requiring skin graft are permitted

Exclusion Criteria:

  • Subjects who have taken preoperative opioids for more than 7 days before surgery (i.e., tolerant)
  • Regular use of opioids (whether recreational/illicit or prescribed) within the six months before injury
  • Subjects who are recommended to receive a regional nerve block or a neuraxial technique (spinal or epidural) by the attending orthopedic surgeon
  • Subjects who refuse general anesthesia
  • Subjects deemed to be moderately or severely hypovolemic
  • External fixator already in place on the injured extremity
  • Presence of other moderate-to-severe or distracting injuries, such as orthopedic, cervical spine, neurological, intra-abdominal, or intra-thoracic injuries. Minor abrasions/lacerations such as "road rash" or open wounds are OK. Associated fibular injuries are OK. Small peripheral injuries such as a finger or toe requiring percutaneous pinning are OK. Small skin grafts (no more than 100 cm^2) are permitted
  • Pregnancy or breastfeeding (verify urine pregnancy test)
  • Associated or pre-existing head injury or TBI
  • Difficulty or inability to understand the study or the protocol
  • Severe obesity (BMI > 36.0 kg/m^2)
  • Known respiratory or cardiovascular problems, such as obstructive sleep apnea, or oxygen saturation of less than 96% on room air
  • Acute bronchial asthma
  • Chronic renal failure (serum creatinine > 2.0 mg/dL)
  • Liver failure (defined as history of cirrhosis or fulminant hepatic failure)
  • History of myocardial infarction or heart failure
  • History of prolonged QT syndrome (QTc 450ms or more for men and 460ms or more for women)
  • Known contraindications to methadone including hypothyroidism, Addison's disease, prostatic hypertrophy, or urethral stricture
  • History of allergic reaction to morphine, methadone, acetaminophen, or hydrocodone
  • Taking medications known to induce or inhibit the cytochrome p450 enzyme systems, such as azole antifungals, macrolide antibiotics, and SSRIs
  • Taking antiretroviral medications (any)
  • Consumption of grapefruit or grapefruit juice within past 5 days
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01430182

Locations
United States, Texas
Ben Taub General Hospital
Houston, Texas, United States, 77030
Sponsors and Collaborators
Baylor College of Medicine
Investigators
Principal Investigator: Neil S Bailard, MD Dept. of Anesthesiology, Baylor College of Medicine
  More Information

Publications:
Responsible Party: Neil S Bailard, Assistant Professor, Department of Anesthesiology, Baylor College of Medicine
ClinicalTrials.gov Identifier: NCT01430182     History of Changes
Other Study ID Numbers: H-28734
Study First Received: September 6, 2011
Last Updated: July 16, 2014
Health Authority: United States: Institutional Review Board

Keywords provided by Baylor College of Medicine:
Adult
Female
Humans
Intraoperative Care/methods
Male
Methadone/administration & dosage
Analgesics/therapeutic use
Methadone/therapeutic use
Morphine/therapeutic use
Middle Aged
Pain Measurement/drug effects
Pain Measurement/methods
Pain, Postoperative/prevention & control
Prospective Studies
Double-Blind Method
Tibial Fractures/surgery
Young Adult
Orthopedics

Additional relevant MeSH terms:
Pain, Postoperative
Postoperative Complications
Pathologic Processes
Pain
Signs and Symptoms
Morphine
Methadone
Therapeutic Uses
Analgesics, Opioid
Narcotics
Central Nervous System Depressants
Physiological Effects of Drugs
Pharmacologic Actions
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Central Nervous System Agents
Antitussive Agents
Respiratory System Agents

ClinicalTrials.gov processed this record on September 18, 2014