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

Overview

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.

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 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.