intraoperative methadone administration for improved pain control in spinal fusion patients

Conditions: Pain, Postoperative

Summary: methadone has several advantages over standard narcotic medications, especially when considering use after a typically painful surgery such as lumbar fusion. methadone is low cost, has a long half-life, has a convenient dosing schedule, has excellent oral bioavailability, and demonstrates slow onset to withdrawal. the literature comparing methadone to more commonly used post-operative narcotics demonstrates that it manages pain better, sustains consistent plasma concentrations, decreases overall narcotic requirement, results in no additional adverse events, and is safe, even in children, across several studies. since the standard of care is non-methadone narcotic usage to manage the significant pain of complex spinal surgery cases, it is understandable that methadone could be a desirable alternative to promote sustained pain control and early ambulation in these patients. the goal of this study is to compare the effect of a single dose of methadone administered intraoperatively in enrolled spinal fusion patients to their historical controls given fentanyl and morphine, and determine if more sustained pain control during the first few days after surgery provides a better subjective experience for the patient with less pain, which allows them to ambulate and leave the hospital sooner than patients given a standard regimen.

methadone is a synthetic opioid analgesic with agonist properties at the µ-opioid receptor binding site that has long been used as an alternative to morphine and hydromorphone in patients with severe pain. it has a diffuse bioavailability and is highly efficacious through its oral form, yet its bioavailability is heavily dependent on variability in cytochrome p450 3a4 enzyme activity, and is quite variable amongst individuals. methadone reaches peak plasma concentrations in 2.5 to 4 hours after oral administration, has a rapid onset, has a half-life is between 20-35 hours (range 5-130 hours), and analgesia may be reported for up to 108 hours after a single dose. additionally, methadone's nmda (n-methyl-d-aspartate) receptor site antagonism acts to inhibit enzymes such as adenyl cyclase and their downstream production of secondary signaling molecules like cyclic amp (adenosine monophosphate). this activity may attenuate opioid tolerance and opioid abstinence syndrome as nmda receptor agonism has been implicated in the development of hyperalgesia, acute and chronic tolerance, and chronic pain states. iv dosing typically ranges from 2.5mg to 10mg every 8-12 hours, with po forms dosed at 5-20mg every 6-8 hours. in a study of surgical patients, 40% required no additional post-operative pain control after a single 20mg iv methadone dose intra-operatively, and the 35% that did require a single additional dose required it on average 18.4±6.6 hours post-operatively. the remainder received additional non-narcotic pain medications post-operatively which were sufficient to control pain to tolerable levels. in a series of 29 patients undergoing multilevel thoracolumbar spine surgeries with instrumentation and fusion, patients were randomized to receive either methadone (0.2mg/kg) or sufentanil infusion of 0.25µg/kg/h after a load of 0.75 µg/kg.post-operative pain control was delivered by patient-controlled analgesia and patients were assessed by visual analogue scale for pain, opioid dose, and side effected at 1, 2, and 3 days post-operatively. patients reported less pain in the methadone group 48 hours post-operatively, as well as used less cumulative narcotic dose than the remifentanil control group. side effects were not significantly different between the two groups. this study however, did not evaluate post-operative functional status, ambulation, and time to discharge. the literature comparing methadone to more commonly used post-operative narcotics demonstrates that it manages pain better, decreases narcotic requirement, results in no additional adverse events, and is safe, even in children. since the standard of care is narcotic usage to manage the significant pain of complex spinal surgery cases, it is understandable that methadone could be a desirable therapy to promote sustained pain control and early ambulation in these patients. the current hypothesis is that methadone use intra-operatively will result in earlier time to ambulate post op and better ability to participate with post-operative physical therapy evaluation, lower narcotic usage, and earlier discharge. it is also foreseeable that since methadone would be administered while the patient was sedated intra-operatively, it could prevent the association between the analgesia and euphoria that may result from self- or nurse-administered narcotics, such as with a patient-controlled analgesia (pca), which could promote early tolerance or reliance. the study plans to enroll the first 30 consecutive patients who met inclusion criteria, with an end goal of 20 patients who will complete the study. patient will be recruited in office at time of consent for surgery by the principal investigator and be scheduled to undergo 1 or 2 level lumbar decompression and fusion surgery. the study outlined will be a prospective, positive-control, triple-blinded study in which the patient, care providers, and investigators will be unaware of the randomization of the patients. only the anesthesiologist treating the patient during surgery will be aware of the administration of methadone or not. on the day of surgery, the patient's pre-operative pain and functional status will be assessed, in addition to a review of the study protocols. an anesthesiologist will be assigned to the case and will administer a 0.2 mg/kg single-dose administration of methadone on incision (not to exceed 20 mg, as used in the literature) with a ketamine infusion of 4 µg/kg/min and a remifentanil infusion starting at 0.1 µg/kg/min and titrating to effect or sufentanil infusion starting with a dose of 0.3 µg/kg/hr and titrating to effect. these standard doses have been well documented and studied in the literature and will be overseen and have been approved by board certified anesthesiologist. for lengthier procedures, there will not be re-dosing of narcotics toward the end of the procedure. the operative procedure will not be altered in any way for the purposes of this study, and is beyond the scope of this protocol, yet can be detailed as requested. the patient will be taken to the recovery room post-operative and will be put on a standard post-operative morphine pca at a rate of 1mg per 6 minute lock-out period. patient's narcotic usage and pain rating will be recorded at the intervals listed above and when stable from a cardiovascular standpoint, will be transition to the neurosurgery floor. once able to bare weight, the patient will be encouraged to work with physical and occupational therapy as per standard post-operative protocol. once the patient uses the pca at a rate of less that once an hour, and can be managed with oral pain medications, the pca will be removed. the remainder of their post-operative care will be according to the standard departmental protocol, and when milestones such as ambulation, voiding, and pain control are met, they will be discharged either to home, an acute care facility, or a subacute rehabilitation center. any adverse events/reactions will be recorded and managed as normally they would be, and naloxone will be available for suspicion of narcotic overdose the subjects of this study will be compared to the historical controls in demonstrating the effect of methadone on post-operative pain, medication usage, and rehabilitation time. a goal of 30 patients will be planned to be enrolled. other than intra-operative narcotic administration, all other portions of the intra-operative and post-operative care will remain the same as for historical patients. the primary outcomes for the study include total narcotic dose post-operative, frequency of narcotic use, the time to first ambulation after surgery with physical therapy, length of stay, and disposition (i.e. level of rehabilitative care). secondary outcomes include better subjective pain control, need for post-operative course of dexamethasone for post-operative/post-fusion radiculopathy or neurapraxia/neuropathy, and fusion at 3-6 months.

Eligibility criteria:
inclusion criteria: * meets age criteria, age between 18-80 * undergoing lumbar fusion surgery, one or two spinal levels * asa (american society of anesthesiologists) grades i-iii exclusion criteria: * patient outside of age criteria * renal failure requiring dialysis * serum creatinine greater than 2.0 * hepatic dysfunction with liver function tests greater than twice the upper limit * pulmonary disease requiring home oxygen therapy * obstructive sleep apnea * severe heart disease * allergy to methadone, morphine, or fentanyl * recent or distant history of opioid abuse * poorly managed psychiatric illness * known history of alcohol abuse * morbid obesity (body mass index \> 50 kg/m2) * treatment with other nmda receptor antagonists * prolonged qtc (corrected qt interval) on pre-operative ekg, * refusal or inability to sign the consent form * current use of hiv-1 protease inhibitors, erythromycin, ketoconazole, rifabutin, carbamazepine, phenytoin, phenobarbital, st. john's wort, fluconazole, fluvoxamine, fluoxetine, paroxetine * grapefruit juice intake within the last week