Intraoperative Methadone Administration for Improved Pain Control in Spinal Fusion Patients

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 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 receptor site antagonism acts
to inhibit enzymes such as adenyl cyclase and their downstream production of secondary
signaling molecules like cyclic AMP. 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, single-blinded study.

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.

Inclusion Criteria:

- Meets age criteria, age between 18-80

- Undergoing lumbar fusion surgery, one or two spinal levels

- ASA 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 on pre-operative EKG,

- Refusal or inability to sign the consent form

- Current use of HIV-1 protease inhibitors, erythromycin, ketoconazol, erifabutin,
carbamazepine, phenytoin, phenobarbital, St. John's Wort, fluconazole, fluvoxamine,
fluoxetine, paroxetine

- Grapefruit juice intake within the last week