Methadone Versus Morphine for Orthopedic Surgery Patients

Patients will receive 1-4 mg midazolam before being transferred to the operating room. All
patients will receive standard ASA monitoring. In the operating room, the anesthesiologist
will open a randomization envelope to determine patient group assignment (see below).
Patients will be anesthetized with 0.2 mg/kg ketamine, 2 µg/kg fentanyl and propofol or
etomidate IV. Muscle relaxant of the anesthesiologist's choice will be given and the patient
will be intubated. After intubation, the computer-generated randomization codes stored in
opaque envelopes will be opened. The patients will be randomized to one of two groups:

1. Methadone group: Patients will receive 0.2 mg/kg of methadone IV immediately after
intubation

2. Control group: Patients will receive 0.2 mg/kg of morphine IV immediately after
intubation

The unblinded investigator will draw the drug and dilute to a total volume of 10 cc. This
syringe will be handed to the anesthesia provider, who will administer the medication after
induction. They will be maintained with oxygen, air and an inhalational agent of
anesthesiologist's choice, targeted at BIS between 40 and 60. Additional analgesia will be
provided with fentanyl in 50 µg increments as required throughout surgery. At the end of
surgery the neuromuscular block will be reversed and patients will breathe spontaneously.
Fentanyl will be titrated to maintain a respiratory rate of 12-15 breaths per minute to
obtain an O2 saturation > 95% and the other extubation criteria are met before tracheal
extubation . The intraoperative use of narcotics, sedatives and anesthetic drugs will be
noted. The type of surgery, the duration of surgery and use of additional analgesics and
antiemetics will be noted.

An investigator blinded to randomization will track the patients in the PACU. If rescue
medication is necessary, morphine IV will be given in 2-4 mg increments up to a total of 20
mg. If the patients continue to report pain (VAS > 4), IV hydromorphone will be given in 0.5
mg dose every 10-15 minutes until the patient has adequate analgesia (VAS < 4), as decided
by the PACU nurse.

Patients will receive morphine patient-controlled analgesia (PCA) for pain relief as the
primary analgesic. Percocet (Acetaminophen/Oxycodone 325 mg/5 mg) or Lortab
(Acetaminophen/Hydrocodone 325/5 mg) will be prescribed as needed to maintain VRS < 4.

In the PACU, vital signs including respiratory rate, heart rate, non-invasive blood
pressure, sedation score and oxygen saturation will be recorded every 15 minutes. VAS scores
for pain will be obtained from the patient every 15 minutes until the patient is discharged
to the floor. VAS (visual analog scale) is a 100-mm scale where 0 = no pain and 100 = worst
pain imaginable. The investigator will record sedation scores every 15 minutes using the
following scale until patient is discharged to the floor:

0-Patient is fully alert

1. Patient has intermittent sedation

2. Patient sedated but responsive to verbal stimuli

3. Patient unresponsive to verbal stimuli

Patients will be seen at 8 am and 4 pm on the following day and will be contacted at home or
in the hospital on POD 2 and 3 for information regarding pain scores and analgesic
requirement. The initial dose of rescue analgesic and time it is given will be recorded. VAS
at rest and on movement will be recorded, when the patients are seen or VRS will be recorded
via phone contact. Morphine or other analgesics required during the first 24 and 48 hours
after surgery, and times to first ambulation, first fluid, solid and flatus will be
recorded, as will incidence and severity of postoperative nausea and vomiting be recorded.

Our primary outcome will be opioid consumption during the 48 hours after surgery. All
analgesics consumed will be converted to morphine equivalent.

The secondary outcomes will be

1. Time to initial dose of rescue analgesic

2. Overall rescue analgesic, converted into equipotent doses compared between the two
groups

3. Side effects with special attention paid to respiratory rate and possible respiratory
depression, and PONV

4. Overall satisfaction of the patient with the analgesic graded on a scale of 1-5 with 1
being very dissatisfied and 5 being extremely satisfied. Patients will be asked give
this score at the end of one hour in PACU and in the mornings of the two days after
surgery.

Inclusion Criteria:

- ASA I-III

- Ages 18-65 years

- Presenting for lower extremity orthopedic surgery involving fracture of long bones at
University of Louisville Hospital

- Surgery expected to last more than one hour

- Patient expected to have moderate to severe post-operative pain

- Patient refused regional anesthesia or has a contraindication to regional anesthesia

Exclusion Criteria:

- Any known contraindications to methadone including hypothyroidism, Addison's disease,
prostatic hypertrophy, or urethral stricture.

- Difficulty or inability to understand the study or protocol

- Known renal or hepatic dysfunction

- BMI> 35

- Known respiratory or cardiovascular problems, such as obstructive sleep apnea or
oxygen saturation of less than 92% on room air

- Taking any of the known drugs that induce or inhibit the cytochrome p450 enzyme
systems. Common examples of these drugs are antifungal, antiretroviral, barbiturates,
dexamethasone, and macrolide antibiotics.

- Pregnancy

- Taking preoperative opioids for more than 2 weeks before the surgery