Methadone and Quality of Postoperative Recovery

Postoperative pain for the adult cardiac surgery patient is complex. Pain can be caused by
incisions, intraoperative tissue retraction and dissection, multiple intravascular
cannulations, chest tubes left after surgery, and multiple invasive procedures that patients
undergo in the operating room and intensive care unit (ICU). Postoperative pain has been
described as one of the primary sources of concern for cardiac surgery patients. In this
patient population, several studies have demonstrated that pain intensity was moderately
severe (approximately 5 on an intensity scale of 10) during the first 2 postoperative days
(POD) and did not begin to decline until POD 3. The primary method of pain management used in
cardiac surgical patients during early recovery in the intensive care unit (ICU) is the
administration of intravenous morphine. Morphine is typically administered per patient
request or during nursing assessments for pain. Studies have demonstrated that relatively
small doses of morphine (or oral analgesics on the ward) are used following cardiac surgery.
The relatively high intensity of postoperative pain and the low doses of analgesics
administered suggest that postoperative pain in cardiac surgical patients is an
under-recognized and under-treated problem in the early recovery period. Therefore, methods
to more successfully manage pain are needed, especially during the first postoperative days.

Opioids remain the primary therapeutic agents for treatment of pain after cardiac surgery.
Intermittent (every 3-4 hour) intravenous administration remains the most common mode of
delivery. This technique results in significant fluctuations in serum levels of opioids and
consequently variability in levels of pain control. An alternative strategy is the use of an
opioid with a long half-life which will provide stable blood concentrations after a single
intravenous dose. Such an opioid could provide prolonged and constant analgesia. Methadone is
an opioid which fulfills these criteria. A primary advantage of methadone is its long
half-life, which ranges from 25-52 hours. This unique property of methadone means that single
daily doses can be used. Although it is best known as a drug used to treat narcotic
addiction, methadone has also been used as an analgesic agent. A number of recent
investigations have demonstrated that methadone is effective in treating a number of chronic
pain conditions. Methadone has also been studied as an agent to provide prolonged
postoperative analgesia. When methadone was administered intravenously to surgical patients,
a half-life of 35 hours was observed, resulting in a median duration of analgesia lasting 26
hours. In patients undergoing abdominal, orthopedic, or gynecologic surgery, the use of a
single dose of methadone (20 mg or 0.25-0.3 mg/kg) at induction of anesthesia resulted in
improved analgesia for the first 24 hours after surgery, when compared to other
intraoperative opioids. In these investigations, patients in the methadone groups required
significantly less postoperative pain medication and reported lower pain scores during the
first postoperative day. Up to 39% of patients required no additional pain medications,
despite undergoing major surgery associated with moderate-to severe-levels of postoperative
pain. No adverse events directly attributable to methadone were reported in these clinical
trials.

Patients undergoing cardiac surgery typically receive a moderate dose of a short-acting
opioid (most-commonly fentanyl) at the time of induction of anesthesia. Many clinicians
believe that the analgesic effects of fentanyl will persist into the postoperative period.
However, when standard doses (500-1000 mcg) of this opioid are given at induction of
anesthesia in cardiac patients, a relatively short plasma half-life is observed (3.3 hours).
An intraoperative opioid with more desirable pharmacokinetic (long half-life and low
clearance) and pharmacodynamic properties may provide for improved postoperative analgesia in
a cardiac surgical patient population. In addition to providing for prolonged pain relief,
methadone has other unique properties that may be advantageous in cardiac surgical patients.
Recent evidence has demonstrated that methadone has the ability to block N-methyl-D-aspartate
(NMDA) receptors. NMDA receptors have been implicated in the development of postoperative
hyperalgesia (amplification of pain stimuli), and techniques that block NMDA receptors reduce
pain. In addition, recent evidence has demonstrated that blockade of NMDA receptors may
reduce depression and improve mood. Furthermore, methadone inhibits the reuptake of serotonin
and norepinephrine; elevation of these monoamines may play a role in antinociception and mood
elevation. Finally, the use of methadone has been reported to be associated with a reduced
incidence of nausea and vomiting, when compared to other standard intraoperative opioids.
These findings suggest that in addition to providing prolonged and consistent pain relief,
methadone may improve several other components of postoperative recovery. Previous studies of
opioid use in patients undergoing cardiac surgery have focused on physiologic variables and
major adverse events as primary endpoints. As the safety of anesthesia and surgery has
improved, assessment of quality of postoperative recovery has become an increasingly
important outcome measure in clinical research. Therefore, a comprehensive assessment of
postoperative recovery should include factors important to both clinicians (hemodynamic
stability, intensive care unit (ICU) length of stay (LOS)) and patients (physical comfort,
mood). In particular, an important component of recovery from anesthesia and surgery is
patient perception of quality of health in the early postoperative period. Several tools have
been recently developed to assess this outcome variable. The QoR-40 is a 40-item scoring
system specifically designed to measure health status following anesthesia. The QoR-40
measures five dimensions of recovery: physical comfort (12 questions); emotional state (9
questions); physical independence (5 questions); psychological support (7 questions); and
pain (7 questions). Each question is rated by the patient on a five-point Likert scale, with
possible scores ranging from 40 (extremely poor quality of recovery) to 200 (excellent
quality of recovery). A systematic review of instruments used to measure patient-based
recovery outcomes determined that the QoR-40 was the only assessment tool that fulfilled the
criteria of appropriateness, reliability, validity, responsiveness, precision,
interpretability, acceptability, and feasibility. The QoR-40 has been used to assess the
impact of anesthetic interventions on recovery after cardiac surgery; furthermore, low
postoperative QoR-40 scores have been associated with complications and increased hospital
LOS in this patient population.

The primary aim of this randomized, double-blind study is to examine the effect of a single
intraoperative dose of methadone on quality of recovery in the early postoperative period.
Quality of recovery will be assessed using the QoR 40 scoring system over the first 3
postoperative days. Secondary outcome measures to be assessed will include postoperative pain
scores and analgesic requirements, as well as other standard recovery variables (length of
postoperative intubation, ICU and hospital length of stay, incidence of nausea or vomiting,
level of sedation). Based upon the pharmacokinetic and pharmacodynamics properties of
methadone, we hypothesize that patients randomized to receive this long-acting opioid will
have improved QoR 40 scores, particularly in the dimensions of physical comfort, emotional
state, and pain.

Study Design Patients: One-hundred patients will be enrolled in this clinical trial. All
patients presenting for elective cardiac surgery with cardiopulmonary bypass will be eligible
for enrollment.

Anesthetic management: Patients will be randomized to receive either methadone or
saline-control on the basis of a computer generated random number table. Patients in the
methadone group will receive a standard intraoperative dose of methadone that will allow for
early tracheal extubation (within 4-8 hours of the conclusion of the surgical procedure).
Patients randomized to the methadone group will be given 0.4 mg/kg of methadone at induction
of anesthesia (maximal dose 30 mg). Patients assigned to the saline-control group will be
administered saline at anesthetic induction. Study drugs will be prepared by the pharmacy.
The syringes will be administered over five minutes at induction of anesthesia. The
administration of all other anesthetic agents will be standardized and reflect the usual
practices of cardiac anesthesiologists at NorthShore. All anesthesia care team members,
nurses, surgeons, and researchers will be blinded to group assignment throughout the hospital
admission.

Data Collection The primary endpoint of the study is the QoR 40 score. The QoR-40 consists of
40 questions designed to assess quality of recovery following anesthesia and surgery. The QoR
40 will be presented to the patient to complete four times in the perioperative period;
immediately before surgery, and the morning (9AM to 11 AM) of postoperative days 1, 2, and 3.
The questionnaire will be completed by the patient. If the patient is unable to circle the
correct responses on the form, a researcher will verbally present the questions to the
patient and then record the responses.

Additional data will be collected by a research assistant at the time the QoR 40 is completed
by the patient. Pain on 11-point verbal analogue scale (0=no pain, 10=worst pain imaginable)
will be assessed at rest and with coughing. Level of sedation will be determined by observers
using a 4-point sedation scale (0=fully awake, 1=mildly sedated (seldom drowsy and easy to
awake), 2=moderately sedated (often drowsy and easy to awake), 3=severely sedated (somnolent,
difficult to awake). Any episodes of nausea and vomiting will be recorded. Patient
satisfaction with overall pain management will be determined using a 100-point verbal rating
scale (1=highly dissatisfied (worst), 100=highly satisfied (best)). The amount of pain
medication used in each study interval (listed above) will be recorded.

Inclusion Criteria:

- All patients presenting for elective cardiac surgery with CPB will be eligible for
enrollment

Exclusion Criteria:

- Preoperative renal failure requiring dialysis or severe renal dysfunction (serum
creatinine > 2.0 mg/dL)

- Significant hepatic dysfunction (liver function tests > 2 times upper normal limit)

- Pulmonary disease necessitating home oxygen therapy

- Preoperative requirement for inotropic agents or intraaortic balloon pump to maintain
hemodynamic stability

- Allergy to methadone or fentanyl

- Significant preoperative pain requiring treatment with opioids or recent history of
opioid abuse

- Inability to speak or read the English language or neurologic conditions that may
impair the ability to complete the QoR 40 questionnaire.