Methadone grand round f

`Methadone in Ambulatory Surgery:
What do we know so far?`
Helga Komen, M.D.
Department of Anesthesiology
Washington University in St Louis

Methadone in Ambulatory Surgery

Pharmacology of methadone
- Synthetic, long-duration opioid, 1938. (1947.)
- 6-dimethylamine-4,4-diphenyl-3-heptanone
- Effect:
- µ-opioid receptor mediated analgesic effects (R-methadone)
- N-metyl-D-aspartate (NMDA) receptor antagonist, serotonin and
norepinephrine uptake inhibition (S-methadone)
- Metabolized by hepatic CYP 2B6
- Inactive metabolites – EDDP, EMDP, methadol
- Excreted by kidneys 20-50%, by feces 10-45%
- Adverse effects – similar to morphine/other opioids
Kharasch ED, Clin Pharmacol Drug Dev, 2017
Fredheim OMS, Acta Anesthesiol Scand, 2008.

Pharmacology of methadone
- t1/2: hydromorphone - 2-3 hours
fentanyl - 4 hours
Ferrari A, Pharmacological Research, 2004.

- Pain scores (NRS, 0-10) were significantly less in the methadone group (medians 2-3) than
they were in the fentanyl group (medians 3-5) during first 72hrs (p<0.001-0.002)

- Median VAS pain scores were lower in the methadone group compared to the hydromorphone group
at all assessment times.
- Patients satisfaction with pain management was higher in the methadone group from PACU admission to POD3

`Methadone in Ambulatory Surgery`
-pilot studies-
Helga Komen, Evan Kharasch, Michael Brunt
• Two arm, randomized, dose-evaluation, double blinded, pilot studies to evaluate
the clinical effectiveness of a single dose of intraoperative methadone in
reducing opioid consumption
• Patients undergoing moderately painful, ambulatory surgical procedures:
• short-stay (overnight stay <24h) group (e.g. Lap. hysterectomy, Lap. hiatal hernia repair)
• true same-day surgery group (e.g. Lap. Cholecystectomy, BSO)
• First ever clinical study to evaluate methadone as the intraoperative opioid for ambulatory
surgery!

• Inclusion Criteria
• Age 18-65 years
• Undergoing general anesthesia and moderately painful, ambulatory surgical
procedures, with anticipated overnight postop stay of < 24 hours or same day
discharge
• Signed, written, informed consent
• Exclusion Criteria
• History of liver or kidney disease
• Females who are pregnant or nursing
• Opioid tolerant patients (e.g. preoperative methadone therapy or use of fentanyl
transdermal patches, chronic opioid use)
• History of allergy to methadone
- short-stay (overnight stay <24h)
- true same-day surgery

• Primary outcomes: Intraoperative and postoperative opioid utilization until
discharge
• Secondary outcomes:
• postoperative pain scores until discharge
• opioid consumption and pain relief within the first 30 postoperative days
• day of surgery and post-discharge opioid related symptoms
- short-stay (overnight stay <24h)
- true same-day surgery

- true same-day surgery -
• Subjects were randomized 1:2 (control:methadone)
• Methadone: dose escalation, received 0.1; 0.15 mg/kg IBW IV (21, 18
subjects respectively) methadone HCl bolus, at induction of anesthesia as
their primary intraoperative opioid.
• Control: did not receive any methadone, received standard intraop opioid,
fentanyl or hydromorphone, at anesthesiologists’ discretion (21 subjects)
• Postoperative pain management for both groups was per standard of care.
• e.g. Lap. Cholecystectomy, BSO

Assessments
• Total intraoperative and postoperative opioid administration during hospitalization was
recorded from the patient’s electronic medical record (morphine equivalents).
• Pain intensity was assessed using the 0-10 Numeric Rating Scale (NRS), at rest, with
coughing, with activity at 15, 30, 45 min, 1, 2, 3, 4 h after admission in the PACU, at
bedtime, at discharge.
• Postoperative sedation was recorded at the same times using Modified Observer`s
Assessment of Alertness/Sedation (MOAA/S), 5=awake, 0=unresponsive.
• Assessment of opioid side effects was performed using Opioid-Related Symptom
Distress Scale (ORSDS), at discharge, 7, 14 and 30 day postdischarge.
• Daily opioid consumption and daily pain self-assessments using NRS was recorded in a
home diary for approx 30 days following surgery (from hospital discharge until postop
clinic visit).
• Statistics: This report of the analysis of Methadone in MAS study is based on the secondary outcomes. For
univariate continuous measures, Kruskal-Wallis test was used. For variables with repeated we used GLM
Mixed model - with binomial distribution for binary outcomes, normal for continuous, and Poisson for count
data. In all repeated measures models we adjusted for time and tested for time by group interaction.
- true same-day surgery -

Results
-true same-day surgery-
- Subject demographics
Control group Methadone 0.1 Methadone 0.15
N 21 18 21
Age (yr) 42±13 37±11 40±11
Sex (M:F) 3:18 2:16 0:21
Weight (kg) 85±16 88±41 86±26
Ideal body weight (kg) 60±5 57±6 57±6
Anesthesia duration (min) 86±21 102±17 84±22
- Lap. tubal ligation 6 1 7
- Lap. salpingectomy ±
oopherectomy
2 6 9
- Lap. cholecystectomy 11 11 5
- Lap. inguinal hernia
repair
2 0 0

• Intraoperative iv opioid, data are mean±SD, *p<0.05
Results – opioid consumption
Control Methadone 0.1 Methadone 0.15
Methadone (mg) 0 5.7±0.9 8.6±0.8
Total nonmethadone opioid, (mg morphine
equivalents)
25.5±8.9* 1.4±3.0 0.3±0.7
Total opioid (mg morphine equivalents) 25.5±8.9* 7.0±2.9 8.7±1.2

• Number of patients not needing PACU opioid , *p<0.05
NO PACU opioid, number of patients (%) 5 (24%) 2 (11%) 12 (57%)*
PACU opioid needed, number of patients (%) 16 (76%) 16 (89%)* 9 (43%)

• Postoperative opioid consumption, data are mean±SD, *p<0.05
PACU total opioid (mg morphine equivalents) 7.8±6.5 7.0±6.8 2.3±3.3*
PACU + postPACU total iv + oral opioid (mg morphine
equivalents)
9.3±7.0 7.6±6.8 3.9±4.3*
Total day of surgery opioid (mg morphine equivalents) 34.7±13.1* 14.6±7.6 12.5±4.1

Results – pain scores
• Influence of methadone on post-op NRS scores (0-1 - NRS scores measured in 15 min increments for
the first hour in PACU, hourly thereafter up to 4 hours/discharge). No significant difference in pain level
between three groups (p=0.177)

• Influence of methadone on post-discharge NRS scores (The NRS scores were compared in post-discharge days
1-30, one measurement per day). There was significant difference in pain at rest between Methadone 0.15 and Control
(p=0.02).
Results – pain scores
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
0 7 14 21 28
NRS
NRS pain at rest
Control
Methadone 0.1
Methadone 0.15

• Influence of methadone on opioid consumption 30 days postdischarge
• Total 30d postop oral opioid pills - There was a significant difference between Control and Methadone
0.15 (p=0.0001) and the two methadone groups (p=0.019). The difference between Control and
Methadone 0.1 was not significant (p=0.087).
Results – opioid consumption postdischarge
0
2
4
6
8
10
12
14
1
Total 30d postop oral opioid pills
Control
Methadone 0.1
Methadone 0.15

• Influence of methadone on day of surgery sedation level (MOAA/S) (Measured in 15 min increments
for the first hour in PACU, hourly thereafter up to 4 hours/discharge). No difference between groups.
• No difference in ventilatory depression (RR<8, SaO2<90% >1 min, reintubation) between groups (not
shown).
0
1
2
3
4
5
0 1 2 3 4 5
MOAAS/S
Sedation: MOAAS/S
Control
Methadone 0.1
Methadone 0.15
Results – side effects of opioids

• Influence of methadone on day of surgery opioid related symptoms (ORSDS)
• Influence of methadone on postdischarge ORSDS – Data were measured at 7, 14 and 30 days
postdischarge. There was no significant difference in between groups at any time point.
Results – side effects of opioids

CONCLUSIONS
• Postoperative pain throughout hospital stay did not differ significantly between control
group and methadone groups. Post-discharge pain scores (30 days) were significantly
different between control and methadone 0.15 groups.
• Sedation level and side effects did not differ significantly between control and methadone
groups.
• Single intraoperative methadone dose (0.15 mg/kg IBW) decreases intraoperative and
postoperative opioid requirements compared to short-duration opioids.
• Single intraoperative methadone dose (0.15 mg/kg IBW) decreases postoperative home
opioid consumption for 30 days.

• Subjects were randomized 1:2 (control:methadone)
• Methadone: dose-escalation, received 0.1; 0.2mg/kg IBW IV (20, 22 subjects
respectively) methadone HCl bolus, at induction of anesthesia as their
primary intraoperative opioid.
• Control: did not receive any methadone, received standard intraop opioid,
fentanyl or hydromorphone, at anesthesiologists’ discretion (28 subjects).
• Postoperative pain management for both groups was per standard of care.
• e.g. Lap. hysterectomy, Lap. hiatal hernia repair
short-stay (overnight stay <24h)

Results
- Average doses of intraoperative methadone (mean ± SD): 6 ± 1mg (0.1 mg/kg group)
11 ± 1mg (0.2 mg/kg group)
- Average intraoperative total nonmethadone morphine equivalents (mean ± SD):
30 ± 8 mg (control)
2 ± 4 mg (0.1mg/kg methadone )
1 ± 3 mg (0.2mg/kg methadone)
Intraoperative methadone (mg/kg IBW)
0.0 0.1 0.2
Morphine
equivalents
(mg)
0
10
20
30
40
50
60
Intraop nonmethadone opioid
PACU opioid
Day of Surgery nonmethadone IV opioid
Day of Surgery total nonmethadone opioid
* *
*
**
*

• Patients receiving a single 0.2 mg/kg methadone dose required significantly less opioids during their
hospital stay, compared to control group (21±7 vs 42±9 mg morphine equivalents; p<0.05).
Results

• Postoperative pain did not differ significantly between control and 0.2 mg/kg methadone group.
• There was considerable variability between patients in all groups at all time point.
Results

• Sedation during hospital stay (MOAA/S) did not differ between groups.
• No difference in ventilatory depression (RR<8, SaO2<90% >1 min, reintubation) between groups (not shown).
• No difference in opioid-related symptoms (ORSDS) between groups (not shown).
Results

• Patients receiving intraoperative methadone used less take-home opioid (p<0.05). Total 30d
opioid averaged 16, 12 and 4 pills, in control, 0.1 mg/kg methadone, and 0.2 mg/kg methadone
groups, and stopped taking opioids earlier.
Results

CONCLUSIONS
• Postoperative pain throughout hospital stay and post-discarge did not differ
significantly between control group and methadone groups.
• Sedation level and side effects did not differ significantly between control
and methadone groups.
• Single intraoperative methadone dose (0.2 mg/kg IBW) decreases
intraoperative and postoperative opioid requirements compared to short-
duration opioids.
• Single intraoperative methadone dose (0.2mg/kg IBW) decreases
postoperative home opioid consumption for 30 days.

Future studies
`Optimizing outpatient anesthesia: Improving analgesia and reducing
opioid misadventure`
• NIH funded (RO1 grant)
• PI: Evan Kharasch; Co-I: Helga Komen, Anshuman Sharma, Michael Brunt
• Hypothesis: Anesthesia with methadone in outpatient surgery, compared with
conventional short-duration opioids, achieves better analgesia, with similar or
diminished side effects and decreases postoperative opioid consumption.
• Study design: Single-center, randomized, double blinded, parallel-group, 2-cohort.
• Cohorts: - short-stay (<24hr)
- same-day outpatient

• Specific Aims:
• compare methadone vs. short-duration opioids influence on postop opioid
consumption, postop pain scores, postop side effects and overall recovery.
• Patient selection:
• Inclusion/Exclusion criteria similar to those in Pilot study
• Target enrollment is 300 evaluable subjects per cohort over 4 year period
• Randomization: 1:1 (control:methadone)
• Methadone group:
• short-stay (<24hr) – 20 mg iv methadone at induction. PACU – 2mg iv methadone prn.
• same-day outpatient – 10 mg iv methadone at induction. PACU – 2mg iv methadone prn.
• Control group: fentanil/hydromorphone intraop. PACU – fentanil/hydromorphone prn.
Future studies
`Optimizing outpatient anesthesia: Improving analgesia and reducing opioid
misadventure`

Disclosure
• Projects funded by:
• Department of Anesthesiology, Division of Clinical and Translational Research
• The Foundation for Barnes and Jewish Hospital

THANK YOU!

Methadone grand round f

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