Is there a difference in post-op opioid usage for patients who receive IV methadone vs PO methadone? Is there a decrease in the amount of narcotics that are used during procedure?

Comment by InpharmD Researcher

A comprehensive literature search identified one retrospective study directly comparing the analgesic effects of oral versus IV methadone in adult patients undergoing spinal deformity surgeries. Results demonstrated equivalent pain relief between oral and IV formulations but increased postoperative opioid consumption with oral methadone during the early postoperative period (e.g., postoperative day 1). Pharmacokinetic and pharmacodynamic profiles suggest the unpredictability of oral methadone dosing, whereas the longer half-life of IV formulation may contribute to more adverse effects. Nevertheless, more robust data are required to elucidate direct comparisons between the two formulations on postoperative outcomes, specifically overall narcotic/opioid use.

Background

A 2019 review describing intraoperative methadone in surgical patients indicates that there may be considerable interindividual and intraindividual variability in the disposition of methadone, which is likely related to genetic polymorphism of hepatic cytochrome P450 (CYP450) genes. Methadone is cleared primarily by CYP-catalyzed N-demythelation. The CYP2B6 genotype affects plasma metabolism and clearance, with certain allele carriers (CYP2B6*6) having higher methadone concentrations and slower elimination and other carriers (CYP2B6*4) having faster elimination and lower plasma concentrations. Notably, this effect is significantly greater after oral methadone administration compared to intravenous (IV) administration, which likely explains the unpredictability of methadone dosing when initiating oral therapy. It is unknown how these pharmacogenomic effects would influence postoperative opioid usage when comparing oral and IV methadone therapy, as there appears to be a lack of studies comparing the two formulations. [1]

A retrospective, single-center cohort study comparing the efficacy of oral versus IV methadone on postoperative pain and opioid requirements after spine surgery indicated the overall lack of published evidence comparing analgesic profiles and postoperative outcomes between oral and IV methadone. As a long-acting opioid agonist and N-methyl-D-aspartate receptor antagonist, IV methadone has demonstrated a promising role in the management of postoperative pain in emerging data. However, concerns have been raised regarding the long half-life of IV methadone due to the potential risk for significant side effects, such as sedation, respiratory depression, ileus, nausea, and vomiting. Use of oral methadone in surgical settings had also gained popularity, as one 2020 single-center experience demonstrated successful use of oral methadone as part of the pain management protocols during a nationwide IV opioid shortage. Additionally, oral methadone may present a cheaper option compared to an equivalent dose of IV methadone. Albeit indirect comparisons of oral and IV formulations of methadone, Table 1 describes the retrospective study conducted to elucidate the comparative use of oral and IV methadone in patients undergoing > 3 level spine surgeries. [2], [3]

A 2011 article also discusses the potential role of methadone in perioperative analgesia. Again, methadone is characterized by a rapid onset of action (approximately 8 min) and the longest known half-life of opioids (24-36 hr half-life). Clinical trials were also reported to favor methadone use compared to other opioids (e.g., morphine and sufentanil) in reducing analgesic requirement postoperation and increasing time to first supplemental opioid dose. However, the studies suffer from small sample sizes and questionable equipotent analgesic doses which may lead to bias. Studied doses of intraoperative methadone use either 0.2 mg/kg or 20 mg. The authors themselves reported satisfactory use of methadone 20 mg IV bolus (15 mg in patients > 60 years) for over 25 years. However, this anecdotal evidence should not be cited without proper data. [4]

A 2020 pharmacotherapeutic review of methadone in the setting of pain management describes that oral methadone is predominantly used as a second-line opioid treatment for select chronic pain conditions such as chronic neuropathic pain and chronic cancer pain. Methadone is suggested to be an appealing option for acute postoperative pain management because it possesses analgesic and antihyperalgesic properties. However, no studies cited in support of this statement utilized oral methadone in the perioperative setting; intravenous methadone was administered either at induction of anesthesia or during the intraoperative period. [5]

Several reviews discussing perioperative management of patients taking methadone advise that methadone should be resumed post-operation. If the patient is on nil per os (NPO) status, other alternatives such as patient-controlled analgesia could be considered, with a transition to oral methadone dosing as soon as the patients are able to tolerate oral intake. [6], [7], [8]

References:

[1] Murphy GS, Szokol JW. Intraoperative Methadone in Surgical Patients: A Review of Clinical Investigations. Anesthesiology. 2019;131(3):678-692. doi:10.1097/ALN.0000000000002755
[2] Esfahani K, Tennant W, Tsang S, Naik BI, Dunn LK. Comparison of oral versus intravenous methadone on postoperative pain and opioid use after adult spinal deformity surgery: A retrospective, non-inferiority analysis. PLoS One. 2023;18(7):e0288988. Published 2023 Jul 21. doi:10.1371/journal.pone.0288988
[3] Salajegheh R, Nemergut EC, Rice TM, et al. Impact of a perioperative oral opioid substitution protocol during the nationwide intravenous opioid shortage: A single center, interrupted time series with segmented regression analysis. PLoS One. 2020;15(6):e0234199. Published 2020 Jun 4. doi:10.1371/journal.pone.0234199
[4] Kharasch ED. Intraoperative methadone: rediscovery, reappraisal, and reinvigoration?. Anesth Analg. 2011;112(1):13-16. doi:10.1213/ANE.0b013e3181fec9a3
[5] Kreutzwiser D, Tawfic QA. Methadone for Pain Management: A Pharmacotherapeutic Review. CNS Drugs. 2020;34(8):827-839. doi:10.1007/s40263-020-00743-3
[6] Cornett EM, Kline RJ, Robichaux SL, et al. Comprehensive Perioperative Management Considerations in Patients Taking Methadone. Curr Pain Headache Rep. 2019;23(7):49. Published 2019 Jun 17. doi:10.1007/s11916-019-0783-z
[7] Peng PW, Tumber PS, Gourlay D. Review article: perioperative pain management of patients on methadone therapy. Can J Anaesth. 2005;52(5):513-523. doi:10.1007/BF03016532
[8] Simpson G, Jackson M. Perioperative management of opioid-tolerant patients. BJA Education. 2017;17(4):124-128. doi:10.1093/bjaed/mkw049
Literature Review

A search of the published medical literature revealed 10 studies investigating the researchable question:

Is there a difference in post-op opioid usage for patients who receive IV methadone vs PO methadone? Is there a decrease in the amount of narcotics that are used during procedure?

Level of evidence

C - Multiple studies with limitations or conflicting results  Read more→


Please see Tables 1-10 for your response.

Comparison of oral versus intravenous methadone on postoperative pain and opioid use after adult spinal deformity surgery: A retrospective, non-inferiority analysis

Design

Retrospective, single-academic center cohort study

N= 1,010

Objective

To compare efficacy of oral versus intravenous (IV) methadone on postoperative pain and opioid requirements after spine surgery

Study Groups

IV methadone (n= 317)

Oral methadone (n= 687)

Inclusion Criteria

Adult patients (age ≥ to 18 years and < 90 years of age); underwent elective, Level > 3 posterior spinal fusion; received either oral or IV methadone immediately prior to surgery

Exclusion Criteria

Received both IV and oral methadone

Methods

Patients' electronic medical records were retrospectively reviewed to identify eligible patients. Each patient received either a single dose of oral methadone preoperatively or a single dose (mg) of IV methadone in the operating room prior to the onset of surgery. Without specific dosing protocols, choice of dosing and formulation was at the discretion of the attending anesthesiologist. Those in the oral methadone group received their dose approximately 30 minutes prior to initiating intraoperative care at the time of patient evaluation. 

Documented methadone doses were subsequently converted to morphine equivalent (mg ME) dose based on the CDC criteria and a conversion ratio of 1:2 for IV to oral methadone. The morphine equivalent conversion is not fixed, with larger doses having an additional correction factor, as illustrated in the CDC table. For example, a 20 mg oral methadone dose was multiplied by 4 morphine equivalents to yield a total of 80 mg ME. For a 25 mg oral methadone dose, the first 20 mg were multiplied by 4, while the remaining 5 mg were multiplied by 8, for a total of 120 mg ME. A total opioid dose was calculated by combining doses of methadone and non-methadone opioids administered during surgery. All patients received standardized intraoperative and postoperative management. Patients may have received IV hydromorphone toward the end of the procedure, and postoperative analgesia included hydromorphone patient-controlled analgesia and oral analgesics.

Duration

Between July 3, 2017 and July 23, 2020

Outcome Measures

Primary: postoperative opioid consumption, reported as a postoperative morphine equivalents (ME) and an 11-point patient-reported verbal rating scale (VRS) pain scores (0-10), measured on postoperative days 1-3

Secondary: time to first bowel movement, reintubation rates, postoperative myocardial infarction, or new-onset arrhythmia and new QTc prolongation

Baseline Characteristics

 

IV methadone (n= 317)

  

Oral methadone (n= 687)

 

Age, years

 65.1 ± 12.35  

64.8 ± 11.4

 

Female

 50.8%  

52.3%

 

Preoperative Opioid Use*

83.3% 

  

94.2%

 
Body mass index, kg/m2 

31.2 ± 6.5

  

31.2 ± 6.7

 

Preoperative medications

Acetaminophen 

Gabapentin*

Benzodiazepines

 

29.3%

2.5%

57.1%

  

 

29.4%

14.6%

50.7%

  

Intraoperative characteristics*

Ketamine, mg 

Lidocaine, mg

Propofol, mg

Dexmedetomidine, mcg 

 

80.2 ± 271.8

985.2 ± 747.7

4,875.3 ± 46,105.7

16.9 ± 53.7

  

 

58.6 ± 53.5

895.6 ± 583.5

1,680.7 ± 1,492.4

16.3 ± 60.7

  

Opioids used*

Dose of methadone, mg ME 

Dose of non-methadone opioids, mg ME

Total opioid used, mg ME 

 

112.4 ± 83

6.7 ± 12.2

119.1 ± 81.4

  

 

59.3 ± 60.9

4.57 ± 10.5

63.9 ± 62.5

  

* p< 0.05

Results

Endpoint

Average pain score

Postoperative opioid consumption
Estimated difference (95% CI) p-value

Estimated difference

 95% CI; p-value

Postoperative day 

0

1

2

3

 

-1.84 (-6.35 to 2.67)

0.54 (-2.81 to 3.89)

1.55 (-1.67 to 4.77)

1.10 (-2.11 to 4.32)

 

0.142

0.863

0.143

0.46

 

1.36 (1.01 to 1.83)

1.35 (1.10 to 1.66)

1.11 (0.87 to 1.41)

0.84 (0.62 to 1.14)

 

0.045

0.004

0.405

0.252

Secondary Endpoints

IV methadone (n= 317)

Oral methadone (n= 687)

p-value

Median time to first BM, days (range)

3 (1 to 11)

3 (0 to 10)

0.01

Reintubation

3 (0.95%)

5 (0.73%)

0.71

Postoperative MI

 2 (0.63%) 3 (0.44%) 0.65

Postoperative arrhythmia 

 20 (6.3%) 30 (4.4%) 0.24

QTc prolongation

 68 (21.5%) 150 (21.8%) 0.1

Abbreviations: CI, confidence interval; MI, myocardial infarction

A positive estimated difference indicates more pain or more opioid consumption in the oral methadone group compared to IV methadone group.

Study Author Conclusions

Our study also demonstrates that oral methadone is both non-inferior and equivalent to IV methadone for both average and maximum pain scores on all postoperative days and was non-inferior for opioid consumption on POD 3. This analysis suggests that oral methadone is a suitable alternative to IV methadone for patients undergoing multi-level spine surgery.

InpharmD Researcher Critique

Despite the retrospective nature of the study, the authors claimed the current study as the first publication evaluating differences in analgesic effects and postoperative outcomes between oral and IV methadone. Still, standardization of prescribed opioids was not feasible from the database collection. 
References:

Esfahani K, Tennant W, Tsang S, Naik BI, Dunn LK. Comparison of oral versus intravenous methadone on postoperative pain and opioid use after adult spinal deformity surgery: A retrospective, non-inferiority analysis. PLoS One. 2023;18(7):e0288988. Published 2023 Jul 21. doi:10.1371/journal.pone.0288988

 

Intraoperative methadone for the prevention of postoperative pain: a randomized, double-blinded clinical trial in cardiac surgical patients

Design

Randomized, double-blinded clinical trial 

N= 156

Objective

To examine the effect of intraoperative methadone on postoperative analgesic requirements, pain scores, patient satisfaction, and clinical recovery

Study Groups

Methadone (n= 77)

Fentanyl (n= 79)

Inclusion criteria

Patients presenting for elective cardiac surgery (coronary artery bypass graft [CABG] surgery, valve surgery, combined CABG/valve procedures, or atrial septal defect repair) with cariopulmonary bypass (CPB) and anticipated extubation within 12 h of surgery.
Exclusion criteria

Preoperative renal failure requiring dialysis or serum creatinine greater than 2.0; significant hepatic dysfunction (liver function tests more than twice the upper limit of normal), ejection fraction less than 30%, pulmonary disease necessitating home oxygen therapy, preoperative requirement for ionotropic agents or intraaortic balloon pump to maintain hemodynamic stability, emergency surgery, allergy to methadone or fentanyl or use of preoperative opioids or recent history of opioid abuse.

Methods

Patients were randomized to receive either methadone 0.3 mg/kg or fentanyl 12 ug/kg intraoperatively in 100 mL bags of normal saline. Midazolam 2 mg was given preoperatively and patients were anesthetized with midazolam 2 to 4 mg, propofol 20 to 100 mg, and rocuronium 0.6 to 0.8 mg/kg. Anesthesia maintenance was conducted with sevoflurane 0.4 to 3.0% titrated to Bispectral Index value of 40 to 60 and mean arterial pressure within 20% baseline values. 

Duration of assessment

Total: 72 h post tracheal extubation

Outcome Measures

Analgesic requirements at 24 hours and pain scores at 12 hours post-cardiac surgery, patient satisfaction scores, postoperative intubation times

Baseline Characteristics

  

Methadone (n=77)

Fentanyl (n=79)

    

Male

 52 (67.5%) 63 (79.8%)    
Age, yr

64.7 ± 10.5

 65.5 ± 11.1    
Weight, kg

87.7 ± 17.6

 82.9 ± 17.3    
Height, cm

171.4 ± 9.6

 173.7 ± 10.0    

ASA physical status (IQR)

4 (3-4)

 4 (3-4)    

CABG

 35 (45.4%) 43 (54.4%)    
Valve

35 (45.4%)

 28 (35.4%)    
CABG and valve

6 (7.8%)

 6 (7.6%)    
Atrial septal defect

1 (1.3%)

 2 (2.5%)    

ASA: American Society of Anesthesiologists, IQR: interquartile range

Results

Endpoint

Methadone (n=77)

Fentanyl (n=79)

Difference (99% confidence interval)

p-value
Morphine total at 24 hours, mg (IQR)

6 (4 to 12)

10 (6 to 22)

−4 (−8 to −2)

 < 0.001

Level of pain (0-10) with coughing at 12 hours (IQR)

 4 (3 to 5) 6 (4 to 8) −2 (−3 to −1) < 0.001

Level of pain (0-10) at rest at 12 hours (IQR)

2 (0 to 4)

 4 (2 to 5) −1 (−2 to 0) < 0.001
Overall patient satisfaction (0-100) at 72 h  (IQR)

100 (90 to 100)

90 (80 to 100)

 5 (0 to 10) < 0.001
Time of post-operative tracheal extubation, h (IQR)

6.5 (5.0 to 9.5)

6.0 (4.75 to 10.5)

 -- 0.693

Adverse Events

Common Adverse Events: nausea (50% methadone vs. 56% morphine), vomiting (24% vs. 19%), itching (22% vs. 12%), hypoventilation (4% vs. 4%), hypoxemia (13% vs. 8%) and sedation (83% vs. 90%)

Study Author Conclusions

The administration of 0.3mg/kg of methadone to cardiac surgical patients at induction of anesthesia resulted in significant reductions in analgesic requirements, improvements in pain scores, and enhanced patient-perceived quality of pain management for 72 h after tracheal extubation. No adverse events related to methadone administration were observed.

InpharmD Researcher Critique

High-risk cardiac patients were excluded from enrolling. The doses for methadone and fentanyl were also considered approximately equipotent based on documented studies that do not provide specific recommendations (one study reported using a ratio of fentanyl/morphine 1:20 ratio but made no conclusive statement that they were equipotent). Data should be compared to one's own institutional opioid conversion guideline.

 

References:

Murphy GS, Szokol JW, Avram MJ, et al. Intraoperative methadone for the prevention of postoperative pain: a randomized, double-blinded clinical trial in cardiac surgical patients. Anesthesiology 2015;122:1112-1122.

 

Clinical Effectiveness and Safety of Intraoperative Methadone in Patients Undergoing Posterior Spinal Fusion Surgery: A Randomized, Double-blinded, Controlled Trial

Design

Parallel-group, randomized trial

N= 115

Objective

 To assess the effect of the long-duration opioid methadone on postoperative (post-op) analgesic requirements, pain scores, and patient satisfaction after complex spine surgery

Study Groups

Methadone (n= 62)

Hydromorphone (n= 53)

Inclusion criteria

Age 18 to 80 years, presenting for elective posterior lumbar, thoracic, or lumbothoracic spinal fusion surgery
Exclusion criteria Preoperative chronic renal insufficiency or failure (defined as a serum creatinine more than 2 mg/dL), significant liver disease (cirrhosis or hepatic failure), American Society of Anesthesiologists (ASA) physical status IV or V, pulmonary disease necessitating home oxygen therapy, preoperative use of methadone or hydromorphone or allergy to either, recent history of opioid or alcohol abuse, inability to use a patient-controlled analgesia (PCA) device or speak the English language, or any patient judged by the anesthesia care team to potentially require prolonged post-op intubation

Methods

Patients were randomized to receive intraoperative doses of either methadone 0.2 mg/kg (actual body weight) or hydromorphone 2 mg. Doses were determined to be equipotent for acute and chronic pain based on past studies. Patients were premedicated with midazolam 2 mg intravenous (IV) and gabapentin 600 mg PO. Anesthesia was induced with propofol 1 to 2 mg/kg, lidocaine 50 mg, fentanyl 100 μg, dexamethasone 10 mg, and rocuronium 0.3 to 0.6 mg/kg. Ondansetron 4 mg and IV acetaminophen 1000 mg were given 30 to 60 minutes before surgery conclusion.

Duration

 3 days post-op

Outcome Measures

Primary: IV hydromorphone use on post-op day 1

Secondary: Pain scores and satisfaction with pain management

Baseline Characteristics

  

Methadone (n= 62)

Hydromorphone (n= 53)

p-value

  

Age, years (IQR)

 64.5 (57–71)

60 (45–66)

 --   

Male

 32 (51.6%) 21 (39.6%) --  

Weight, kg

 83.3 ± 20.8 80.7 ± 22.1 --  

Height, cm

 170.2 (160–180.3) 167.6 (160–172.7) --  

Opioid pain medication before surgery

 33 (53.2%) 28 (52.8%) --  

Smoking history

Drinking history

8 (12.9%)

2 (3.2%)

8 (15.1%)

5 (9.4%)

 --  

ASA physical status

 2 (2-3) 2 (2-3) --   

Anesthesia time, min

 310  (254–401) 342 (255–410) 0.456  

Duration of hospitalization, days

 4 (3–5) 4 (3–4.75) 0.332  

Required additional IV methadone in the operation room

 15 (24.2%) 14 (26.4%) 0.954   

IQR: interquartile range

Results

Endpoint

Methadone (n=62)

Hydromorphone (n=53)

Difference (99% CI)

 p-value

IV hydromorphone use on post-op day 1

 4.56 (2.30–7.10) 9.90 (6.45–13.20) -4.80 (-6.90 to -2.60) < 0.0001

Overall satisfaction with pain management

At admission (IQR)

1h after admission (IQR)

2h after admission (IQR)

Post-op day 1 AM (IQR)

Post-op day 2 AM (IQR)

Post-op day 3 AM (IQR)

 

80 (70-90)

80 (70-90)

80 (70-90)

92.5 (85-100)

90 (85-100)

95 (90-100)

 

50 (20-70)

60 (40-80)

60 (45-77.5)

80 (70-90)

82.5 (70-90)

90 (77.5-95)

 

30

19

20

10

10

5

 

< 0.0001

< 0.001

< 0.0001

< 0.0001

< 0.001

p=0.001

CI: confidence interval

Adverse Events

No difference between nausea/vomiting, itching, hypoventilation, or hypoxemic events from admission to day 3

Study Author Conclusions

Patients undergoing posterior spinal fusion surgery randomized to receive intraoperative methadone had significantly reduced postoperative analgesic requirements, improved pain scores, and enhanced perception of pain management, compared to patients administered the traditional intermediate-duration opioid hydromorphone. Dose–response studies are needed to further define the optimal dose of methadone in this patient population with severe postoperative pain.

InpharmD Researcher Critique

Based on the past studies the authors referenced, it is unknown how methadone 0.2 mg/kg may be approximately equipotent to hydromorphone 2 mg. Different institutions may utilize different dose equivalence strategies when comparing methadone and hydromorphone. While post-op hydromorphone requirements were lower, all patients in the methadone group still required additional IV hydromorphone post-op. The authors noted that 0.2 mg/kg may not be clinically effective and their practicing institution now administers larger doses at 0.3 to 0.4 mg/kg intraoperatively as a result.

 

References:

Murphy GS, Szokol JW, Avram MJ, et al. Clinical effectiveness and safety of intraoperative methadone in patients undergoing posterior spinal fusion surgery: a randomized, double-blinded, controlled trial. Anesthesiology 2017;126:822-833.

 

Intraoperative Methadone Improves Postoperative Pain Control in Patients Undergoing Complex Spine Surgery

Design

Prospective, randomized, single-blinded study

N=29

Objective

 To explore the efficacy and examine the side effects of a single intraoperative dose of methadone compared with continuous sufentanil infusion in patients undergoing major lumbar spinal surgery

Study Groups

Sufentanil (n= 16)

Methadone (n= 13)

Inclusion criteria

Age 18 to 75 years undergoing multilevel thoracolumbar spine surgery with instrumentation and fusion

Exclusion criteria

Preoperative methadone therapy; morbid obesity with a body mass index 36.0 kg/m2; patients with chronic renal failure defined by serum creatinine 2.0 mg/dL; or liver failure defined as a history of cirrhosis or fulminant hepatic failure. Patients with preoperative alcohol or drug abuse, patients with a history of myocardial infarction or heart failure, and patients with American Society of Anesthesiologists (ASA) physical status III (except patients with a history of restrictive lung disease secondary to severe scoliosis) or more

Methods

Patients were randomized to receive an initial loading dose of sufentanil 0.75 mcg/kg or methadone 0.2 mg/kg before surgery. Patients were premedicated with midazolam 2 mg intravenously (IV) and propofol 1.5 to 3.0 mg/kg IV. Anesthesia was maintained with propofol 50 to 150 mcg/kg/min with continual dose adjustment to achieve a bispectral index level of 40 to 50. Inadequate anesthesia was treated with sufentanil bolus of 1.0 mcg/kg IV every 2.5 min at the discretion of the anesthesiologist. Patients were administered their favored opioid analgesic converted into morphine equivalents when needed postoperative. 

Duration

 3 days postoperation

Outcome Measures

 Time after surgery to first pain medication, postoperative opioid requirement at 48 and 72 hours, reported side effect for hypotension, respiratory depression, hypoxemia, arrhythmia, nausea, and vomiting

Baseline Characteristics

  

Sufentanil (n=16)

Methadone (n=13)

p-value

Age, years

 53.1 ± 15 62.9 0.051

Weight, kg

 79.2 ± 15.60 73.6 0.351

Height, cm

 168 ± 10.1 167 0.775

Body mass index, kg/m2

 28.1 ± 4.7 26.3 0.323

Sex, M/F

 6/7  5/11 0.466

ASA physical status, I/II

 0/16 1/12 0.448

Preoperative opioid consumption, (mg ME)

 7.5 8.0 0.771

Length of surgery, min (IQR)

 329 (283–475) 285 (248–467.5) 0.313

ME: morphine equivalent, IQR: interquartile range

Results

Endpoint

Sufentanil (n=16)

Methadone (n=13)

p-value

Time after surgery to first pain medication, min

 57 ± 49.1 89 ± 64.3 0.149

Postoperative opioid requirement at 48 hours, mg (IQR)

 63 (27.3–86.1) 25 (16.5–31.5) 0.023

Postoperative opioid requirement at 72 hours, mg (IQR)

 34 (19.9–91.5) 15 (8.8–27.8) 0.024

Reported side effects

Hypotension

Respiratory depression

Hypoxemia

Arrhythmia

Nausea

Vomiting

 

2

1

3

1

4

3

 

0

0

3

0

4

1

 

0.187

0.360

0.775

0.360

0.730

0.390

Study Author Conclusions

 Perioperative treatment with a single bolus of methadone improves postoperative pain control and reduces opioid requirements in patients undergoing complex spine surgery. The effect of methadone persists for at least 72 hours and is not associated with an increased incidence of adverse events.

InpharmD Researcher Critique

 Sufentanil 0.75 mcg/kg may not be equipotent to methadone 0.2 mg/kg and the authors admit the possibility as a limitation. Greater requirements in the sufentanil group may be due to the potentially higher equipotent dose administered possibly leading to higher opioid resistance. Patients able to access their favored opioid postoperatively may have created additional inconsistencies.

 

References:

Gottschalk A, Durieux ME, Nemergut EC. Intraoperative methadone improves postoperative pain control in patients undergoing complex spine surgery. Anesth Analg 2011;112:218-23.

 

Perioperative Methadone and Ketamine for Postoperative Pain Control in Spinal Surgical Patients: A Randomized, Double-blind, Placebo-controlled Trial

Design

Randomized, double-blind, placebo-controlled trial

N= 130

Objective

To test the primary hypothesis that patients recovering from spinal fusion surgery who are given ketamine and methadone use less hydromorphone on the first postoperative day than those given methadone alone

Study Groups

Methadone (n= 61)

Methadone/ketamine (n= 66)

Inclusion Criteria

Age 18-80 years, undergoing elective spinal fusion surgery of one or more sacral, lumbar, and/or thoracic levels

Exclusion Criteria

American Society of Anesthesiologists (ASA) Physical Status IV or V, preoperative renal insufficiency or failure (serum creatinine ≥ 2mg/dL), pulmonary disease necessitating home oxygen therapy, significant liver disease (cirrhosis or hepatic failure), recent history of alcohol or opioid abuse, allergy to methadone, hydromorphone, or ketamine, inability to use patient-controlled analgesia (PCA)

Methods

Patients were randomized (1:1) to either methadone group (intraoperative methadone 0.2 mg/kg and a dextrose 5% in water infusion) or methadone/ketamine group (intraoperative methadone 0.2 mg/kg and ketamine 0.3 mg/kg/h infusion until surgical closure followed by ketamine 0.1 mg/kg/h for the following 48 hours). All medications were dosed using ideal body weight. Patients also received standardized anesthetic care. With adequate postoperative pain control, patients were transitioned to hydromorphone PCA (initial programming: a demand dose of 0.2mg with a 10 min lockout interval, a 1 h limit of 1.2mg). Once the patients could tolerate oral intake, they were transitioned to hydrocodone 5mg and acetaminophen 325mg tablets. 
Duration

Follow-up: 3 days

Outcome Measures

Primary: intravenous (IV) hydromorphone requirement on postoperative day 1 after spine surgery

Secondary: hydromorphone requirements on postoperative days 2 and 3, pain scores, patient satisfaction with pain management, and any potential complications associated with methadone or ketamine administration

Baseline Characteristics

  

Methadone (n= 61)

Methadone/ketamine (n= 66)

    

Age, years (IQR)

 66 (58 to 72)

61.5 (47.3 to 69)

    

Female

34 (56%)

34 (52%)

    

ASA physical status (IQR)

 2 (2 to 3) 2 (2 to 2)    

Actual body weight, kg

90 ± 21

84 ± 20

    

Ideal body weight, kg

62 ± 11

64 ± 11

    

Methadone dose, mg

 12.5 ± 2.1

12.9 ± 2.2

    

Fentanyl dose, mcg

 152 ± 96 143 ± 89    

IQR: interquartile range

No significant differences between groups

Results

Endpoint

Methadone (n= 61)

Methadone/ketamine (n= 66)

Difference (confidence interval [CI])

p-value

Median IV hydromorphone dose, mg (IQR)

First 24 hours

Second 24 hours

Third 24 hours

 

4.6 (3.2 to 6.6)

1.2 (0 to 3.0)

0 (0 to 0)

 

2.0 (1.0 to 3.0)

0 (0 to 1.2)

0 (0 to 0)

 

2.5 (95% CI 1.8 to 3.3)

0.5 (99% CI 0 to 1.3)

0 (99% CI 0 to 0)

 

< 0.0001

--

--

Median pain scores on postoperative day 3 (IQR)

At rest

While coughing

While moving



3 (2 to 4)

4 (3 to 5)

4 (3 to 5)



2 (2 to 3)

3 (2 to 3)

3 (3 to 4)



1 (99% CI 0 to 2)

1 (99% CI 1 to 2)

1 (99% CI 0 to 2)



< 0.0001

< 0.0001

< 0.0001

Median patient satisfaction with pain management on postoperative day 3 (IQR)

 9 (8 to 10) 9 (8 to 10) 0 (99% CI -1 to 0) 0.216

Postoperative complications

Respiratory

Gastrointestinal

Cardiac

Renal

Neurologic

 

2 (3%)

1 (2%)

2 (3%)

1 (2%)

1 (2%)

 

0

0

0

0

0

 

3% (99% CI -6 to 15)

2% (99% CI -8 to 13)

3% (99% CI -6 to 15)

2% (99% CI -8 to 13)

2% (99% CI -8 to 13)

 

0.457

0.961

0.457

0.961

0.961

Adverse Events

See Results section

Study Author Conclusions

Postoperative analgesia was enhanced by the combination of methadone and ketamine, which act on both N-methyl-d-aspartate and μ-opioid receptors. The combination could be considered in patients having spine surgery.

InpharmD Researcher Critique

Intraoperative fentanyl and hydromorphone could be given, in addition to the baseline remifentanil infusion, at the discretion of the anesthesia care team, which may have confounded the results due to variation in provider practice. Further studies are needed to identify the optimal dose of methadone and ketamine when two agents are combined. 



References:

Murphy GS, Avram MJ, Greenberg SB, et al. Perioperative Methadone and Ketamine for Postoperative Pain Control in Spinal Surgical Patients: A Randomized, Double-blind, Placebo-controlled Trial. Anesthesiology. 2021;134(5):697-708. doi:10.1097/ALN.0000000000003743

 

The perioperative combination of methadone and ketamine reduces post-operative opioid usage compared with methadone alone

Design

Randomized, double-blind study

N= 22

Objective

 To compare post-operative opioid requirements in patients undergoing multilevel lumbar arthrodesis after the administration combined methadone–ketamine (MK) or methadone (ME) alone

Study Groups

ME group (n= 11)

MK group (n= 11)

Inclusion Criteria

 Adult patients with a physical status classified as American Anesthesiology Society I-III

Exclusion Criteria

Severe chronic obstructive pulmonary disease, severe heart disease, liver disease, renal impairment, allergies to any of the drugs, psychiatric illness, known history of alcohol abuse or obesity, treatment with other N-methyl-D-aspartate (NMDA) receptor antagonists, use of tricyclic antidepressants

Methods

Patients were randomized to receive ketamine bolus 0.5 mg/kg after tracheal intubation, followed by a 2.5 mcg/kg/min infusion in the KE group; or a bolus of physiological saline plus infusion. During the 24 to 48 hours post-operative period, the patient received patient-controlled analgesia (PCA) pump that delivered a bolus of 1 mL (lockout 10 min, max 3 bolus/hour). The MK group's PCA contained 0.25 mg of methadone plus 0.5 mg of ketamine per bolus, and the ME group's PCA contained 0.5 mg of methadone.

Duration

 Post-surgical follow-up: 48 hours

Outcome Measures

Primary: Post-operative methadone consumption

Secondary: Intraoperative and recovery room outcomes and opioid consumption

Baseline Characteristics

 

   ME group (n= 10)

MK group (n= 10)

  

Age, years

 61.30 ± 11.66 52.90 ± 12.62  

Weight, kg

 75.89 ± 9.81 69.50 ± 7.16  

Female 

 7 (70%) 7 (70%)  

American Society of Anesthesiologists

I

II

III

 

0

7 (70%)

3 (30%)

 

3 (30%)

6 (60%)

1 (10%)

  

One patient from each treatment group was excluded from follow-up and analysis due to emergency reoperation, and the surgeon withdrew PCA, respectively. 

Results

Endpoint

ME group (n= 10)

MK group (n= 10)

p-value

Methadone consumption by patient-controlled analgesia

24 hours after surgery

48 hours after surgery

 

15 (9.65 to 17.38)

9.5 (3.5 to 13.75)

 

3.43 (1.9 to 6.5)

2 (0.5 to 3.63)

 

<0.001

0.001

Recovery room

Ramsay scale (1 to 6)

Numerical rating scale (0 to 10)

Methadone, mg

Time to start patient-controlled analgesia, min

 

2 (1.75 to 2.25)

7 (3.5 to 9)

4 (0.5 to 5.5)

37.5 (15 to 63.75)

 

2 (2 to 2)

6 (4.25 to 8)

3.5 (0.5 to 5.5)

45 (34 to 90)

 

0.731

0.400

1.0

0.412

Intra-operative

Surgery time, min

Remifentanil use, mcg/kg/min

Ketamine use, mg

Methadone use, mg

 

107 (67 to 204)

0.2 (0.15 to 0.25)

--

6 (3 to 7.75)

 

121 (71.75 to 132.50)

0.36 (0.25 to 0.52)

48 (42.25 to 55)

6 (4.68 to 7)

 

0.549

0.004

--

0.853

Adverse Events

Common Adverse Events: ME vs. MK 24 hours after surgery - nausea (10% vs. 10%), vomiting (0 vs. 20%), itching (0 vs. 10%); at 48 hours - vomiting (0 vs. 10%), headache (0 vs. 10%)

None of the patients experienced respiratory depression or psychotomimetic effects.

Study Author Conclusions

 Perioperative ketamine–ME combination significantly decreased opioid consumption by PCA.

InpharmD Researcher Critique

 The purpose of the study was to compare methadone with a combination methadone-ketamine treatment during the perioperative period. Therefore, there was no control group. The primary outcome was the surrogate marker of opioid consumption after the operation. Post-operative pain intensity was a secondary outcome. Lastly, there is a small patient population.



References:

Pacreu S, Fernández Candil J, Moltó L, Carazo J, Fernández Galinski S. The perioperative combination of methadone and ketamine reduces post-operative opioid usage compared with methadone alone. Acta Anaesthesiol Scand. 2012;56(10):1250-1256. doi:10.1111/j.1399-6576.2012.02743.x

 

Analgesic Effects of Methadone and Magnesium Following Posterior Spinal Fusion for Idiopathic Scoliosis in Adolescents: A Randomized Controlled Trial

Design

Prospective, randomized, blinded trial

N= 60

Objective

To evaluate the potential of methadone or magnesium to prevent remifentanil-induced hyperalgesia

Study Groups

Remifentanil (n= 19)

Remifentanil + methadone (n= 22)

Inclusion Criteria

Adolescents presenting for posterior spinal fusion to treat idiopathic scoliosis

Exclusion Criteria

Not explicitly stated

Methods

Patients were randomized to receive remifentanil alone, remifentanil + methadone (0.1 mg/kg IV over 15 minutes, administered just after induction of anesthesia), or remifentanil + magnesium (50 mg/kg bolus over 30 minutes followed by 10 mg/kg/h). Patients received oral premedication with midazolam 20 mg followed by the inhalation of 70% nitrous oxide in oxygen to provide analgesia. Anesthesia was then induced with propofol 2.5 mg/kg and remifentanil 2.5 mcg/kg. Rocuronium 0.3 mg/kg was used to facilitate endotracheal intubation. Maintenance anesthesia consisted of desflurane titrated to maintain the bispectral index at 50–60 and a remifentanil infusion starting at 0.05 µg/kg/min and increased up to 0.3 µg/kg/min to maintain the mean arterial pressure (MAP) at 55–65 mmHg.

Intravenous acetaminophen (15 mg/kg up to 1,000 mg) was administered intraoperatively and continued every 6 h for 36 h postoperatively as an adjunct to opioid analgesia. Following completion of the instrumentation and the need for neurophysiological monitoring, the remifentanil infusion was discontinued, and hydromorphone (incremental doses of 0.2 mg) was administered to achieve a respiratory rate of 8 to 12 breaths/minute. Additional doses of hydromorphone were administered following tracheal extubation and in the post-anesthesia care unit as needed to optimize analgesia. Hydromorphone was used for postoperative analgesia delivered via patient-controlled analgesia (PCA) device with a bolus dose of 4 to 10 µg/kg, a lockout period of 10 min, and no basal infusion. If analgesia was inadequate, the bolus dose was increased up to 20 µg/kg. A basal infusion (2–5 µg/kg/hr) was added for patients with severe pain (pain scores ≥ 7) if increasing the bolus did not provide adequate analgesia. On a postoperative day one, intravenous ketorolac was started and continued for a total of 20 doses.

Outcome Measures

Primary outcomes: opioid requirements and postoperative pain scores

Secondary outcomes: intraoperative anesthetic requirements, and emergence times

Baseline Characteristics

  

Remifentanil (n= 19)

Remifentanil + methadone (n= 22)

  

Age, years

 14.2 ± 1.4 15.4 ± 1.2  

Female

16 (84%) 17 (77%)  

Weight, kg

 55.9 ± 11.8 64.5 ± 20  

American Society of Anesthesiologists status

1

2


7 (37%)

12 (63%)


5 (23%)

17 (77%)

  

Surgery time, minutes

246 ± 102

250 ± 66

  

Results

Endpoint

Remifentanil (n= 19)

Remifentanil + methadone (n= 22)

p-value (95% confidence interval)

Total hydromorphone consumption in OR + PACU + inpatient ward, mg/kg*

 0.34 ± 0.11 0.26 ± 0.1 0.035 (-0.14 to -0.01)

VAS pain score in PACU and on inpatient ward†

 4.6 ± 2.2 5.1 ± 1.8 0.386 (-0.7 to 1.8)

Intraoperative anesthetic requirements

Remifentanil dose, μg/kg/min

Desflurane concentration

Rocuronium dose, mg/kg

Labetalol total dose, mg/kg


0.19 ± 0.03

3.7 ± 0.3

4.6 ± 1.3

0.17 ± 0.19


0.16 ± 0.04

3.8 ± 0.3

4 ± 0.6

0.06 ± 0.1


0.016 (-0.05 to -0.01)

 

NS

NS

0.018 (-0.16 to -0.06)

Emergence times

Time to eye opening, minutes

Time to following commands, minutes

Time to tracheal extubation, minutes

Hospital length of stay, days


2.6 ± 1.4

2.9 ± 1.6

2.5 ± 1.8

4.6 ± 1.3


2.5 ± 2.9

3.3 ± 2.9

2.9 ± 2.8

4 ± 0.6


NS

NS

NS

NS

*Data missing for 2 remifentanil cases

†Data missing for 1 remifentanil case

Adverse Events

One patient receiving methadone experienced intraoperative excessive bleeding.

Study Author Conclusions

With the dosing regimens in the current study, the only benefit noted with methadone was a decrease in perioperative opioid requirements. However, given the potential for hyperalgesia with the intraoperative use of remifentanil, adjunctive use of methadone appears warranted.

InpharmD Researcher Critique

This study is limited by its small sample size and lack of blinding protocol. Additionally, missing data for patients may have confounded the results considering the small sample size.



References:

Martin DP, Samora WP 3rd, Beebe AC, et al. Analgesic effects of methadone and magnesium following posterior spinal fusion for idiopathic scoliosis in adolescents: a randomized controlled trial. J Anesth. 2018;32(5):702-708. doi:10.1007/s00540-018-2541-5

 

Pharmacodynamics and pharmacokinetics of methadone during the perioperative period

Design

Pharmacokinetic and pharmacodynamic study

N= 23

Objective

 Methadone intravenous (IV) bolus was observed to determine blood concentrations and duration of analgesia after surgery. Furthermore, the relationship between methadone pharmacokinetics and pharmacodynamics was observed relating to treatment of postoperative pain.

Study Groups

Pain-free post-op (n= 9)

Narcotic post-op (n= 8)

Non-narcotic post-op (n= 6)

Inclusion criteria

Healthy, adult patients with American Society of Anesthesiologist status I or II

Exclusion criteria

 N/A

Methods

Surgical and orthopedic patients were administered methadone 20 mg IV bolus following anesthesia and were divided based on whether they were pain-free, required additional narcotic injections, or requested non-narcotic analgesia. Patients were premedicated with droperidol 0.1 mg/kg one hour prior to induction at 0800h. Anesthesia was induced with thiopentone 4-5 mg/kg and pancuronium 0.1 mg/kg. Methadone bolus was administered 5-10 minutes postintubation with stable cardiovascular event. No other narcotic was used in the preceding 24 hours.

Duration

 N/A

Outcome Measures

Duration of adequate analgesia before intervention

Minimum effective analgetic blood methadone concentration

Mean methadone clearance rate

Mean terminal half-life

Overall resulting median duration

Baseline Characteristics

  

Pain-free post-op

(n= 9)

Narcotic post-op

(n= 8)

Non-narcotic post-op

(n= 6)

Age, years

 46.3 45.1 59.5

Gender, M/F

 4/5 5/3 2/4

Weight, kg

 67.2 69.4 51.9

Results

Endpoint

Pain-free post-op

(n= 9)

Narcotic post-op

(n= 8)

Non-narcotic post-op

(n= 6)

Duration of adequate analgesia before intervention, hours

 - 18.4 26.5

Minimum effective analgetic blood methadone concentration, ng/mL

 - 30 33

Mean methadone clearance rate, mL/min

 178    

Mean terminal half-life, hour

 35    

Overall resulting median duration, hours

 27    

Adverse Events

Events of depressed respiratory rate: not significant (i.e. rate < 10 breaths/min)

No naloxone use was required.

Nausea/vomiting: n= 11

Study Author Conclusions

Prolonged postoperative analgesia (median duration of analgesia, 27 h, n=23) is similar to the terminal half-life (35 +/- 22 h) determined in the same patients following an appropriate dose of methadone (20 mg). There is a relationship between blood methadone concentration and analgetic response. It may be possible to predict the duration of postoperative analgesia following methadone using the proposed formula. However, a larger study is needed to substantiate these findings. It may be possible to predict the minimum effective analgetic blood methadone concentration for postoperative pain using the formula proposed.

InpharmD Researcher Critique

While the study demonstrated prolonged postoperative analgesia postoperatively, their results concluded that over 50% of patients (14 out of 23) still needed additional analgesics.

 

References:

Gourlay GK, Wilson PR, Glynn CJ. Pharmacodynamics and pharmacokinetics of methadone during the perioperative period. Anesthesiology. 1982;57(6):458-67.

 

Preoperative oral methadone for postoperative pain in patients undergoing cardiac surgery: A randomized double-blind placebo-controlled pilot

Design

Single-center, randomized, double-blind, placebo-controlled pilot study

N= 24

Objective

To investigate the effect of preoperative oral methadone on pain scores, analgesia requirements, and opioid-induced side effects

Study Groups

Methadone (n= 9)

Placebo (n= 12)

Inclusion Criteria

Undergoing sternotomy for elective, isolated coronary artery bypass graft (CABG surgery)

Exclusion Criteria

Age < 18 years, concomitant valve replacement, preoperative renal failure requiring dialysis or serum creatinine > 176 μmol/L, significant hepatic dysfunction (liver function tests > twice the upper limit of normal), ejection fraction < 30%, corrected QT interval (QTc) on electrocardiogram (ECG) > 440 ms for men and > 450 ms for women, pulmonary disease necessitating home oxygen therapy, preoperative requirement for inotropic agents or intra-aortic balloon pump to maintain hemodynamic stability, emergency surgery, allergy to methadone, use of preoperative opioids, or recent history of opioid abuse, opioid-tolerant (taking at least oral morphine 60 mg daily or equianalgesic dose of another opioid for 1 week or longer)

Methods

Participants were randomized (1:1) to receive oral liquid methadone or an equal volume of sweetened syrup. Methadone was dispensed as 10 mg/mL and diluted to a total volume of 5 mL in a sugary syrup to mask any potential bitter taste. A 5-mL syringe containing either methadone (dose of 0.3 mg/kg up to a maximum of 30 mg) plus diluent or placebo plus diluent was self-administered by mouth in the holding area prior to entering the operating room.

Patients received midazolam 2 mg prior to being transported to the operating room. Anesthesia was induced with midazolam (0 to 4 mg), sufentanil (0.5 mcg/kg), propofol titrated to loss of lash reflex, and rocuronium (0.6 to 1 mg/kg). Sevoflurane (0.4% to 2.3%) and propofol (0 to 50 mcg/kg/min) were used to maintain anesthesia and were titrated to the bispectral index (values of 40 to 60) and to mean arterial pressure no less than 20% of baseline. Additionally, a propofol infusion (10 to 60 mcg/kg/min) was given initiated at sternal closure and maintained until the patient was transported to the intensive care unit (ICU).

In the ICU, morphine (2 to 5 mg) intravenously (IV) up to every 5 minutes was given as needed for pain until extubated. Propofol was infused as per the institution's weaning protocol at a rate of 10 to 60 mcg/kg/min for sedation until extubated. If analgesia was required after extubation, IV morphine 0.05 mg/kg was given every 10 minutes until either the patient appeared to be resting comfortably or a maximum of 5 doses had been given. When the patient's baseline analgesia was established, they were provided with a patient-controlled analgesia (PCA) pump programmed to administer morphine 0.015 mg/kg, with a lockout interval of 6 minutes. Acetaminophen 650 mg was given by mouth every 6 hours while awake for 96 hours and then 325 to 650 mg by mouth every 4 hours as needed (not to exceed 4,000 mg/24 hours). 

Duration

Recruitment: February to August 2016

Postoperative observation: 72 hours

Outcome Measures

Primary: postoperative pain scores for 72 hours postoperatively using a validated 0- to 10-point Verbal Rating Scale (VRS)

Secondary: 24-hour postoperative morphine requirements, time to extubation, level of sedation, opioid-related side effects, total operating room time, total sufentanil, total midazolam

Baseline Characteristics

  

Methadone (n= 9)

Placebo (n= 12)

Age, years

 73 65

Weight, kg

 76 91

History, n

Previous heart surgery

Chronic pain



2

0



2

2

Of the 24 patients that were randomized, one patient was excluded due to significant intraoperative complications requiring prolonged ICU stay and abandonment of protocol. Another patient withdrew due to an inability to tolerate the PCA. Lastly, another patient was removed due to anesthesia protocol violation (high-dose ketamine).

Results

Endpoint

Methadone (n= 9)

Placebo (n= 12)

VRS at rest

24 hours

48 hours

72 hours


2.8

1.4

1.3


4.0

1.4

1.2

VRS with cough

24 hours

48 hours

72 hours


4.8

3.3

3.6


5.0

3.5

2.6

Time to extubation, minutes

673

643

Richmond Agitation-Sedation Score (RASS)

24 hours

48 hours

72 hours


-0.1

0

0


-0.1

0

0

Oral methadone did not reduce pain scores (p= 0.008).

Postoperative morphine requirement during the 24 hours was reduced by a mean of 23 mg in the methadone group (99% confidence interval [CI] 37 to 13; p < 0.005). Additionally, nurse-administered morphine pre-PCA resulted in a significant reduction between the methadone and placebo groups of 11.2 vs. 20 mg (mean difference -8.8, 99% CI 20.0 to 11.2; p= 0.007).

There was no difference in pain scores or PCA morphine observed after 24 hours postoperatively. Total intraoperative sufentanil, total operating room time, and postoperative midazolam also did not differ between groups.

Adverse Events

There was no difference in the incidence of opioid-related side effects (nausea, vomiting, pruritus, constipation, urinary retention, hypoventilation, and hypoxia) between groups throughout the postoperative period.

Study Author Conclusions

Though preoperative oral methadone did not reduce pain scores, morphine requirements were reduced in the first 24 h post-CABG.

InpharmD Researcher Critique

This study had a small sample size and was conducted at a single institution. Additionally, there were strict exclusion criteria, which potentially limits its generalizability and external validity. This trial was underpowered to demonstrate the superiority of methadone.

 

References:

Bolton TM, Chomicki SO, McKay WP, Pikaluk DR, Betcher JG, Tsang JC. Preoperative oral methadone for postoperative pain in patients undergoing cardiac surgery: A randomized double-blind placebo-controlled pilot. Can J Pain. 2019;3(1):49-57. Published 2019 Apr 9. doi:10.1080/24740527.2019.1575695

 

Use of Chronic Methadone Before Total Knee Arthroplasty

Design

Retrospective, case-control study

N= 72

Objective

To compare the opioid requirements and the immediate postoperative course for patients on methadone maintenance with those who are not, after a total knee arthroplasty (TKA)

Study Groups

Control (n= 36)

Methadone (n= 36)

Inclusion Criteria

Underwent a unilateral TKA for end-stage degenerative joint disease by a single surgeon

Methadone: on chronic methadone maintenance (patients who self-reported or had documentation of receiving methadone as an outpatient for > 6 months)

Control: patients who did not self-report or had no documentation of previous intake of methadone

Exclusion Criteria

Not disclosed

Methods

Chart review and analysis of eligible patients were performed. The control group was matched with the methadone group based on gender, age, and body mass index. Institutional standard postoperative pain management protocol included ketorolac 15 mg intravenously (IV) every 6 hours as needed for pain, oxycodone 5 mg oral every 4 hours as needed for pain, acetaminophen 975 mg oral every 8 hours standing, and pregabalin 50 mg twice a day standing. Furthermore, on postoperative day 0, hydromorphone 0.5 mg IV every 4 hours as needed for pain and IV patient-controlled analgesia (PCA) morphine 1 mg with a 6-minute lockout were used. The hydromorphone and morphine PCA were weaned aggressively on postoperative day 1. If the patient did not tolerate weaning and/or the full regimen was not sufficient to control the patient's postoperative pain, a pain management anesthesia consult was obtained. The patient's preoperative dose of methadone was continued through the postoperative period.

Duration

Chart review: 2005 to 2010

Outcome Measures

 Postoperative inpatient hospitalization period, PO morphine equivalent dose

Baseline Characteristics

  

Control (n= 36)

Methadone (n= 36)

 p-value

Age, years

 53.9 53.6 NS

Female

 19 19 -

Body mass index, kg/m2

 33.1 31.5 NS

Median follow-up, month

 42 19.5 NS

Mean methadone dose, mg

 - 86.8 -

Results

Endpoint

Control (n= 36)

Methadone (n= 36)

p-value

Median postoperative inpatient stay, days (range)

3 (2 to 6)

4 (2 to 15)

0.004

Anesthesia used: spinal/general

Regional block used

15/21

23 (64%)

16/20

23 (64%)

0.727

-

Morphine equivalent dose, mg

Median average daily PO morphine equivalent opioid usage (range)

Median total PO morphine equivalent via PCA (range)

 

57.5 (0.4 to 110.8)

75.3 (0 to 302.5)

 

687.6 (252.8 to 2,106.8)

204.0 (0 to 846.0)

 

< 0.001

< 0.001

In-house pain management consult

0

4 (11%)

0.03

Adverse Events

There was no difference in reoperation rates (13% in methadone group, 8% in controls; p= 0.29). In the methadone group, 3 revisions were for mechanical failure, and 3 revisions were for periprosthetic infection (one of which required 3 operations). In the control group, 2 revisions were for mechanical failure, and 1 revision was for periprosthetic infection. No patients in either group required manipulation under anesthesia for joint stiffness.

Study Author Conclusions

There is a significantly higher opioid requirement, length of stay, and pain management consults in patients on methadone maintenance compared with those who are not after a TKA. These patients may benefit from a nonroutine approach to perioperative care in TKA.

InpharmD Researcher Critique

Given the retrospective nature of the study, unmeasured confounding factors other than methadone dependence may have affected the observed results. Moreover, the methadone group had a relatively shorter follow-up than the control group, potentially leading to an underestimation of the complications and reoperations in this group. 

 

References:

Chan FJ, Schwartz AM, Wong J, Chen C, Tiwari B, Kim SJ. Use of Chronic Methadone Before Total Knee Arthroplasty. J Arthroplasty. 2017;32(7):2105-2107. doi:10.1016/j.arth.2017.02.048