Methadone for Post-Op Pain? A Drug to Watch

Posted on 09/18/19 by Dr. Edward Digiamarino, M.D.

What medical practitioner hasn’t struggled with pain management before, during and after surgery? The relief of postoperative pain, in particular, continues to challenge practitioners today. As you know, even after minor surgical procedures, more than 50% of patients experience moderate to severe pain. So, it naturally follows: We are always looking for the next best thing to relieve our patients’ pain, and to make our jobs easier.

Consider intraoperative methadone—an alternative opioid. While methadone is certainly not a new drug, and has a reputation or stigma for its use with opiate dependence, that being said, it may be time to revisit methadone for post-op pain. Is it effective in this scenario? According to a recent review in Anesthesiology of almost twenty clinical investigations since the 1970s, there may still be potential for its use in surgery.

But here’s what we do know about this unique drug, and how it may benefit your patient population.

What Is Methadone?

Methadone is a long-acting opioid with central nervous system effects. It is both a potent μ-receptor agonist (FOOT 4) as well as an N-methyl-D-aspartate (NMDA) receptor antagonist. In addition, methadone inhibits the reuptake of the neurotransmitter’s serotonin and norepinephrine in the brain, and may potentially provide a mood-elevation effect during post-op.

Methadone has “a long half-life that provides stable blood concentrations after a single intraoperative dose, without the fluctuations associated with repeated injections of high clearance agents like morphine or hydromorphone.”

Because it has a long elimination half-life of 24 to 36 hours, it may be useful for surgical patients. But is it the answer? Here’s what we know.

What Early Trials Reveal (the Key Findings)

Give a Single Dose at the Start of Surgery
To date, the majority of studies have administered a single dose of methadone at the beginning of anesthesia while avoiding the use of other intraoperative opioids.

In 1982, a very small study investigated the effects of a single dose of methadone at the beginning of anesthesia, and since, other small studies have followed. Most investigations found that patients who were administered with methadone before surgery reported:

1. lower pain scores and
2. lower post-op narcotic requirements.

A single dose before surgery was found to be more effective in reducing postoperative analgesic requirements than a dose given at the end of surgery.
Early clinical trials have included more minor surgeries such as: hip replacements, gynecologic and obstetric patients (hysterectomy); ambulatory surgical patients (laparoscopic cholecystectomy, tubal ligation, salpingectomy, oophorectomy or salpingectomy with oophorectomy); pediatric surgical patients; and more.

Additionally, two investigations looked at adults undergoing major spine surgery; and two Brazilian studies examined cardiac surgical patients. In fact, the largest intraoperative clinical trial using methadone with 156 cardiac surgical patients found that “a dose of methadone given before surgery provided a prolonged analgesia benefit”; patient satisfaction with pain management was reported as higher than subjects in the fentanyl group.

What We Don’t Know (Research Limitations)

The primary questions that medical practitioners want answered are these: Is methadone safe? And, is methadone effective? Here’s what we don’t know, or the limitations of the current research.

Small Sample Sizes Are Underpowered
The sample sizes of the studies are simply too small to garner any solid evidence at this point in time. Of all the studies done — less than 20 — only four studies enrolled 100 patients or more. As you know, small sample sizes can not only produce false positives, but can also result in inconclusive findings. Higher-powered studies are needed.

High-Risk Patients Largely Excluded
In addition to the limitations of sample size, many of the early studies excluded high-risk patients, choosing instead to enroll relatively healthy patients who had no significant medical comorbidities.

Findings in Morbidly Obese Patients Are Inconclusive
Although morbidly obese patients were not excluded from the early clinical trials on methadone, the literature at this point suggests that “more cautious dosing and monitoring of the effects of methadone may be required in this patient population.” As this patient population may have a greater sensitivity to the respiratory depressant effects of opioids, proceed with caution when administering this drug.

Keep Your Eye of Methadone, and Use Caution When Administering

At this time, the majority of methadone investigations have been small in sample size and should be considered mere pilot studies. The efficacy and safety of methadone for use in patients during the post-op period is still unclear. Many more randomized and large-scale studies are needed in order to solidify initial findings. Data from such studies is needed before the routine use of methadone can be safely recommended for surgical patients.

So, while it’s still too soon to tell, methadone may be a drug to keep your eye on for future use as new trials bring new data to our operating rooms.



1. Kharasch ED: Intraoperative methadone: Rediscovery, reappraisal, and reinvigoration? Anesth Analg 2011; 112:13–6
2. Davis AM, Inturrisi CE: d-Methadone blocks morphine tolerance and N-methyl-d-aspartate–induced hyperalgesia.J Pharmacol ExpTher 1999;289:1048–53
__Sotgiu ML,Valente M, Storchi R, Caramenti G, Biella GE: Cooperative N-methyl-d-aspartate (NMDA) receptor antagonism and μ-opioid receptor agonism mediate the methadone inhibition of the spinal neuron pain-related hyperactivity in a rat model of neuropathic pain. Pharmacol Res 2009; 60:284–90
3. CoddEE,ShankRP,SchupskyJJ,Ra aRB:Serotonin and norepinephrine uptake inhibiting activity of centrally acting analgesics: Structural determinants and role in ant- inociception. J Pharmacol Exp Ther 1995; 274:1263–70
___Rojas-Corrales MO, Berrocoso E, Gibert-Rahola J, Micó JA: Antidepressant-like effects of tramadol and other central analgesics with activity on monoamines reuptake, in helpless rats. Life Sci 2002; 72:143–52
4. Kharasch ED, 2011
5. Gourlay GK,Wilson PR,Glynn CJ:Pharmacodynamics and pharmacokinetics of methadone during the perioperative period. Anesthesiology 1982; 57:458–67
___Gourlay GK,Willis RJ,Wilson PR: Postoperative pain control with methadone: Influence of supplementary methadone doses and blood concentration–response relationships. Anesthesiology 1984; 61:19–26
6. Gourlay GK,Wilson PR,Glynn CJ, 1982
7. Gottschalk A, Durieux ME, Nemergut EC: Intraoperative methadone improves postoperative pain control in patients undergoing complex spine surgery. Anesth Analg 2011; 112:218–23
8. Udelsmann A, Maciel FG, Servian DC, Reis E, de Azevedo TM, Melo Mde S: Methadone and morphine during anesthesia induction for cardiac surgery: Repercussion in postoperative analgesia and prevalence of nausea and vomiting. Rev Bras Anestesiol 2011; 61:695–701
9. Murphy GS, Szokol JW, Avram MJ, Greenberg SB, Marymont JH, ShearT,Parikh KN,Patel SS,Gupta DK: Intraoperative methadone for the prevention of post- operative pain: A randomized, double-blinded clinical trial in cardiac surgical patients. Anesthesiology 2015; 122:1112–22
10. Glenn S. Murphy, Joseph W. Szokol; Intraoperative Methadone in Surgical Patients: A Review of Clinical Investigations. Anesthesiology 2019;131(3):678-692. doi: 10.1097/ALN.0000000000002755
11. Ibid
12. Cozowicz C, Chung F, Doufas AG, Nagappa M, Memtsoudis SG: Opioids for acute pain management in patients with obstructive sleep apnea: A systematic review. Anesth Analg 2018; 127:988–1001


Privacy Notice:
This is a non-secure message form. By clicking the "I Accept" button below and submitting your message, you are acknowledging that any personally identifiable medical information you choose to send through this form, or email messages we send in reply have a risk of being intercepted by or disclosed to unauthorized third parties.