Perioperative Methadone
Myron Yaster MD and Rita Agarwal MD
There are many recurrent themes in the pediatric anesthesia, critical care medicine, and pain management literature. The use of perioperative methadone, a unique opioid analgesic, is one. We’ve discussed methadone as a perioperative analgesic on several previous occasions in the PAAD and I’m sure there will be many more in the future. Today’s article1 and its accompanying excellent editorial2 is a pro/con debate, mostly focused on adult patients, that provides an excellent overview of this topic. Finally, both papers deal extensively with how (or if) we should overcome the hesitancy of many anesthesiologists in using it perioperatively. Myron Yaster MD
Editorial
Pan S, Anderson TA. Perioperative Methadone: Perilous or Pain Panacea? Anesth Analg. 2023 Jul 1;137(1):72-75. doi: 10.1213/there.0000000000006332. Epub 2023 Jun 16. PMID: 37326865.
Original article
D'Souza RS, Esfahani K, Dunn LK. Pro-Con Debate: Role of Methadone in Enhanced Recovery After Surgery Protocols-Superior Analgesic or Harmful Drug? Anesth Analg. 2023 Jul 1;137(1):76-82. doi: 10.1213/ANE.0000000000006331. Epub 2023 Jun 16. PMID: 37326866.
Methadone is a unique, rapidly acting (6-8 minutes), long duration analgesic (36-72 hours) that is both a mu opioid agonist AND an NMDA antagonist AND a reuptake inhibitor of serotonin and norepinephrine neurotransmitters in the brain. Most commonly thought of as a drug to use in opioid use disorder, it is increasingly being used as a first line analgesic in acute and chronic pain and in palliative care. For the anesthesiologist, its speed of onset (6-8 minutes) is about the same as fentanyl3,4 and its long duration of action make it ideal for surgical procedures in which postoperative pain is expected (e.g., Nuss procedures, spine surgery, trauma etc.)5
We have so many other opioid and non-opioid analgesics, why should we care or switch? Postoperative pain remains poorly controlled and failure to treat it may lead to chronic persistent pain.6,7 Perioperative methadone has been shown to significantly lower pain scores and opioid consumption in the first postoperative 72 hours at rest with an even larger reduction in pain scores in the subgroup analysis with movement for methadone compared with other opioids.8 Further, D’Souza et al. found no difference in time-to-extubation and complications (including nausea, sedation, respiratory depression, and hypoxemia) between the methadone and control groups. Finally, because of its NMDA antagonism, methadone is particularly effective in patients in whom neuropathic pain may become a problem.
OK, if methadone is so great and the evidence to support its use in pain management is so overwhelming, why the hesitancy in using it? Indeed, Pan and Anderson2 ask “When does avoidance of evidence-based practice become a professional or ethical issue? Is it acceptable for physicians not to use a medication because of unfamiliarity, even when it has been shown to be superior to those they use?”9 We think this hesitancy is not unique to methadone. It takes years for new ideas to become mainstream. I (MY) like to use the “bite the bullet” story. During the American Civil War (1861-1865) non-lethal musket/rifle injuries often required limb amputations. Soldiers were tied down, restrained and had to “bite down on a bullet” while the surgeon, who had to be fast, did his/her work. And yet as many of you know, general anesthesia was discovered in 1847, 15 years before the civil war. Why wasn’t it used routinely for everyone? It simply takes time to change practice and thinking. I (RA) was an initially hesitant and relatively late adopter for perioperative analgesia because of my experiences in the pain medicine, partly because it just seemed too good to be true. However, once we started using it in our practice, I have become an enthusiastic supporter.
Is methadone absolutely safe? Of course not. Like all opioids it is a respiratory depressant. And because of its long duration of action, that respiratory depression can occur after many hours when nursing staff and others are not monitoring patients as closely. It is associated with QT interval prolongation and an increased risk of torsades de pointes. Its inhibition of serotonin transport within the brain may lead to development of serotonin syndrome, particularly in patients on antidepressants. Aside from respiratory depression, these other side effects are extremely rare. There is a great deal of variability in oral absorption, and ideal dose (mg/kg) or interval has not been well defined. Although methadone has been relatively well studied in pediatric patients having spine or major orthopedic surgery, it hasn’t been well studied in many patient populations. In fact, in an on-line ahead of print article, Dr Sapna Kudchadkar and colleagues specifically state that “we cannot make strong recommendations for the regular use of methadone in the perioperative setting at this time.” And that their review of the literature on methadone for perioperative pain management in children highlights the need for further large, well designed randomized studies. We will review this paper in much greater detail when it is published in print.
One final thought. Is it expensive (or cheaper) compared to other opioids like fentanyl, morphine or hydromorphone? After many years of trying to figure this out I (MY) could never find the answer to this question because much of this pharmacy information is proprietary. One thing for sure though, is that methadone is very effective when given orally or intravenously and oral formulations which can be given as a preoperative medication are certainly going to be less expensive than IV formulations.
What do you do in your practice? Do any of you know what the unit cost of methadone is in your hospital? If you do and have other thoughts on this subject send to Myron who will post in the Friday Reader Responses.
References
1. D'Souza RS, Esfahani K, Dunn LK. Pro-Con Debate: Role of Methadone in Enhanced Recovery After Surgery Protocols-Superior Analgesic or Harmful Drug? Anesthesia and analgesia. Jul 1 2023;137(1):76-82. doi:10.1213/ane.0000000000006331
2. Pan S, Anderson TA. Perioperative Methadone: Perilous or Pain Panacea? Anesthesia and analgesia. Jul 1 2023;137(1):72-75. doi:10.1213/ane.0000000000006332
3. Kharasch ED, Clark JD, Adams JM. Opioids and Public Health: The Prescription Opioid Ecosystem and Need for Improved Management. Anesthesiology. Jan 1 2022;136(1):10-30. doi:10.1097/aln.0000000000004065
4. Komen H, Brunt LM, Deych E, Blood J, Kharasch ED. Intraoperative Methadone in Same-Day Ambulatory Surgery: A Randomized, Double-Blinded, Dose-Finding Pilot Study. Anesthesia and analgesia. Apr 2019;128(4):802-810. doi:10.1213/ane.0000000000003464
5. Murphy GS, Szokol JW. Intraoperative Methadone in Surgical Patients: A Review of Clinical Investigations. Anesthesiology. Sep 2019;131(3):678-692. doi:10.1097/aln.0000000000002755
6. Apfelbaum JL, Chen C, Mehta SS, Gan TJ. Postoperative pain experience: results from a national survey suggest postoperative pain continues to be undermanaged. AnesthAnalg. 8/2003 2003;97(2):534-40. Not in File.
7. Gan TJ, Habib AS, Miller TE, White W, Apfelbaum JL. Incidence, patient satisfaction, and perceptions of post-surgical pain: results from a US national survey. Current medical research and opinion. Jan 2014;30(1):149-60. doi:10.1185/03007995.2013.860019
8. Machado FC, Vieira JE, de Orange FA, Ashmawi HA. Intraoperative Methadone Reduces Pain and Opioid Consumption in Acute Postoperative Pain: A Systematic Review and Meta-analysis. Anesthesia and analgesia. Dec 2019;129(6):1723-1732. doi:10.1213/ane.0000000000004404
9. D'Souza RS, Gurrieri C, Johnson RL, Warner N, Wittwer E. Intraoperative methadone administration and postoperative pain control: a systematic review and meta-analysis. Pain. Feb 2020;161(2):237-243. doi:10.1097/j.pain.0000000000001717