Methadone

Myron Yaster MD and Lynne G. Maxwell MD

Today’s PAAD by Azamfirei et al.¹ is a SCOPING  review on the use of intraoperative methadone in pediatric patients.  You, like I, may be wondering what is a SCOPING review and how is it different from a SYSTEMATIC review?² I’m pretty sure you’ve heard of systematic reviews like the Cochrane reviews which became popular in the 1990s.  According to the Cochrane handbook, a systematic review ‘”uses explicit, systematic methods that are selected with a view to minimizing bias, thus providing more reliable findings from which conclusions can be drawn and decisions made.”³  Scoping reviews are equally rigorous and are “an ideal tool to determine the scope or coverage of a body of literature on a given topic and give clear indication of the volume of literature and studies available as well as an overview (broad or detailed) of its focus. Scoping reviews are useful for examining emerging evidence when it is still unclear what other, more specific questions can be posed and valuably addressed by a more precise systematic review.”^2,4 

Clear as mud?  Because there are so many papers that use these methodologies, I think a thorough discussion of how these reviews are performed and their differences is in order.  I’ve asked one of the authors of today’s PAAD, Dr. Sapna Kudchadkar of Johns Hopkins, to assist in that endeavor.  Hopefully, Sapna and I will get it done in the next couple of weeks so keep your eyes peeled!  Myron Yaster MD

Original article

Azamfirei R, Procaccini D, Lobner K, Kudchadkar SR. The Effects of Intraoperative Methadone on Postoperative Pain Control in Pediatric Patients: A Scoping Review. Anesth Analg. 2024 Aug 1;139(2):263-271. doi: 10.1213/ANE.0000000000006548. Epub 2024 Jun 7. PMID: 37285308.

We’ve discussed methadone as a perioperative analgesic on several previous occasions in the PAAD. Methadone is a unique, rapidly acting (2-8 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 (2-8 minutes) is about the same as fentanyl and its long duration of action makes it ideal for surgical procedures in which postoperative pain is expected (e.g., Nuss procedures, spine surgery, trauma etc.).^5-8  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.⁹

“Despite the many advantages of methadone, reports of perioperative pediatric use remain limited with no attempts to systematically synthesize the effects of intraoperative methadone on postoperative analgesia in pediatric populations. The objective of this study is to review postoperative analgesia outcomes in pediatric patients receiving intraoperative methadone compared to patients receiving other intraoperative opioids or placebo.”¹ 

In today’s scoping review, Azamfirei et al found that “methadone appears to be associated with decreased consumption of opioids in the first 24 hours postoperatively compared to patients receiving other shorter-acting opioids or pain management strategies. This is the first review formally examining the quality of the evidence surrounding methadone usage in pediatric patients.“¹

This scoping review focused mainly on intraoperative methadone use and not pre and post operative use, although one of the included studies did include postoperative intravenous methadone bolues.⁹  Dosing ranged widely from 0.1-0.4 mg/kg.  In our own practice we used 0.15-0.2 mg/kg as loading doses in the OR and supplemented with 0.05- 0.1 mg/kg every 3-4 hours as needed (and subsequently in the PACU).  Further, because methadone has excellent bioavailability and is extremely inexpensive in its oral formulations (pennies a dose), I (MY) often gave it together with acetaminophen in the PREOP holding area before transport to the OR.

Azamfirei et al “could NOT make strong recommendations for the regular usage of methadone based on these studies, as only a small number of interventional studies were available for analysis. The results underscore the need for large, well-designed randomized trials to fully evaluate the safety and efficacy of intraoperative methadone in diverse surgical populations.”¹

Because of current patterns of use of intraoperative methadone in pediatric patients, 3 of the 5 studies reviewed by the authors involved patients undergoing spine surgery,⁸ while the remaining two studies, conducted more than 30 years ago, involved a broader spectrum of surgical interventions. The mention of diverse surgical populations in the authors’ conclusion above, highlights this issue. Studies of same day or overnight stay surgical procedures should be undertaken, similar to that reported by Kharasch et al. which was a dose finding study of intraoperative methadone in adult surgical patients who were discharged one day after surgery.¹⁰  Because of the included surgeries (hysterectomy, laparoscopic and vaginal and laparoscopic hiatal hernia repair) most of the patients were female.

The 800 lb gorilla in the room is that to most people, patients, and other physicians and nurses, methadone has only one use: the treatment of opioid use disorder.  Using it therapeutically is often problematic because of this stigma. If we could only change its name, we could perhaps use it much more commonly.  Are you using methadone perioperatively?  What hurdles do you have to overcome and can you overcome them?  Send your thoughts and comments to Myron who will post in a Friday reader response.

References

1.            Azamfirei R, Procaccini D, Lobner K, Kudchadkar SR. The Effects of Intraoperative Methadone on Postoperative Pain Control in Pediatric Patients: A Scoping Review. Anesthesia and analgesia 2024;139(2):263-271. (In eng). DOI: 10.1213/ane.0000000000006548.

2.            Munn Z, Peters MDJ, Stern C, Tufanaru C, McArthur A, Aromataris E. Systematic review or scoping review? Guidance for authors when choosing between a systematic or scoping review approach. BMC medical research methodology 2018;18(1):143. (In eng). DOI: 10.1186/s12874-018-0611-x.

3.            Higgins J, Thomas J, Chandler J, Cumpston M, Page MJ, Welch VA. Cochrane Handbook for Systematic Reviews of Interventions version 6.4 (updated August 2023)2023.

4.            Armstrong R, Hall BJ, Doyle J, Waters E. Cochrane Update. 'Scoping the scope' of a cochrane review. J Public Health (Oxf) 2011;33(1):147-50. (In eng). DOI: 10.1093/pubmed/fdr015.

5.            Kharasch ED, Clark JD, Adams JM. Opioids and Public Health: The Prescription Opioid Ecosystem and Need for Improved Management. Anesthesiology 2022;136(1):10-30. (In eng). DOI: 10.1097/aln.0000000000004065.

6.            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 2019;128(4):802-810. (In eng). DOI: 10.1213/ane.0000000000003464.

7.            Murphy GS, Szokol JW. Intraoperative Methadone in Surgical Patients: A Review of Clinical Investigations. Anesthesiology 2019;131(3):678-692. (In eng). DOI: 10.1097/aln.0000000000002755.

8.            Ye J, Myung K, Packiasabapathy S, et al. Methadone-based Multimodal Analgesia Provides the Best-in-class Acute Surgical Pain Control and Functional Outcomes With Lower Opioid Use Following Major Posterior Fusion Surgery in Adolescents With Idiopathic Scoliosis. Pediatr Qual Saf 2020;5(4):e336. (In eng). DOI: 10.1097/pq9.0000000000000336.

9.            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 2019;129(6):1723-1732. (In eng). DOI: 10.1213/ane.0000000000004404.

10.         Kharasch ED, Brunt LM, Blood J, Komen H. Intraoperative Methadone in Next-day Discharge Outpatient Surgery: A Randomized, Double-blinded, Dose-finding Pilot Study. Anesthesiology 2023;139(4):405-419. (In eng). DOI: 10.1097/aln.0000000000004663.