More than 30 years ago, Dr. Charles (“Chuck”) Berde and his colleagues at the Boston Children’s Hospital published one of the first papers on the use of methadone as “a poor man’s alternative to IV PCA” in children.[1] It radically changed my thinking and I became a true “believer”. And you had to be a believer because there was and continues to be an enormous amount of resistance to using methadone from families, surgeons, colleagues, and pharmacists. Methadone is a long-acting, inexpensive opioid and the only mu-opioid agonist that is also an NMDA receptor antagonist. These properties make it a fabulous analgesic for acute perioperative and neuropathic chronic pain, cancer pain, sickle cell vaso-occlusive crisis pain, and opioid use disorder. Its onset is as rapid as fentanyl’s but it has a longer duration of action. It reduces the need for short-acting opioids and lowers the risk for chronic postsurgical pain. Hence, Chuck’s view that it is a poor man’s alternative to IVPCA.[1] I only wish methadone had a different name… For most, methadone is only associated with addiction, rather than with its many salutary effects. Further and unfortunately, based on my experiences in Colorado, many of you and your OR pharmacists may have little experience with using it or may even be afraid of using it because of the fear of respiratory depression or prolonged QT. Fears that in my experience are widely overblown and not supported by the facts when methadone is dosed appropriately.[2]
Yesterday I reposted the PAAD from August 21,2021 which reviewed the paper by Sadhasivam et al.[2] on methadone PK and PD. Today’s PAAD reviews the paper by Mok et al. [3] which continues this theme. I’ve asked Dr. Megan Brockel a colleague, friend and mentee and an expert on pediatric ERAS to write this with me. Myron Yaster MD
Original article
Mok V, Sweetman S, Hernandez B, Casias T, Hylton J, Krause BM, Noonan KJ, Walker BJ. Scheduled methadone reduces overall opioid requirements after pediatric posterior spinal fusion: A single center retrospective case series. Paediatr Anaesth. 2022 Oct;32(10):1159-1165 PMID: 35816392
Posterior spinal fusion surgery to correct adolescent idiopathic scoliosis notoriously produces severe and prolonged postoperative pain. As part of an ERAS protocol, Mok et al. retrospectively studied 3 different treatment strategies, hydromorphone IV PCA without methadone, hydromorphone IV PCA with pre-incisional methadone, and postoperative methadone without a PCA (but with nurse administered IV hydromorphone given on a PRN basis for breakthrough pain).
“Group PCA only (n = 26) consumed 0.33 mg/kg (95% CI [0.28, 0.38]) total hydromorphone equivalents, Group PCA + methadone (n = 39) 0.30 mg/kg (95% CI [0.25, 0.36]) total hydromorphone equivalents, and Group methadone (n = 22) 0.18 mg/kg (95% CI [0.15, 0.21]) total hydromorphone equivalents (p = .00096). Thus, the addition of methadone cut cumulative hydromorphone doses by 45% with similar analgesia. This strategy removed the need for a PCA and acute pain service consultation at our center.”[3]
The take home message is the Chuck Berde is always right and methadone is the poor man’s PCA.
Ok, is anyone surprised by these findings? We’re not. Indeed, using methadone intermittently is equivalent to using a background basal opioid infusion in the IV PCA pump. In this study protocol, basal infusions in the IV pump were not routinely used except at night. Having a basal infusion or methadone (the equivalent) will almost certainly make patients more comfortable. Pain is not constant and the need for breakthrough analgesia will always be a feature of postoperative pain control. Patients may be absolutely comfortable at rest, but intense pain can occur when the patient gets out of bed or coughs. Indeed, that’s the whole idea behind PCA. When patients need pain relief they can self administer a demand dose of an opioid. In this study, even in the no PCA group, patients had availability of nurse administered IV hydromorphone PRN for breakthrough pain. Further, the whole idea behind PCA is to remove the need for IV PRN dosing by a nurse (“eliminate the middleman”). If you are a patient waiting for the nurse to respond to the “call button”, the need to draw up a drug, and have another nurse check that the dose is correct is a process that takes time and if you are in pain, time matters.
Why was this study done? Multi-modal, opioid-sparing analgesia is a central tenet of ERAS protocols. Analgesic adjuncts (acetaminophen, NSAIDS, alpha agonists, NMDA antagonists, local anesthetics) are optimized with opioids used sparingly as needed to ensure patients are comfortable enough to move and participate in rehabilitation efforts. Opioids are associated with side effects some of which are common (nausea, vomiting, constipation, pruritus, sedation and mental clouding) and some that are not (respiratory depression). By reducing total opioid consumption in an ERAS protocol, the expectation is that there will be fewer opioid induced side effects and, with less nausea, vomiting, constipation, and sedation, patients will be able to eat, drink, ambulate, and return home sooner. Unfortunately, the reduction of opioid induced side effects nor changes in length of stay were not a part of this study. Thus, did the reduction in hydromorphone really matter?
Mok et al also state that “eliminating the need for a PCA can reduce drug waste, cost to patients, and the workload of the Acute Pain Service (APS)”.[3] This may or may not be true. We’ve learned from past experiences that cost and drug waste require robust analysis which did not occur here. Finally, because this was a retrospective study in which group one was done first (no methadone), a protocol change was made (adding methadone) and then analyzed, and finally a third change occurred (the elimination of PCA), the results may have been significantly affected by changes in other elements in management that may have occurred over time as well.
How should we proceed? Clearly a randomized prospective clinical trial that looks at the incidence of opioid induced side effects, length of stay AND total opioid consumption with and without methadone is needed. Unfortunately, with the publication of this paper that may not be possible in your practice because of a loss of equipoise. “How can we deny the benefit of methadone to our patients when it clearly works”? If on the other hand, you are non-believer and/or work in a large enough hospital to perform this study prospectively we think that would be great and we encourage you to do it, Let us know if we can be of assistance.
References
1. Berde, C.B., et al., Comparison of morphine and methadone for prevention of postoperative pain in 3- to 7-year-old children. J.Pediatr., 1991. 119(1 ( Pt 1): p. 136-141.
2. Sadhasivam, S., et al., A Novel Perioperative Multidose Methadone-Based Multimodal Analgesic Strategy in Children Achieved Safe and Low Analgesic Blood Methadone Levels Enabling Opioid-Sparing Sustained Analgesia With Minimal Adverse Effects. Anesth Analg, 2021. 133(2): p. 327-337.
3. Mok, V., et al., Scheduled methadone reduces overall opioid requirements after pediatric posterior spinal fusion: A single center retrospective case series. Paediatr Anaesth, 2022. 32(10): p. 1159-1165.