Topics of Interest
Perspective on Opioids: Methadone
By Sophie R. Pestieau, MD
Associate Chief, Clinical Affairs
Children’s National Health System
Associate Professor of Anesthesiology, Critical Care Medicine, and Pediatric
George Washington University School of Medicine and Health Sciences
Washington, District of Columbia
Methadone was developed in 1937 by order of the then German leader, to solve Germany's opioid shortage. Morphine supply had been plummeting and the search for a synthetic opioid was on. It received the trade name of Dolophine, after the first name of Adolf Hitler although it may also come from the origins of the Latin words dolor and fins which mean (pain) and (end) in Latin.
Methadone differs from other opioids in so many ways, from its excellent bioavailability, multiple receptor affinities, and perhaps most importantly its pharmacokinetics. Looking at its receptor affinity, methadone is an opioid agonist that acts by binding to μ, κ and δ receptors. Its pharmacodynamic properties, such as analgesia, are primarily triggered by μ opioid receptor. Methadone is also an NMDA receptor antagonist, and as such is responsible for mitigating opioid induced hyperalgesia and tolerance. Both enantiomers are NMDA receptor antagonists but differ in regards to other receptor affinity. Unlike R-methadone, S-methadone is seemingly inactive as an opioid but promotes strong serotonin and norepinephrine uptake inhibition. So in addition to providing analgesia and preventing tolerance, methadone may also play a role in positively influencing mood which distinguishes it from other more conventional opioids
Although providing adequate pain relief is a top priority for anesthesiologists, the trend increasingly relies on the use of short-acting opioids, leading to patients awakening in discomfort, and then attempting to play “catch-up”. Ideally the duration of analgesia should match the duration of pain. What determines how anesthesiologists choose opioids is often based on speed of onset and elimination half-life. Perhaps a reason for methadone’s under- utilization in the operating room, is the misconception that the onset of methadone analgesia is slow. To the contrary, central nervous system methadone concentrations rapidly equilibrate with plasma concentrations. This rapid onset of effect (8 min) is comparable to that of fentanyl (5 min) and sufentanil (6 min), both well known for their quick onset1,2.
Another great attribute of methadone is its potential for long duration. The relationship between elimination half-life and duration of effect depends in part on the dose given. Because methadone has rapid distribution but very slow elimination, analgesia duration is critically dependent on the magnitude of the loading dose. In order to provide prolonged analgesia the loading dose needs to be large enough for the plasma level to remain well above the minimal effective analgesic concentration until after the end of the distribution phase3. With small loading doses plasma levels are only slightly above minimal effective analgesic concentrationat the end of distribution phase which results in shorter duration of analgesia, roughly 4h vs. 14h. So targeting doses and concentrations as high as possible above the minimal analgesic concentration, but below the threshold for respiratory depression, will in fact achieve long-lasting analgesia.
Berde et al illustrated this concept by randomizing 35 children to receive a single intraoperative dose of 0.2mg/kg of methadone or morphine for a variety of complex surgeries. Children who were dosed with methadone required significantly fewer opioids on the day of surgery, and reported significantly lower pain scores. The incidence of severe pain was also significantly decreased. The authors developed a protocol suggesting an intraoperative dose of methadone (0.2mg/kg), and postoperative rescue doses of 0.03-0.08mg/kg. More recently, for patients undergoing complex spine surgery, Gottschalk et al randomized patients to receive an intraoperative sufentanil infusion (0.25 μg/kg/h after a loading dose of 0.75 μg/kg) or a single bolus dose of methadone. Patients who received methadone required significantly less opioids for 72h postoperatively. They also reported significantly less pain. Here are two studies 20 years apart where the same dose of methadone given intraoperatively significantly improved postoperative analgesia while significantly decreasing opioid use after complex surgery. Seeking these same benefits, perioperative methadone has recently been incorporated as part of clinical care pathways and the perioperative surgical home model for spinal fusion surgery, to provide prolonged analgesia and ultimately improve outcomes4,5.
While there are still many unanswered questions about perioperative use of methadone, such as its effectiveness and safety for outpatient surgery, this quick review highlights the uniqueness of methadone in regards to its onset of effect, duration of action and prolonged analgesia.
- Sharma A, Tallchief D, Blood J, Kim T, London A, Kharasch ED. Perioperative pharmacokinetics of methadone in adolescents. Anesthesiology 2011;115:1153-61.
- Kharasch ED. Intraoperative methadone: rediscovery, reappraisal, and reinvigoration? Anesthesia and Analgesia 2011;112:13-6.
- Berde CB, Beyer JE, Bournaki MC, Levin CR, Sethna NF. Comparison of morphine and methadone for prevention of postoperative pain in 3- to 7-year-old children. J Pediatr 1991;119:136-41.
- Thomson K, Pestieau SR, Patel JJ, et al. Perioperative Surgical Home in Pediatric Settings: Preliminary Results. Anesthesia and Analgesia 2016;123:1193-200.
- Muhly WT, Sankar WN, Ryan K, et al. Rapid Recovery Pathway After Spinal Fusion for Idiopathic Scoliosis. Pediatrics 2016;137.