Annual Meeting Research
Demystifying Perioperative Methadone Administration in Children
By Senthil Packiasabapathy, MD and Senthilkumar Sadhasivam, MD, MPH
Riley Hospital for Children at Indiana University Health
Indianapolis, Indiana
Methadone has been used for maintenance therapy in opioid use disorders for a long time now. Its effectiveness in managing cancer and non-cancer related chronic pain has also been well recognized. Of late, we are witnessing a resurgence of its use for the treatment of acute pain following surgery. Some of the unique properties of methadone make it stand apart from the rest of the opioids. Importantly, the long elimination half-life helps maintain steady therapeutic blood levels, without peaks and troughs, after a single bolus dose, precluding infusion, or repeated dosing requirements.
Additionally, the NMDA blocking property aids in blocking opioid tolerance and opioid-induced hyperalgesia. It is also beneficial in reducing post-surgical opioid use and the prevention of chronic persistent surgical pain. Methadone is also a serotonin-norepinephrine reuptake inhibitor. Addictive habit-forming properties are minimal with methadone, compared to other opioids. This is relevant because, in an era of opioid epidemic, methadone might prove to be a safe, effective, long-acting alternative to the traditional shorter-acting opioids.
Use in pediatrics is not new. Neonatologists have been using methadone for the treatment of neonatal opioid withdrawal syndrome. The hesitancy in adapting methadone in the perioperative setting has been due to reports of disproportionately high opioid-related mortality being attributed to methadone, especially when used for chronic pain management. Within this context, it is noteworthy that doses as high as 120 mg per dose have been used for outpatient management of chronic pain. The main problem in implementing a methadone-based perioperative analgesic regimen is the current lack of consensus on the best dosing strategy. Most centers use a single large intraoperative dose, in the order of 20-30 mg. This has been shown to be effective up to 12-24 hours after surgery. But it could also lead to a greater incidence of sedation, respiratory depression, and nausea/vomiting.
At Riley Hospital for Children, we implemented a small and repeated methadone dose administration regimen. We use a dose of 0.1 mg/kg, a maximum of 5 mg per dose intraoperatively in most cases. This dose is repeated every 12 hours postoperatively for 2 to 4 doses. The first dose is administered via intravenous route, intraoperatively. Subsequent doses could be oral or IV, given the excellent 85-90% oral bioavailability. When used as part of a multimodal regimen, we have observed a significant decrease in the requirement of other opioids, even after very painful surgeries like posterior spine fusion and pectus repair. The patient/parent satisfaction is excellent, pain is well controlled, recovery enhanced, and length of stay is minimal (1-2 days for most of the spine fusions). Sustained analgesia is achieved at peak plasma methadone levels (25 ng/ml) that are much lower than the historically described toxic levels (100 ng/ml). We have not observed any respiratory depression, QT prolongation with this dose.
Another concerning issue with the use of methadone is the perplexing variability in its response. We do notice an occasional patient who requires significantly higher rescue opioid doses despite the same low dose methadone regimen, while some other patients are sedated, requiring a dose reduction. This might be due to inter-child variability in methadone metabolism, variations in the volume of distribution, and variations at the receptor and signaling pathways. Recently, we demonstrated significant variations in peak plasma concentrations after methadone administration. We demonstrated novel findings on variable expression/activity of metabolizing enzyme, CYP2B6, in addition to the pharmacogenetic basis for these variations for the first time in the perioperative setting. We have also found that the protein that binds to methadone, alpha-acid glycoprotein, an acute phase reactant, increased after surgery and contributes to pharmacokinetic variability.
There is still a long way to go to achieve the goal of ‘personalized methadone analgesia’ with precision dosing. This includes elucidation of the role played by other genetic variants affecting pharmacokinetics and pharmacodynamics before we could reach a point of being able to use genetic information to tailor methadone dose. This research at our institution is happening with the background of a larger scope of research on 'personalizing opioid analgesia in children' which also includes high-risk pediatric patients, such as those with obstructive sleep apnea and other opioids such as morphine. The long-term goal is to ensure better safety and efficacy in the management of perioperative pain in the pediatric population.
