Management of Severe Chronic Pain with Methadone in Pediatric Patients with Sickle Cell Disease
Authors: LeBlanc Zachary , Vance Chris , Zhang Jie , Macksoud Sabrina R , Battle Steffane , Hilliard Lee , Lebensburger Jeff D. , Howard Thomas H. 
Published: November 2019

Abstract
Introduction
Patients with sickle cell disease (SCD) experience acute painful events; some patients develop chronic pain requiring daily short acting opioids, and frequent emergency department (ED) visits, and inpatient hospitalization. From the Cooperative Study of Sickle Disease (Platt, NEJM 1991), only 1% of patients with SCD experience more than 6 pain events per year. Methadone is a synthetic opioid used in chronic pain, but there is a paucity of data on its use and effectiveness in the pediatric SCD population. We hypothesized that methadone can be used safely in pediatric patients with SCD with severe chronic pain and would reduce ED visits and hospitalizations.
Methods
We conducted a retrospective cohort study (IRB approved) of 16 pediatric patients with SCD who received methadone for chronic pain management, indicating having more than 5 pain events per year. These patients were among 1100 total patients with SCD at our center. Primary SCD providers escalated doses to maximal effect and when clinically stable, doses were weaned. Follow-up started at time of methadone initiation and ended when a patient was weaned or transitioned to adult care; the 1 year period before treatment initiation was defined as the baseline period. We calculated descriptive statistics to characterize the study population. We compared clinical outcomes (ED visits or hospitalization for pain) for the baseline period and 1 year post methadone initiation using paired T test. To evaluate methadone dosing and dependency, we identified the mean dose, percentage of time at highest dose, and wean of methadone. We assessed withdrawal and safety by reviewing outpatient encounters, EKG screening for QTc > 450, eGFR by cystatin C to determine either a decrease in eGFR by 20% or an eGFR <80, and microalbumin/creatinine urinary excretion.
Results
Among the 16 participants, 10 (62.5%) were male and the genotypes of each patient were: 14 SS, 1 S/β0-thalassemia, 1 SC. The mean age was 15.5 (±2.8) years at time of methadone initiation and there was a medium follow-up of 2.1 years. Clinically, 13 (81.3%) had previous cholecystectomy, 6 (37.5%) had previous splenectomy, 7 (43.8%) had radiographic evidence of infarction of a long bone within the year prior to initiation of methadone, 10 (62.5%) were receiving chronic transfusion during methadone, and 10 (62.5%) received psychosocial counseling for depression and/or anxiety. The average number of ED visits per month was 0.31 (±0.27) in the baseline period and were 0.28 (±0.28, p=0.658) and 0.31 (±0.25, p=0.921) in the 1 year post and entire follow-up periods. The rate of hospitalizations per month decreased from 0.35 (±0.19) in the baseline period to 0.19 (±0.17, p=0.016) and 0.22 (±0.21, p=0.05) in the 1 year post and entire follow-up periods. The average initial starting dose was 12.5 mg and the mean highest dose was 26.6 mg. In 14 (87.5%) patients the final dose was less than the highest dose and 4 (25.0%) patients were weaned completely off of methadone. For the entire cohort, each patient spent a median of 183 days at their highest dose, a mean of 34% of the total time treated with methadone. No patients experienced signs consistent with opioid withdrawal during the follow-up period. The most common subjective complaints were sedation (12%), nausea and/or vomiting (24%) and constipation (6%). We found no documented new abnormal QTc intervals, changes in eGFR, or new onset proteinuria during the follow up period.
Conclusion
Methadone use in pediatric patients with SCD is well-tolerated and may lead to improved pain control as evidence by significant reduction in hospitalizations. Additionally, when followed closely, methadone can be used safely without concern for physiologic dependency; this is supported by our ability to wean patients off methadone entirely or weaning to a lower dose than their highest dose in the majority of the cohort. Hematologists should consider methadone as a part of chronic pain management in patients with SCD and severe chronic pain.

Disclosures
Lebensburger: ASH: Research Funding; NHLBI K23: Research Funding.