Pharmacokinetics and analgesic effects of methadone in children and adults with sickle cell disease

Abstract

Background: Vaso-occlusive episodes (VOEs) are a significant source of morbidity among children and adults with sickle cell disease (SCD). There is little information on methadone use for SCD pain. This investigation evaluated methadone pharmacokinetics in children and adults with SCD, with a secondary aim to assess pain relief and opioid consumption.

Procedure: Participants included children (<18 years) and adults with a VOE requiring hospitalization. Patients were randomly assigned to receive standard care (opioid patient-controlled analgesia; control group) or one dose of intravenous methadone (0.1-0.125 mg/kg) in addition to standard care (methadone group). Venous methadone and metabolite concentrations were measured. Pain scores, pain relief scores, and opioid consumption were recorded.

Results: Twenty-four children (12 methadone, 12 controls) and 23 adults (11 methadone, 12 controls) were studied. In children, the half-life of R- and S-methadone enantiomers was 34 ± 16 and 24 ± 9 hr, respectively. In adults, R- and S-methadone half-lives were 52 ± 17 and 38 ± 12 hr, respectively. Pain scores were lower (P = 0.002) and pain relief scores were higher (P = 0.0396) in children receiving methadone versus controls. There was no difference in pain scores and pain relief in adults receiving methadone versus controls. There was no difference in opioid consumption between methadone and control groups, in both adults and children.

Conclusions: Intravenous methadone disposition in children and adults with SCD was comparable to that in subjects without SCD from prior studies. Methadone produced more pain relief than standard care in children with SCD. Higher methadone doses may be more effective and should be evaluated in both children and adults with SCD.

Trial registration: ClinicalTrials.gov NCT00761085.

Keywords: analgesics; methadone; pediatric; sickle cell disease.

Figure 1

Flow diagram for enrollment of pediatric participants.

Figure 2

Flow diagram for enrollment of adult participants.

Figure 3

Plasma concentrations of methadone and EDDP. Results are shown as the mean ± SD for children (left, n=12) and adults (right, n=11). All subjects received 0.1mg/kg methadone, except 3 children and 1 adult, who received 0.125 mg/kg. Children received a 10 minute infusion and adults received a bolus. Times are relative to the start of methadone dosing.

Figure 4

Effect of methadone on pain relief and opioid consumption in children. Day 1 denotes the day of methadone administration. In controls, data were obtained on the comparable hospital day. (A) Pain relief scores. Results are the mean ± SD (*p<0.05 between groups) (B) Daily total opioid consumption (morphine equivalents, mg). Results are the median, and upper and lower interquartile ranges. There were no significant differences between groups.

Figure 5

Effect of methadone on pain relief and opioid consumption in adults. (A) Pain relief scores. Results are the mean ± SD (B) Daily total opioid consumption. Results are the median, and upper and lower interquartile ranges. There were no significant differences between groups.