Perioperative pharmacokinetics of methadone in adolescents

Abstract

Background: Methadone is frequently administered to adults experiencing anesthesia and receiving pain treatment. Methadone pharmacokinetics in adults are well characterized, including the perioperative period. Methadone is also used in children. There is, however, no information on methadone pharmacokinetics in children of any age. The purpose of this investigation was to determine the pharmacokinetics of intravenous methadone in children undergoing surgery. Perioperative opioid-sparing effects were also assessed.

Methods: Eligible subjects were children 5-18 yr undergoing general anesthesia and surgery, with an anticipated postoperative inpatient stay exceeding 3 days. Three groups of 10 to 11 patients each received intravenous methadone hydrochloride after anesthetic induction in ascending dose groups of 0.1, 0.2, and 0.3 mg/kg (up to 20 mg). Anesthetic care was not otherwise changed. Venous blood was obtained for 4 days, for stereoselective determination of methadone and metabolites. Pain assessments were made each morning. Daily and total opioid consumption was determined. Perioperative opioid consumption and pain was determined in a second cohort, which was matched to age, sex, race, ethnicity, surgical procedure, and length of stay, but not receiving methadone.

Results: The final methadone study cohort was 31 adolescents (14 ± 2 yr, range 10-18) undergoing major spine surgery for a diagnosis of scoliosis. Methadone pharmacokinetics were linear over the dose range 0.1-0.3 mg/kg. Disposition was stereoselective. Methadone administration did not dose-dependently affect postoperative pain scores, and did not dose-dependently decrease daily or total postoperative opioid consumption in spinal fusion patients.

Conclusions: Methadone enantiomer disposition in adolescents undergoing surgery was similar to that in healthy adults.

Figure 1

Methadone and 2-ethylidene-1.5-dimethyl-3.3diphenylpyrrolidine (EDDP) enantiomer plasma concentrations after intravenous methadone. Subjects received 0.1 (circles), 0.2 (squares), or 0.3 (triangles) mg/kg intravenous racemic (RS)-methadone HCl. Solid symbols and lines show R-methadone and R-EDDP, open symbols and dotted lines show S-methadone and S-EDDP. Each data point is the mean ± SD (n=10–11). Some SD are omitted for clarity. The inset shows the period from 0–12 hr.

Figure 2

Dose-adjusted methadone plasma concentrations after intravenous methadone. Subjects received 0.1 (circles), 0.2 (squares), or 0.3 (triangles) mg/kg intravenous racemic (RS)-methadone HCl. Solid symbols and lines show R-methadone, open symbols and dotted lines show S-methadone. Each data point is the mean. The inset shows the period from 0–12 hr.

Figure 3

Dose-adjusted methadone and 2-ethylidene-1.5-dimethyl-3.3diphenylpyrrolidine (EDDP) enantiomer plasma concentrations after intravenous methadone in all subjects. Solid symbols and lines show R-methadone and R-EDDP, open symbols and dotted lines show S-methadone and S-EDDP. Each data pint is the mean ± SD (n=31). The insets show dose-adjusted methadone and EDDP enantiomer plasma concentrations from 0–12 hr, and plasma R/S-methadone concentration ratios.

Figure 4

Influence of intraoperative methadone on analgesic requirements. Subjects received 0.1, 0.2, or 0.3 mg/kg intravenous racemic (RS)-methadone HCl. Controls received no intraoperative methadone. Day 1 was the day of surgery. Results are shown for (A) postoperative patient-controlled analgesia use, (B) postoperative oral opioid use, and (C) total (day 1–6) perioperative opioid use. Intraoperative opioids, patient controlled analgesia (morphine or hydromorphone), oral opioids (typically oxycodone) were converted to morphine equivalents. There were no significant differences between controls and patients receiving methadone.

Figure 5

Influence of intraoperative methadone on pain scores. Time zero was the beginning of surgery. Results are shown for (A) pain scores based on patients facial expression using the Wong-Baker FACES scale (0–5), (B) pain scores based on patient report using a Colored-Visual Analog Scale (0–10), and (C) ward nurse assessment of pain scores using a verbal analogue scale (0–10). Only nurse assessment of pain scores were determined for all groups. There were no significant differences between controls and patients receiving methadone.