PATIENT-CONTROLLED ANALGESIA FOR MUCOSITIS PAIN IN CHILDREN - A 3-PERIOD CROSSOVER STUDY COMPARING MORPHINE AND HYDROMORPHONE

Objectives: (I) To test the safety and efficacy of a clinical protocol for administering opioid by using patient-controlled analgesia (PCA) far the management of mucositis pain in children after bone marrow tra nsplantation, (2) to compare the efficacy, side-effect profile, and po tency ratio of morphine with those of hydromorphone by using PCA as th e method of opioid administration, and (3) to obtain pharmacokinetic d ata on hydromorphone and morphine in this population of children. Meth ods: In this double-blind, three-period crossover study, patients were randomly assigned to receive either morphine (group 1) or hydromorpho ne (group 2) initially by means of PCA on days 1, 2, and 3 (period 1), to be followed on days 4, 5, and 6 (period 2) with the alternative op ioid, followed by the opioid used at the commencement of the study on days 7, 8, and 9 (period 3), A clinical protocol for calculating the P CA commencement opioid dose and subsequent opioid-dose escalation was tested by measures of safety and efficacy. Measures of pain intensity and opioid side effects were made during the three periods, On the las t study day (day 10), patients received a continuous infusion of opioi d derived from the previous 24-hour PCA opioid requirement, and brood specimens were collected and stored for subsequent opioid analysis. Re sults: Ten patients were enrolled in this study. Rapid escalation in o pioid requirement commonly occurred at the commencement of PCA, follow ed by a variable plateau phase and then deescalation of opioid require ment after mucositis resolution. The measures demonstrated the safety and efficacy of the clinical protocol. In the concentrations used, the re was no statistical difference between the mean daily pain, sedation , nausea and vomiting, and pruritus scores for both opioids (Friedman test), The analysis of variance of the log-total opioid doses per pati ent during periods 1, 2, and 3 indicated that patients used 27% more h ydromorphone than expected from its presumed 7:1 ratio relative to mor phine potency used in the PCA infusions. The mean plasma hydromorphone concentration was 4.7 ng/ml (range, 1.9 to 8.9 ng/ml), and the mean c learance was 51.7 ml/min per kilogram of body weight (range, 28.6 to 9 8.2 ml/min per kilogram). The mean plasma morphine, morphine-6-glucuro nide, and morphine-3-glucuronide concentrations were 40.0 ng/ml (range , 15 to 62.5), 168.2 ng/ml (range, 54.4 to 231.9), and 391.0 ng/ml (ra nge, 149.4 to 921.7), respectively. The mean morphine clearance was 34 .3 ml/min per kilogram of body weight (range, 19.3 to 58.3). The mean molar ratios of morphine-6-glucuronide/morphine, morphine-3-glucuronid e/morphine, and morphine-3-glucuronide/morphine-6-glucuronide were 2.4 8 (range, 1.4 to 3.3), 5.82 (range, 3.4 to 9.1), and 2.46 (range, 1.1 to 3.3), respectively. Conclusions: The safety and efficacy of a clini cal protocol for the administration of opioids by means of PCA for muc ositis pain after bone marrow transplantation was demonstrated In this smalt study, hydromorphone was not superior to morphine in terms of a nalgesia or the side-effect profile: a larger study would be needed to show a difference. The clearances of hydromorphone and morphine in th e children studied were generally greater than those previously record ed, but this finding may be related to disease or treatment variables. Apart from clearance, the morphine pharmacokinetics in the study popu lation were similar to those previously recorded. Hydromorphone may be less potent in this population of children than indicated by adult eq uipotency tables.