RESUMO
OBJECTIVES: (1) To test the safety and efficacy of a clinical protocol for administering opioid by using patient-controlled analgesia (PCA) for the management of mucositis pain in children after bone marrow transplantation, (2) to compare the efficacy, side-effect profile, and potency ratio of morphine with those of hydromorphone by using PCA as the method of opioid administration, and (3) to obtain pharmacokinetic data on hydromorphone and morphine in this population of children. METHODS: In this double-blind, three-period crossover study, patients were randomly assigned to receive either morphine (group 1) or hydromorphone (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 opioid, 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 PCA 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 last study day (day 10), patients received a continuous infusion of opioid derived from the previous 24-hour PCA opioid requirement, and blood specimens were collected and stored for subsequent opioid analysis. RESULTS: Ten patients were enrolled in this study. Rapid escalation in opioid requirement commonly occurred at the commencement of PCA, followed by a variable plateau phase and then deescalation of opioid requirement after mucositis resolution. The measures demonstrated the safety and efficacy of the clinical protocol. In the concentrations used, there 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 patient during periods 1, 2, and 3 indicated that patients used 27% more hydromorphone than expected from its presumed 7:1 ratio relative to morphine 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 clearance was 51.7 ml/min per kilogram of body weight (range, 28.6 to 98.2 ml/min per kilogram). The mean plasma morphine, morphine-6-glucuronide, 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 (range, 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-glucoronide/morphine, and morphine-3-glucuronide/morphine-6-glucuronide were 2.48 (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 clinical protocol for the administration of opioids by means of PCA for mucositis pain after bone marrow transplantation was demonstrated. In this small study, hydromorphone was not superior to morphine in terms of analgesia or the side-effect profile: a larger study would be needed to show a difference. The clearances of hydromorphone and morphine in the children studied were generally greater than those previously recorded, but this finding may be related to disease or treatment variables. Apart from clearance, the morphine pharmacokinetics in the study population were similar to those previously recorded. Hydromorphone may be less potent in this population of children than indicated by adult equipotency tables.
Assuntos
Analgesia Controlada pelo Paciente , Analgésicos Opioides/uso terapêutico , Hidromorfona/uso terapêutico , Morfina/uso terapêutico , Mucosa , Dor/tratamento farmacológico , Adolescente , Analgésicos Opioides/efeitos adversos , Analgésicos Opioides/farmacocinética , Análise de Variância , Criança , Estudos Cross-Over , Método Duplo-Cego , Humanos , Hidromorfona/efeitos adversos , Hidromorfona/farmacocinética , Inflamação/complicações , Morfina/efeitos adversos , Morfina/farmacocinética , Dor/etiologia , Medição da Dor , Equivalência Terapêutica , Resultado do TratamentoRESUMO
Between 1980 and 1984, of 107 patients receiving 16 mg/d of dexamethasone for spinal cord compression, three (2.8%) developed gastrointestinal (GI) perforation and two (1.9%) GI bleeding; of 226 being tapered from 100 mg/d of dexamethasone, perforation occurred in six (2.7%) and GI bleeding in eight (3.5%). Of 125 patients with GI perforations treated between 1979 and 1986, 41 (33%) were on steroids, 24 for neurologic disease. Median duration of steroid therapy was 24 days; 20 (91%) of the neurologic patients perforated within 30 days. The steroid group had more free peritoneal involvement (p less than 0.00001), but fewer signs and symptoms of peritonitis (p less than 0.000001) than the nonsteroid group. Seventeen patients were receiving steroids for cord compression; they had significantly more rectosigmoid perforations (p less than 0.014) and associated constipation (p less than 0.000001) than the 108 remaining patients. GI perforation is a less well-recognized complication of steroid therapy in neurologic patients than is GI bleeding though it occurs as frequently, is more difficult to diagnose, and far more serious. In steroid-treated patients, prevention of constipation might avert this serious complication, while early diagnosis will improve the outcome.