The optimal dose of prophylactic intravenous naloxone in ameliorating opioid-induced side effects in children receiving intravenous patient-controlled analgesia morphine for moderate to severe pain: a dose finding study

Abstract

Background: Opioid-induced side effects, such as pruritus, nausea, and vomiting are common and may be more debilitating than pain itself. A continuous low-dose naloxone infusion (0.25 μg/kg/h) ameliorates some of these side effects in many but not all patients without adversely affecting analgesia. We sought to determine the optimal dose of naloxone required to minimize opioid-induced side effects and to measure plasma morphine and naloxone levels in a dose escalation study.

Methods: Fifty-nine pediatric patients (24 male/35 female; average age 14.2 ± 2.2 years) experiencing moderate to severe postoperative pain were started on IV patient-controlled analgesia morphine (basal infusion 20 μg/kg/h, demand dose 20 μg/kg, 5 doses/h) and a low-dose naloxone infusion (initial cohort: 0.05 μg/kg/h; subsequent cohorts: 0.10, 0.15, 0.25, 0.40, 0.65, 1, and 1.65 μg/kg/h). If 2 patients developed intolerable nausea, vomiting, or pruritus, the naloxone infusion was increased for subsequent patients. Dose/treatment success occurred when 10 patients had minimal side effects at a naloxone dose. Blood samples were obtained for measurement of plasma morphine and naloxone levels after initiation of the naloxone infusion, processed, stored, and measured by tandem mass spectrometry with electrospray positive ionization.

Results: The minimum naloxone dose at which patients were successfully treated with a <10% side effect/failure rate was 1 μg/kg/h; cohort size varied between 4 and 11 patients. Naloxone was more effective in preventing pruritus than nausea and vomiting. Concomitant use of supplemental medicines to treat opioid-induced side effects was required at all naloxone infusion rates. Plasma naloxone levels were below the level of assay quantification (0.1 ng/mL) for infusion rates ≤0.15 μg/kg/h. At rates >0.25 μg/kg/h, plasma levels increased linearly with increasing infusion rate. In each dose cohort, patients who failed therapy had comparable or higher plasma naloxone levels than those levels measured in patients who did not fail treatment. Plasma morphine levels ranged between 3.52 and 172 ng/mL, and >90% of levels ranged between 10.2 and 61.6 ng/mL. Plasma morphine levels were comparable between patients who failed therapy and those patients who achieved symptom control.

Conclusions: Naloxone infusion rates ≥1 μg/kg/h significantly reduced, but did not eliminate, the incidence of opioid-induced side effects in postoperative pediatric patients receiving IV patient-controlled analgesia morphine. Patients who failed therapy generally had plasma naloxone and morphine levels that were comparable to those who had good symptom relief suggesting that success or failure to ameliorate opioid-induced side effects was unrelated to plasma levels.

Figure 1

Plasma naloxone levels measured after 5 half-lives of naloxone infusion for subjects who achieved adequate symptom control (Rx success, ●) and subjects who failed therapy (Rx failure, ○) are shown. In treatment responders, average plasma naloxone levels increased linearly with increasing infusion rate (straight line, , R² = 0.76). Patients who failed treatment (dashed line, ) had higher average plasma naloxone levels than those who did not fail treatment (comparison of slopes, P = 0.009). The minimum level of assay quantification, 0.1 ng/mL, is represented by a dash-dot-dot line ().

Figure 2

Plasma morphine level as a function of morphine consumption for subjects who achieved adequate symptom control (Rx success, ●) and subjects who failed therapy (Rx failure, ○). At the time the second plasma morphine level was measured, plasma morphine level was independent of morphine consumption for patients in both groups, and average plasma morphine levels did not differ between groups (34.7 ± 5.1 vs 29.2 ± 3.2 ng/mL for responders and treatment failures, respectively).

Figure 3

Average self-reported pain scores for male (○) and female (●) subjects who achieved adequate symptom control. Female subjects reported significantly (*) higher pain scores than male subjects at 8, 20, and 24 hours after initiation of therapy (P = 0.039, P = 0.023, and P = 0.002, respectively).