Society for Pediatric Anesthesia
`
`Section Editor: Peter J. Davis
`
`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
`Constance L. Monitto, MD,* Sabine Kost-Byerly, MD,* Elizabeth White, RN,* Carlton K. K. Lee, PharmD,†‡
`Michelle A. Rudek, PharmD, PhD,§ Carol Thompson, MS, MBA,储 and Myron Yaster, MD*‡
`
`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 ␮g/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 ␮g/kg/h, demand dose 20 ␮g/kg, 5 doses/h) and a low-dose naloxone
`infusion (initial cohort: 0.05 ␮g/kg/h; subsequent cohorts: 0.10, 0.15, 0.25, 0.40, 0.65, 1, and
`1.65 ␮g/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 measure-
`ment 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 ␮g/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 ⱕ0.15 ␮g/kg/h. At rates ⬎0.25 ␮g/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 ⱖ1 ␮g/kg/h significantly reduced, but did not elimi-
`nate, 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.
`(Anesth Analg 2011;113:834 –42)
`
`In patients of all ages, opioids are the analgesics most
`
`frequently prescribed for the management of moderate
`to severe pain. Regardless of their method of adminis-
`tration, all opioids produce undesired side effects, includ-
`ing nausea and vomiting, pruritus, constipation, urinary
`
`From the *Department of Anesthesiology and Critical Care Medicine,
`Division of Pediatric Anesthesiology and Critical Care Medicine; †Depart-
`ment of Pharmacy; ‡Department of Pediatrics; and §Department of Oncol-
`ogy, Division of Chemical Therapeutics, The Johns Hopkins University
`School of Medicine, Baltimore; and 储Department of Biostatistics, The Johns
`Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
`Accepted for publication June 17, 2011.
`Funding: Richard J. Traystman Endowed Chair.
`The authors declare no conflicts of interest.
`
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`
`retention, respiratory depression, cognitive impairment,
`opioid-induced hyperalgesia, dependence, and tolerance.
`Some of these side effects, such as nausea, vomiting,
`pruritus, and opioid-induced bowel dysfunction are com-
`mon and can be so debilitating that patients would rather
`
`Reprints will not be available from the authors.
`Address correspondence to Constance L. Monitto, MD, Department of
`Anesthesiology and Critical Care Medicine, Division of Pediatric Anesthe-
`siology and Critical Care Medicine, The Johns Hopkins University School of
`Medicine, 600 North Wolfe St., Blalock 904, Baltimore, MD 21287. Address
`e-mail to cmonitt1@jhmi.edu.
`Copyright © 2011 International Anesthesia Research Society
`DOI: 10.1213/ANE.0b013e31822c9a44
`
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`be in pain than experience the consequences of opioid
`therapy. Additionally, physicians are often reluctant to
`prescribe opioids because of these side effects and because
`of their fear of other less common, but more serious
`complications such as respiratory depression. Indeed, the
`amelioration or elimination of these side effects is increas-
`ingly one of the most important challenges in acute pain
`management.
`Naloxone, a ␮-opioid receptor antagonist, is effective at
`reducing and antagonizing both desired and undesired
`opioid effects. The coadministration of low-dose naloxone
`(0.25 ␮g/kg/h) with opioid analgesics has shown promise
`as a method of ameliorating undesired side effects, specifi-
`cally pruritus, and nausea and vomiting, without impairing
`the quality of analgesia.1 Indeed, we previously demon-
`strated the success of this technique in children and ado-
`lescents receiving IV morphine to treat moderate to severe
`postoperative pain.2 Inclusion of a low-dose naloxone
`infusion decreased the incidence of pruritus from 77% to
`20% and the incidence of nausea from 70% to 35% in
`children and adolescents receiving IV patient-controlled
`analgesia (PCA) after surgery.2 However, in that study,
`more than one-third of patients still experienced intolerable
`opioid-related side effects despite the use of low-dose
`naloxone. Because this prior study tested only 1 naloxone
`infusion rate, we did not know if either a smaller or larger
`dose might more effectively decrease the incidence of
`opioid-induced side effects in our patients, or if treatment
`failure could be explained in individual patients by sub-
`therapeutic naloxone or increased morphine plasma levels.
`Thus, the primary purpose of this study was to use a
`dose escalation study method to determine the naloxone
`infusion rate that would most effectively reduce the inci-
`dence of intolerable opioid-induced side effects (failure rate
`⬍10%) without affecting analgesia or opioid analgesic
`requirements in pediatric patients receiving IV PCA mor-
`phine. Our secondary aim was to measure plasma levels of
`morphine and naloxone at each of the naloxone infusion
`rates used, to determine whether specific naloxone or
`morphine plasma levels correlated with therapeutic success
`or failure.
`
`METHODS
`After obtaining IRB approval, written parental informed
`consent, and, when applicable, written patient assent, pa-
`tients older than 6 and younger than 18 years of age, with
`acute, moderate to severe postoperative pain were enrolled
`and studied. Exclusion criteria included patients who re-
`mained tracheally intubated postoperatively, who required
`preoperative benzodiazepine administration, who were
`unable to communicate verbally, or who were unable to
`initiate a bolus (demand) dose via the PCA device as a
`result of mental or physical disability. Additionally, pa-
`tients who were allergic to opioids, were in any investiga-
`tional drug trial within 1 month of the treatment day of the
`study, who had received opioids within 7 days of the study,
`or who had a parent with a psychiatric illness that impaired
`their ability to provide consent were also excluded. Surgical
`procedures included posterior spinal fusion and pectus
`excavatum repair. Patients were recruited by a study
`
`investigator before surgery, and the study protocol was
`instituted in the immediate postoperative period.
`Although intraoperative general anesthetic manage-
`ment was not standardized, all patients enrolled in this
`study underwent general anesthesia during which they
`were routinely monitored, paralyzed with nondepolarizing
`muscle relaxants, and endotracheally intubated. After an-
`tagonism of neuromuscular blockade with neostigmine and
`atropine or glycopyrrolate, patients’ tracheas were extu-
`bated and patients were transported to either the pediatric
`postanesthesia care unit or the pediatric intensive care unit
`for recovery. Upon arrival, patients were started on IV PCA
`(CADD威-Solis; Smiths Medical, St. Paul, MN). The PCA
`pump cassette contained 100 mg morphine sulfate in 100
`mL normal saline (1 mg/mL). The following routine set-
`tings were established: an initial loading dose of up to 100
`␮g/kg or more to achieve patient comfort, a maintenance
`basal infusion rate of 20 ␮g/kg/h, a demand dose of 20
`␮g/kg, a lockout time interval of 8 minutes, and a maxi-
`mum of 5 doses per hour (maximum hourly morphine
`0.12 mg/kg).
`Naloxone was administered by a continuous infusion
`pump “piggy-backed” into the patient’s IV catheter. The
`naloxone solution was prepared using a standard naloxone
`infusion consisting of 2 mg naloxone in 250 mL 0.9% saline
`(final concentration ⫽ 8 ␮g/mL).2 The initial naloxone
`infusion rate evaluated (cohort 1) was chosen to be 0.05
`␮g/kg/h. This dose was doubled for the second cohort
`(0.10 ␮g/kg/h). Subsequent infusion rates were defined as
`the sum of the prior 2 infusion rates (0.10, 0.15, 0.25, 0.40,
`0.65, 1, and 1.65 ␮g/kg/h, respectively).
`Every 4 hours while awake, patients were evaluated by
`their bedside nurse for the presence and severity of pain
`and opioid-related side effects. Subjective pain scores were
`assessed using self-report, either the Wong-Baker FACES™
`scale,3 or, in older children, a numerical 0 to 10 scale.4
`Patients were also assessed by a study nurse to determine
`side effect severity. They were asked to self-assess pruritus
`and nausea (0 ⫽ none, 1 ⫽ present but tolerable, 2 ⫽ severe,
`intolerable), and if they had vomited. In addition, bedside
`nursing flow sheets were scrutinized for documented epi-
`sodes of nausea and/or vomiting. Vital signs, including
`arterial blood pressure, respiratory rate, and oxyhemoglo-
`bin saturation were monitored and recorded every 4 hours.
`Use of “rescue” antiemetics and antipruritics, opioid
`consumption, and the occurrence of respiratory depression
`were recorded. Patients who developed opioid-induced
`side effects were treated symptomatically by a protocol-
`driven algorithm. Nausea and/or vomiting was treated
`with IV dolasetron 0.35 mg/kg (maximum dose 12.5 mg)
`every 8 hours or ondansetron 0.1 mg/kg (maximum dose 4
`mg) every 4 hours as needed. IV diphenhydramine 1
`mg/kg (maximum dose 50 mg) every 4 to 6 hours was used
`as a second-line antiemetic rescue therapy and the primary
`antidote to treat pruritus. If these maneuvers did not
`relieve the patient’s symptoms, the study was terminated,
`and the IV naloxone infusion was increased to 1 ␮g/kg/h.
`The amount of morphine used and the requirements for
`supplemental analgesia or symptomatic treatment during
`the 24-hour study period were recorded. Finally, if respi-
`ratory depression occurred (respiratory rate ⬍8 breaths/
`
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`Optimal Dose of Prophylactic Naloxone
`
`Table 1. Patient Demographics
`No. of subjects
`Naloxone infusion
`rate (␮g/kg/h)
`(success/failure)
`0.05
`5 (3/2)
`0.10
`5 (3/2)
`0.15
`11 (9/2)
`0.25
`4 (2/2)
`0.40
`8 (6/2)
`0.65
`5 (3/2)
`1
`11 (10/1)
`1.65
`10 (10/0)
`
`Age (y)
`(mean ⴞ SEM)
`12.7 ⫾ 2.5
`16.9 ⫾ 1.3
`15.0 ⫾ 2.1
`13.6 ⫾ 2.0
`15.1 ⫾ 1.5
`13.3 ⫾ 1
`14.2 ⫾ 2.5
`13.8 ⫾ 2.3
`
`Sex,
`male/female
`3/2
`3/2
`5/6
`0/4
`3/5
`3/2
`7/4
`0/10
`
`Posterior spine fusion/
`pectus excavatum
`3/2
`1/4
`10/1
`4/0
`7/1
`2/3
`9/2
`10/0
`
`Overall
`
`59 (46/13)
`
`14.4 ⫾ 2.2
`
`24/35
`
`36/13
`
`Cause of failure
`P ⫻ 1, N/V and P ⫻ 1
`P ⫻ 2
`P ⫻ 2
`P ⫻ 1, N/V ⫻ 1
`P ⫻ 1, N/V ⫻ 1
`P ⫻ 2
`N/V ⫻ 1
`None
`P ⫻ 9
`N/V ⫻ 3
`N/V and P ⫻ 1
`
`N/V ⫽ nausea/vomiting; P ⫽ pruritus.
`
`min, oxygen saturation ⬍90%, and the patient was un-
`arousable), the IV PCA was to be turned off and the patient
`was ordered to receive naloxone 1 ␮g/kg IV as a bolus dose
`every minute until respiratory depression resolved.
`Dose/treatment failure at any naloxone infusion rate
`occurred when 2 patients experienced intolerable side
`effects despite the naloxone infusion and the use of rescue
`medications. When this occurred, the naloxone infusion
`rate was increased for subsequent patients. Dose/treatment
`success and study completion occurred when 10 patients
`were successfully treated at a given dose with no more than
`1 failure in that treatment cohort. The maximum number of
`patients in any cohort, therefore, was 11. After determining
`this minimum effective dose, the naloxone dose was in-
`creased 1 final time to determine whether a higher dose
`was associated with adverse events, such as reversal of
`analgesia as demonstrated by an increase in opioid
`consumption.
`
`Serology
`Blood samples (5 mL) were obtained from a dedicated
`indwelling IV catheter for measurement of plasma mor-
`phine, naloxone, and naloxone-3-glucoronide levels after
`initiation of the naloxone infusion, and at a later time point
`between 12 and 24 hours after the start of the infusion.
`Additionally,
`in patients who failed therapy, a blood
`sample was obtained before termination of the study. Blood
`samples were collected in EDTA-containing tubes and were
`processed within 30 minutes of collection by centrifugation
`for 10 minutes at 1500g. The plasma supernatant was stored
`at ⫺20°C until subsequent analysis using a validated liquid
`chromatography/tandem mass spectrometry method de-
`veloped by the Kimmel Cancer Center at Johns Hopkins
`University Analytical Pharmacology Core Laboratory.
`Briefly, salirasib was extracted from plasma using acetoni-
`trile precipitation. Separation of morphine, naloxone, and
`naloxone-3-glucuronide and the internal standard, morphine-
`(N-methyl-d3), was achieved on a Waters XTerra威 C-18 (3.5
`␮m, 150 ⫻ 2.1 mm internal diameter) analytical column
`using a mobile phase consisting of acetonitrile/2 mM
`ammonium acetate (65:35, v/v) containing 0.1% formic acid
`and an isocratic flow of 0.20 mL/min. The analytes were
`monitored by tandem mass spectrometry with electrospray
`positive ionization. Detection was performed by monitor-
`ing the ion transitions from m/z 286.0 3 152.0 for mor-
`phine, 328.1 3 310.0 for naloxone, 504.0 3 310.0 for
`
`naloxone-3-glucuronide, and 289.0 3 152.0 for the internal
`standard. The linear calibration curves were generated over
`the range of 5 to 500 ng/mL for morphine and 0.1 to 10
`ng/mL for naloxone. The presence of naloxone-3-
`glucuronide was qualitatively assessed. Plasma samples
`that were diluted 1:10 (v/v) with pooled plasma were
`accurately quantified. The accuracy and within- and
`between-day precision met the acceptance criteria for bio-
`analytical assays.5 An analytical run was deemed accept-
`able if 75% of calibrators tested were within ⱕ15% from the
`nominal concentration (ⱕ20% for the lower limit of quan-
`tification) and 66% of the quality controls tested were
`within ⱕ15% from the nominal concentration.
`
`Data Analysis
`Patient characteristics, efficacy, plasma naloxone and mor-
`phine levels, and side effect scores were summarized by
`cohort level and over all cohorts. Data are presented as
`mean ⫾ SEM. Analyses between genders and dose catego-
`ries on naloxone and morphine levels as well as pain scores
`were performed using regression analyses with robust
`estimates of standard errors. Similar analyses on side
`effects were performed with logistic regression.
`
`RESULTS
`Patient characteristics are displayed in Table 1. Overall, 59
`patients participated in this study. There were 24 males and
`35 females. One female and 11 males underwent repair of
`pectus excavatum, and the remaining 47 underwent poste-
`rior spinal fusion. Cohort size varied between 4 and 11
`subjects. Thirteen patients were treatment failures (7 fe-
`male, 6 male). The minimum naloxone infusion rate at
`which 10 patients were successfully treated with no more
`than 1 failure was 1 ␮g/kg/h. Increasing the naloxone dose
`to 1.65 ␮g/kg/h resulted in no patients failing treatment
`because of intolerable side effects.
`Naloxone was more effective in preventing pruritus
`than nausea and vomiting (Table 2). The overall incidence
`of pruritus was 27%, whereas only 2 of 21 patients reported
`any pruritus at naloxone doses ⱖ1 ␮g/kg/h. Patients were
`next stratified into 3 naloxone dose ranges: low (0.05–0.15
`␮g/kg/h), moderate (0.25–0.65 ␮g/kg/h), and high (1–1.65
`␮g/kg/h). Naloxone infusion rates between 0.05 and
`0.15 ␮g/kg/h were grouped together as a low-dose cohort
`based on the observation that most previous studies have
`considered 0.25 ␮g/kg/h as a low-dose infusion. Thus,
`
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`Table 2. Efficacy of Naloxone in Ameliorating Pruritus and Nausea and Vomiting
`Naloxone
`No. of patients
`studied (success/
`infusion
`failure)
`rate
`Low
`21 (15/6)
`Moderate
`17 (11/6)
`High
`21 (20/1)
`Overall
`59 (46/13)
`
`Pruritus
`score ⴝ 0
`52%
`76%
`90%a
`73%
`
`Pruritus
`score ⴝ 1
`29%
`12%
`10%
`17%
`
`Pruritus
`score ⴝ 2
`19%
`12%
`0%
`10%
`
`N/V
`score ⴝ 0
`55%
`35%
`48%
`47%
`
`N/V
`score ⴝ 1
`30%
`41%
`48%
`40%
`
`N/V
`score ⴝ 2
`15%
`24%
`4%
`14%
`
`Use of rescue
`antipruritic
`therapy
`43%
`24%
`10%b
`25%
`
`Use of rescue
`antiemetic
`therapy
`43%
`65%
`57%
`54%
`
`N/V ⫽ nausea/vomiting.
`a The odds of pruritus was decreased by 88% at high-dose as compared with low-dose naloxone infusions (P ⫽ 0.013).
`b The odds of receiving rescue therapy (diphenhydramine) to treat pruritus was decreased by 86% at high-dose as compared with low-dose naloxone infusions
`(P ⫽ 0.024).
`
`all dose cohorts (48% vs 48% vs 39% for low-, moderate-,
`and high-dose cohorts, respectively), its use to specifi-
`cally treat pruritus was significantly decreased in the
`high-dose naloxone cohort (P ⫽ 0.024). However, we
`found no difference in the use of rescue antiemetic
`therapy across dose cohorts (Table 2).
`and morphine
`Naloxone-3-glucoronide,
`naloxone,
`plasma levels were measured for those patients who re-
`ceived naloxone infusions of ⱖ0.15 ␮g/kg/h. Naloxone-3-
`glucoronide levels were below the measurement limits of
`the assay (0.1 ng/mL) for all samples tested. Plasma
`naloxone levels were below the measurement limits of the
`assay at an infusion rate of 0.15 ␮g/kg/h, and generally
`below assay limits at an infusion rate of 0.25 ␮g/kg/h. At
`infusion rates ⬎0.25 ␮g/kg/h, in patients who achieved
`adequate symptom control, average plasma levels in-
`creased linearly with increasing infusion rate (R2 ⫽ 0.76).
`At comparable naloxone infusion rates, patients who failed
`treatment had similar or higher plasma naloxone levels
`than mean plasma naloxone levels measured in those who
`did not fail treatment (comparison of slopes P ⫽ 0.009) (Fig.
`1 and Table 3).
`Average 24-hour morphine consumption was 1.41 ⫾
`0.08 mg/kg/d and ranged from 1.13 ⫾ 0.22 to 1.64 ⫾ 0.63
`mg/kg/d across cohorts (Table 3). Female subjects con-
`sumed significantly more morphine than males (1.57 ⫾ 0.10
`vs 1.17 ⫾ 0.12 mg/kg/24 h, P ⬍ 0.025). However, observing
`each gender individually, we found no significant differ-
`ence in 24-hour morphine consumption as a function of
`naloxone infusion dose cohort (Table 4).
`Whereas the overall average plasma morphine level was
`31.8 ⫾ 2.3 ng/mL (Table 3), interindividual variability was
`moderately high with morphine levels ranging between a
`minimum of 3.52 and a maximum of 172 ng/mL (Fig. 2).
`However, ⬎75% of measured plasma morphine levels
`decreased between 16 and 46 ng/mL, whereas ⬎90%
`ranged between 10.2 and 61.6 ng/mL. Comparing plasma
`morphine levels between responders and treatment fail-
`ures, we found that at the time the second plasma mor-
`phine level was measured (⬎12 hours after initiation of
`PCA and naloxone infusion), mean plasma morphine levels
`did not differ significantly between the 2 groups (34.7 ⫾ 5.1
`vs 29.2 ⫾ 3.2 ng/mL for responders and treatment failures,
`respectively). In addition, the slopes of the lines correlating
`morphine plasma level and morphine consumption were
`approximately equal to zero, suggesting that morphine
`level was generally stable and independent of morphine
`consumption for patients in both groups. Finally, beyond
`
`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, E) are shown. In treatment responders, average plasma
`naloxone levels increased linearly with increasing infusion rate
`, R2 ⫽ 0.76). Patients who failed treatment
`(straight line,
`) had higher average plasma naloxone
`(dashed line,
`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 (
`
`grouping these doses together allowed us to examine
`whether doses lower than the previously studied low dose
`might be effective. Infusion rates of 1 and 1.65 ␮g/kg/h
`were cohorted together as high-dose naloxone because both
`doses led to treatment success. Comparing cohorts, we
`found that the odds of pruritus was decreased by 88% at
`high-dose as compared with low-dose infusions (P ⫽
`0.013). However, there was no difference in the incidence of
`nausea and vomiting among the 3 naloxone infusion co-
`horts. Overall, 47% of patients studied reported no nausea
`or vomiting, and 48% reported no nausea or vomiting at
`doses ⱖ1 ␮g/kg/h. The incidence of severe side effects
`(pruritus or nausea/vomiting score ⫽ 2) did trend toward
`lower levels as naloxone infusion rate was increased.
`Severe pruritus occurred in 19%, 12%, and 0% of patients,
`whereas severe nausea/vomiting occurred in 15%, 24%,
`and 4% of patients, respectively. However, this trend did
`not reach statistical significance. Concomitant use of
`supplemental medicines to treat opioid-induced side ef-
`fects was
`required at all naloxone infusion rates.
`Whereas the likelihood of receiving diphenhydramine to
`treat opioid-induced side effects was comparable across
`
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`Optimal Dose of Prophylactic Naloxone
`
`0.25
`
`0.40
`
`0.65
`
`1
`1.65
`Overall
`
`BLQ
`
`0.10 ⫾ 0.02
`
`0.25 ⫾ 0.02
`
`0.37 ⫾ 0.06
`0.54 ⫾ 0.07
`
`Table 3. Plasma Naloxone and Morphine Levels and 24-Hour Consumption for Naloxone Infusion Cohorts
`and Subjects Who Failed Therapy
`Equilibrateda
`Naloxone levels for
`Naloxone
`treatment failuresb
`naloxone level
`infusion
`rate (␮g/kg/h)
`(ng/mL)
`(time measured)
`0.05
`N/A
`N/A
`0.10
`N/A
`N/A
`0.15
`BLQ
`BLQ (15 h, 18 h)
`BLQ (15 h, 21 h)
`BLQ (1 h)
`0.11 (15 h)
`0.12 (15 h)
`BLQ, 0.17 (1.5 h, 22 h)
`0.17, 0.26 (1 h, 22 h)
`0.25 (16 h)
`0.61, 0.88 (8 h, 13 h)
`No failures
`
`Morphine level
`(ng/mL)
`N/A
`N/A
`24.6 ⫾ 2.9
`
`21.2 ⫾ 2.0
`
`30.9 ⫾ 3.1
`
`33.7 ⫾ 4.8
`
`29.4 ⫾ 2.5
`33.8 ⫾ 4.8
`31.8 ⫾ 2.3
`
`Morphine levels for
`treatment failuresb
`(time measured)
`N/A
`N/A
`16.0, 30.0, 14.0 (15 h, 18 h, 22 h)
`19.0, 21, 24.9 (15 h, 21 h, 23 h)
`24.2 (1 h)
`18.4 (15 h)
`10.2 (15 h)
`30.9, 37.6 (1.5 h, 22 h)
`83.1, 22.8 (1 h, 22 h)
`41 (16 h)
`29.1, 34.2 (8 h, 13 h)
`No failures
`
`24-Hour morphine
`consumption (mg/kg)
`1.13 ⫾ 0.22
`1.16 ⫾ 0.24
`1.38 ⫾ 0.19
`
`1.23 ⫾ 0.05
`
`1.54 ⫾ 0.17
`
`1.38 ⫾ 0.28
`
`1.44 ⫾ 0.25
`1.64 ⫾ 0.17
`1.41 ⫾ 0.08
`
`Data are presented as mean ⫾ SEM.
`BLQ ⫽ below level of quantification; N/A ⫽ not available.
`a Equilibrated naloxone levels were calculated as the mean value measured after 5 half-lives of drug infusion (⬎400 minutes).
`b Data presented are individual naloxone and morphine levels measured in patients who failed treatment at time after start of naloxone infusion.
`
`Table 4. Twenty-Four-Hour Morphine Consumption
`for Male and Female Subjects
`24-hour morphine consumption
`(mg/kg)
`
`Naloxone
`infusion rate
`Low
`Moderate
`High
`Overall
`
`Males
`1.03 ⫾ 0.12
`1.22 ⫾ 0.06
`1.35 ⫾ 0.36
`1.17 ⫾ 0.12
`
`Females
`1.57 ⫾ 0.21
`1.51 ⫾ 0.15
`1.62 ⫾ 0.17
`1.57 ⫾ 0.10*
`
`Data are presented as mean ⫾ SEM.
`* Significantly different from overall males (P ⬍ 0.025).
`
`Figure 3. Average self-reported pain scores for male (E) 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).
`
`the initial postoperative period, the highest plasma mor-
`phine level measured in any patient who failed therapy
`was 41 ng/mL.
`Comparing pain scores over the first 24 hours after
`surgery in those patients who did not fail treatment, we
`found that females reported significantly higher pain scores
`than males at 8, 20, and 24 hours after the start of the
`naloxone infusion (4.9 ⫾ 0.5 vs 3.4 ⫾ 0.5, P ⫽ 0.039, 4.7 ⫾
`0.4 vs 2.9 ⫾ 0.6, P ⫽ 0.023, and 5.0 ⫾ 0.5 vs 2.5 ⫾ 0.7, P ⫽
`0.002, respectively) (Fig. 3). However, we did not observe
`any difference in analgesia in female patients over time as
`the naloxone infusion rate was increased. In male patients,
`pain scores trended lower over time in the low- and
`moderate-dose infusion rate groups, but not in the high-
`dose group. This difference was statistically significant at
`24 hours, but this observation is limited by the fact that pain
`
`Figure 2. Plasma morphine level as a function of morphine consump-
`tion for subjects who achieved adequate symptom control
`(Rx
`success, ●) and subjects who failed therapy (Rx failure, E). 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).
`
`838
`
`www.anesthesia-analgesia.org
`
`ANESTHESIA & ANALGESIA
`
`Nalox1042
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`Page 5 of 9
`
`

`

`scores were obtained on less than half of all patients at this
`time point.
`
`DISCUSSION
`In this prospective, dose finding study in children and
`adolescents being treated with IV PCA morphine after
`major surgery, we found that a naloxone infusion of ⱖ1
`␮g/kg/h significantly reduced, but did not eliminate, the
`incidence of opioid-induced side effects, and that this
`infusion rate was more effective than lower doses studied.
`We also found that patients who failed therapy generally
`had plasma naloxone and morphine levels that were com-
`parable to those who had good symptom relief. This
`finding suggests that a specific naloxone plasma level is not
`correlated with therapeutic success or failure and should
`not be a target of therapy. Finally, comparing all doses
`studied here, we could not demonstrate either an opioid-
`sparing effect or a significant increase in opioid consump-
`tion in our study patients.
`Opioids are the analgesics most frequently prescribed
`for the management of moderate to severe pain and,
`regardless of the method of administration, produce unde-
`sired side effects. Some of these side effects, such as nausea,
`vomiting, and pruritus are common and often so debilitat-
`ing that patients would rather be in pain than experience
`them. Crain and Shen6 in a series of laboratory experiments
`demonstrated that when administered in combination with
`opioids, ultralow-dose opioid antagonists may decrease
`opioid-induced side effects, such as hyperalgesia and tol-
`erance, and improve pain control. Possible explanations for
`this effect include the hypothesis that at very low doses,
`opioid antagonists inhibit ␮-opioid receptor excitatory
`G-protein complexes (Gs) while leaving the inhibitory
`G-protein receptors (Gi) available for pain control.6,7 Sub-
`sequently, consistent with these results, Gan et al.1 showed
`that administration of a naloxone infusion of 0.25 ␮g/kg/h
`in combination with IV PCA morphine attenuated opioid-
`induced side effects and significantly reduced 24-hour
`opioid consumption in women after abdominal hysterecto-
`mies. However, results from other trials have been more
`variable, with some showing no improvement. From our
`review of the literature, we believe that one possible
`explanation for the failure of opioid antagonist prophylaxis
`in these studies may relate to how the opioid antagonist
`was prepared and administered. In some trials in which the
`antagonist was ineffective, morphine and naloxone were
`mixed together
`in saline and delivered via a PCA
`pump.8 –10 Thus, patients received only small doses of
`naloxone intermittently when the PCA pump was trig-
`gered. How much naloxone was administered and how
`long it remained at its effector sites varied within and
`between patients. However, in studies in which an antag-
`onist was effective, the opioid antagonist was often either a
`long-acting drug, such as nalmefene,11 or a shorter-acting
`drug, naloxone, administered as an independent, continu-
`ous infusion as was done here.1,2 Of note, however, opioid
`sparing has been inconsistently found even when the
`antagonist has been administered continuously.
`In our previous prospective study, a continuous 0.25
`␮g/kg/h naloxone infusion significantly ameliorated pru-
`ritus and, to a lesser degree, nausea and vomiting in
`
`two-thirds of the children and adolescents studied.2 Why it
`failed in one-third of patients, however, was unclear.
`Because we did not know whether a higher or lower
`infusion rate might be more effective or might, conversely,
`be unsuccessful, we undertook this dose finding study. We
`found that plasma naloxone levels increased in a linear
`fashion with increasing infusion rate, and that naloxone
`infusion rates ⱖ1 ␮g/kg/h reduced the treatment failure
`rate to ⬍10%. Moreover, patients who failed therapy had
`comparable or higher plasma naloxone levels than those
`levels measured in patients who did not fail treatment,
`suggesting that a strategy to target IV infusions to achieve
`an effective plasma level would fail.
`Other investigators have reported side effect ameliora-
`tion at naloxone doses as low as 0.006 to 0.065 ␮g/kg/h,
`with worsening of analgesia at higher doses.8,9,12 Although
`we also found side effect amelioration at lower doses in our
`study, higher doses (ⱖ1 ␮g/kg/h) were more consistently
`effective. A possible explanation for these different results
`may simply be related to how IV PCA was provided in this
`study. Specifically, all pediatric patients in our institution
`are treated with a continuous basal opioid infusion. The use
`of a continuous infusion may be associated with increased
`total opioid consumption13 as well as opioid-related side
`effects including respiratory depression.14 –16 Although the
`use of a continuous basal opioid infusion is not universal in
`pediatric pain management, it is more frequently used2,14,17
`than in adult practice.1,8,9,12,16 Our findings that a higher
`naloxone infusion rate more effectively reduced pruritus in
`children receiving basal/bolus IV PCA than the lower
`doses reported to be effective in adult patients receiving
`bolus-only PCA are similar to those reported in a small
`pilot study of patients with sickle cell anemia who received
`morphine via continuous infusion in combination with
`naloxone.18
`Maxwell et al.2 found in their placebo-controlled trial
`that low-dose naloxone was more effective in ameliorating
`pruritus than nausea and vomiting. Our results support
`this. Indeed, in our study, increasing the naloxone infusion
`rate did not affect the overall incidence of gastrointestinal
`side effects as opposed to pruritus. This may be explained
`in part by the fact that pruritus is a more purely opioid-
`related side effect than nausea and vomiting. Postoperative
`nausea and vomiting are due only in part to the impact of
`opioids on central nervous system vomiting centers and
`gut motility.19 After surgery, other factors including the
`release of neurogenic, hormonal,
`inflammatory, and
`pharmacologic mediators can also contribute to dis-
`turbed gastrointestinal motility.20 As a result, nausea and
`vomiting may not be effectively reversed by opioid
`antagonism alone and will require, as in our treatment
`algorithm, other antiemetics, such as serotonin (5-HT3)
`receptor antagonists and/or antihistamines.
`Although we did find moderate variability in plasma
`morphine levels between patients, success or failure of
`low-dose naloxone could not be exp