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* From the Department of Anesthesia, Pharmacology and Therapeutics, BC Children’s Hospital, University of British Columbia; Vancouver, British Columbia; and the
Department of Anesthesiolgy and Pain Management, Stollery Children’s Hospital, University of Alberta, Edmonton, Alberta, Canada.
Address correspondence to: Dr. C. Montgomery, Pediatric Anesthesia and Pain Management, British Columbia Children’s Hospital, University of British Columbia, 4480 Oak Street, Vancouver, British Columbia V6H 3V4, Canada. Phone: 604-875-2711; Fax: 604-875-3221; E-mail: cmontgomery{at}cw.bc.ca
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Abstract |
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Methods: After Ethics Board approval, the dual site, tertiary care teaching centre study recruited 212 subjects, age 
seven years, who received opioid analgesia postoperatively. A modified, self-report colour analogue scale (CAS) scored pruritus intensity (PrI). Subjects who reported PrI score 5/10 were randomized to treatment with nalbuphine 50 µg·kg–1 iv (max 5 mg) or saline placebo. A pruritus intensity difference (PrID) 50% was considered a positive outcome.
Results: Of 260 subjects approached, 212 consented and 184 received opioids. Median age was 13 yr (range 7–19) and median weight was 51 kg (range 19.6–134.8 kg). Pruritus intensity 5/10 occurred in 37 (20.1%) subjects. Intravenous morphine [patient-controlled analgesia (PCA)/continuous infusion] was associated with Pr in 68% of subjects over a wide dose range (9.4–63.2 µg·kg–1·hr–1). Pruritis occurred in 36% of patients in the PCA group compared to continuous opioid infusion (27%) and epidural administration (27%). Pruritus intensity difference 50% was achieved in 55.6% of nalbuphine and 57.9% of saline-treated subjects.
Conclusion: This preliminary report suggests that nalbuphine 50 µg·kg–1 iv is not effective in treating postoperative opioid-induced pruritus in pediatric patients. The modified CAS score and PrID warrant further investigation.
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Introduction |
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The mechanisms of opioid-induced pruritus are uncertain.1–5 A distinct neuronal pathway for peripheral itch has been identified and a pain/analgesic modulation mechanism described.6 Centrally administered opioids cause segmental pruritus without activation of primary peripheral neurons. The incidence and intensity of itch is likely multi-factorial and may depend on patient factors such as atopic tendency, route of opioid administration (systemic vs neuraxial), dose of opioid and opioid type (phenylpiperidine class vs morphine derivative). For synthetic opioids such as fentanyl, direct opioid action on the central nervous system, (µ and 
opioid receptors, serotonin receptors) rather than opioid-induced dermal and systemic histamine release, may be responsible for pruritus.
Therapy with various drug classes including non-selective anti-histamines such as diphenhydramine, µ-receptor antagonists such as naloxone, and the µ-receptor partial agonist-antagonists such as nalbuphine and butorphanol have been studied.7 While nalbuphine has been investigated as an analgesic-sedative in pediatrics, only butorphanol has been investigated as an anti-pruritic in this population.8–12
The treatment of opioid-induced pruritus and other disorders with diphenhydramine is recommended for pediatric patients based on historical and descriptive evidence.13,14 In adults, in the setting of intrathecal morphine-induced pruritus, nalbuphine was more effective.15 The sedative effect of diphenhydramine may decrease the reporting of subjective symptoms such as pruritus. Low dose naloxone (
1 µg·kg–1·hr–1) is effective in treating opioid-induced pruritus, however, both larger and cumulative doses of naloxone have been associated with decreased analgesia.16
Nalbuphine (Nubain©, DuPont Pharma, Wilmington, DE, USA) is a µ-receptor agonist-antagonist. Its analgesic and possibly certain anti-pruritic effects are mediated via actions on the µ and -receptors. 17 Adult studies, including those in obstetrical patients, report the efficacy of nalbuphine (30–100 µg·kg–1) in treating opioid-induced pruritus without reversal of analgesia or other significant side effects. Larger doses of nalbuphine (150–300 µg·kg–1) have been associated with increased sedation.16,18,19 This preliminary study was undertaken to determine the efficacy of nalbuphine 50 µg·kg–1 iv for the treatment of postoperative opioid-induced pruritus in a pediatric population. The null hypothesis was that nalbuphine would be no more effective than saline administration in subjects with a pre-defined pruritus intensity, evaluated at 60 min after treatment.
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Methods |
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Written informed parental/guardian consent and assent was obtained for all subjects. Recruitment was performed by the research assistants in the surgical daycare unit or pre-admission clinic at the two pediatric hospital sites on the day of surgery. The study design was a prospective, randomized, double-blind, placebo-controlled trial. Included were subjects seven years of age, receiving postoperative continuous opioid analgesia by any route, postoperative monitoring by the Acute Pain Service, and the ability to understand the self-report tool.
Patients were excluded for any of: pruritus of an etiology other than opioid use, such as pre-existing dermatitis; contraindication to opioid administration; contraindication or hypersensitivity to nalbuphine; gabapentin, dimenhydrinate or diphenhydramine administration at the time of enrolment or within eight hours of a pruritic episode, and previous participation in this study. Subjects were allocated by site-specific, computer-generated block randomization to one of the two study groups: nalbuphine (N) or normal saline placebo (P).
Perioperatively, opioid type, dose and route were determined by the attending anesthesiologist. An intraoperative dose of prophylactic antiemetic, ondansetron, 100 µg·kg–1 iv (maximum cumulative dose 8 mg) was permitted. All subjects were enrolled on the Pain Service for follow-up for the study period of at least 24 hr postoperatively, or for as long as continuous opioids were administered.
Assessments and data collection
Pruritus was defined as a self-reported symptom of a sensation that provoked the desire to scratch in the general areas of the face and trunk. Focal pruritus due to dressings or casts was not included. The occurrence of pruritus, side-effect assessments and data collection were conducted by clinical research assistants.
The pruritus intensity (PrI) was assessed using a modified colour analogue scale (mCAS) that was originally designed to evaluate pain intensity.20 This scale is a continuous gradient scale of colour progressing from white to dark red; white represents no pruritus and dark red represents the greatest intensity of pruritus. Pain word anchors were removed from the scale. Subjects were taught to use the scale at the time of recruitment. A predetermined dialogue and technique of presenting the scale was developed. Subjects were asked to point on the scale to indicate the intensity of pruritus. The spot was marked by the research assistant and then converted to a numerical value using a non-metric ruler with a scale of 0 to 10 to an accuracy of 0.5 gradations. Only subjects with PrI 5/10 were eligible for treatment randomization. Nalbuphine (N) (10 mg·mL–1 preparation) was diluted in normal saline to a concentration of 0.5 mg·mL–1 by the research pharmacy. According to the randomization schedule, the study medication nalbuphine 50 µg·kg–1 iv (maximum 5 mg), or an equal volume of normal saline placebo (P) was administered over 60 sec by a study physician or nurse. Investigators and the subjects were blinded with respect to the treatment assignment for the duration of the study.
The efficacy of treatment was determined by the pruritus intensity difference (PrID), derived by subtracting the post-treatment PrI score at 60 min from the subject’s pre-treatment score at baseline (t = 0). A PrID 50% was scored as a positive outcome. The pain score, sedation score, and any side effects including vomiting, headache and dizziness were recorded at zero, 30 and 60 min. The pain scale was a 0–10, 11-point, self-report numerical rating scale. The sedation scale was a five category observer scale: awake and alert; easy to arouse with verbal stimulation; difficult to arouse with verbal stimulation, responds only to physical stimulation; does not respond to verbal or physical stimulation.
At 60 min, if PrI was 5/10, or if the subject or caregiver requested further treatment, a dose of nalbuphine 50 µg·kg–1 iv (maximum 5 mg) was administered. For subjects who had no or sub-threshold pruritus (PrI < 5) while receiving opioids, the maximum mean hourly dose (µg·kg–1·hr–1) of administered opioid was calculated from the maximum four consecutive hours of exposure to the opioid during the hospital stay. For subjects who reached the threshold level of pruritus (PrI 5), the mean dose (µg·kg–1·hr–1) of the four hours immediately prior to administration of the study drug, as well as the drugs, doses, and administration times of all adjuvants, were recorded. The study was conducted during daytime hours between 0700–1700. For subjects who experienced pruritus outside of designated study hours, the same data as for the threshold pruritus subjects was collected. These subjects received naloxone 1 µg·kg–1 iv (maximum 75 µg) and no further assessments were performed on these subjects. Subjects were withdrawn from the study and alternative anti-pruritic treatments were provided for the following adverse effects: PrI 9/10 after the rescue dose of nalbuphine; pain score 9/10; or sedation score 3/5.
Statistical analysis
Statistical analysis was performed using StatsDirect (version 2.4.6. Cheshire, UK). It was assumed that the incidence of pruritus would be 30% (combined data from both BCCH and SCH). We expected a placebo response of 30% and sought an 80% response in the treatment group, taking into consideration potential side effects of using higher doses of nalbuphine. To demonstrate a 50% reduction in pruritus with a power of 80% at a significance level 0.05, 208 patients receiving postoperative opioids would have to be recruited. We made an appropriate allowance for error in our assumed incidence of pruritus and subject dropout.
Hypothesis testing for the equality of the two proportions was performed using mid-P approach to Fisher’s exact test and a confidence interval for the difference between the proportions determined using the iterative method of Miettinen and Nurminen.21 Nominal data were compared using the 
2 test; ordinal data were compared using the Kruskal-Wallis test; and analysis of variance was applied to continuous data. The level of significance was set at P < 0.05.
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). Demographic data including gender, age, weight and pain treatment modalities were similar in both groups (Table I). The mCAS was readily accepted and understood by all subjects. No subject had previously used the mCAS for either pain or PrI reporting, and none experienced adverse surgical or anesthetic complications perioperatively.
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5 and were randomized to either the N group (n = 18) or P group (n = 19). A second rescue dose of nalbuphine 50 µg·kg–1 iv was given at 60 min to three (16.7%) N subjects and to five (26.2%) subjects in Group P.
Postoperative pruritus ( PrI 5 ) and opioid utilization
The incidence of pruritus (PrI 5) was 20% (37/184), being highest in patients who received PCA (17/37, 46%), vs continuous opioid infusion (10/37, 27%) and epidural analgesia (10/37, 27%). Pruritus occurred over a wide range of opioid doses (9.4–63.2 µg·kg–1 ·hr–1 iv morphine equivalents); however, the mean doses of opioid were similar within the pruritus group, and were similar between treatment groups (Tables II, III).
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50% was achieved in 21 (56.8%) subjects, of whom 10 and 11 were in the N and P groups, respectively (Figure 2). The response rate (PrID 50%) was no different whether giving children nalbuphine or placebo, (55.5% vs 57.9%) giving a difference of 2.34% (P = 0.89 with a 95% confidence interval of the difference of –28.7% to 33.0%; standard normal deviate = 0.144). The frequencies of complete resolution of pruritus (PrI = 0, 100% efficacy) at 30 min or 60 min (P = 0, n = 4) were similar when comparing the active drug, placebo or any of the opioid subgroups within each treatment arm. The number of subjects in the nalbuphine vs placebo groups, opioid treatment categories (COI and PCA/ epidural) and opioid doses are presented in Table III
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5) outside of study hours. All received a single dose of naloxone 1 µg·kg–1 iv that was clinically efficacious. No subject was withdrawn from the study or required alternative anti-pruritic therapy. There was no reversal of analgesia or increase in sedation ( 3/5) as determined from the pain and sedation scores. This includes the five subjects who received a cumulative dose of nalbuphine 100 µg·kg–1. |
Discussion |
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50% as the definition of successful treatment, nalbuphine 50 µg·kg–1 iv was no more effective than normal saline placebo iv in treating postoperative opioid-induced pruritus in a pediatric tertiary care setting. The global incidence of pruritus (20%) from multiple opioids via multiple routes in this study is lower than that reported in a recent adult meta-analysis, but similar to recent epidural data (fentanyl/bupi-vacaine was administered to 91% of subjects) from SCH (26.1%) and higher than data from iv morphine utilization at BCCH (12.7%).14,22,23 Differences in incidence may be due to symptom definition and outcome tools used in different studies. Pruritus occurred over a wide range of iv morphine doses suggesting wide individual variability of susceptibility to this symptom. It was not possible to show that iv hydromorphone is superior to iv morphine in reducing pruritus due to the small number of patients who received iv hydromorphone.24
The use of placebo is equipoise in this preliminary study, as use of alternate agents such as anti-histamines, while common practice, has not been critically evaluated. In addition, the symptom of pruritus is a subjective sensation requiring self-report. The placebo effect is significant due to altered neuropsychological and neurophysiological factors resulting from conditioning and the expectation of an improvement of symptoms. In pain studies, the placebo effect may account for a 30% response rate. The placebo effect may be even higher in children and adolescents.25,26 Placebo effect could have been minimized in this study by adding a true non-treatment arm to the study, but we did not feel that this was ethical as the entry criterion was a PrI of 5.
In order to decrease the bias in self-report of a subjective symptom, a reduction of 50% in pruritus intensity (PrID) was used. This method is adopted from pain treatment outcome studies.27 The subject’s own symptom intensity is compared pre and post-treatment rather than pooling data on multiple subjects. The outcome was similar whether PrID of 50%, 30% or no pruritus (complete efficacy) was used. Even the mean difference between the PrID in the two groups (Figure 2) was very small (0.8).
There are several limitations to this preliminary study. The outcome tool (mCAS) has not been validated but may have the advantage of greater sensitivity than a three- to five-point categorical scale. Data extrapolated from pain studies would suggest that the category scales used in other studies may be equivalent to the following clinically important ratings: zero = 0, mild < 4, moderate 4 – < 7, severe 7. We chose 5 as a treatment threshold as we wanted to study only moderate to severe pruritus. In calculating our sample size we used a large effect size justified by our concerns regarding increased risk associated with the use of nalbuphine. A smaller effect size would have necessitated a larger sample size and may have shown a significant difference. We think this is unlikely due to the small observed difference.
A second limitation is that this study included three different opioids administered by two different routes as is typical of a pediatric pain management service. The etiology of the pruritus is likely multi-factorial, depending on patient, opioid, dose and route and quality of analgesia. For example, increased cutaneous histamine release may be a factor in the asymptomatic but atopic patient who receives systemic morphine. Central nervous system effects on nociceptive and serotonin systems may be a factor in patients receiving epidural opioids. The effect of recent administration of adjuvants such as non-steroidal anti-inflammatory drugs, steroids and 5HT3 receptor antagonists may also have affected the outcome. The efficacy of nalbuphine may depend on the principle etiology of the pruritus. Regardless, the question was to assess the global efficacy of nalbuphine in a tertiary care pediatric pain service setting, accepting that there are multiple etiologies of the symptom.
A third limitation is that the initial dose of nalbuphine 50 µg·kg–1 may not have been an optimum dose. We chose to study this dose based on current recommendations that suggested efficacy without adverse effects.28 Three of our subjects received a second dose, for a total dose of 100 µg·kg–1 without adverse effects. It is possible that the risk of sedation may be higher if 100 µg·kg–1 is administered as a single bolus.
A final constraint of the study was that we lacked sufficient resources to observe the subjects for a longer follow-up period to evaluate the duration of the effect of intervention. It is unlikely that a delayed or peak effect of the agent was overlooked, but we may have missed observing a therapeutic value to nalbuphine that may have lasted longer than a placebo effect. Although the investigators were blinded, on several occasions, one of the physicians (S.M.) noted a clinically apparent transient increase in sedation during administration of the study drug. This effect was not detected using a discontinuous five category sedation score.
Many subjects received a single dose of ondansetron intraoperatively. No subject received postoperative dosing. Ondansetron has been described as an effective anti-pruritic in adults and children.29,30 The proposed mechanism of action is via modulation of the central serotonic system. As all subjects were to receive continuous opioids postoperatively and were thus at higher risk for postoperative nausea and vomiting, we decided that an effective, non-sedating antiemetic should be given prophylactically. This may have decreased the number of subjects who experienced pruritus.
This study showed no difference in the resolution of pruritus between children given nalbuphine or placebo. However, the small sample size does not allow us to conclude that placebo is equivalent to nalbuphine in the treatment of clinically significant pruritus. The wide confidence interval around the difference between the two treatment outcomes (–29% to 33%) includes differences that might be considered clinically relevant. A larger sample size would be required to confirm the equivalence of placebo compared to nalbuphine.
Unfortunately, the commercial distribution of nalbuphine has been discontinued. Further studies evaluating anti-pruritic efficacy of nalbuphine for epidural hydromorphone vs epidural fentanyl in pediatric populations will not be possible. Butorphanol, an alternate mixed opioid agonist-antagonist, only available as an intranasal medication in Canada, is one of the currently-recommended treatments for opioid-induced pruritus.31 As with nalbuphine and non-selective anti-histamines, excessive sedation is a dose related side-effect of this class of drugs. A low dose naloxone infusion (1 µg·kg–1·hr–1) is also standard therapy but requires the ward nursing management of an infusion which may present an excessive workload if required for 20% of patients. Ultra-low dose or combined naloxone-opioid infusion combinations have not been investigated in children.32,33
The ideal analgesic would have limited adverse side-effects and no associated pruritus. The ideal anti-pruritic would be effective, simple to administer, and would avoid sedation, reversal of analgesia, or dysphoria. Results of investigations of healing burn-wound pruritus suggest that combined therapy with nonsedating H1 and H2 agonists is more effective than the traditional sedating anti-histamines. A preliminary study of gabapentin has also shown decreased scratching in pediatric burn patients.34
Future research should be directed at further evaluating the mCAS tool as a pruritus intensity measurement. Study design should anticipate up to a 30% placebo effect. In the absence of effective opioid-free analgesic regimens, further evaluation of alternate anti-pruritic agents or combinations to treat postoperative opioid-induced pruritus should be pursued. In summary, in this preliminary study, nalbuphine 50 µg·kg–1 iv was no more effective than saline in treating postoperative opioid-induced pruritus in a pediatric tertiary care setting.
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Footnotes |
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References |
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2 Ko MC, Song MS, Edwards T, Lee H, Naughton NN. The role of central mu opioid receptors in opioidinduced itch in primates. J Pharmacol Exp Ther 2004; 310: 169–76.
3 Szarvas S, Harmon D, Murphy D. Neuraxial opioid-induced pruritus: a review. J Clin Anesth 2003; 15: 234–9.[Medline]
4 Twycross R, Greaves MW, Handwerker H, et al. Itch: scratching more than the surface. QJM 2003; 96: 7–26.
5 Greaves MW, Khalifa N. Itch: more than skin deep. Int Arch Allergy Immunol 2004; 135: 166–72.[Medline]
6 Ikoma A, Rukwied R, Stander S, Steinhoff M, Miyachi Y, Schmelz M. Neurophysiology of pruritus: interaction of itch and pain. Arch Dermatol 2003; 139: 1475–8.
7 Kjellberg F, Tramer MR. Pharmacological control of opioid-induced pruritus: a quantitative systematic review of randomized trials. Eur J Anaesthesiol 2001; 18: 346–57.[Medline]
8 Jaillon P, Gardin ME, Lecocq B, et al. Pharmacokinetics of nalbuphine in infants, young healthy volunteers, and elderly patients. Clin Pharmacol Ther 1989; 46: 226–33.[Medline]
9 Milnes AR, Maupome G, Cannon J. Intravenous sedation in pediatric dentistry using midazolam, nalbuphine and droperidol. Pediatr Dent 2000; 22: 113–9.[Medline]
10 Rita L, Seleny F, Goodarzi M. Comparison of the calming and sedative effects of nalbuphine and pentazocine for paediatric premedication. Can Anaesth Soc J 1980; 27: 546–9.[Medline]
11 Bailey AG, Valley RD, Freid EB, Calhoun P. Epidural morphine combined with epidural or intravenous butorphanol for postoperative analgesia in pediatric patients. Anesth Analg 1994; 79: 340–4.
12 Lawhorn CD, Schmitz ML. Altering epidural morphine side effects with butorphanol in children. Anesth Analg 1995; 81: 1112.[Medline]
13 Simons FE. H1-antihistamines in children. Clin Allergy Immunol 2002; 17: 437–64.[Medline]
14 Esmail Z, Montgomery C, Court C, Hamilton D, Kestle J. Efficacy and complications of morphine infusions in postoperative paediatric patients. Paediatr Anaesth 1999; 9: 321–7.[Medline]
15 Alhashemi JA, Crosby ET, Grodecki W, Duffy PJ, Hull KA, Gallant C. Treatment of intrathecal morphineinduced pruritus following caesarean section. Can J Anaesth 1997; 44: 1060–5.
16 Kendrick WD, Woods AM, Daly MY, Birch RF, DiFazio C. Naloxone versus nalbuphine infusion for prophylaxis of epidural morphine-induced pruritus. Anesth Analg 1996; 82: 641–7.[Abstract]
17 Togashi Y, Umeuchi H, Okano K, et al. Antipruritic activity of the kappa-opioid receptor agonist, TRK- 820. Eur J Pharmacol 2002; 435: 259–64.[Medline]
18 Penning JP, Samson B, Baxter AD. Reversal of epidural morphine-induced respiratory depression and pruritus with nalbuphine. Can J Anaesth 1988; 35: 599–604.
19 Somrat C, Oranuch K, Ketchada U, Siriprapa S, Thipawan R. Optimal dose of nalbuphine for treatment of intrathecalmorphine induced pruritus after caesarean section. J Obstet Gynaecol Res 1999; 25: 209–13.[Medline]
20 McGrath PA, Seifert CE, Speechley KN, Booth JC, Stitt L, Gibson MC. A new analogue scale for assessing children’s pain: an initial validation study. Pain 1996; 64: 435–43.[Medline]
21 Miettinen O, Nurminen M. Comparative analysis of two rates. Stat Med 1985; 4: 213–26.[Medline]
22 Wu CL, Cohen SR, Richman JM, et al. Efficacy of post-operative patient-controlled and continuous infusion epidural analgesia versus intravenous patient-controlled analgesia with opioids: a meta-analysis. Anesthesiology 2005; 103: 1079–88.[Medline]
23 Tsui BC, Wagner A, Cave D, Kearney R. Thoracic and lumbar epidural analgesia via the caudal approach using electrical stimulation guidance in pediatric patients: a review of 289 patients. Anesthesiology 2004; 100: 683–9.[Medline]
24 Quigley C, Wiffen P. A systematic review of hydromorphone in acute and chronic pain. J Pain Symptom Manage 2003; 25: 169–78.[Medline]
25 Lewis DW, Winner P, Wasiewski W. The placebo responder rate in children and adolescents. Headache 2005; 45: 232–9.[Medline]
26 Finniss DG, Benedetti F. Mechanisms of the placebo response and their impact on clinical trials and clinical practice. Pain 2005; 114: 3–6.[Medline]
27 Cepeda MS, Africano JM, Polo R, Alcala R, Carr DB. Agreement between percentage pain reductions calculated from numeric rating scores of pain intensity and those reported by patients with acute or cancer pain. Pain 2003; 106: 439–42.[Medline]
28 Brislin RP, Rose JB. Pediatric acute pain management. Anesthesiol Clin North America 2005; 23: 789–814.[Medline]
29 Iatrou CA, Dragoumanis CK, Vogiatzaki TD, Vretzakis GI, Simopoulos CE, Dimitriou VK. Prophylactic intravenous ondansetron and dolasetron in intrathecal morphine- induced pruritus: a randomized, double-blinded, placebo-controlled study. Anesth Analg 2005; 101: 1516–20.
30 Arai L, Stayer S, Schwartz R, Dorsey A. The use of ondansetron to treat pruritus associated with intrathecal morphine in two paediatric patients. Paediatr Anaesth 1996; 6: 337–9.[Medline]
31 Schecter NL, Berde CB, Yaster M. Pain in Infants, Children, and Adolescents, 2nd ed. Philadelphia, PA: Lippincott Wiliams & Wilkins; 2003.
32 Cepeda MS, Alvarez H, Morales O, Carr DB. Addition of ultralow dose naloxone to postoperative morphine PCA: unchanged analgesia and opioid requirement but decreased incidence of opioid side effects. Pain 2004; 107: 41–6.[Medline]
33 Sartain JB, Barry JJ, Richardson CA, Branagan HC. Effect of combining naloxone and morphine for intravenous patient-controlled analgesia. Anesthesiology 2003; 99: 148–51.[Medline]
34 Mendham JE. Gabapentin for the treatment of itching produced by burns and wound healing in children: a pilot study. Burns 2004; 30: 851–3.[Medline]
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