Oxycodone Vs Placebo in Children with Undifferentiated Abdominal Pain a Randomized, Double-Blind Clinical Trial of the Effect of Analgesia on Diagnostic Accuracy
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ARTICLE Oxycodone vs Placebo in Children With Undifferentiated Abdominal Pain A Randomized, Double-blind Clinical Trial of the Effect of Analgesia on Diagnostic Accuracy Hannu Kokki, MD; Hannu Lintula, MD; Kari Vanamo, MD; Marjut Heiskanen, RN; Matti Eskelinen, MD Background: Analgesics for children with acute ab- Main Outcome Measures: Pain intensity difference, dominal pain are often withheld for fear that they might presence or absence of abdominal guarding, and diag- mask physical examination findings and thus might be nostic accuracy. unsafe. This viewpoint has been challenged recently. Results: The demographic characteristics, initial pain Objective: To evaluate the effects of buccal oxy- scores, and physical signs and symptoms were similar be- codone on pain relief, physical examination findings, di- tween the 2 groups. Both study drugs were associated with agnostic accuracy, and final clinical outcomes in chil- decreasing pain scores. The summed pain intensity dif- dren with acute abdominal pain. ference over 7 observations was significantly greater in the oxycodone group, 22±18 cm, than in the placebo Design: Prospective, randomized, double-blind, and pla- group, 9±12 cm (mean difference 13 cm, with a 95% con- cebo-controlled trial between December 2001 and No- fidence interval of 2-24 cm; P=.04). The diagnostic ac- vember 2003. curacy increased from 72% to 88% in the oxycodone group and remained at 84% in the placebo group after study Setting: University teaching hospital in Finland. drug administration. Laparotomy was performed in 17 Patients: A total of 104 children aged 4 to 15 years with patients in the oxycodone group and in 14 patients in abdominal pain of less than 7 days’ duration were the placebo group. Four patients without appendicitis un- screened, and 63 children with pain scores of 5 or higher derwent exploratory laparotomy in each group. One pa- on a 10-cm visual analog scale were eligible for the trial. tient in the placebo group was initially diagnosed as hav- ing nonspecific abdominal pain, but at 14 hours, she was Intervention: Children were randomized to receive buc- operated on for appendiceal perforation. cally either 0.1 mg/kg−1 of oxycodone hydrochloride (n=32) or the same volume of normal saline (n=31). The Conclusions: Early administration of buccal oxy- same surgeon described the physical findings and indi- codone provides a significant pain relief to children with cated a provisional diagnosis and a provisional disposi- acute abdominal pain, without adversely altering the clini- tion before the children received the study medication cal signs or obscuring the surgical diagnosis. and at 1 hour and 3.5 hours after initial dosing. Pain scores were recorded at baseline and every 30 minutes for 3.5 hours after the first study drug administration. Arch Pediatr Adolesc Med. 2005;159:320-325 LASSIC TEACHING IN SUR- sue of analgesia for undifferentiated ab- gery has dictated that the dominal pain in children.7 In this study, the use of analgesics should be authors demonstrated effective pain relief withheld from children with intravenous morphine in children with with acute abdominal pain acute abdominal pain without causing ad- Cuntil a surgeon establishes a definitive treat- verse affects or a delay in diagnosis. Author Affiliations: ment plan. It has been claimed that anal- Departments of Anesthesiology gesia masks symptoms and physical find- See also page 326 and Intensive Care (Dr Kokki), ings, delays diagnosis, and leads to increased Pediatric Surgery (Drs Lintula morbidity. Over the past few years, this tra- Oxycodone, a semisynthetic µ opioid re- and Vanamo and Ms Heiskanen), ditional belief has been challenged. Recent ceptor agonist derived from thebaine, has and Surgery (Dr Eskelinen), studies in adults have suggested that the a similar analgesic efficacy as morphine in Kuopio University Hospital, and 8 Department of Pharmacology early administration of opioid analgesics is patients undergoing surgery. However, be- and Toxicology, University of safe and does not interfere with the ability cause oxycodone does not cause the re- Kuopio, Kuopio, Finland to make a correct diagnosis.1-6 Until re- lease of histamine, it might cause less nau- (Dr Kokki). cently, only 1 study has addressed the is- sea and vomiting, it is less sedating, and it (REPRINTED) ARCH PEDIATR ADOLESC MED/ VOL 159, APR 2005 WWW.ARCHPEDIATRICS.COM 320 ©2005 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 causes fewer neurological adverse effects than morphine.9 Because children dislike injections, there has been grow- Table 1. Baseline Characteristics of the 63 Randomized ing interest in noninvasive methods of opioid administra- Participants According to Study Group* tion. Transmucosally (buccal route) administered oxy- Oxycodone Placebo codone has been recently shown to be effective in the (n = 32) (n = 31) treatment of persistent postoperative pain in children,10 and becausethetasteofoxycodoneisneutral,childrenhavereadily Age, y 11 ± 3 11 ± 3 Sex, M/F 19/13 13/18 accepted this route. To our knowledge, no study has evalu- Weight, kg 41 ± 14 41 ± 14 atedtheuseofbuccaloxycodoneforthemanagementofacute Fever Ն37.5°C, yes/no† 8/24 10/21 abdominal pain in children. Therefore, we designed this pro- Migration of pain, yes/no† 10/22 16/15 spectiveclinicaltrialtoevaluatetheeffectofbuccaloxycodone Vomiting, yes/no† 9/23 12/19 on pain reduction, physical examination findings, diagnos- Right lower quadrant pain, yes/no† 28/4 29/2 tic accuracy, and clinical outcome in children with acute un- Abnormal bowel sounds, yes/no† 2/30 2/29 Rebound tenderness, yes/no† 27/5 22/9 differentiated abdominal pain. Guarding, yes/no† 16/16 13/18 Pain score, cm 7.1 ± 1.7 6.9 ± 1.4 METHODS *Values are numbers of children or mean ± SD. †The “yes” number indicates the number of children with a clinical STUDY DESIGN AND ETHICS symptom or sign that is suggestive of a surgical disease. The “no” number is the number of children who showed no clinical symptom or sign. This prospective, randomized, double-blind, and placebo- controlled clinical trial with 2 parallel groups took place dur- ing a 24-month period ending in November 2003 at the Kuo- cm tall containing a red triangle that increased in size from left pio University Hospital (Kuopio, Finland). The trial was to right. The children expressed the pain score while the re- approved by the local ethics committee and was conducted in search nurse exerted a light pressure on the abdomen. accordance with the Declaration of Helsinki. All parents who Pain scores were recorded at baseline and at 0.5, 1, 1.5, 2, agreed to their children’s participation gave written informed 2.5, 3, and 3.5 hours after the first dose of study medication. consent, and the children provided assent. At each point, the research nurse recorded vital signs (eg, oxy- Children were eligible to participate in the study if they were gen saturation with pulse oximetry, blood pressure, and ven- aged 4 to 15 years, they came to the emergency department (ED) tilation frequency) and all adverse effects (eg, nausea and vom- with undifferentiated acute abdominal pain of less than 7 days’ iting, sedation, and hypotension) with the pain scores. duration, and they had pain scores 5 cm or higher on a 10-cm- long visual analog scale. Children with abdominal trauma, SURGICAL ASSESSMENT asthma, hypotension (systolic blood pressure Ͻ90 mm Hg), known contraindication to oxycodone, and analgesia use prior All 3 surgeons participating in the trial were briefed on the ab- to ED arrival were excluded from the study. dominal examination technique. The most important clinical find- ings suggestive of surgical disease were recorded on a special form INTERVENTION (Table 1). The surgeon indicated a provisional diagnosis (acute appendicitis, nonspecific abdominal pain [NSAP], or other), a Participants were randomized into 2 groups by a computer- differential diagnosis, a provisional disposition (observation or generated allocation sequence, and a sealed envelope method was operation), and whether abdominal guarding was present or ab- used for blinding. A study nurse not involved in the treatment of sent. Guarding was defined as voluntary contraction of the abdomi- the child prepared a 2-mL syringe of the study solution with an nal muscles when palpatory pressure was exerted on the abdomen. identical appearance and taste to the saline solution, thus ensur- The guarding sign was interpreted as positive if tenderness was ing that children, parents, research nurses, and physicians were detected either in the right lower quadrant or more diffusely in the blinded to allocation. In 20 cases, the surgeon was asked to judge right lower quadrant and in other abdominal quadrants. whether the patient had received oxycodone or placebo. The sur- The same surgeon reexamined the patient at 1 hour after geon was able to correctly identify the type of study medication the first dose of the study drug. The surgeon again indicated a for 6 children in the oxycodone group and 6 children in the pla- provisional diagnosis, a differential diagnosis, a provisional dis- cebo group. The surgeon gave a wrong guess for 6 children in position, and the presence or absence of abdominal guarding. the oxycodone group and 2 children in the placebo group. If the diagnosis and final disposition were not established at 1 The study medication was administered when the children hour, the patient was reevaluated at 3.5 hours and, if neces- reported a pain score of 5 cm or higher. The patients in the sary, at 6 and 9 hours. oxycodone group received buccally 0.1 mg/kg−1 of oxycodone All children were taken to the hospital and followed up for hos- hydrochloride (Oxanest 10 mg/mL−1 solution for injection; pital course, discharge diagnosis, and complications. Children for Leiras Oy, Turku, Finland), and the patients in the placebo group whom a definitive diagnosis was not obtained in the ED were fol- received the same volume of 0.9% sodium chloride.