ARTICLE Oxycodone vs Placebo in Children With Undifferentiated 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 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 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- untilC 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 , it is less sedating, and it

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©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 . 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, 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 , 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. If the pain lowed up until symptoms resolved spontaneously. These patients score was 5 cm or higher in follow-up measurements, the study were considered to have had self-limited NSAP. Patients with NSAP medication was repeated 1 or 2 times. No other analgesics were were followed up by telephone calls at 4 weeks. The final diag- allowed during the 3.5-hour study period. nosis was established by reviewing inpatient records. Acute ap- pendicitis was confirmed by histological examination. PAIN ASSESSMENT OUTCOME MEASURES After screening, the children were instructed to use a visual ana- log scale to score their pain (left end, no pain; right end, worst The main outcome measurements were the maximal pain in- imaginable pain).11 The scale was a rectangle 10 cm long and 2 tensity difference (PID) and the summed pain intensity differ-

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©2005 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 Assessed for Eligibility (n = 104)

Excluded (n = 41) Did Not Meet Inclusion Criteria (n = 31) Refused to Participate (n = 10)

Randomized (n = 63)

Oxycodone Group (n = 32) Saline Group (n = 31)

Observation (n = 15) Laparotomy (n = 17) Observation (n = 17) Laparotomy (n = 14)

Nonspecific Pain (n = 15) Appendicitis (n = 12) Nonspecific Pain (n = 16) Appendicitis (n = 9) Ileum Perforation (n = 1) Unnecessary Laparotomy (n = 1) Unnecessary (n = 4) at 3 wk (n = 1) Unnecessary (n = 4)

Figure 1. Flow of participants through the trial.

nificance. With a 2-sided method, the calculated sample size 10 Oxycodone Placebo was 21. To compare the 2 study groups, we analyzed continuous vari- ables by means of a 2-tailed t test for 2 independent samples. For categorical variables, we used the ␹2 test and Fisher exact test. A P value Յ.05 was considered statistically significant. All analyses were performed using a statistical program (SPSS for 5 Windows 10.0, SPSS Inc, Chicago, Ill). Pain Score, cm RESULTS

0 A total of 104 children with acute abdominal pain were 0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 assessed for eligibility, but 41 were excluded; 10 re- Time After First Dose, h fused to participate, and 31 did not meet the inclusion Ͻ Figure 2. Pain scores in the 2 study groups after the first dose of study criteria (with pain scores 5), thus leaving 32 children medication. Error bars indicate mean ± SD. in the oxycodone group and 31 children in the placebo group. Most of the children had a primary care referral, ence (SPID),12 the presence of abdominal guarding before and so half of the children had indications for surgery when after medication, and the diagnostic accuracy between the oxy- they arrived at the hospital (Figure 1). At baseline, the codone and placebo groups. The maximal PID reflects the peak 2 groups were similar in terms of sex, age, weight, symp- of the analgesic effect and the area under the time–analgesic toms, clinical findings, and pain scores (Table 1). effect curve for the intensity; the SPID reflects the cumulative Both oxycodone and normal saline had a significant response to the intervention. Pain intensity difference was cal- analgesic efficacy. The mean SPID was more significant culated as PID =P –P where P is the pain intensity at base- t 0 t 0 in the oxycodone group, 22±18 cm, than in the placebo line and Pt the pain at subsequent observations at 0.5, 1, 1.5, 2, 2.5, 3, and 3.5 hours after the first dose of study medica- group, 9±12 cm (mean difference 13 cm, with a 95% con- tion. Summed pain intensity difference was calculated as fidence interval of 2-24 cm; P=.04) (Figure 2). The mean 12 SPID=PID0-0.5+PID0-1+...+PID0-3.5. We compared also the maximal PID was 3.7±2.8 cm in the oxycodone group clinical examination sensitivity (the ability to diagnose a sur- and 2.7±2.6 cm in the placebo group (mean difference gical disease), specificity (the ability to diagnose a nonsurgical 1.0 cm, with a 95% confidence interval of –0.4 to 2.4 cm; condition), and diagnostic accuracy (true surgical diseases and P=.14). A total of 67 study drug doses (2.1±0.9) was ad- true nonsurgical conditions as a proportion of all results) in ministered in the oxycodone group and 74 doses the 2 groups both before and after study drug administration. (2.4±0.8) in the placebo group. Sensitivity was calculated as a/a+c, specificity as d/b+d,and At baseline, the diagnostic accuracy was nonsignifi- diagnostic accuracy as a+d/a+b+c+d,where a represents true surgical diseases, d represents true nonsurgical conditions, b cantly lower in the oxycodone group (72%) but represents false-positive decisions, and c represents false- improved to the level of the placebo group after the negative decisions. administration of study medication (88%, P=.12, com- pared with baseline). In the placebo group, diagnostic SAMPLE SIZE AND STATISTICAL ANALYSIS accuracy remained at 84% predose and postdose (Table 2). Predose abdominal guarding was present in We designed the study to have an 80% power to detect a 2-fold 16 of 32 patients in the oxycodone group and in 13 of difference in SPID between the 2 groups at a .05 level of sig- 31 patients in the placebo group. After the administra-

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©2005 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 tion of study medication, 7 patients altered their guard- ing; guarding was normalized in 3 patients and became Table 2. Diagnostic Sensitivity, Specificity, and Accuracy in positive in 3 patients in the oxycodone group compared the 2 Study Groups with 1 normalized guarding in the placebo group Oxycodone Placebo Difference (P=.05). Children with postdose guarding underwent (n = 32) (n = 31) in % (95% CI) appendectomy for acute appendicitis. Predose and post- dose guarding was absent in 3 children (in 1 in the oxy- Predose, No. of patients/ total patients (%) codone group and in 2 in the placebo group) with acute Sensitivity 8/13 (62) 9/10 (90) −28 (−64 to 8) appendicitis. Specificity 15/19 (79) 17/21 (81) −2 (−27 to 23) Seventeen of 32 patients in the oxycodone group and Diagnostic accuracy 23/32 (72) 26/31 (84) −12 (−32 to 8) 14 of 31 patients in the placebo group underwent ex- Postdose, No. of patients/ ploratory laparotomy. In all children, except 1 in the pla- total patients (%) cebo group, the decision to operate was made at 1 hour Sensitivity 13/13 (100) 9/10 (90) +10 (−7 to 27) Specificity 15/19 (79) 17/21 (81) −2 (27 to 23) after triage. Two patients with localized abscesses, 1 in Diagnostic accuracy 28/32 (88) 26/31 (84) +4 (−13 to 21) the placebo group and 1 in the oxycodone group, were operated on at 20 and 24 hours after triage. In clinical Abbreviation: CI, confidence interval. examination, both had mild abdominal tenderness, and a correct surgical diagnosis was established already in the ED. However, clinical findings were atypical and confir- buccal saline. Oxycodone did not adversely influence the matory computed tomography was performed before sur- clinical examination or the appropriateness of the deci- gery. Delay in the operations had no clinical conse- sion to operate; actually, a small, nonsignificant improve- quence for these 2 patients because neither of them had ment in the diagnostic accuracy was noted in children generalized at the time of surgery. A 15-year- treated with oxycodone. Moreover, no serious adverse old girl in the placebo group had no abdominal tender- effects or any major untoward outcomes occurred in as- ness at the time of predose or postdose clinical exami- sociation with the opioid administration. The only mis- nation, and she was taken to the pediatric ward for diagnosed case was in the placebo group. follow-up. On the ward, she developed an intensive ab- One of the main limitations of the present study was dominal pain with persistent abdominal tenderness and that although we enlisted only 3 surgeons to make the was operated on for perforated appendicitis with local- abdominal evaluations because we wanted to standard- ized peritonitis at 14 hours after triage. ize the clinical examination, the same surgeon per- Twelve patients in the oxycodone group and 9 in the formed the pre–study medication and post–study medi- placebo group had histologically confirmed appendici- cation examinations for each child. Thus, the previous tis. The appendix was abscessed in 1 patient and perfo- assessments might have biased the post–study medica- rated in 2 patients in the placebo group. Two patients tion diagnoses. Another limitation is that all the pa- had another surgical disease; 1 patient in the oxy- tients were admitted to the pediatric ward for observa- codone group had perforation of the distal ileum and an tion, so the results should not necessarily be generalized abscess caused by a plastic splinter, and 1 patient in the to outpatients. The small sample size might also be con- placebo group had previously undiagnosed Crohn dis- sidered a limitation of the present trial because evaluat- ease with partial bowel obstruction in the terminal il- ing the adverse outcomes of patients, for example, re- eum. Four (23%) of 17 patients underwent laparotomy quires more subjects. Lee et al13 found that 750 patients without appendicitis in the oxycodone group compared in both arms of a study should be evaluated to deter- with 4 (28%) of 14 patients in the placebo group. For 14 mine whether the use of opioids alters the outcome com- children in the oxycodone group and 17 in the saline pared with placebo. However, the present study had a group, symptoms resolved before a definitive diagnosis power to evaluate the SPID between the 2 study groups, occurred. One child in the oxycodone group had a small and for that, the power of study was sufficient. Finally, confirmed by ultrasonography. in the present trial, a surgeon evaluated all children, and One child experienced headaches and another devel- therefore, it is open for discussion whether analgesia oped urticaria after receiving oxycodone. No sedation, should be deferred until after physical examination by hypoxia, or hypotension was observed. the surgeon: could children with severe pain be pro- Three patients in the placebo group and 1 in the oxy- vided with analgesic treatment before a surgeon’s evalu- codone group were readmitted. In the placebo group, one ation? 11-year-old girl experienced abdominal pain 3 weeks af- The dangers of early analgesia for patients with acute ter discharge, and she underwent exploratory lapa- abdominal pain have long been emphasized. Withhold- rotomy with normal findings. Abdominal pain resolved ing analgesia has had a theoretical foundation in a de- spontaneously in the other 3 patients. All children were sire to avoid masking physical signs. Because the hy- asymptomatic at 4 weeks from final discharge. pothesis was logical, its validity was uncontested for many years. This long-held surgical dogma has recently come under increased scrutiny. Our results are consistent with COMMENT several recent prospective randomized studies in adults addressing the effects of opioid analgesia on definitive Even though the placebo effect was significant, buccal diagnosis and treatment in patients with acute abdomi- oxycodone provided significantly better analgesia than nal pain, which have failed to give any evidence that pro-

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©2005 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 viding opioid analgesia prior to definitive diagnosis is ing as the single most important examination finding harmful.1-6 Studies among adults have demonstrated that because 80% to 91% of children with acute appendicitis judicious administration of opioids can effectively re- exhibit guarding behavior.14-16 In our study, preoperative duce pain to a greater degree than it does the localiza- guarding was absent in 3 children with acute appendi- tion of tenderness and thus might even improve diag- citis. After oxycodone administration, 3 children with nostic accuracy. final diagnoses of appendicitis developed peritoneal ten- To our knowledge, only 1 randomized clinical study derness, and guarding disappeared in 3 children with about the safety of opioid analgesics in children with acute self-limited abdominal pain. Opioid administration did not abdominal pain has been published. Kim et al7 assessed mask or hide clinical examination evidence of peritoneal the effects of intravenous morphine on physical exami- irritation. Thus, the examination changes represented im- nations, diagnostic accuracy, and adverse effects. Pedi- provements of the earlier examination findings. The pre- atric emergency physicians and surgeons indepen- cise reason for the change in abdominal tenderness is un- dently indicated areas of tenderness to palpation and known. Decrease in abdominal tenderness might be related percussion before and after the administration of either more to the spontaneous resolution of symptoms in chil- morphine or normal saline. The investigators also re- dren with self-limited abdominal pain. corded provisional diagnoses at 15 and 30 minutes after Recent literature reports divergent results concern- triage. Morphine administration was associated with a ing the effects of opioids on diagnostic accuracy. Some decrease in the number of areas of tenderness as evalu- authors suggest that early pain relief would actually fa- ated by pediatricians, but surgeons found no difference cilitate a definitive diagnosis,1,2 and others conclude that in the examination. All children in the morphine group opioid analgesia is not associated with harmful effects on undergoing laparotomy had persistent tenderness to pal- diagnostic accuracy.3,7 Our study showed relationships pation and percussion after analgesia. The authors con- between the use of oxycodone and an altered diagnosis cluded that intravenous morphine provided significant or treatment. In 5 children, the provisional diagnosis of pain relief to children with acute abdominal pain with- NSAP changed to the correct diagnosis of appendicitis out adversely affecting the examination. Furthermore, after the administration of oxycodone; postdose guard- morphine administration did not adversely affect diag- ing developed in 3 children, but peritoneal tenderness nostic accuracy. was present already in 2 children with the initial diag- In the present trial, buccal oxycodone appeared to be nosis of NSAP. Diagnostic sensitivity, the ability to di- effective in controlling severe abdominal pain because agnose a surgical disease, increased after the adminis- significant pain relief (reduction in pain scores from 7 tration of oxycodone, although no changes were noted to 4.5 cm; P=.05) was attained even at 30 minutes after in diagnostic specificity, the ability to diagnose a non- the first oxycodone dose. Oxycodone is the most com- surgical disease. In contrast to our results, Kim et al7 re- monly used opioid for surgical patients in Finland.9 It is ported higher specificity in the morphine group, sug- as potent as morphine, but oxycodone does not release gesting that morphine might help in finding diagnoses histamine and it is less sedating than morphine.8,9 In this for those children with nonsurgical conditions. Al- trial, we evaluated the use of buccal oxycodone because though administering morphine might facilitate the di- it is an attractive option for opioid administration in chil- agnosis of nonsurgical disease, Kim et al noted that their dren who do not have intravenous lines in place. The bio- sample size was insufficient to address the question of availability of buccal oxycodone (55%) is relatively high, diagnostic accuracy,7 which is consistent with our re- and although the time to peak plasma concentration is sults with oxycodone. relatively long, in most patients significant plasma con- Appendicitis is the most common indication for emer- centrations are achieved in 15 to 30 minutes postdos- gency laparotomies in children, which meant that in this ing.10 It should be noted that buccal drug administra- study, the clinical examination focused especially on chil- tion seems to have a significant placebo effect because dren with suspected appendicitis or those with condi- the children receiving saline also attained moderate pain tions mimicking appendicitis. Most children presenting relief at 30 minutes. However, after 60 minutes, oxy- to the hospital with acute abdominal pain have either acute codone performed significantly better than placebo, which appendicitis or NSAP,17 and surgical conditions other than is consistent with the pharmacokinetics of buccal oxy- appendicitis are rare in children aged 4 to 15 years. In codone.10 the present study, all patients except 3 had either acute Abdominal signs are critical for the diagnostic pro- appendicitis or NSAP. In some patients, the diagnosis of cess in children with abdominal pain, but few studies have appendicitis might become clear only after some hours attempted to evaluate which and how much clinical signs of observation, as occurred in the present study in 1 child change with the administration of opioids. In 4 previ- with a perforated appendicitis and local peritonitis. She ous studies in adults, the investigators concluded that the had no abdominal tenderness in predose and postdose administration of opioids to patients with abdominal pain clinical examinations, and she was initially misdiag- resulted in some clinical finding changes,1,2,4,6 whereas nosed as having NSAP, but at 14 hours after triage, she 1 study reported no changes in peritoneal tenderness.3 was operated on for appendiceal perforation. This pa- The literature describes no standards for what consti- tient had fewer symptoms and signs of appendicitis than tutes a significant clinical examination change in acute children whose diagnosis was made initially at the ED. abdomen. Although the decision to operate on the pa- Physician errors occur on patients whose symptoms are tient is based not on a single sign but on a combination atypical of the appendix, and errors and delays in sur- of findings, we used the presence or absence of guard- gery will correlate with adverse effects. On the other

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©2005 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 hand, delay often occurs before an accurate diagnosis is analgesics in patients with acute abdominal pain. J Emerg Med. 1997;15:775- established. Eight unnecessary laparotomies were per- 779. 5. Vermeulen B, Morabia A, Unger PF, et al. Acute appendicitis: influence of early formed on patients without appendicitis who had clini- pain relief on the accuracy of clinical and US findings in the decision to oper- cal findings that were similar to those of patients with ate—a randomised trial. Radiology. 1999;210:639-643. histologically confirmed appendicitis. However, the 6. Mahadevan M, Graff L. Prospective randomised study of analgesic use for ED “unnecessary” appendectomy rate—4 (23%) of 17 patients with right lower quadrant abdominal pain. Am J Emerg Med. 2000; patients in the oxycodone group and 4 (27%) of 14 18:753-756. 7. Kim MK, Strait RT, Sato TT, Hennes HM. A randomised clinical trial of analgesia patients in the control group—is similar to that reported in children with acute abdominal pain. Acad Emerg Med. 2002;9:281-287. 18 previously. 8. Silvasti M, Rosenberg P, Seppälä T, Svartling N, Pitkänen M. Comparison of an- In conclusion, early administration of buccal oxy- algesic efficacy of oxycodone and morphine in postoperative intravenous patient- codone provides significant pain relief to children with controlled analgesia. Acta Anaesthesiol Scand. 1998;42:576-580. acute abdominal pain. Results of this trial support a large- 9. Pöyhiä R, Vainio A, Kalso E. A review of oxycodone’s clinical pharmacokinetics and pharmacodynamics. J Pain Symptom Manage. 1993;8:63-67. scale trial to further evaluate whether this approach is 10. Kokki H, Rasanen I, Reinikainen M, Suhonen P, Vanamo K, Ojanperä I. Pharma- safe and whether early analgesic treatment affects the abil- cokinetics of oxycodone after intravenous, buccal, intramuscular and gastric ad- ity to diagnose a surgical abdomen. ministration in children. Clin Pharmacokinet. 2004;43:613-622. 11. Tigerstedt I, Tammisto T. A modified visual analogue scale (VAS) for evaluation Accepted for Publication: September 14, 2004. of pain intensity during immediate postoperative recovery. Schmerz Pain Douleur. 1988;9:27-31. Correspondence: Hannu Kokki, MD, Department of 12. McQuay H, Moore A. An Evidence-Based Resource for Pain Relief. Oxford, En- Anesthesiology and Intensive Care, Kuopio University gland: Oxford University Press, 1998. Hospital, PO Box 1777, FI-70211 Kuopio, Finland (hannu 13. Lee JS, Stiell IG, Wells GA, Elder BR, Vandemheen K, Shapiro S. Adverse out- [email protected]). comes and opioid administration in acute abdominal pain. Acad Emerg Med. 2000; 7:980-987. 14. Jones PF. Acute abdominal pain in childhood, with special references to cases REFERENCES not due to appendicitis. BMJ. 1969;1:284-286. 15. Janik JS, Firor HV. Pediatric appendicitis: a 20-year study of 1,640 children at 1. Zoltie N, Cust MP. Analgesia in the . Ann R Coll Surg Engl. 1986; Cook County (Illinois) Hospital. Arch Surg. 1979;114:717-719. 68:209-210. 16. Bower RJ, Bell MJ, Ternberg JL. Controversial aspects of appendicitis manage- 2. Attard AR, Corlett MJ, Kidner NJ, Leslie AP, Fraser IA. Safety of early pain relief ment in children. Arch Surg. 1981;116:885-887. for acute abdominal pain. BMJ. 1992;305:554-556. 17. Dickson JA, Jones A, Telfer S, de Dombal FT. Acute abdominal pain in children. 3. Pace S, Burke TF. Intravenous morphine for early pain relief in patients with acute Scand J Gastroenterol. 1988;144(suppl):43-46. abdominal pain. Acad Emerg Med. 1996;3:1086-1092. 18. Lintula H, Kokki H, Vanamo K. Single-blind randomized clinical trial of laparo- 4. LoVecchio F, Oster N, Sturmann K, Nelson LS, Flasher S, Finger R. The use of scopic versus open appendicectomy in children. Br J Surg. 2001;88:510-514.

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