PEDIATRICS/ORIGINAL RESEARCH

The PICHFORK (Pain in Children Fentanyl or Ketamine) Trial: A Randomized Controlled Trial Comparing Intranasal Ketamine and Fentanyl for the Relief of Moderate to Severe Pain in Children With Limb Injuries Andis Graudins, MBBS, PhD*; Robert Meek, MBBS, MClinEpi; Dianna Egerton-Warburton, MBBS, MClinEpi; Ed Oakley, MBBS; Robert Seith, MBBS *Corresponding Author. E-mail: [email protected].

Study objective: We compare the analgesic effectiveness of intranasal fentanyl and ketamine in children. Methods: This was a double-blind, randomized, controlled trial comparing fentanyl at 1.5 mg/kg with ketamine at 1 mg/kg in children aged 3 to 13 years and weighing less than 50 kg, with isolated limb injury and pain of more than 6 of 10 at triage. The sample size was 40 in each arm. Subjects were coadministered oral ibuprofen at 10 mg/kg. The primary outcome was median pain rating reduction at 30 minutes. Secondary outcomes were pain rating reduction at 15 and 60 minutes, subjective improvement and satisfaction, University of Michigan Sedation Score, adverse events, and rescue analgesia. Results: Eighty children enrolled, and 73 were available for analysis: 37 fentanyl and 36 ketamine. Median age was 8 years; 63% were male children; median baseline pain rating was 80 mm. At 30 minutes, median reductions for ketamine and fentanyl were 45 and 40 mm, respectively (difference 5 mm; 95% confidence interval [CI] 10 to 20 mm). Reductions exceeded 20 mm for ketamine and fentanyl in 82% and 79% of patients, respectively (difference 3%; 95% CI 22% to 16%). Pain rating reduction was maintained to 60 minutes in both groups. Satisfaction was reported for ketamine and fentanyl by 83% and 72% of patients, respectively (difference 11%; 95% CI 9% to 30%). Adverse events, mainly mild, were reported for ketamine and fentanyl by 78% and 40% of patients, respectively (difference 38%; 95% CI 58% to 16%). Three ketamine patients had a moderate degree of sedation by University of Michigan Sedation Score. Conclusion: Intranasal fentanyl and ketamine were associated with similar pain reduction in children with moderate to severe pain from limb injury. Ketamine was associated with more minor adverse events. [Ann Emerg Med. 2014;-:1-8.] Please see page XX for the Editor’s Capsule Summary of this article. 0196-0644/$-see front matter Copyright © 2014 by the American College of Emergency Physicians. http://dx.doi.org/10.1016/j.annemergmed.2014.09.024

INTRODUCTION

Importance

Background

The current most frequently available concentration of fentanyl in Australasian emergency departments (EDs) is 50 mg/mL. This concentration results in dosing limitations in patients weighing more than 50 kg. As a result, we believed that the assessment of the intranasal effectiveness of another analgesic agent commonly available in most EDs would provide useful information for clinicians. If a headto-head comparison of fentanyl and ketamine suggested that ketamine and fentanyl were equally effective, then ketamine could be considered as an intranasal analgesic option in children, particularly when intranasal fentanyl or other opioids are contraindicated. To our knowledge, this is the first randomized controlled trial comparing intranasal analgesics in children in the ED.

The intranasal route for drug delivery is commonly used in pediatric emergency medicine for the provision of analgesia in place of parenteral opioids. Fentanyl is the most common opioid used intranasally and is reported to be effective in a number of observational studies.1-5 Recently, we described an observational study using subdissociative doses of ketamine intranasally in children with moderate to severe pain from limb injuries.6 Ketamine produced significant reductions in pain, comparable to that reported in similar observational studies using intranasal fentanyl.2,3 In addition, ketamine in a dose of approximately 1 mg/kg was well tolerated and was not associated with significant sedation or dissociative effects.6 Volume

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Editor’s Capsule Summary

What is already known on this topic Intranasal analgesia is increasingly used for children because it can be delivered quickly, with minimal upset. What question this study addressed How does intranasal fentanyl 1.5 mg/kg compare with intranasal ketamine 1 mg/kg? What this study adds to our knowledge Similar pain reduction was observed with either agent in this randomized double-blinded trial of 73 children with limb injuries. Ketamine had more adverse effects, but none serious. How this is relevant to clinical practice In the doses studied, intranasal ketamine appeared similarly effective to intranasal fentanyl.

Goals of This Investigation

We aimed to compare intranasal ketamine and fentanyl in a double-blind fashion in children presenting to the ED with moderate to severe pain from isolated limb injury. The primary outcome was reduction in pain rating at 30 minutes postadministration of analgesic. MATERIALS AND METHODS Study Design and Setting

This was a randomized, controlled, double-blind, intention-to-treat study conducted in the EDs of 2 Monash Health hospitals: Monash Clayton (tertiary referral; pediatric ED annual census 29,000 patients) and Monash Dandenong (urban district; mixed ED with annual pediatric census of 14,000 patients). Recruitment took place at Monash Clayton from November 2012 to November 2013 and at Monash Dandenong from November 2012 to February 2013. The trial protocol has been published previously7 and is registered with the Australian and New Zealand Clinical Trials Registry (ACTRN12612000795897), and conduct was approved by the Monash Health Human Research and Ethics Committee. Selection of Participants

Inclusion criteria were children aged 3 to 13 years, weight less than 50 kg, isolated limb injury, moderate to severe pain as evidenced by reported severity greater than or equal to 6 (by child or parental estimate) on the standard 11-point verbal rating scale (0¼none and 10¼worst pain imaginable) at triage, and intranasal fentanyl as the norm 2 Annals of Emergency Medicine

for analgesia. Exclusion criteria included inability to gain informed consent from parent or guardian; treatment with serotonergic antidepressants; previous administration of parenteral or intranasal analgesics or opioid analgesia; opioid antagonist use; allergy to ketamine, fentanyl, or ibuprofen; aberrant nasal anatomy or acute or chronic nasal problems or nasal trauma that may have precluded adequate intranasal delivery; and presence of multiple trauma or head injury with loss of consciousness or cognitive impairment. Use of simple analgesia such as paracetamol or ibuprofen or inhalational methoxyflurane within 4 hours before ED arrival did not exclude participation. Study medications were fentanyl citrate 50 mg/mL (DBL Fentanyl; Hospira Pty Ltd, Melbourne, Australia) and ketamine 200 mg/2 mL (Ketalar; Hospira Pty Ltd). Drugs were prepared in prefilled syringes labeled “study drug.” Fentanyl syringes were made by drawing up 1.5 mL of fentanyl citrate parenteral solution for injection (50 mg/mL) into a 3-mL syringe. Ketamine syringes were prepared by diluting 0.5 mL ketamine parenteral solution (100 mg/mL) with 1.0 mL of sodium chloride 0.9% to make a final concentration of 50 mg/1.5 mL (33.3 mg/mL). The trial syringes had an expiry of 1 week from manufacture. Four syringes of the block-randomized batch were prepared weekly by the pharmacy at each hospital site, and unused syringes were destroyed by the pharmacy. Unused, expired syringes were remade with the same numbers and drug allocations until all syringe numbers were used. Subjects received either intranasal ketamine (1 mg/kg) or fentanyl (1.5 mg/kg) by blinded syringe and mucosal atomization device in a standardized volume at 0.03 mL/ kg, with a maximum volume of 1.5 mL. For analgesic dose volumes equal to and less than 0.5 mL, the entire dose was administered in 1 of the nares. Doses greater than 0.5 mL were divided equally to both nares. All subjects were also to receive oral ibuprofen (Fenpaed; AFT Pharmaceuticals Pty Ltd., Sydney, Australia) (10 mg/kg) in the first 15 minutes after intranasal drug administration unless they had received this in the previous 4 hours. Eighty-four numbered syringes were block-randomized to contain either ketamine or fentanyl, using a 4-block randomization table as described by Altman and Bland.8 Each syringe was prepared as allocated, and the unique number was recorded on the patient prescription accompanying the syringe. Methods of Measurement

Pain rating was undertaken with a methodology similar to that used in our pilot study.6 For children aged 3 to 6 years, the Faces Pain Scale–Revised was used. The line of 6 faces was labeled “no pain” at the left and “very much Volume

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pain” at the right and was numerically rated as 0, 20, 40, 60, 80, and 100 from left to right. The visual analog scale (VAS) was used for children aged 7 years and older, which required marking of a standard 100-mm line labeled “no pain” at the left end and “worst pain ever” at the right end. The severity rating at a single point is the measurement (millimeters) from the left end of the line. For both scales, change in severity is recorded as positive for movement to the left (less pain) and negative toward the right (more pain). Amount of change at 15, 30, and 60 minutes was in comparison with the baseline reading. The subjective description of change in severity of pain was assessed by asking whether pain was “a lot less,” “a little less,” “the same,” “a little more,” or “a lot more.” For outcome reporting, this was dichotomized to improved (a lot less or a little less) versus not improved (all other options). The subject, parent, or guardian assessment of satisfaction with reduction in pain severity requested a choice of “satisfied,” “not satisfied,” or “no opinion.” For outcome reporting, this was dichotomized to “satisfied” or “other” (not satisfied or no opinion). The degree of sedation was assessed by attending medical staff and the patient, parent, or guardian. The attending physician used the University of Michigan Sedation Scale. Scores were 0¼awake and alert, 1¼minimally sedated, 2¼moderately sedated, 3¼deeply sedated, and 4¼unrousable. This has been validated in analgesic and sedation studies in children.9 The patient, parent, or guardian was asked to subjectively describe the degree of sedation as “too sedated,” “sedated enough,” “unchanged,” or “not sedated enough.” On identification of an eligible patient, a standardized verbal consent script was read to the parent or guardian by the attending physician. Baseline pain ratings and sedation score were then recorded. The next numbered study pack was identified and the drug was administered intranasally with a mucosal atomizer device (MAD; Wolf Troy Medical, Salt Lake City, UT). Oral ibuprofen was also administered within the first 15 minutes of intranasal drug administration unless this drug had been given in the previous 4 hours. A full written participant information and consent form was then given to the parent or guardian to consent for ongoing participation and data collection. The requirement for rescue analgesia was assessed both throughout the study period and specifically at the 15-, 30-, and 60-minute points. Further participation in the study was terminated at rescue medication administration. Rating of satisfaction with analgesia was recorded at the conclusion of study involvement. This was the earliest of 60 minutes post–study drug administration, ED discharge, or the time of administration of any rescue medication. Data collected Volume

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to time of termination were retained and included in the statistical analyses. Depending on the treating physician’s preference, rescue analgesia was either additional intranasal fentanyl or intravenous morphine. Outcome Measures

The primary outcome measure was the median reduction in pain rating at 30 minutes after the administration of study medication. Secondary outcome measures included change in pain rating at 15 and 60 minutes and number (percentage) of patients with reductions of greater than or equal to 20 mm. Because reported figures for the minimum clinically significant difference have varied between 10 and 28 mm for different severity subgroups, we defined it as 20 mm for this population in anticipation of reasonably balanced numbers of patients with moderate and severe pain.10-13 Other secondary outcome measures included subjective improvement in symptoms, satisfaction, sedation score, adverse events, and need for and timing of rescue analgesia. We calculated our sample size according to the lower 95% confidence level for our chosen minimum clinically significant difference value of 20 mm,10-13 assuming a mean VAS reduction of 40 mm (SD 25 mm) for intranasal ketamine.6 Similar pain relief was shown by Crellin et al2 for intranasal fentanyl; however, it was not possible to calculate variance from that article. This resulted in a sample size of 36 per group, which we increased to 40 patients per group to provide a 10% buffer for dropouts. Primary Data Analysis

Data analysis was undertaken with Stata (version 8.0; StataCorp, College Station, TX). The intention-to-treat principle was used. Pain ratings from the Faces Pain Scale–Revised and VAS were combined, as supported in the original research by Hicks et al14 and the more recently expanded research by de Tovar et al.15 This was also the approach taken by Crellin et al2 in the 2010 observational study involving intranasal fentanyl. Differences in outcome between groups are reported with 95% confidence intervals (CIs). RESULTS During the study period, 80 patients were randomized, 75 (93.8%) at Monash Clayton and 5 (6.2%) at Monash Dandenong, where recruitment ceased after 3 months because of the low enrollment rate. Patient flow is summarized in Figure 1. Baseline characteristics, including patient age, sex, initial severity rating, University of Michigan Sedation Score, and Annals of Emergency Medicine 3

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5 (13.5%), 5 (13.5%), and 0 of the fentanyl group and 32 (88.9%), 3 (8.3%), 0, and 1 (2.8%) of the ketamine group, respectively. We found similar pain reductions between groups at all points. Primary outcome data at 30 minutes are summarized in Figure 2. Pain reduction data for other time points are summarized in Table 2. Secondary outcomes were also similar between groups (Table 3). However, the difference in adverse events was significant between groups, with a total of 24 adverse events being reported by 15 of 37 patients (40.5%; 95% CI 24.8% to 57.9%) in the fentanyl group and 67 being reported by 28 of 36 patients (77.8%; 95% CI 60.8% to 89.9%) in the ketamine group (Table 4). The assessment of sedation with the University of Michigan Sedation Score for each group at each point was similar and is illustrated in Figure 3. In Tables E1 and E2 (available online at http://www. annemergmed.com) we present outcomes of post hoc stratification by use of the Faces Pain Scale–Revised or the VAS. In general, younger children were more likely to report greater pain rating reductions and lower rates of subjective symptom improvement and satisfaction, and had higher receipt of rescue analgesia.

Figure 1. Consort diagram of patient flow.

median intranasal drug dose administered for each study group, are shown in Table 1. Diagnoses of upper limb fracture, upper limb soft tissue injury, lower limb fracture, and lower limb soft tissue injury were made in 27 (73.0%), Table 1. Comparison of baseline characteristics between groups. Variable

Fentanyl (n[37)

Ketamine (n[36)

Age, median (IQR), y 9 (6 to 11) 7 (6 to 9.5) Male, No. (%) [95% CI] 24 (65) [47.5 to 79.8] 22 (61) [43.5 to 76.9] Enrollment pain rating, 80 (70 to 100) 80 (69 to 96) median (IQR), mm Enrollment UMSS, 0 (0 to 1) 0 (0 to 1) median (range) Median intranasal drug 1.53 mg/kg 1.01 mg/kg dose administered (IQR) (1.45 to 1.57) (0.96 to 1.05) Patients receiving 33 (89) 33 (92) ibuprofen, No. (%) Median time to 0 (–70 to 60) 0 (–28 to 50) administration of ibuprofen after intranasal drug delivery, (range), min IQR, Interquartile range; CI, confidence interval; UMSS, University of Michigan Sedation Score.

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LIMITATIONS Use of a nonconsecutive convenience sample leaves the possibility of selection bias. We have no information on the total number of nonrecruited eligible patients during the study period. Without a placebo arm, it is not possible to know how other factors, for which we did not control, may have influenced pain perception. These include reassurance by staff, arrival of a parent, or splinting of the affected limb. Also we cannot assess whether the effect of such factors was additive or independent to drug use. Similarly, administration of ibuprofen was intended to occur within 15 minutes of that of the intranasal drug, if not before. Recording of times was incomplete, and although most patients appeared to receive ibuprofen early, some received it later. Recording of out-of-hospital paracetamol and methoxyflurane use was thought too unreliable to report, so difference in receipt and timing of these other analgesics may have affected some individual ratings. We believe that numbers were small and that any effects were random rather than systematic. Consequently, it is unlikely that there would be any significant effect on results. Predefining the minimum clinically significant difference for a population is also difficult. Estimates vary, depending on the baseline severity mix, and for reasons stated, the minimum clinically significant difference was Volume

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A

B

Figure 2. Parallel line plot of change in pain rating for individual subjects receiving either intranasal ketamine or fentanyl from time 0 to the primary outcome point of time 30 minutes (A) and to time 60 minutes (B). The length of the line portrays the magnitude of change in pain rating for each subject. The box-and-whisker plot to the right represents median change in pain rating for each group (solid line represents median, box represents interquartile range, whiskers represent range, and open circles represent individual subject changes).

defined as 20 mm for this study population. The 95% CI of the small difference between groups, of –10 to 20 mm, suggests that any potential difference between the drugs is unlikely to be clinically significant because this range falls within 20 mm either way, but research on how rating reductions beyond the minimum clinically significant difference relate to additional clinical effect is lacking. Rescue medication is a problematic secondary outcome measure because the decision was at the discretion of the attending ED clinicians. Without any formal or objective criteria to dictate its administration, the true need for it is difficult to know. Volume

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The sample size was too small to analyze differences between injury subgroups or subjects of varying age. Table E2 (available online at http://www.annemergmed. com) suggests that there may be differences in outcomes related to age. However, the study was not powered to assess this. Patient cooperation during study drug delivery, along with the technique of the administrator, may also result in variations in the amount of drug received. However, all nurses underwent standardized training in the use of the mucosal atomizer device. There are also other outcome measures of interest that were not assessed in this study. Duration of analgesic effect Annals of Emergency Medicine 5

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Table 2. Comparison of median rating reductions at each point between both groups and number of subjects achieving a reduction of more than 20 mm at each point. Variable Rating Rating Rating Rating Rating Rating

change at 30 min, median (IQR), mm reduction >20 mm at 30 min, No. (%) change at 15 min, median (IQR), mm reduction >20 mm at 15 min, No. (%) change at 60 min, median (IQR), mm reduction >20 mm at 60 min, No. (%)

Fentanyl

Ketamine

40 (20 to 45) 27/34 (79) 30 (15 to 40) 25/35 (71) 50 (20 to 60) 25/31 (81)

45 (20 to 60) 28/34 (82) 30 (16 to 42) 26/36 (72) 50 (30 to 61) 28/31 (90)

may have been different between drugs. We observed a trend of more patients in the fentanyl group requiring rescue analgesia after the 60-minute rating. However, numbers were too small to draw conclusions about this. The more frequent adverse effects in the ketamine group may have led to greater lengths of ED stay or even affected ED disposition, but we did not collect information on this. DISCUSSION In this randomized, controlled, double-blind comparison of intranasal ketamine and fentanyl, we demonstrated similar reductions in pain ratings over time for both drugs, each of relatively rapid onset, in children with moderate to severe pain resulting from isolated limb injury. At the primary endpoint of 30 minutes, both groups had clinically significant reductions in VAS ratings, with approximately 80% of subjects in both groups exceeding our defined minimum clinically significant difference of 20 mm.11-13 In addition, most subjects also reported a subjective improvement in symptoms and were satisfied with their treatment. Both treatments provided a significant analgesic effect to 60 minutes postadministration. Ketamine administration was associated with a higher reported rate of adverse events. These Table 3. Comparison of rescue analgesia, satisfaction, and selfreported sedation level between groups.

Variable Rescue analgesia, No. (%) Satisfied at final rating, No. (%) Sedation at final rating, No. (%) Too much Enough None Not enough Symptoms improved at final rating, No. (%)

Fentanyl

Ketamine

Difference (Ketamine vs Fentanyl) (95% CI)

12/37 (32)

5/36 (14)

18 (37 to 3)

26/36 (72)

29/35 (83)

11 (9 to 30)

1/36 (3) 10/36 (28) 25/36 (69) 0/36 28/36 (78)

0/35 18/35 16/35 1/35 31/35

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(51) (46) (3) (89)

3 23 23 3 11

(8 to 3) (1 to 45) (42 to 2) (3 to 8) (28 to 6)

Difference in Medians (95% CI) (Ketamine to Fentanyl) 5 (10 3 (16 0 (20 1 (20 0 (13 9 (8

to 20) to 22) to 20) to 22) to 13) to 27)

were primarily related to a greater frequency of dizziness and drowsiness; however, adverse events tended to be mild and seemed to be well tolerated by subjects. No subject developed any self-reported or parent-reported degrees of unwanted sedation in either group, which correlated with the mild, objective University of Michigan Sedation Score ratings. These findings are consistent with those of our earlier study on the effectiveness of intranasal ketamine for children with limb injury,6 with the dose of 1 mg/kg used here being the same as in that study, which also demonstrated a 30-minute VAS reduction of approximately 40 mm. Adverse events were of a similar nature in both studies, with dizziness being the most commonly reported. There were no cases of emergence phenomena or distress from hallucinations at the dose used. To our knowledge, this is the first study to compare intranasal analgesic agents in a blinded fashion in children in the ED. We chose fentanyl as the comparator because it is currently the most commonly used intranasal analgesic in children in Australasian EDs. Previous observational studies have reported significant reductions in pain ratings over time with this agent,2,4 In an unblinded, observational study of children with isolated limb injuries, Crellin et al2 reported reductions in VAS pain ratings similar to those observed in this study and in our initial intranasal dose-finding study for ketamine.6 They also demonstrated that in children Table 4. Total adverse effects for each group.* Variable

Fentanyl

Ketamine Difference (95% CI)

Patients with any adverse 15/37 (40) 28/36 (78) event at any time Bad taste in mouth 10 (42) 17 (25) Drowsiness 5 (21) 11 (16) Dizziness 4 (17) 20 (30) Itchy nose 3 (12) 3 (4) Nausea 1 (4) 4 (6) Dysphoria 1 (4) 3 (4) Hallucinations 0 4 (6) Other 0 5 (7)

38 (58 to 16) 17 5 13 8 2 0 6 7

(39 to 6) (23 to 14) (5 to 32) (22 to 6) (8 to 12) (9 to 10) (0 to 12) (1 to 14)

*For fentanyl, 15 patients reported 24 adverse events; for ketamine, 28 patients reported 67 adverse events. Data are reported as No. (%).

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Number of subjects

35 30 25

Moderate

20

Minimal

15

Awake

10 5

am

K

Fe

et K

nt

in e a n T0 yl T0

et am Fe ine nt an T 1 5 yl T1 5 K et am Fe ine nt T an 3 0 yl T3 0 K et am Fe ine nt an T 6 0 yl T6 0

0

Figure 3. Number of patients in each University of Michigan Sedation Scale category for each group at each point.

weighing less than 50 kg, the most commonly available concentration of fentanyl (50 mg/mL) can be used intranasally. For this reason, we used the same concentration of fentanyl, in the same dose. Crellin et al2 did not report any adverse events with intranasal fentanyl use. In the current randomized controlled trial, almost half of the children receiving fentanyl reported at least 1 adverse event, the most common being a bad taste in the mouth after intranasal administration, followed by dizziness and drowsiness. Other reports of intranasal ketamine use in children for acute analgesia are limited to case reports and observational studies. Reid et al16 described the single case of a 9-year-old boy with burns, who was administered 0.5 mg/kg of intranasal ketamine for transfer to hospital. Nielsen et al17 reported an observational open-label study in which a mixture of intranasal ketamine (0.5 mg/kg) and sufentanil (0.5 mg/kg) was administered to children undergoing painful procedures such as drain removal or dressing changes. The primary outcome for that study was reduction of pain score to less than 5 of 10 during the procedures, and this was achieved in 78% of subjects. They reported that ketamine had an intranasal bioavailability of 36%. Other pediatric studies describing intranasal ketamine use have primarily been in the setting of medication before procedures, in which doses were higher (3 to 9 mg/kg).18-20 Ketamine has also been used intranasally in adults with acute pain in the ED. Andolfatto et al21 described an observational case series in which intranasal ketamine produced a clinically significant reduction in pain for adults presenting to the ED with orthopedic injuries. Similarly, we have reported a case series of adults with moderate to severe pain (VAS rating greater than 6 of 10) from all causes, treated with intranasal ketamine, in which the median VAS reduction at 30 minutes was 24 mm.22 This was markedly less than that observed in children with isolated limb injury in either our previous observational study or this current RCT. However, in other studies, successful use of intranasal ketamine has Volume

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been reported in adults for the management of acute postoperative pain, migraine, and exacerbations of chronic pain in the nonemergency medicine setting.23-26 In conclusion, ketamine is an effective alternative intranasal analgesic for children with moderate to severe pain from limb injury. Adverse effects were more frequent with ketamine; however, these were all relatively mild. Intranasal ketamine could be considered for children who have some contraindication to fentanyl or other opioid use. Areas for further research were identified, including assessing the effectiveness of ketamine as an analgesic in which intranasal fentanyl has failed, assessment of intranasal ketamine at the same or a lower dose or as an adjunct to fentanyl or other opioids, and exploration of the differences in pain perception and management between younger and older children. Supervising editor: Steven M. Green, MD Author affiliations: From the Monash Health Emergency Medicine Research Group, Department of Medicine, School of Clinical Sciences at Monash Health, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia (Graudins, Meek, Egerton-Warburton); the Pediatric Emergency Department, Monash Medical Center (Seith), and Monash Health Emergency Medicine Program (Graudins, Meek, EgertonWarburton, Seith), Monash Health, Clayton, Victoria, Australia; and the Department of Paediatrics, University of Melbourne, and Department of Emergency Medicine, the Royal Children’s Hospital, Parkville, Victoria, Australia (Oakley). Author contributions: AG conceived the study. AG, RM, and EO designed the trial. AG and EO obtained research funding. AG, RM, and DE-W supervised the conduct of the trial and data collection. RM, EO, and RS supervised recruitment at participating centers. RM provided statistical advice on sample size and study design and analyzed the data. AG drafted the article and all authors contributed to revision. AG takes responsibility for the paper as a whole. Funding and support: By Annals policy, all authors are required to disclose any and all commercial, financial, and other relationships in any way related to the subject of this article as per ICMJE conflict of interest guidelines (see www.icmje.org). The authors have stated that no such relationships exist. This study was funded by an unrestricted grant from the Jack Brockhoff Foundation. Publication dates: Received for publication June 30, 2014. Revisions received July 28, 2014; and September 8, 2014. Accepted for publication September 26, 2014.

REFERENCES 1. Prommer E, Thompson L. Intranasal fentanyl for pain control: current status with a focus on patient considerations. Patient Prefer Adherence. 2011;5:157-164. 2. Crellin D, Ling RX, Babl FE. Does the standard intravenous solution of fentanyl (50 microg/mL) administered intranasally have analgesic efficacy? Emerg Med Australas. 2010;22:62-67.

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The PICHFORK Trial 3. Borland M, Milsom S, Esson A. Equivalency of two concentrations of fentanyl administered by the intranasal route for acute analgesia in children in a paediatric emergency department: a randomized controlled trial. Emerg Med Australas. 2011;23:202-208. 4. Holdgate A, Cao A, Lo KM. The implementation of intranasal fentanyl for children in a mixed adult and pediatric emergency department reduces time to analgesic administration. Acad Emerg Med. 2010;17:214-217. 5. Middleton PM, Bendall J, Simpson P, et al. Efficacy of out-of-hospital administration of morphine, fentanyl and methoxyflurane in adults: a single centre observational comparative study of over 38,000 patients. J Emerg Primary Health Care. 2010;14(4):439-447. 6. Yeaman F, Oakley E, Meek R, et al. Sub-dissociative dose intranasal ketamine for limb injury pain in children in the emergency department: a pilot study. Emerg Med Australas. 2013;25:161-167. 7. Graudins A, Meek R, Egerton-Warburton D, et al. The PICHFORK (Pain in Children Fentanyl or Ketamine) trial comparing the efficacy of intranasal ketamine and fentanyl in the relief of moderate to severe pain in children with limb injuries: study protocol for a randomized controlled trial. Trials. 2013;14:208. 8. Altman DG, Bland JM. How to randomise. BMJ. 1999;319:703-704. 9. Malviya S, Voepel-Lewis T, Tait AR, et al. Depth of sedation in children undergoing computed tomography: validity and reliability of the University of Michigan Sedation Scale (UMSS). Br J Anaesth. 2002;31:241-245. 10. Bird SB, Dickson EW. Clinically significant changes in pain along the visual analog scale. Ann Emerg Med. 2001;38:639-643. 11. Kelly AM. The minimum clinically significant difference in visual analogue scale pain score does not differ with severity of pain. Emerg Med J. 2001;18:205-207. 12. Powell CV, Kelly AM, Williams A. Determining the minimum clinically significant difference in visual analog pain score for children. Ann Emerg Med. 2001;37:28-31. 13. Bailey B, Gravel J, Daoust R. Reliability of the visual analog scale in children with acute pain in the emergency department. Pain. 2012;153:839-842.

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14. Hicks CL, von Baeyer CL, Spafford PA, et al. The Faces Pain Scale–Revised: toward a common metric in pediatric pain measurement. Pain. 2001;93: 173-183. 15. de Tovar C, von Baeyer CL, Wood C, et al. Postoperative self-report of pain in children: interscale agreement, response to analgesic, and preference for a faces scale and a visual analogue scale. Pain Res Manag. 2010;15:163-168. 16. Reid C, Hatton R, Middleton P. Case report: prehospital use of intranasal ketamine for paediatric burn injury. Emerg Med J. 2011;28:328-329. 17. Nielsen BN, Friis SM, Rømsing J, et al. Intranasal sufentanil/ketamine analgesia in children. Paediatr Anaesth. 2014;24:170-180. 18. Weksler N, Ovadia L, Muati G, et al. Nasal ketamine for paediatric premedication. Can J Anaesth. 1993;40:119-121. 19. Weber F, Wulf H, Gruber M, et al. S-ketamine and s-norketamine plasma concentrations after nasal and i.v. administration in anesthetized children. Paediatr Anaesth. 2004;14:983-988. 20. Diaz JH. Intranasal ketamine preinduction of paediatric outpatients. Paediatr Anaesth. 1997;7:273-278. 21. Andolfatto G, Willman E, Joo D, et al. Intranasal ketamine for analgesia in the emergency department: a prospective observational series. Acad Emerg Med. 2013;20:1050-1054. 22. Yeaman F, Meek R, Egerton-Warburton D, et al. Sub-dissociative-dose intranasal ketamine for moderate to severe pain in adult emergency department patients. Emerg Med Australas. 2014;26:237-242. 23. Huge V, Lauchart M, Magerl W, et al. Effects of low-dose intranasal (S)-ketamine in patients with neuropathic pain. Eur J Pain. 2010;14:387-394. 24. Carr DB, Goudas LC, Denman WT, et al. Safety and efficacy of intranasal ketamine for the treatment of breakthrough pain in patients with chronic pain: a randomized, double-blind, placebo-controlled, crossover study. Pain. 2004;108:17-27. 25. Christensen K, Rogers E, Green G, et al. Safety and efficacy of intranasal ketamine for acute postoperative pain. Acute Pain. 2007;9:183-192. 26. Afridi SK, Giffin NJ, Kaube H, et al. A randomized controlled trial of intranasal ketamine in migraine with prolonged aura. Neurology. 2013;80:642-647.

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Graudins et al

The PICHFORK Trial

Table E1. Baseline characteristics by subgroup, using VAS or Faces Pain Scale–Revised for assessment of pain rating.

Variable Age, median (IQR) Male, No. (%) [95% CI] Enrollment severity rating, median (IQR) Enrollment UMSS, median (range)

Fentanyl Total (n[37)

Fentanyl Where FPS-R Used (n[16)

Fentanyl Where VAS Used (n[21)

Ketamine Total (n[36)

Ketamine Where FPS-R Used (n[12)

Ketamine Where VAS Used (n[24)

9 (6–11) 24 (64.9) [47.5–79.8] 80 (70–100) 0 (0–1)

5 (5–7) 9 (56.3) [29.9–80.2] 80 (60–100) 0 (0–1)

11 (9–12) 15 (71.4) [47.8–88.7] 80 (70–87) 0 (0–1)

7 (6–9.5) 22 (61.1) [43.5–76.9] 80 (69–96) 0 (0–1)

5 (5–6) 8 (66.7) [34.9–90.1] 90 (75–100) 0 (0–1)

8.5 (7–11) 16 (66.7) [44.7–84.4] 80 (66.5–88) 0 (0–1)

FPS–R, Faces Pain Scale–Revised.

Table E2. A comparison of outcome measures between younger patients, using the Faces Pain Scale–Revised, and older patients, using the VAS: for all patients (regardless of study group) and for those in the fentanyl and ketamine treatment groups. Variable

FPS–R Used

All patients (regardless of study group) Change in VAS 30 min, median (IQR) Change in VAS 15 min, median (IQR) Change in VAS 60 min, median (IQR) Symptoms improved, No. (%) [95% CI] Rescue analgesia given, No. (%) [95% CI] Satisfaction, No. (%) [95% CI] Fentanyl Change in VAS 30 min, median (IQR) Change in VAS 15 min, median (IQR) Change in VAS 60 min, median (IQR) Symptoms improved, No. (%) [95% CI] Rescue analgesia given, No. (%) [95% CI] Satisfaction, No. (%) [95% CI] Ketamine Change in VAS 30 min, median (IQR) Change in VAS 15 min, median (IQR) Change in VAS 60 min, median (IQR) Symptoms improved, No. (%) [95% CI] Rescue analgesia given, No. (%) [95% CI] Satisfaction, No. (%) [95% CI]

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60 40 60 18/27 10/28 18/27

VAS Used

Difference (95% CI)

(20 to 80) [n¼27] (20 to 60) [n¼27] (40 to 80) [n¼21] (66.7) [46.0 to 83.5] (35.7) [18.6 to 55.9] (66.7) [46.0 to 83.5]

33 (20 to 50) [n¼41] 23.5 (15 to 30) [n¼44] 50 (30 to 52) [n¼41] 41/44 (93.2) [81.3 to 98.6] 7/45 (15.6) [6.5 to 29.5] 37/44 (84.1) [69.9 to 93.4]

27 15 10 26.5 20.2 17.4

(10.0 to 44.0) (4.3 to 25.7) (2.1 to 22.1) (7.2 to 45.8) (40.8 to 5.1) (38.2 to 3.4)

40 (20 to 80) [n¼15] 40 (20 to 60) [n¼15] 60 (10 to 90) [n¼12] 9/15 (60.0) [32.3 to 83.7] 8/16 (50.0) [24.7 to 75.3] 7/15 (46.7) [21.3 to 73.4]

33 (20 to 40) [n¼19] 20 (15 to 30) [n¼20] 40 (34 to 50) [n¼19] 19/21 (90.5) [69.6 to 98.8] 4/21 (19.0) [5.4 to 41.9] 19/21 (90.5) [69.6 to 98.8]

7 20 20 30.5 31.0 43.8

(6.2 to 20.2) (3.8 to 36.2) (1.9 to 38.1) (2.758.3) (1.2 to 60.7) (15.6–72.0)

35 (20 to 50) [n¼21] 26.5 (12.5 to 34.50) [n¼24] 50 (20 to 54) [n¼22] 22/23 (95.7) [78.1 to 99.9] 3/24 (12.5) [2.7 to 32.4] 18/23 (78.3) [56.3 to 92.5]

25 12 10 20.7 4.2 13.4

(13.5 to 36.5) (2.5 to 26.5) (6.2 to 26.2) (5.2 to 46.5) (20.7 to 29.1) (9.6 to 36.4)

60 (20 to 60) [n¼13] 40 (20 to 60) [n¼12] 60 (60 to 70) [n¼9] 9/12 (75.0) [42.8 to 94.5] 2/12 (16.7) [2.1 to 48.4] 11/12 (91.7) [61.5 to 99.8]

Annals of Emergency Medicine 8.e1

The PICHFORK (Pain in Children Fentanyl or Ketamine) trial: a randomized controlled trial comparing intranasal ketamine and fentanyl for the relief of moderate to severe pain in children with limb injuries.

We compare the analgesic effectiveness of intranasal fentanyl and ketamine in children...
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