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Original article
Sublingual ketorolac versus sublingual tramadol for moderate to severe post-traumatic bone pain in children: a double-blind, randomised, controlled trial
  1. Elena Neri1,
  2. Alessandra Maestro2,
  3. Federico Minen3,
  4. Marcella Montico4,
  5. Luca Ronfani4,
  6. Davide Zanon2,
  7. Anna Favret3,
  8. Gianni Messi1,
  9. Egidio Barbi1
  1. 1Pediatric Emergency Department, Institute for Maternal and Child Health—IRCCS “Burlo Garofolo”, Trieste, Italy
  2. 2Clinical Services of Pharmacy, Institute for Maternal and Child Health—IRCCS “Burlo Garofolo”, Trieste, Italy
  3. 3University of Trieste, Trieste, Italy
  4. 4Epidemiology and Biostatistics Unit, Institute for Maternal and Child Health—IRCCS “Burlo Garofolo”, Trieste, Italy
  1. Correspondence to Dr Federico Minen, University of Trieste, Trieste, 34100, Italy; federicominen{at}gmail.com

Abstract

Objectives To assess the effectiveness of sublingual ketorolac versus sublingual tramadol in reducing the pain associated with fracture or dislocation of extremities in children.

Patients and methods A double-blind, randomised, controlled, non-inferiority trial was conducted in the paediatric emergency department of a research institute. One hundred and thirty-one children aged 4–17 years with suspected bone fracture or dislocation were enrolled. Eligible children were randomised to ketorolac (0.5 mg/kg) and placebo, or to tramadol (2 mg/kg) and placebo by sublingual administration, using a double-dummy technique. Pain was assessed by the patients every 20 min, for a maximum period of 2 h, using the McGrath scale for patients up to 6 years of age, and the Visual Analogue Scale for those older than 6 years of age.

Results The mean pain scores fell significantly from eight to four and five in the ketorolac and tramadol groups, respectively, by 100 min (Wilcoxon sign rank test, p<0.001). The mean pain scores for ketorolac were lower than those for tramadol, but these differences were not significant at any time point (Mann–Whitney U Test, p values: 0–20 min: 0.167; 20–40 min: 0.314; 40–60 min: 0.223; 60–80 min: 0.348; 80–100 min: 0.166; 100–120 min: 0.08). The rescue dose of paracetamol-codeine was administered in 2/60 children in the ketorolac group versus 8/65 in the tramadol group (Fisher exact test, p=0.098). There were no statistically significant differences between the two groups in the frequency of adverse effects.

Conclusions Both sublingual ketorolac and tramadol were equally effective for pain management in children with suspected fractures or dislocations.

  • Analgesia
  • General Paediatrics
  • Pain

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What is already known on this topic

  • Ketorolac and tramadol are effective analgesic drugs for severe pain in adults. There is limited data regarding the optimal management of acute fractures in children.

What this study adds

  • Sublingual ketorolac and tramadol are both effective for children with acute fractures or dislocation.

Introduction

Fractures are common, with one-third of children sustaining at least one fracture before the age of 16 years.1 Fractures and dislocations in children can be very painful, and the pain underestimated.2 The optimal pain management treatment remains challenging due to the lack of evidence on the effectiveness and safety of analgesic drugs. Oral ibuprofen is reported to be more effective than both paracetamol and codeine for acute pain relief in children with musculoskeletal trauma3; codeine analgesic efficacy may be not optimal for nearly 7–10% of individuals who have at least one reduced functioning allele resulting in suboptimal conversion of codeine to active analgesic.4 The proportion of treatment failures for ibuprofen and paracetamol with codeine are reported as high as 20.3% and 31.0%, respectively.5

Ketorolac and tramadol are widely used for the treatment of moderate to severe pain in adults for similar clinical conditions. Ketorolac is a non-steroidal anti-inflammatory drug (NSAID).6 The most important adverse effects are bleeding and gastritis which typically occur after repeated doses. Tramadol is a synthetic 4-phenylpiperidine analogue of codeine. It is considered a weak u-opioid receptor agonist and it also inhibits the neuronal reuptake of serotonin and norepinephrine and displaces serotonin stores within the spinal cord, facilitating descending inhibitory pain pathways. The main potential adverse effects are drowsiness, nausea and vomiting.7–9 In adult patients, many studies have established the efficacy of these two drugs.10–13 Numerous studies have compared the analgesic effect of ketorolac versus tramadol and other opioids in surgical settings showing similar effectiveness and reduced adverse effects, as well as a morphine-sparing effect for ketorolac.14–21 Yet, to date, no study has been published comparing tramadol versus ketorolac in adults treated for fractures or dislocations. Both ketorolac and tramadol are effective as post-traumatic, intraoperative and postoperative analgesia in children.6 ,11 ,22 ,23 To the best of our knowledge, there are no randomised controlled studies comparing ketorolac and tramadol in fracture-related pain.

The sublingual route of administration may be beneficial for analgesic agents. It should have a more rapid onset of action than oral administration. It has previously been used and shown to be effective in adults.24 ,25 Children from the age of 6 years onwards have been shown to be able to take sublingual drugs with adequate interactions and support by nurses.26 ,27

We conducted a non-inferiority, double-blind, randomised, controlled trial to compare the effectiveness of the two drugs in paediatric care for fractures and dislocations.

Methods

This is a randomised (allocation ratio 1:1), double-blind, double-dummy, parallel, clinical trial conducted between February 2008 and April 2012 at a single tertiary urban paediatric emergency department (ED) in Trieste, Italy. The Independent Bioethical Committee of the Institute approved the study. The study protocol has been registered on ClinicalTrials.gov (ID Number NCT00560443); nevertheless, the study design has been changed from the original one. The original study design included only children with dislocations; we decided to modify the design before the beginning of the study in order to enrol more children. The ethical approvals were obtained for the revised protocol.

Inclusion criteria were: age 4–17 years; presence of suspected fracture or dislocation; presence of pain >6, evaluated at ED admission with the 10-point Visual Analogue Scale (VAS) or faces pain rating scale, depending on patient's age.

Children with finger trauma, analgesic drugs usage in the preceding 24 h, history of hypersensitivity to NSAIDs, chronic illnesses and comorbidities were excluded.

After written informed consent was obtained from a parent or legal guardian, eligible subjects were randomly allocated by the doctor of the ED to receive sublingual:

  • ketorolac or the equivalent placebo, 0.5 mg/kg, to a maximum of 20 mg (=0.025 ml/kg of the solution, maximum 1 ml);

  • tramadol or the equivalent placebo, 2 mg/kg, to a maximum of 100 mg (=0.020 ml/kg ml of the solution, maximum 1 ml).

Each enrolled child received both the active drug and a matched placebo of the other treatment. Oral solutions, 20 mg/ml for ketorolac (Toradol) and 100 mg/ml for tramadol (Contramal) were used for sublingual administration.

The statistical package, STATA, was used to generate the randomisation list using fixed block size of ten. Following randomisation, the pharmacy dispensed consecutively numbered administration sets to the ED, each consisting of two single-use vials (one containing the active drug and one the placebo). All the study investigators, medical staff and participants were unaware of the patient's assignment to the randomised groups.

Primary study outcome was the comparison of pain reduction between the two groups. Pain was assessed by the patients with the linear 1–10 VAS pain scale or, for children 4–6 years old, with the analogue McGrath-type scale. Every 20 min, children were asked to mark the pain score: if no pain control was achieved at 120 min (pain >5), the patients were given paracetamol-codeine by mouth as a rescue analgesic, at the dosage of paracetamol 12.5 mg/kg and codeine 0.75 mg/kg. Patients who underwent orthopaedic procedures requiring procedural sedation (midazolam, propofol) underwent the last pain evaluation at the time of the procedure.

Secondary outcomes were: pain relief within groups, need for administration of the rescue drug and the presence of adverse effects. x-Ray was scheduled for all enrolled children with suspected fracture or dislocation, and performed after the drug was taken.

We wanted to establish non-inferiority of ketorolac in pain relief as compared with tramadol. We defined a very little difference in pain score (1 point) and set the non-inferiority threshold to 50% of this value (0.5 point). Using this non-inferiority threshold, with an estimated SD of 1, we estimated that a sample size of 120 patients (60 per group) would provide a power of 80% to demonstrate that ketorolac is non-inferior to tramadol with a level of significance of α=0.05. To confirm the non-inferiority of ketorolac, the upper limit of the 95% CI of the mean difference of pain scores between ketorolac and tramadol should be under the non-inferiority margin of 0.5 point.

Data are presented as frequencies and percentages for categorical variables, and as medians and IQRs for continuous variables. We used the Fisher exact test to analyse the differences between groups for categorical variables and the Mann–Whitney test for continuous variables. Wilcoxon sign rank test was used to analyse paired data (within-group differences). Risk difference and relative 95% CI was calculated for the use of rescue dose and for adverse events. Since we hypothesised that a weight greater than 50 kg could influence pain scores, we further stratified results by this variable.

Non-inferiority was assessed calculating the 95% CI for the mean differences of pain score between the treatments at each time, and evaluating if they contained the chosen non-inferiority limit. All the analyses were carried out with the software Stata V.9.2 (Stata, College Station, Texas, USA).

Results

Of the 144 children asked to enter the study, 131 were enrolled. Sixty-seven patients were allocated to receive tramadol and 64 ketorolac; 2 (3.0%) and 4 (6.2%) patients, in the tramadol and ketorolac group respectively, were lost to follow-up (figure 1). Pain evaluation was missing at different time points (1 observation at time 40; 11 observations at time 60; 9 at time 80; 9 at time 100; and 10 at time 120). No violation of the randomisation occurred. Both solutions were well tolerated, none of the patients spat it out or immediately swallowed it.

There were no relevant differences between the two groups, except for the side of the trauma (table 1).

Table 1

Characteristics of the enrolled subjects

The mean pain scores fell significantly from eight to four and five in the ketorolac and tramadol groups, respectively, by 100 min (Wilcoxon sign rank test, p<0.001) (figure 2). The mean pain scores for ketorolac were lower than those for tramadol, but these differences were not significant at any time point (Mann–Whitney test, p values: 0–20 min: 0.167; 20–40 min: 0.314; 40–60 min: 0.223; 60–80 min: 0.348; 80–100 min: 0.166; 100–120 min: 0.08).

Figure 2

Change in pain score during the 120 min follow-up in children receiving ketorolac versus tramadol (medians and IQRs).

The 95% CI of mean differences between ketorolac and tramadol confirmed the non-inferiority of ketorolac at each time point. Stratification of pain scores by weight (≤50 kg versus >50 kg) was not associated with any statistical difference both within and between groups (Wilcoxon and Mann–Whitney tests, respectively).

The rescue dose of paracetamol-codeine was administered in 2 out of 60 children (3.3%) in the ketorolac group versus 8 out of 65 (12.3%) in the tramadol group (risk difference −9.0%, 95% CI form −19.4% to 1.0%; Fisher exact test p=0.098).

There were no statistically significant differences in adverse events between the groups. However, three children (4.6%) reported side events in the tramadol group (2 vomiting, 1 vomiting and dry mouth) versus 0 in ketorolac group (risk difference between ketorolac and tramadol −4.6, 95% CI from −12.7 to 2.1; Fischer exact test p=0.244).

No problems were experienced by any of the patients following sublingual administration of medicines. A few patients stated that the drug was bitter, but no one spat it out or swallowed the medicine.

Discussion

This study shows that both sublingual ketorolac and tramadol are effective analgesics in children with suspected bone fractures.

Only one similar prospective study11 evaluated the analgesic properties of tramadol in comparison with metamizole sodium and diclofenac sodium given intravenously to both adults and children with isolated traumatic injuries, and concluded that tramadol was the most effective agent, producing an earlier onset of analgesia compared with the other agents.

The sublingual route of administration is safe and efficacious, both for ketorolac and opioids, as highlighted in various studies.24 ,25

In the trauma setting, intranasal fentanyl or diamorphine administration are both reported as highly efficacious for severe pain.28–30 The target of our study was mainly moderate to severe pain since the proportion of treatment failures in this setting for ibuprofen and acetaminophen with codeine are reported as high as 20.3% and 31.0%.5 Furthermore, intranasal administration can be unpleasant and cause discomfort, or be of limited efficacy in the case of rhinitis and nasal bleeding.

In our series, vomiting has been a minor adverse effect of tramadol (3 patients) but not of ketorolac. The importance of pharmacogenetics as a risk factor for tramadol adverse effects has been highlighted.31 This drug is bioactivated by CYP2D6 to the opioid receptor agonist O-desmethyltramadol; carriers of CYP2D6 gene duplication present a statistically significant higher risk of developing opioid adverse events (50% of 11 patients in the carrier group presented nausea compared with only 9% of 11 patients in the non-carrier group), without pharmacokinetic differences. Tramadol may frequently cause adverse effects in southern European and northern African populations due to a high proportion of gene duplication (up to 7% in Spain and Turkey, and 30% in Ethiopia and Saudi Arabia).

A possible limit of our study is the maximum dose of both drugs: the maximum dose of tramadol was 100 mg, and that of ketorolac was 20 mg. This dosage could be relatively small for overweight adolescents. In any case, no significant differences in pain scores for patients below and over 50 kg were observed for both drugs.

Our study suggests that both ketorolac and tramadol are effective following sublingual administration for the treatment of acute pain following fractures in children.

Although statistically not significant, the pain scores were lower in the ketorolac group, and less children required rescue treatment. Additionally, there were fewer side effects reported in the ketorolac group.

Acknowledgments

The authors wish to thank doctor Edoardo Guglia for the pivotal contribution to this study and for all his ideas, mentoring and commitment throughout all his years in the ED.

References

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Footnotes

  • Contributors EN recruited most of the patients and carried on the original idea of the study of Dr Edoardo Guglia. She helped in drafting the manuscript and approved the final manuscript as submitted. AM conceptualised the pharmacological part of the study, reviewed and revised the manuscript. FM helped in recruiting the patients, drafted the initial manuscript, and approved the final manuscript as submitted. MM designed the data collection instruments, and coordinated and supervised data collection, critically reviewed the manuscript, and approved the final manuscript as submitted. LR designed the data collection instruments, and coordinated and supervised data collection, critically reviewed the manuscript, and approved the final manuscript as submitted. DZ conceptualised the pharmacological part of the study and revised the manuscript. AF helped in recruiting the patients, drafted the initial manuscript and approved the final manuscript as submitted. GM coordinated and supervised data collection, and approved the final manuscript as submitted. EB coordinated and supervised data collection, critically reviewed the manuscript, and approved the final manuscript as submitted.

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval The Independent Bioethical Committee of the Institute.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Clinical Trial Registration: RCT on Ketorolac and Tramadol in Bone Fractures Pain of Child. NCT00560443

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