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Clinical bottom line
Opioid regimens were not superior to non-opioid regimens in improving pain relief (grade B).
A slightly higher incidence of side effects was reported with opioid regimens when compared with non-steroidal anti-inflammatory drugs (grade A).
Available evidence does not support the routine use of opioids in children with musculoskeletal injuries attending the emergency department (grade B).
A 9-year-old girl arrives at the paediatric emergency department (ED), after falling while skating.
On arrival, the girl is fine, but she feels severe pain in her left wrist. She reports a pain level 8 on a rating scale of 0–10. The examination does not reveal any bone deformity, but the left wrist is swollen, and the movements of the left hand are limited.
Which would be the ideal analgesic drug to manage pain in this girl?
Is opioid analgesia preferable to non-opioids in children with musculoskeletal injuries in terms of efficacy and safety?
Primary sources: PubMed from January 2000 to June 2019 using (pharmacological treatment OR opioid OR morphine OR fentanyl OR codeine OR tramadol OR NSAID OR ibuprofen OR ketoprofen OR ketorolac OR diclofenac OR indomethacin OR acetaminophen OR paracetamol) AND (emergency) AND (musculoskeletal OR trauma OR injury OR pain) AND (children OR adolescents). We identified 273 unique articles, and reviewed 12 full articles. Five studies were excluded: one investigating the management of pain from different acute conditions, such as abdominal and musculoskeletal pain, without a specific subgroup analysis regarding patients with musculoskeletal injuries,1 another one addressing the pharmacological treatment for postdischarge pain control,2 and three studies comparing opioids with ketamine, as the latter is not routinely used in the paediatric ED setting.3–5 This review included seven studies, all double-blind randomised controlled trials (RCTs), selected in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement6 (table 1). Methodological quality was assessed, according to the revised Cochrane risk of bias tool for randomised trials (RoB 2).7
Cochrane Library with similar Medical Subject Headings terms revealed only one study investigating the use of intranasal fentanyl in the management of acute pain caused by injury or medical illness.8 This review did not include it, due to the lack of a subgroup analysis regarding patients with musculoskeletal trauma.
Pain is a common reason for children and adolescents to seek evaluation in the ED, and trauma-related complaint represents approximately one-fourth of all paediatric ED visits.9 Since the 1990s, several scientific organisations have highlighted the inadequate assessment and management of acute painful conditions in the hospital setting, particularly in the paediatric population.10 Moreover, the medical literature has thoroughly demonstrated the detrimental effect of inadequately treated pain.11 12 Year after year, the attention to pain by emergency physicians has improved, and today appropriate analgesia is hopefully provided to all the children attending the ED, although some grey areas persist.
Children with musculoskeletal injuries commonly experience moderate to severe pain,13 without a close relationship with the presence of bone fractures.14 In the ED setting, pain management significantly varies among institutions and emergency physicians. A survey performed in North America showed that even though ibuprofen was the most commonly used analgesic, 85% of the interviewed physicians prescribed oral opioids in the previous 6 months, both in the ED and postdischarge.15 Indeed, in North America, a debate is ongoing about the so-called ‘opioid epidemic’. Opioid-related deaths in the USA have more than tripled during the last 20 years, and they are now one of the leading causes of death in the adult population.16–18 Although the relative contribution of EDs to the use of opioids is modest, in these wards, the percentage of painful paediatric conditions leading to opioid prescriptions increased by 30% from 2001 to 2010,19 20 possibly being a concomitant cause of a significant escalation of opioid misuse and abuse in the last years. Opioid routine use in this setting as first-line treatment for analgesia is becoming increasingly controversial21–25 with a growing body of literature regarding the adult population supporting the suitability of non-opioid medications to provide effective analgesia and spare opioid prescriptions in the ED in different clinical settings.20 21 26–28
In this review, we included seven RCTs comparing the effectiveness of opioid analgesia and non-opioid analgesia in children with acute pain related to musculoskeletal injuries at the ED.29–35
First of all, we should highlight that there is a high level of heterogeneity among the existing studies in terms of examined populations (age, type of musculoskeletal injury and baseline pain severity), analgesic regimens, medication type, dose and route of administration.
The analysed studies reported on a total of 1234 children and adolescents (with a number of enrolled patients in each trial ranging from 66 to 456), with a minimum age between 4 and 6 years and a maximum age between 17 and 18 years and with different baseline pain intensity (any pain intensity, or a minimum intensity ranging from 3 to 7 according to a self-reported visual analogue scale or an equivalent Faces Pain Scale). Investigated analgesic regimens included ibuprofen, acetaminophen and ketorolac among non-steroidal anti-inflammatory drugs (NSAIDs), and fentanyl, morphine, oxycodone and tramadol among opioids. Drugs were administered at different dosages and through different routes (oral, sublingual, intranasal). Although the aggregate sample size of all included studies was reasonably large, the comparisons for individual regimens were smaller and often were only with one or two studies.
Analgesic efficacy, expressed as a reduction in self-reported pain intensity, was assessed at different times after drug administration. No statistically significant difference in pain intensity reduction between opioids and non-opioids was reported at 15–20, 30–40 and 90 min after the drug administration. Ibuprofen was found superior to opioids in pain control at 60 and 120 min by two studies, respectively: one study compared ibuprofen with both acetaminophen and codeine given separately at 60 min (ibuprofen −24 mm, acetaminophen −12 mm, codeine −11 mm, p<0.01),29 and the other one compared ibuprofen with both morphine and ibuprofen+morphine at 120 min (ibuprofen −27 mm, morphine −16 mm, ibuprofen+morphine −21 mm, p=0.02).35 No one of the four studies investigating the need for rescue analgesia after drug administration found a difference between opioids and non-opioids given as the first treatment.29 32 34 35
All the examined studies reported the occurrence of adverse events (AEs), which were always minor (mainly nausea, drowsiness-dizziness and vomiting), with no studies reporting severe AEs. The NSAIDs were reported to cause sleepiness, drowsiness, dizziness, fatigue, headache, pruritus, nausea, constipation and vomiting; the same AEs were observed after the administration of opioids, which moreover caused dysphoria, talkativeness, hallucinations, visual disturbance, itchy nose, rash, abdominal pain, dry mouth/bad taste in mouth/throat and transient hypotension. The occurrence of AEs with NSAIDs ranged from 0 with ibuprofen and ketorolac,31–33 to a maximum of 30.9% after ibuprofen.34 The frequency of AEs with opioids varied from 0.02% after the combination of codeine and ibuprofen,32 to 56.1% after morphine.34 Considering opioids and NSAIDs, the frequency of AEs was superior with opioids in three studies, comparing ibuprofen and oxycodone30 and ibuprofen and morphine.34 35 A slightly higher incidence of minor AEs, although not statistically significant, was observed after tramadol compared with ketorolac in another study.33
With the limits imposed by the heterogeneity of the included studies, none of the analysed trials showed the superiority of opioid analgesia when compared with non-opioid analgesia.
Among oral medications, ibuprofen was not inferior to codeine,29 the combination of acetaminophen and codeine,31 morphine34 35 and oxycodone.30 The combination of ibuprofen and opioids, when investigated, was not superior to the use of ibuprofen alone.30 32 35 Sublingual ketorolac and tramadol were similarly effective, but with a trend in favour of the former.33
In recent years, the administration of drugs through the intranasal route is spreading in the ED.36 Among analgesics, fentanyl is the most suitable for this route of administration. In children with bone fractures, the use of intranasal fentanyl became popular after the evidence that a single dose of intranasal fentanyl was as effective as a dose of intravenous morphine.37 To date, no studies are available comparing intranasal fentanyl with any NSAID administered through any route.
In conclusion, RCTs comparing the effectiveness of opioid and non-opioid analgesia in children with musculoskeletal trauma are heterogeneous, and they do not allow conclusions about the optimal analgesic regimen. Nevertheless, in this clinical setting, there is no evidence supporting the routine use of opioids.
The authors thank Martina Bradaschia for the English revision of the manuscript.
Contributors GC conceived and designed the work. LCW, GC and FP analysed the data and drafted the first version of the text. EB reviewed and edited the work. All authors approved the final version of the manuscript.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Patient consent for publication Not required.
Provenance and peer review Not commissioned; internally peer reviewed.