Introduction

Pain is among the most common reasons for seeking healthcare and choosing appropriate pain medication is critical [1–3]. The American Academy of Pediatrics and the World Health Organization have mandated that children’s pain be addressed as a fundamental human right [4,5] and sub-optimal treatment is no longer accepted by patients, families, or healthcare providers [6–8]. Children’s fracture pain is under-treated both in the hospital and in the at-home setting [9–12]. Non-steroidal anti-inflammatory drugs (NSAIDs) alone, or in combination with oral opioids, are the most commonly prescribed analgesics for fracture pain [13–15]. While ibuprofen has emerged as the current first-line medication for this type of pain [15], it has also been shown to be inadequate for those with more significant pain [16]. Opioids are commonly used for moderate to severe traumatic pain in children, but this practice has come under recent scrutiny, in light of the current opioid crisis and concerns of misuse potential after short-term use [17–20]. While oral morphine has been shown to have similar effectiveness as oral ibuprofen for fracture-related pain management [21–24], oxycodone has not been studied to the same extent. As such, limited evidence exists to inform an evidence-based approach to management of fracture pain in children. Our study objectives were to describe the at-home clinical effectiveness and safety of ibuprofen and oxycodone when they are recommended for use and determine effects on short-term functioning for children discharged home from the emergency department (ED) with a limb fracture.

Materials and methods

Results

Demographic characteristics

For this study, 2539 children were screened of which 2210 were excluded; top reasons for exclusion were a) did not receive a prescription for the drug of interest, b) fracture was greater than 24 hours old, and c) the patient was admitted. A total of 329 children (n = 217 ibuprofen, n = 112 oxycodone) were included (Table 1).

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Table 1. Demographics characteristics (n = 329).

https://doi.org/10.1371/journal.pone.0257021.t001

Pain medication use

Fig 1 reports the number of doses of ibuprofen or oxycodone used, by group. Mean dose of administered ibuprofen was 9.2 mg/kg/dose (SD 3.5) on Day 1, 9.0 mg/kg (SD 3.8) on Day 2, and 8.5 mg/kg (SD 3.8) on Day 3; these are all within the recommended dosing range of 5-10mg/kg/dose. Mean dose of administered oxycodone was 0.11 mg/kg/dose (SD 0.05) on Day 1, 0.10 mg/kg (SD 0.04) on Day 2, and 0.09 mg/kg (SD 0.04) on Day 3; these are all within the recommended dosing range of 0.05–0.15 mg/kg/dose. On Day 1, a total of 19% (41/213) of the ibuprofen group used other medication(s) for pain treatment compared to 42% (47/112) in the oxycodone group (p < 0.001). On Day 2, a total of 18% (37/212) of the ibuprofen group used other medication(s) for pain treatment compared to 48% (52/108) in the oxycodone group (p < 0.001). On Day 3, a total of 12% (25/209) of the ibuprofen group used other medication(s) for pain treatment compared to 46% (47/103) in the oxycodone group (p < 0.001). See Table 2 for medications used.

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Fig 1. Number of doses of recommended medication used per day (Days 1–3).

https://doi.org/10.1371/journal.pone.0257021.g001

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Table 2. At-home pain management.

https://doi.org/10.1371/journal.pone.0257021.t002

Pain measures

Table 3 provides a summary of mean pain scores and pain reduction from Days 1–3. On Day 1, 90% (293/325) of children reported pain, with 88% (188/213) in the ibuprofen group and 94% (105/112) in the oxycodone group (p = 0.17). The mean reduction in pain score (maximum pain–post-treatment pain) as measured by the FPS-R for Day 1 was 3.6 (SD 1.9) (ibuprofen) and 3.8 (SD 2.1) (oxycodone) (p = 0.50). On Day 2, 83% (267/320) of children reported pain, with 80% (169/212) in the ibuprofen group and 91% (98/108) in the oxycodone group (p = 0.019). The mean reduction in pain score on Day 2 was 3.6 (SD 1.8) (ibuprofen) and 3.7 (SD 1.6) (oxycodone) (p = 0.56). On Day 3, 69% (214/312) of children reported pain, with 64% (133/209) in the ibuprofen group and 79% (81/103) in the oxycodone group (p = 0.011). The mean reduction in pain score for Day 3 was 3.7 (SD 1.7) (ibuprofen) and 3.3 (SD 1.7) (oxycodone) (p = 0.24).

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Table 3. Mean pain scores, Days 1–3.

https://doi.org/10.1371/journal.pone.0257021.t003

Adverse events

Table 4 presents cumulative adverse events by study group and type. On Day 1, 58% (188/325) of all children reported adverse events, with 51% (109/213) in the ibuprofen group and 71% (79/112) in the oxycodone group (p = 0.001). On Day 2, 43% (138/319) of all children reported adverse events, with 37% (78/211) in the ibuprofen group and 56% (60/108) in the oxycodone group (p = 0.002). On Day 3, 28% (88/312) of all children reported adverse events, with 24% (50/209) in the ibuprofen group and 37% (38/103) in the oxycodone group (p = 0.024).

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Table 4. Cumulative adverse events (Days 1–3) by study group.

https://doi.org/10.1371/journal.pone.0257021.t004

Functional outcomes

Fig 2A–2C presents function affected by group. Fig 3 presents functional outcomes by pain severity.

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Fig 2.

A. Functional outcomes by group (Day 1). B. Functional outcomes by group (Day 2). C. Functional outcomes by group (Day 3).

https://doi.org/10.1371/journal.pone.0257021.g002

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Fig 3. Function affected vs. pain severity (n = 329).

https://doi.org/10.1371/journal.pone.0257021.g003

Discussion

Children with fractures experience pain and functional limitations at home. The current study demonstrated that children reported moderate pain during the first three days after fracture, and that pain medications were used with varying daily frequency. No differences were seen in maximum and minimum pain scores between groups. More children in this observational cohort study had ibuprofen recommended for at-home pain treatment than oxycodone, which is in keeping with current clinical practice [10]. Children in both ibuprofen and oxycodone groups experienced reduced maximum pain to the mild/moderate range with comparable analgesic effectiveness. Adverse events were reported in approximately two-thirds of children; notably, those in the ibuprofen group experienced significantly less adverse events compared to the oxycodone group. Functional outcomes (i.e., appetite, play, school, sleep) were significantly more negatively affected in the oxycodone group compared to the ibuprofen group on the first and second days after discharge.

This cohort study’s findings regarding the clinical effectiveness of prescribing ibuprofen and oxycodone are similar to an ED trial comparing ibuprofen, oxycodone, and the combination of both medications which demonstrated no significant differences among the groups in terms of analgesia [32]. It also mirrors results of trials that have looked at other oral opioids for orthopedic injury and minor surgery-related pain. A pediatric study that compared ibuprofen versus oral morphine for post-operative pain management after minor orthopedic surgery found that both drugs decreased pain similarly; however, oral morphine resulted in greater adverse events [22]. Another post-surgical study followed outpatients after discharge and found no significant differences in pain scores between acetaminophen/codeine versus acetaminophen/ibuprofen and also demonstrated that the use of acetaminophen/codeine resulted in more adverse events and higher discontinuation rates [33]. Lastly, a randomized trial comparing outpatient ibuprofen versus acetaminophen with codeine use in children with arm fractures showed no significant differences in pain reduction between the medication groups; notably, the proportion of children who had any function affect by pain was lower in the ibuprofen group along with lower reported adverse events [28]. Health Canada and FDA warnings [34,35] from recent years have now steered clinicians away from codeine, and despite these early studies, we have yet to find an appropriate oral opioid for orthopedic injury-related pain.

Among children with acute fracture pain, the presented results support clinical trial evidence that oxycodone has no analgesic benefit over ibuprofen for first-line treatment of moderate to severe orthopedic-injury related pain [32,33]. To our knowledge, this is the one of few studies to compare analgesic effectiveness between ibuprofen and oxycodone, and the only one to study its effects after discharge from the ED. The after discharge, post-market analysis of these medications is essential to understanding the true effectiveness of these medications and represents a needed complement to controlled clinical trials. Notably, in this study, over 40% of the oxycodone group used alternative non-opioid medication on the first day after discharge; this information would potentially not have been captured in a clinical trial, if limitations were placed on the use on non-assigned trial medications. It is important to note that when one considers that there may be some inherent clinical or demographic differences in the participants included in each of the cohorts, coupled with the use of other pain medications besides their original assignment, our study results do not necessarily reflect the ‘pure’ clinical efficacy of oxycodone, but rather, the clinical effectiveness of prescribing it for fracture-related pain.

While pain score reduction was not statistically different between ibuprofen and oxycodone groups, important differences were observed for children in terms of adverse events. In the current study, those prescribed oxycodone had a significantly worse adverse event profile compared to children prescribed ibuprofen, with over 80% of children in the oxycodone group reporting cumulative adverse events in the first three days after discharge compared to 60% in the ibuprofen group. The report of adverse events in the current study was comparable to that of other orthopedic injury-related analgesia trials in the outpatient setting [22,32,33]. This is also consistent with a systematic review that concluded that ibuprofen and acetaminophen have similar reported adverse event profiles, and notably less adverse events than opioids [24]. A recent randomized trial comparing oral morphine versus ibuprofen or both in combination in children with orthopedic injury resulted in significantly more adverse events in the morphine arms (21%) than those in the ibuprofen only arm (6.6%) [13]. The most common adverse events seen in the morphine arms were nausea, abdominal pain and drowsiness. Similarly, in the current study, one of the most commonly reported adverse events was drowsiness experienced in two-thirds of the oxycodone group and just under half of the ibuprofen group. This is in keeping with previous studies, as well [22,23].

While pain associated with fractures has been well described and studied, related functional impairment is less well understood [28]. Just over three-quarters of children with fractures in our study experienced decreased functional activity in at least one domain, which included appetite, play, school and sleep. This is similar to a previous study which described 80% of children with compromise in at least one domain [27]. Function is a critical and patient-focused indicator of good fracture pain management and correlates with child and parent satisfaction [9]. Despite this, it remains under-utilized in research and literature. Improving functional outcomes is a child-oriented outcome measure that provides a more holistic approach to pediatric fracture pain management. For every day of persistent pain for a child, there are associated decreases in health-related quality of life and family disruptions [36]. Measuring and improving such outcomes may avoid the undertreatment of pain and functional limitations along with associated negative consequences [37].

There were several potential limitations to the current study. The study design was observational in nature and not a clinical trial. As such, direct causal relationships cannot be confirmed regarding therapeutic effectiveness and safety. Nonetheless, the quality of data and methods applied may allow for meaningful preliminary conclusions to be drawn. Second, parents administered analgesic medication at their discretion and there likely exists variability between parents’ threshold to provide their child with pain medication. We could not limit their use of alternative or adjuvant agents; as such, results reflect the ‘true-world’ effectiveness of prescribed regimens, but not the exact effects of the medications of interest. Third, only children with an isolated acute fracture were included in this study and it is unclear whether results can be applied to other musculoskeletal injuries (e.g., sprains, strains). Fourth, there were small demographic imbalances between the two cohorts (i.e., slightly older, more fracture reductions, less buckle fractures, and more procedural sedations in the oxycodone group). This might suggest that fractures deemed clinically more important were selected into the oxycodone group. Still, this represents the reality of who received oxycodone in our clinical setting, as opioids tend to be prescribed less for younger children, and more often after reductions. These demographic imbalances should be considered when interpreting our results, in terms of applicability to local clinical populations. Finally, the Faces Pain Scale–Revised has not been formally validated for home use. We chose it as the current recommended self-report tool to assess pain levels for our study age group and has been successfully employed in the at-home setting in previous similar work [26,28].

With the over-arching goal of improving pain management, functional outcomes, and quality of life for children, further research is needed to evaluate the effectiveness of oral analgesic agents, especially in the at-home setting. Future work would benefit from utilizing a standardized approach to collection and reporting of adverse events, such as MedDRA [30]. This will allow more meaningful comparisons of adverse events across studies, as more and more, we are seeing current oral analgesic options to be reported as equipotent. Furthermore, identifying functional outcomes important to parents and children represent key patient-oriented outcome measures, ensuring future research remains relevant to children and families. Finally, future exploration of combinations of non-opioid analgesics, more potent opioids, and/or non-pharmacologic therapies is needed to determine optimal pain management strategies, particularly for more severe pain, as we have yet to identify the optimal oral agent/combination of agents to relieve orthopedic injury-related pain.

Conclusion

A large cohort of over 300 children receiving recommendations to use either ibuprofen or oxycodone experienced similar analgesic effectiveness when treating acute fracture pain at home. Children who were prescribed oxycodone reported significantly more adverse events compared to those who received recommendations to use ibuprofen and experienced more negative impact on their functional outcomes. Children who were prescribed oxycodone used other pain medications more often than those told to use ibuprofen. Recommending that families use oxycodone to treat fracture-related pain does not appear to confer any benefit over ibuprofen for pain relief and, in fact, is associated with greater reporting of adverse events and functional limitations for the child. This study, when combined with results of previously published clinical trials, suggests that at this time, recommending ibuprofen as first-line therapy for acute fracture pain is the better option. Future clinical trials are needed to confirm these findings.

Supporting information

Acknowledgments

Pediatric Emergency Research Canada (PERC) membership can be found at https://perc-canada.ca/pages/34-executive-committee. Current PERC executive members include Dr. Stephen B. Freedman (University of Calgary, Calgary, Alberta), Dr. Roger Zemek (University of Ottawa, Ottawa, Ontario), Dr. Samina Ali (University of Alberta, Edmonton, Alberta), Dr. Amanda S. Newton (University of Alberta, Edmonton, Alberta), Dr. Garth Meckler (University of British Columbia, Vancouver, British Columbia), Dr. Maala Bhatt (University of Ottawa, Ottawa, Ontario), Dr. Cathie-Kim Le (University of Toronto, Toronto, Ontario), Candice McGahern (University of Ottawa, Ottawa, Ontario), and Becky Emerton (University of Calgary, Calgary, Alberta). Becky Emerton is the primary contact for PERC at rebecca.emerton@ahs.ca. We thank Iram Usman for her assistance with statistical analyses. We thank the families who so kindly agreed to support our work by agreeing to participate in this study.