The Case

An 8-year-old boy presents to the emergency department with a painful wrist injury after falling at the playground. His parents gave him an appropriate dose of ibuprofen before arriving at the emergency department. His pain is a 7/10, and the triage nurse asks you for some additional medication for his pain while he is waiting for his X-ray.

Background

Children represent a group of patients who aren’t likely to receive adequate analgesia.1,2 This phenomenon is known as oligoanalgesia, or poor pain management through the underuse of analgesics. Despite three decades of research in this area, recent evidence confirms that ED pain management in children is still suboptimal.

A retrospective cohort study of children presenting to the emergency department with an isolated long-bone fracture showed almost one-third received inadequate medication, and 59 percent received no pain medications during the critical first hour of assessment.3 Other studies have demonstrated that only 35 percent of children presenting to a pediatric emergency department with fractures or severe sprains receive any analgesics.4,5 Two potential options for providing faster-acting, effective, and easy-to-administer pain medications to children are intranasal (IN) fentanyl and ketamine.

IN fentanyl is an excellent alternative to oral or IV opioids when rapid pain management is desired or IV placement is not otherwise necessary. Fentanyl at doses of 1.5–2 mcg/kg (maximum 100 mcg) provides effective and rapid analgesia comparable to that of IV morphine.

Ketamine is a noncompetitive N-methyl-D-aspartate (NMDA) and glutamate receptor antagonist that provides analgesia by virtue of decreasing central sensitization “wind-up” phenomenon (“a progressive increase in the number of action potentials elicited per stimulus that occurs in dorsal horn neurons”⁶) and pain memory. Sub-dissociative ketamine has been used in the adult population as an effective opioid-sparing alternative that is associated with higher rates of minor but generally well-tolerated adverse effects.

The sub-dissociative ketamine dose for children is 0.5–1 mg/kg. It can provide rapid pain management for children who lack vascular access with the added benefit of lasting longer (60 minutes) compared to IN fentanyl (30 minutes).

Clinical Question

In children with acute extremity injuries, is IN ketamine noninferior to IN fentanyl for pain management?

Reference

1. Frey TM, Florin TA, Caruso M, et al. Effect of intranasal ketamine vs fentanyl on pain reduction for extremity injuries in children: the PRIME randomized clinical trial. JAMA Pediatr. 2019;173(2):140-146.

• Population: Children ages 8 to 17 years presenting to the emergency department with moderate to severe pain due to traumatic limb injuries (visual analogue scale >35 mm).
  • Exclusions: Significant head, chest, abdomen, or spine injury; Glasgow Coma Scale <15 or inability to report a visual analogue scale score; nasal trauma or aberrant nasal anatomy; active epistaxis; ketamine or fentanyl allergy; history of psychosis; opioid administration prior to arrival; non-English speaking; in police custody; and postmenarchal girls without a negative pregnancy test.
• Intervention: IN ketamine 1.5 mg/kg (max 100 mg)
• Comparison: IN fentanyl 2 mcg/kg (max 100 mcg)
• Outcomes:
  • Primary Outcome: Pain reduction after 30 minutes.
  • Secondary Outcomes: Sedation level, capnometry values, adverse events, the need for rescue analgesia, and change in vital signs.

Authors’ Conclusions

“Ketamine provides effective analgesia that is noninferior to fentanyl, although participants who received ketamine had an increase in adverse events that were minor and transient. Intranasal ketamine may be an appropriate alternative to intranasal fentanyl for pain associated with acute extremity injuries. Ketamine should be considered for pediatric pain management in the emergency setting, especially when opioids are associated with increased risk.”

Key Results

The trial enrolled 90 children, with 50 percent allocated to each group. The mean age was 12 years. Ketamine was shown to be noninferior to fentanyl for pain reduction at 30 minutes after administration of the study medication.

• Primary Outcome:
  • Ketamine: 30.6 (95% CI, −35.8 to −25.4)
  • Fentanyl: 31.9 (95% CI, −37.2 to −26.6)
  • The 95% confidence intervals did not cross the prespecified noninferiority margin of 10 mm.
• Secondary Outcomes:
  • No significant differences were observed in the highest achieved sedation scores, mean capnometry values, vital signs, or need for rescue
    analgesia.
  • Overall, more adverse events were observed in the ketamine group (49) versus the fentanyl group (14). All adverse events were minor and transient. Except for the 15-minute assessment, where the ketamine group had much more drowsiness (17 versus 4), there was no significant difference in the number of adverse events between groups at each assessment point.
  • No difference occurred in the need for additional analgesia (11 in the ketamine group and nine in the fentanyl group).

Evidence-Based Medicine Commentary

1. Blinding: They used sealed envelopes, but they did not specifically state that they were opaque envelopes. Computer randomization is considered a more secure system and less likely to be broken. To confirm blinding, they asked the staff to guess group allocation at the 30-minute assessment. Sixty-three percent of staff guessed correctly, suggesting blinding was not maintained. These two factors could have introduced bias into the study.
2. Selection Bias: The patients were not recruited consecutively but rather represented a convenient sample of patients. More than one-fifth (22 percent) of eligible patients were excluded for a variety of reasons. One reason was clinician preference. This could introduce selection bias and impact the conclusion of noninferiority.
3. Co-administration: The study design did not allow for co-administration of ibuprofen with the IN medication. Ibuprofen is an effective analgesic and is opioid-sparing. While this design allowed the researchers to answer the question about the effectiveness of the two medications in question, this is not how we would manage these patients in the real world. Often, parents have provided some analgesia (ibuprofen or acetaminophen) before arrival, or children will be given a dose in the emergency department.

Bottom Line

IN ketamine is a noninferior analgesic compared to IN fentanyl for children with acute extremity injuries but does cause more minor adverse events.

Case Resolution

You instruct the nurse to administer 1.5 mg/kg of IN ketamine to the boy while he waits for his X-ray. His pain decreases to 5/10, and the X-ray confirms a buckle fracture. You splint him, which provides even more pain relief.

Thank you to Dr. Samina Ali, a pediatric emergency physician, clinician-scientist, and professor of pediatrics and emergency medicine at the University of Alberta in Edmonton.

Remember to be skeptical of anything you learn, even if you heard it on the Skeptics’ Guide to Emergency Medicine.

References

1. Brown JC, Klein EJ, Lewis CW, et al. Emergency department analgesia for fracture pain. Ann Emerg Med. 2003;42(2):197-205.
2. Selbst SM, Clark M. Analgesic use in the emergency department. Ann Emerg Med. 1990;19(9):1010-1013.
3. Dong L, Donaldson A, Metzger R, et al. Analgesic administration in the emergency department for children requiring hospitalization for long-bone fracture. Pediatr Emerg Care. 2012;28(2):109-114.
4. LeMay S, Johnston C, Choinière M, et al. Pain management interventions with parents in the emergency department: a randomized trial. J Adv Nurs. 2010;66(11):2442-2449.
5. Kircher J, Drendel AL, Newton AS, et al. Pediatric musculoskeletal pain in the emergency department: a medical record review of practice variation. CJEM. 2014;16(6):449-457.
6. Wind-up. AnaesthesiaUK website. Accessed Feb. 21, 2019.