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Date: January 22nd , 2019

Reference:  Frey et al Effect of Intranasal Ketamine vs Fentanyl on Pain Reduction for Extremity Injuries in Children: The PRIME Randomized Clinical Trial. JAMA Pediatrics December 2018

Guest Skeptic: Dr. Samina Ali is a pediatric emergency physician, clinician-scientist, and Professor of Pediatrics & Emergency Medicine at the University of Alberta in Edmonton. Her research is focused on improving the assessment and treatment of children’s pain. Dr. Ali is currently an executive member of Pediatric Emergency Research Canada (PERC), a Faculty member with Pain in Child Health (PICH), co-chair of the PERC Pain Interest Group, pain content advisor for TREKKand faculty member of BEEM.

Case: A 10-year-old girl presents to your emergency department (ED) after falling off a zipline at the playground. She used her arms to break her fall sparing her head in the process. She immediately realized that her left wrist was very sore, and her parents bring her to the hospital. She is crying and states that her pain is 8/10 at triage. There is a 3-4 hour wait in your ED that day. You want to provide pain management until she can be further assessed. Incidentally, her mother had severe hypotension after receiving IV opioids, and they are scared to use them with their daughter.

Background: Pain is the most common reason for an ED visit in children. Patients who experience adequate pain relief during their ED stay have significant reductions in distress, improved rapport with their physician, improved intent to comply with discharge instructions and higher levels of personal and caregiver satisfaction.

Conversely, untreated pain in childhood leads to short and long-term problems including anxiety, needle phobia, hyperesthesia, and fear of medical care as adults. Effective pain management is being increasingly regarded as a cornerstone of high-quality care. In fact, the importance of providing optimal pain treatment is supported by the World Health Organization, the American Academy of Pediatrics, and the Joint Commission (USA).

Children represent one group of patients that are less likely to receive adequate analgesia (Brown et al, Selbst and Clark). This phenomenon is known as oligoanalgesia or poor pain management through the underuse of analgesia. We have covered pediatric pain with PEM super hero Dr. Anthony Crocco on SGEM#78. He even did a RANThony on this issue.

Musculoskeletal (MSK) injury is a very common cause for ED visits for children with pain, with a child’s risk of sustaining a fracture ranging from 27-42% by the age of 16 years (Spady et aland CIHI). MSK injury is known to generate moderate to severe pain in most children and the ED serves as the critical entry point for these injured children.

Despite three decades of pain 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 ED with an isolated long-bone fracture showed almost 1/3 received inadequate medication and 59% received no pain medications during the critical first hour of assessment (Dong et al).

Previous studies have demonstrated that only 35% of children presenting to a Canadian pediatric ED with fractures or severe sprains received any analgesic (LeMay et al and Kircher et al). Further, a medical record review of two Canadian EDs showed unacceptably long delays in the provision of initial analgesia, with children waiting a mean of 118 minutes to the provision of first analgesia (Kircher et al).

As such, clinicians have sought faster-acting, effective, and easy to administer pain medications to children with acute MSK pain injury and moderate to severe pain. Two potential options are intranasal ketamine and intranasal fentanyl.

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, and pain memory. Sub-dissociative ketamine has gained recent popularity for pain management in trauma, as another opioid-sparing alternative. Its use is associated with higher rates of minor but generally well-tolerated adverse effects.

We have covered low-dose ketamine (LDK) a number of times on the SGEM:

  • SGEM#233: Larry in the Den with Kiwis (LDK) – Low dose ketamine vs. opioids for acute pain
  • SGEM#198: Better Slow Down – Push vs. short infusion of low dose ketamine for pain in the emergency department
  • SGEM#130: Low Dose Ketamine for Acute Pain Control in the Emergency Department
  • SGEM#111: Comfortably Numb – Low dose ketamine as adjunct for ed pain control

Sub-dissociative ketamine appears to have the same analgesic efficacy as intranasal (IN)  fentanyl or intravenous (IV) morphine in early studies for fracture pain in the ED. Intravenous dosing of sub-dissociative ketamine is 0.1–0.4 mg/kg and intranasal dosing for sub-dissociative ketamine is 0.5-1 mg/kg.

Similar to IN fentanyl, IN ketamine shares the advantages of early and rapid pain management for children who lack vascular access but confers the added benefit of longer-lasting analgesia (60 minutes for IN ketamine vs 30 minutes for IN fentanyl).

Intranasal fentanyl is an excellent alternative to oral or IV opioids when rapid acute pain management is desired (eg grossly displaced forearm fracture), or IV placement is not otherwise necessary (eg clavicular fracture). Intranasal fentanyl at doses of 1.5 to 2 micrograms/kg (minimum 20 mcg and maximum 100 mcg) provides adequate and rapid analgesia comparable to that of IV morphine.

The time to administration of analgesia is reduced when IN fentanyl is compared with IV analgesics such as morphine. IN fentanyl, administered via mucosal atomizer device, is an excellent medication choice for the rapid treatment of moderate to severe pain, while awaiting topical anesthetic cream to take effect, prior to IV cannulation. It is also useful in the prehospital setting.

Clinical Question: Is intranasal ketamine non-inferior to intranasal fentanyl for pain management in children presenting with acute extremity injuries?

Reference: Frey et al Effect of Intranasal Ketamine vs Fentanyl on Pain Reduction for Extremity Injuries in Children: The PRIME Randomized Clinical Trial. JAMA Pediatrics December 2018

  • Population: Children aged 8 to 17 years presenting to the emergency department with moderate to severe pain due to traumatic limb injuries (with VAS >35mm).
    • Exclusions: There were ten exclusions. Significant head, chest, abdomen or spine injury, GCS <15 or inability to report a VAS 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: Intranasal ketamine 1.5 mg/kg (max 100mg)
  • Comparison: Intranasal fentanyl 2mcg/kg (max 100 mcg)
  • Outcome:
    • Primary Outcome: The difference in pain reduction between groups 30 minutes after treatment, as measured by the VAS.
    • Secondary Outcomes: Sedation level as measured by the University of Michigan Sedation Scale, capnometry values, adverse events, the need for rescue analgesia and the change in vital signs (using PALS as a reference).

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.”

Quality Checklist for Randomized Clinical Trials:

  1. The study population included or focused on those in the emergency department. Yes
  2. The patients were adequately randomized. Yes
  3. The randomization process was concealed. Yes
  4. The patients were analyzed in the groups to which they were randomized. Yes
  5. The study patients were recruited consecutively (i.e. no selection bias). No
  6. The patients in both groups were similar with respect to prognostic factors. Yes and No.
  7. All participants (patients, clinicians, outcome assessors) were unaware of group allocation. Yes
  8. All groups were treated equally except for the intervention. Yes
  9. Follow-up was complete (i.e. at least 80% for both groups). Yes
  10. All patient-important outcomes were considered. Unsure
  11. The treatment effect was large enough and precise enough to be clinically significant. Yes

Key Results: They enrolled 90 children with half allocated to each group. The mean age was 12 years.

Ketamine was noninferior to fentanyl with regard to the primary outcome of pain reduction 30 minutes after study medication administration.

  •  Primary Outcome:
    • Ketamine −30.6 (95% CI −35.8 to −25.4)
    • Fentanyl −31.9 (95% CI −37.2 to −26.6)
    • As the 95% confidence intervals crossed 0 but did not cross the prespecified noninferiority margin of 10mm.

  • Secondary Outcomes:
    • There were no significant differences observed in the highest achieved sedation scores, mean capnometry values, vital signs, or need for rescue analgesia between the two groups.
    • There was a total of 47 patients that experienced 63 adverse events. More adverse events were observed in the ketamine group (49) vs. the fentanyl group (14). All the adverse events were minor and transient. The relative risk of adverse events in the ketamine group was 2.5 (95% CI 1.5 to 4.0). There was no significant difference in the number of adverse events between groups at each assessment point, except for the 15-minute assessment, where ketamine group had much more drowsiness (17 vs 4).
    • Twenty patients (23%) requiring additional analgesia, 11 in the ketamine group and 9 in the fentanyl group (relative risk, 0.89; 95% CI, 0.5- 1.6).

1. Blinding – They used sealed envelopes, but they did not specifically say they were opaque envelopes. This could have led to some gaming of the system and introduced selection bias. As previously stated, computer randomization is considered more secure and less likely to be broken.

2. Blinding (2) – We really like that they asked the staff to guess group allocation at the 30-minute assessment. Because more than 50% guessed correctly (63%) it suggests blinding was not maintained and could have introduced bias.

3. Selection Bias – They did not have consecutive patients but rather a convenient sample of patients. Thirty-one out of 140 eligible patients (22%) were excluded because the research coordinator was not present, patient was not in proper location, study enrollment was on hold for regulatory purposes, and clinician preference. This could have introduced some selection bias into the study and impacted the results and the conclusion of non-inferiority.

Another point to consider is why did the authors choose 35mm as the pain threshold for inclusion in the study? This seems kind of low.  In my practice I would use oral pain medication first before considering intranasal medication. In general, I don’t use intranasal pain medications as a first line option for 35mm of pain.  In our soon to be launched multi-centre trial, the NO OUCH study, we will be using >49 mm for inclusion into the study, as our medication choices include a stronger oral opioid.

4. Removal of Co-Dosing – They removed co-dosing of ibuprofen with intranasal medication in the study design. Ibuprofen works, it is opioid-sparing, and while in need of a study to confirm, it likely provides smoother and more sustained pain reduction over the ED visit, when combined with IN medication. While this design allowed for a ‘pure’ answer to the effectiveness question of these two meds, this is not how we should use it in practice.

5, Medication Dosing – One of my pet peeves is when a study shows no difference between arms and one or more arms used sub-optimal dosing of a drug! So, their dosing regimen helps me feel more confident in their results.

Comment on Authors’ Conclusion Compared to SGEM Conclusion: The authors’ main conclusion regarding non-inferiority for efficacy seems reasonable and congruent with their results. However, I find the statement regarding pre-procedural sedation analgesia limiting of opioids to not be consistent with my decision-making. If I think opioid will provide the best pain relief and adverse event profile, I would use it and be mindful when dosing for procedural sedation analgesia. From the Bhatt paper they continually make this point:

“Although we do not recommend limiting opioid use to treat preprocedural pain, we believe that awareness of this risk factor will help clinicians prepare for sedation and anticipate potential adverse events.”

As such, I don’t agree when they stress this as a reason to use ketamine. I think of ketamine as another valid pain-relieving tool in my toolkit, to be considered when making clinical decisions at the patient-level.

SGEM Bottom Line: Intranasal ketamine appears to be non-inferior to intranasal fentanyl for efficacy, but with more adverse events.

Case Resolution: In consultation with the emergency department physician, the triage nurse administers 10mg/kg of ibuprofen orally and 1.5 mg/kg ketamine intranasal. The pain at 15 minutes is reduced from 80 to 50mm using the VAS. At 60 minutes, it is 40mm. She goes on to receive her x-ray, confirm her diagnosis of minimally displaced and minimally angulated distal radius fracture, splinted (SGEM#19) and sent home with appropriate follow-up, pain management and when to return to the ED if necessary.

Dr. Samina Ali

Clinical Application: This is another reasonably well-executed study that shows that intranasal ketamine is a valid pain-relieving tool in our toolkits, to be considered when making clinical decisions at the patient-level. If monitoring neurological status is important to the clinical presentation (ie concomitant head injury), then intranasal fentanyl may be the better choice. However, some families voice strong opinions regarding the avoidance of opioids, and ketamine allows this to be respected. However, personally, I don’t see ketamine as a ‘safer’option for addiction/dependence risk, as it is also a drug of abuse.

What Do I Tell My Patient?  There is no reason your child needs to be in pain while we sort this out. If you have hesitations using opioids, I have another option for rapid pain relief. It works as well as opioids but will likely make your child drowsy or dizzy in the first hour after its use.

Keener Kontest: There was no winner last week for the second week in a row. The answer Justin was looking for was there are  references to opium use in Mesopotamia around 3400 BCE. They referred to the opium poppy as “hul gil” or “the joy plant”.

Listen to the SGEM podcast on iTunes to hear this the new keener question. If you know the answer send an email to TheSGEM@gmail.com with “keener” in the subject line. The first correct answer will receive a cool skeptical prize.

Other FOAMed: 

  • St. Emlyn’s: Intranasal Ketamine vs. Fentanyl for kids.
  • SGEM#123: Intranasal Fentanyl – Oh, What a Feeling
  • PEM Playbook: Intranasal Medications and You
  • ALiEM: Tricks of the trade: Intranasal fentanyl for pediatric patients
  • EM Cases: Episode 67 Pediatric Pain Management

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

 

Other Key References:

  • Randomized Controlled Feasibility Trial of Intranasal Ketamine Compared to Intranasal Fentanyl for Analgesia in Children with Suspected Extremity Fractures. Reynolds SL, Bryant KK, Studnek JR, Hogg M, Dunn C, Templin MA, Moore CG, Young JR, Walker KR, Runyon MS. Acad Emerg Med. 2017 Dec;24(12):1430-1440. doi: 10.1111/acem.13313. Epub 2017 Nov 3. PMID: 28926159
  • 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. Graudins A, Meek R, Egerton-Warburton D, Oakley E, Seith R. Ann Emerg Med. 2015 Mar;65(3):248-254.e1. doi: 10.1016/j.annemergmed.2014.09.024. Epub 2014 Nov 18. PMID: 25447557
  • Analgesic Efficacy of Intranasal Ketamine Versus Intranasal Fentanyl for Moderate to Severe Pain in Children: A Prospective, Randomized, Double-Blind Study. Quinn K, Kriss S, Drapkin J, Likourezos A, Pushkar I, Brady J, Yasavolian M, Chitnis SS, Motov S, Fromm C. Pediatr Emerg Care. 2018 Jul 24. PMID: 30045355
  • Demonstration of analgesic effect of intranasal ketamine and intranasal fentanyl for postoperative pain after pediatric tonsillectomy.
  • Yenigun A, Yilmaz S, Dogan R, Goktas SS, Calim M, Ozturan O. Int J Pediatr Otorhinolaryngol. 2018 Jan;104:182-185. doi: 10.1016/j.ijporl.2017.11.018. Epub 2017 Nov 23. PMID: 29287863
  • Intranasal ketamine for analgesia in the emergency department: a prospective observational series.Andolfatto G, Willman E, Joo D, Miller P, Wong WB, Koehn M, Dobson R, Angus E, Moadebi S. Acad Emerg Med. 2013 Oct;20(10):1050-4. doi: 10.1111/acem.12229. PMID:24127709
  • Sub-dissociative dose intranasal ketamine for limb injury pain in children in the emergency department: a pilot study. Yeaman F, Oakley E, Meek R, Graudins A. Emerg Med Australas. 2013 Apr;25(2):161-7. doi: 10.1111/1742-6723.12059. Epub 2013 Mar 20. PMID: 23560967
  • Intranasal fentanyl for the management of acute pain in children. Murphy A, O’Sullivan R, Wakai A, Grant TS, Barrett MJ, Cronin J, McCoy SC, Hom J, Kandamany N. Cochrane Database Syst Rev. 2014 Oct 10;(10):CD009942. doi: 10.1002/14651858.CD009942.pub2. Review PMID: 25300594