Pain Profiles: Intranasal Analgesics: What’s Your Pick? – Part I

Author: David Cisewski, MD (@PainProfiles – EM Resident Physician, Icahn School of Medicine at Mount Sinai) // Edited by: Manpreet Singh, MD (@MPrizzleER), Alex Koyfman, MD (@EMHighAK), and Brit Long, MD (@long_brit)

This edition of Pain Profiles will be the first of two posts in a series evaluating intranasal analgesics. Stay tuned for Part II!

Intranasal Analgesics: What’s Your Pick?

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, et al. Acad Emerg Med. 2017;24(12):1430-40.

I don’t have time for this article; give me the one-liner.

Intranasal (IN) ketamine given to kids with musculoskeletal pain resulted in an acceptable increase in side effects over IN fentanyl, while neither drug proved more efficacious in pain reduction, supporting the feasibility of a larger pediatric trial to assess efficacy and safety of IN ketamine for acute extremity pain management in pediatric patients in the future.

Okay, I have little more time… why were they doing this study?

As previously discussed at Pain Profiles, IN medications can be administered with little training or expertise beyond our core knowledge of analgesic medications.  This is great for kids who are tough sticks when agitated.  But the question is, what’s the best analgesic?  Recall from the previous discussion, there are a number of options to choose from:

Given of our current opioid epidemic, Dr. Reynolds, et al sought to shed light on the subject.  This was a feasibility trial, meaning it was a small-scale study to see if a large-scale, multicenter, non-inferiority trial that assesses the efficacy and tolerability would be both safe and warranted; that is to say, whether we would be willing to ‘tolerate’ the side effects of IN ketamine in exchange for the efficacy of IN ketamine.  The tolerability threshold used by Reynolds, et al for future RCT feasibility was based on the PICHFORK consensus which indicated no RCT would be possible if any of the following occurred: the side effects of ketamine were greater than 3-times fentanyl; a difference in efficacy was observed between ketamine and fentanyl; the study could not be completed in less than one calendar year.

What kind of study was this?

This was a double-blind, randomized controlled trial conducted in a single urban, tertiary, pediatric Level II trauma center in Charlotte, NC (Levine Children’s Hospital Emergency Department).

Who were the patients?

Children, 4-17 years old, verbal, presenting to the ED with acute pain from a suspected single-extremity fracture defined as a deformity or pain to palpation in a single extremity in a patient with an initial Wong-Baker FACES Pain Scale-Revised (FPSR) Score of ≳4 (for patients 4–10 years) or an Adult Pain Rating Scale score of ≳3 (for patients ages 11–17).

Who was excluded from the study?

Children with GCS <15 at ED presentation, reported allergy or adverse reaction to ketamine or fentanyl, pregnancy, intoxication, hypotension at presentation (SBP <70 mm Hg + 2 x age (if <10 years old) or <90 mm Hg (if ≳10 years old)), weight >70 kg, prior treatment with opioids, multiple injuries, non-verbal (developmental delay), or nasal anatomy that prevented IN medications.

What was the intervention?

Each patient was randomized to receive either 1 mg/kg IN ketamine or 1.5 mcg/kg IN fentanyl delivered via a mucosal atomizer (maximum volume 1cc to avoid run off).  Patients were allowed to receive a second dose per physician discretion at 20 minutes (0.5 mg/kg IN ketamine or 0.75 mcg/kg IN fentanyl).  All patients also received 15 mg/kg un-blinded oral acetaminophen (maximum dose of 650 mg) or 10 mg/kg ibuprofen (maximum dose of 600 mg).  

What were they looking for?

Primary outcome was side effect/adverse events at 60 minutes post-administration.  Secondary outcomes were mean pain reduction (as measured using a visual analog scale) and percentage of clinically significant pain reduction were assessed at 20 minutes post medication administration (defined as >20/100 pain reduction).

What did the study find?

Of the 629 patients screened for eligibility, 91 were enrolled, and 87 received the study drug.  The groups were similar in terms of age, sex, race, ethnicity, injury pattern, and baseline pain score, and all received adjunct oral acetaminophen or ibuprofen prior to study medication.  Fracture management and degree of injury was the same among both groups, with displaced forearm fracture being the most common injury.

• Primary outcome – 100% of ketamine patients (41/41) and 61% (25/41) of the fentanyl patients reported adverse events (risk difference = 39% [95% CI = 24% to 54%]).  All adverse effects were minor.  The cumulative number of side effects was 2.2-times higher in the ketamine group (less than predetermined 3-fold threshold).   The most common side effects of ketamine were bad taste in the mouth (37; 90%), dizziness (30; 73%), and sleepiness (19; 46%). The most common side effects of fentanyl were sleepiness (15; 37%), bad taste in the mouth (9; 22%), itchy nose (9; 22%), and dizziness (6; 15%).  No patient demonstrated nystagmus, and both groups had a similar amount of dysphoria (ketamine – 2%; fentanyl – 5%).
• Secondary outcome – there was no observed difference in efficacy between drugs. The mean pain scale score reduction at 20 minutes was 44 (+/- 36) for ketamine and 35 (+/- 29) for fentanyl (mean difference = 9 [95% CI = –5 to 23].  77% in the ketamine group and 80% in the fentanyl group achieved a clinically significant reduction in pain at 20 minutes (risk difference = – 3% [95% CI = –20% to 15%]). 23% in the ketamine group and 32% in the fentanyl group required a second dose of drug at 20 minutes (risk difference = –9 [95% CI = –27 to 10]). 16% of the ketamine group and 18% of the fentanyl group required additional opioid rescue during their stay (risk difference = –2% [95% CI = – 18% to 14%]).  Both groups went on to require similar rates of procedural sedation prior to ED discharge (ketamine – 65%; fentanyl – 57%).

Looks good…. should I trash the IN opioids and start using IN ketamine going forward?

As stated by the authors, the purpose of this study was to assess of the feasibility of a future, larger study – not to assess the efficacy or superiority of one medication over another.  Though the results are encouraging and IN ketamine appeared efficacious, larger studies are still needed for definitive evidence.

So what’s the upshot?

IN ketamine resulted in an acceptable (tolerable) increase in side effects over IN fentanyl, and neither drug proved more efficacious in pain reduction. Having met each of these threshold criteria, the authors confirm that a larger pediatric trial to assess efficacy and safety of IN ketamine for acute extremity pain management is needed.  IN administration is already a well-established technique, and this study is a further step toward a promising opioid-sparing analgesic alternative and delivery for pain management.

References/Further Reading:

1. SAEM Open letter with Dr. James Miner – Finding What We Need to Know to Determine Intranasal Ketamine’s Role in Pain Management
2. Pediatric EM Morsels by Sean Fox, MD – Intranasal Analgesia
3. Emergency Physicians Monthly article by Tim Veloriate and Amy Levine, MD – Nose Candy
4. An incredibly comprehensive website on all-things intranasal – net
5. Mucosal atomizer device (MAD) instructional video
6. The use of intranasal analgesia for acute pain control in the emergency department: A literature review. Sin B, Wiafe J, Ciaramella C, Valdez L, Motov SM. Am J Emerg Med. 2018;36(2):310-8.