Last year we reviewed a pilot RCT comparing IN Fentanyl vs IN Ketamine in kids1,2. We concluded that they were probably similar in analgesic effect but that Ketamine had a higher adverse event rate.
Here in Virchester that previous paper did not change practice as we use IN Diamorphine, but we are aware that there are plenty of people out there using Fentanyl in the UK (which we imagine is probably similar to Diamorphine as it’s an opiate), and a few centres using IN Ketamine.
This week JAMA Paediatrics has published a similarly sized RCT comparing the two drugs for children with extremity trauma3. The abstract is below, but as we always say, please go read the full paper yourself before drawing any conclusions or changing your practice.
What kind of paper is this?
It’s an RCT which is exactly what we want to see when comparing two treatments. More precisely this is an RCT designed to show non-inferiority, in other words a trial to investigate that the two treatments are so similar that it does not really matter which one we use. That seem reasonable based on past data in small trials which indeed suggests that this is the case.
I’m a little confused as to whether this trial was originally designed as a superiority or a non-inferiority trial. The original description of the trial on clinicaltrials.gov4 is unclear in this regard, but arguably looks more like a superiority trial. I cannot see a stats analysis plan.
Tell me about the patients.
Patients were recruited from a single centre paediatric ED in the US (note that US PEDs take kids up to age 18 as opposed to 16 in the UK). Those with a painful extremity injury and with a pain score of greater than 35 out of 100 were eligible for inclusion (with the usual exclusions such as low GCS etc.).
Interestingly there were only 90 patients in this trial which seems a small number to me. Non-inferiority trials usually require more patients than classical RCTs seeking a difference against a null hypothesis. It’s also a very similar number to the previous ‘pilot’ trial that advocated a much larger number in any future study. The sample size study is described in the paper, concluding that only 90 patients are required to show non-inferiority of an overall (mean) difference of 10mm on a 100mm scale. I think my concern in small trials like this is that just analysing mean scores may miss important, but small numbers of patients who have a poor outcome.
What did they do?
Patients received either 1.5mg/Kg ketamine or 2ug/Kg fentanyl IN via an atomiser device. Participants and practitioners were masked to the intervention, although anyone who has ever used ketamine will know that it’s often pretty easy to tell who has had it, and so the effectiveness of masking in these trials is always open to question.
Data was collected both by direct observation and interestingly by video monitoring which allowed minute by minute monitoring and review.
What were the main results?
In terms of analgesia (the main outcome), there was little difference between the two medications, and both medications were effective in reducing pain. From the perspective of the principle outcome measure the data supports the assertion that there is little difference between the two medications at 15, 30 or 60 mins post administration.
The main secondary outcome in this trials was the incidence of adverse events, which is important as it’s one of the main reasons clinicians decide between ketamine or opiates depending on which particular side effects the clinician is most concerned about.
In this study there were more adverse events in the ketamine group (49 patients) vs. fentanyl (14 patients) although these were all minor and perhaps expected.
Global health perspective
It is worth noting that fentanyl is not included in the World Health Organization’s essential drug list for children5 (diamorphine is not included at all). Ketamine on the other hand is included in IV form. This is in no way a reflection of whether any, or all of these drugs would be available in countries around the globe, or even emergency care settings within countries. It is highly likely that most global health clinicians would stick to ketamine – and likely use it IM and not intranasal (irrespective whether atomisers are available or not). We would urge clinicians to familiarise themselves with the ketamine side-effects reported in this study, and specifically make provision within a low-resourced setting that these can be effectively managed if needed prior to using it.
Any other concerns?
We’ve now seen several small trials in this area specifically looking at ketamine vs fentanyl1–4,6. The future must surely be a much larger and definitive trial and/or a meta-analysis. We are unlikely to learn much more from any future small trials of 50-100 patients.
If you follow twitter then no doubt you will have thought at some point that ketamine is the best drug for anything and everything. Whilst I do think it’s a great drug, this paper is a reminder that it isn’t always the best, and that twitter memes are not CPD.
What’s the bottom line?
In this small study there was little difference between the two medications in terms of analgesia but a higher number of adverse events with ketamine. For us this means that we would favour fentanyl. In Virchester it means we will be sticking with Diamorphine as although not tested in the study it’s likely to be closer in action to fentanyl as opposed to ketamine.
- 1.Carley S. Intranasal ketamine vs fentanyl for kids. St Emlyn’s. https://www.stemlynsblog.org/jc-intranasal-ketamine-vs-fentanyl-for-kids-st-emlyns/. Published 2018. Accessed 2019.
- 2.Reynolds SL, Bryant KK, Studnek JR, et al. Randomized Controlled Feasibility Trial of Intranasal Ketamine Compared to Intranasal Fentanyl for Analgesia in Children with Suspected Extremity Fractures. Miner JR, ed. Acad Emerg Med. November 2017:1430-1440. doi:10.1111/acem.13313
- 3.Frey TM, Florin TA, Caruso M, Zhang N, Zhang Y, Mittiga MR. Effect of Intranasal Ketamine vs Fentanyl on Pain Reduction for Extremity Injuries in Children. JAMA Pediatr. February 2019:140. doi:10.1001/jamapediatrics.2018.4582
- 4.PRIME I. Pain Reduction With Intranasal Medications for Extremity Injuries (PRIME). clinicaltrials.gov. https://clinicaltrials.gov/ct2/show/NCT02778880. Published 2016. Accessed 2019.
- 5.WHO W. Model list of essential medicines. WHO. https://www.who.int/selection_medicines/list/en/. Published June 2017. Accessed November 2019.
- 6.Graudins A, Meek R, Egerton-Warburton D, Oakley E, Seith R. 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. Annals of Emergency Medicine. March 2015:248-254.e1. doi:10.1016/j.annemergmed.2014.09.024