Determining efficacy of the analgesia via inhalation.
Background
I am a big fan of ketamine analgesia. I do not believe a shift goes by when I do not use this medication to relieve pain in one or several patients in my care. It works. Maybe not all the time, but it works. And the reward of seeing patients feeling better and expressing their gratitude is priceless.
I firmly believe that at present, little or no doubts at all should surround the utilization of ketamine analgesia in the ED either as an adjunct to other analgesics, or as a single agent, or both.
I am even a bigger fan of doing research on ketamine analgesia in the ED. My research team has been pushing the boundaries of Emergency Medicine algiatry by studying analgesics efficacy and safety of sub-dissociative dose ketamine given either intravenously or intranasally in managing a variety of painful syndromes in the ED.
But, in a never-ending pursuit of finding an additional way to utilize ketamine for pain relief, we have entertained the idea of using the inhalation route. Nebulized ketamine? Really?
For starters, the nebulized route provides a non-invasive, rapid and titratable way of delivering ketamine analgesia. Its effectiveness is impressive as patients with post-operative sore throat achieved up to 50% pain relief despite low systemic bioavailability of the inhalational route (20% to 40% of the intravenous route).
Additionally, using a breath-actuated nebulizer (BAN) would empower patients to be in charge of their own pain control by virtue of receiving analgesic upon taking a breath. In a situation when IV access is not readily available and an intranasal route is not feasible, nebulization comes in handy.
Lastly, knowing that data on ketamine inhalation for pain relief is very limited and primarily focused on alleviating post-intubation sore throat, I have embarked on the quest to explore the role of nebulized ketamine in pain relief.
Research/Findings
Research started with several small case series of adult and pediatric patients receiving ketamine via BAN. After they demonstrated acceptable pain relief without serious adverse effects, my research team moved to a prospective randomized clinical trial where adult ED patients with a variety of acute painful conditions received three different dosing regimens of nebulized ketamine: 0.75mg/kg, 1 mg/kg, and 1.5 mg/kg.
We hypothesized that based on the dose-dependent manner with which ketamine works, the 1.5 mg/kg dosing regimen would provide better analgesia at 30 minutes after administration.
Prior to starting this trial, we did a lot behind-the-scenes work with respect to educating our clinical staff (doctors and nurses) on nebulized ketamine analgesia and to working with our clinical pharmacists on the logistics of delivering nebulized ketamine to patients (drug preparation, administration and wastage).
Our main goals were two-fold: we looked and compared analgesic efficacy of three different dosing regimens of nebulized ketamine (30 minutes as a primary outcome with overall patient follow-up to 120 minutes) and safety (based on the incidence of adverse effects that included sedation/agitation and psycho-perceptual disturbances like feeling of unreality).
Findings
I won’t go into a detailed description of the actual study, but I want to mention two points. First, at any time point during the study all patients were eligible for rescue analgesia that included either additional doses of nebulized ketamine or intravenous morphine. Second, we were able to measure the residual volume of the medication in nebulizer and subsequently compared the dose administered to the dose received.
Let’s take a look at what we found. We enrolled 120 patients with 40 patients per group. The majority of patients in each group suffered from acute non-traumatic and traumatic musculo-skeletal pain with an average initial pain score of 8.6 on a Numeric pain rating scale.
We found no difference in pain relief between all three dosing regimens of nebulized ketamine at 30 minutes post-medication administration. All groups had a clinically significant pain reduction (mean pain score of 4.1). Furthermore, the occurrences of adverse effects (dizziness, fatigue and feeling of unreality) were about 25% with similar proportions of patients in each group.
I really got excited about the findings of the study. The fact that we found no difference in pain relief for short-term analgesia between three dosing regimens is encouraging as I am firm believer in initiating any analgesia with the lowest effective dose with titration to effect, let alone ketamine.
The overall pain reduction from the baseline of 45% to 50% validates the efficacy of ketamine via inhalation and validates the results of post-operative sore throat studies. The overall incidence of adverse effect of 25% is nearly as twice as less as the incidence (56%) in our intravenous sub-dissociative dose ketamine studies.
Conclusion
Based on all these findings, I am so eager to call nebulized ketamine an excellent modality for pain control in the ED but… I must control my excitement. The study had numerous limitations including convenience sample, small sample size, short duration of the study and lack of standardization of inhalation time, that warrant further validation, investigation and comparison to different analgesics.
I am still excited to know that nebulized ketamine is a viable option for pain management in the ED. I am very much looking forward to our next trial when we will compare analgesic efficacy and safety of nebulized ketamine to intravenous sub-dissociative dose ketamine in the ED.
References:
- Motov S. Diminishing the pain. EPMonthly. 5/3/2021. https://epmonthly.wpengine.com/article/diminishing-the-pain/
- Salim Rezaie, “The KetaBAN Trial: Nebulized Ketamine for Analgesia in the ED”, REBEL EM blog, July 5, 2021. Available at: https://rebelem.com/the-ketaban-trial-nebulized-ketamine-for-analgesia-in-the-ed/
- Dove D, Fassassi C, Davis A, Drapkin J, Butt M, Hossain R, Kabariti S, Likourezos A, Gohel A, Favale P, Silver M, Marshall J, Motov S. Comparison of Nebulized Ketamine at Three Different Dosing Regimens for Treating Painful Conditions in the Emergency Department: A Prospective, Randomized, Double-Blind Clinical Trial. Ann Emerg Med. 2021 Jul 3:S0196-0644(21)00338-3. doi: 10.1016/j.annemergmed.2021.04.031. Epub ahead of print. PMID: 34226073.
