The trial: Le Cornec C, Le Pottier M, Broch H, Marguinaud Tixier A, et al. Ketamine compared with morphine for out-of-hospital analgesia for patients with traumatic pain: A randomized clinical trial. JAMA Netw Open. 2024 Jan 2;7(1):e2352844. doi: 10.1001/jamanetworkopen.2023.52844. PMID: 38285446; PMCID: PMC10825723.
The population. 251 patients over the age of 18 who presented to one of 11 emergency medical services in France with of severe (>5/10) acute traumatic pain were randomly assigned (1:1) to the intervention group or the comparator group.
The intervention. The experimental group (109 patients) received ketamine 20mg IV over 2 minutes. Every 5 minutes, they received another 10 mg until: the pain score was less than/equal to three, there was a serious adverse effect or arrival at the emergency department.
The comparator. The control group (105 patients) received morphine IV push (weight <60 kg, 2 mg; weight >60 kg, 3 mg). Every 5 minutes, they received the same dose until: the pain score was less than/equal to three, there was a serious adverse effect or arrival at the emergency department.
The outcome. The primary outcome was the change in verbal numeric pain scale as measured 30 minutes from treatment.
Results
1. The mean pain score change was -3.7 (95% CI, -4.2 to -3.2) in the ketamine group; the mean pain score change was -3.8 (95% CI, -4.2 to -3.4) in the morphine group.
2. Adverse events were more common in the ketamine group (40.8% [95% CI, 32%-49.6%]) versus the morphine group (16.8% [95% CI, 10.4%-25.0%]).
3. Most common adverse effects: in the ketamine group was emergence phenomenon (24 of 120 [20%]), in the morphine group was nausea (12 of 113, [10.8%]).
Discussion
The opioid epidemic has many questioning if there are safer alternatives to narcotics for managing pain. Ketamine, a non-opioid, has been identified as a potential option for analgesia because of a better side effect profile (less depression of airway reflexes) and lower risk of dependency. However, recent guidelines for its use in place of IV opioids in the prehospital environment were made with a very low certainty of evidence, based on research performed in the emergency department [2].
A group of researchers in France explored whether ketamine would be as effective as morphine in the prehospital management of traumatic pain. Using a non-inferiority trial, they concluded that the reduction in numeric pain scale (the primary outcome) was similar between the patients receiving morphine and ketamine.
The study has several strengths. The participants were randomized and blinded, it was a multi-center trial, and the patients enrolled in the morphine and the ketamine groups were similar (in age, gender, medical complaints, etc.). All of the patients who were enrolled and did not complete the trial were accounted for.
While the authors state that ketamine is equal (well technically, not worse) than morphine, there are a few factors that need to be considered before accepting that conclusion. The drugs were dosed differently. In the ketamine group, everyone received 20 mg up front, followed by 10 mg every 5 minutes. Those receiving morphine had the same dose repeated every 5 minutes. There was also weight-based dosing in the morphine group (under 60 kg got 2 mg per dose; over 60 kg got 3 mg). Everyone in the ketamine group got the same dose regardless of their weight. It is possible that some of the findings, for example, that ketamine had faster reduction in pain scale than morphine (-0.09 [95% CI, -0.10 to -0.08] vs -0.07 [95% CI, -0.08 to -0.05]), could be the result of dosing differences.
Another factor was that the physicians providing care were not blinded to which drug they were giving and they “used clinical judgement on dosing according to patient age and body weight” [1]. Because they knew which drug was being administered, the physician’s preferences or previous experience could have biased their choices. The authors did not report how many times protocol was followed or how many times the dose was determined by judgement, making it difficult determine how much influence this could have on the outcome.
Finally, it is worth noting that the protocol for KETAMORPH was published prior to the trial [3]. The protocol originally called for a much larger sample size (>400) and was to include both traumatic and non-traumatic pain. The authors did not explain why they deviated from the original protocol.
Before you trade in your morphine for ketamine, the adverse events need to be discussed. While neither drug produced any severe reactions, those in the ketamine group experienced adverse events almost 2.5 times more often than those in the morphine group. This difference was mostly a result of visual disturbances and emergence phenomenon. Twenty-four patients (20%) who received ketamine experience dysphoria, agitation or hallucinations. This is compared to only one patient who received morphine. Admittedly, these results were not the primary objective of the research, but the clinical impact needs to be considered and is deserving of its own research.
The study is important for several reasons. First, even though physician-staffed ambulances are not common in the North American model, conducting research in the prehospital environment adds validity to the results for paramedics who are working the road. As well, the finding that no severe (requiring intervention) adverse events were described in either group, supports the safe use of both agents prehospitally. Finally, individual studies are rarely practice changing and the result of a placebo-controlled trial with better blinding would be more definitive. KETAMORPH does make considering prehospital ketamine for traumatic pain appear to be a reasonable and defensible alternative to morphine.
Memorable quotes
- “The single-blind design could have introduced performance bias.”
- “ … no clinically meaningful differences between the analgesic effects of these two drugs and suggest that the use of intravenous ketamine represents an alternative to intravenous opioid analgesics for the treatment of adult patients with traumatic pain in an out-of-hospital setting.”
- “Based on our findings, ketamine, which presents low addiction liability … could help to mitigate the opioid crisis by reducing out-of-hospital opioid prescriptions.”
Top takeaways
This supports the use of low dose ketamine as an alternative to morphine in prehospital traumatic pain, especially in the context of reducing opioid use. Ketamine has an adverse effect profile distinct from morphine and the clinical effects of this must be considered.
There are numerous potentials for bias within the study; the results must be interpreted with these in mind. This study alone should not be considered practice changing.
References
1. Le Cornec C, Le Pottier M, Broch H, Marguinaud Tixier A, et al. Ketamine compared with morphine for out-of-hospital analgesia for patients with traumatic pain: A randomized clinical trial. JAMA Netw Open. 2024 Jan 2;7(1):e2352844. doi: 10.1001/jamanetworkopen.2023.52844. PMID: 38285446; PMCID: PMC10825723.
2. Lindbeck G, Shah MI, Braithwaite S, Powell JR, et al. 2023. Evidence-based guidelines for prehospital pain management: Recommendations, prehospital emergency care, 27:2, 144-153, DOI: 10.1080/10903127.2021.2018073
3. Le Cornec C, Lariby S, Brenckmann V, Hardouin JB, et al. Is intravenously administered, subdissociative-dose KETAmine non-inferior to MORPHine for prehospital analgesia (the KETAMORPH study): study protocol for a randomized controlled trial. Trials. 2018 May 2;19(1):260. doi: 10.1186/s13063-018-2634-3. PMID: 29716637; PMCID: PMC5930801.
