Le Cornec C, Le Pottier M, Broch H, 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. (Original study)

IMPORTANCE: Pain is a common out-of-hospital symptom among patients, and opioids are often prescribed. Research suggests that overprescribing for acute traumatic pain is still prevalent, even when limits restricting opioid prescriptions have been implemented. Ketamine hydrochloride is an alternative to opioids in adults with out-of-hospital traumatic pain.

OBJECTIVE: To assess the noninferiority of intravenous ketamine compared with intravenous morphine sulfate to provide pain relief in adults with out-of-hospital traumatic pain.

DESIGN, SETTING, AND PARTICIPANTS: The Intravenous Subdissociative-Dose Ketamine Versus Morphine for Prehospital Analgesia (KETAMORPH) study was a multicenter, single-blind, noninferiority randomized clinical trial comparing ketamine hydrochloride (20 mg, followed by 10 mg every 5 minutes) with morphine sulfate (2 or 3 mg every 5 minutes) in adult patients with out-of-hospital trauma and a verbal pain score equal to or greater than 5. Enrollment occurred from November 23, 2017, to November 26, 2022, in 11 French out-of-hospital emergency medical units.

INTERVENTIONS: Patients were randomly assigned to ketamine (n = 128) or morphine (n = 123).

MAIN OUTCOMES AND MEASURES: The primary outcome was the between-group difference in mean change in verbal rating scale pain scores measured from the time before administration of the study drug to 30 minutes later. A noninferiority margin of 1.3 was chosen.

RESULTS: A total of 251 patients were randomized (median age, 51 [IQR, 34-69] years; 111 women [44.9%] and 140 men [55.1%] among the 247 with data available) and were included in the intention-to-treat population. The mean pain score change was -3.7 (95% CI, -4.2 to -3.2) in the ketamine group compared with -3.8 (95% CI, -4.2 to -3.4) in the morphine group. The difference in mean pain score change was 0.1 (95% CI, -0.7 to 0.9) points. There were no clinically meaningful differences for vital signs between the 2 groups. The intravenous morphine group had 19 of 113 (16.8% [95% CI, 10.4%-25.0%]) adverse effects reported (most commonly nausea [12 of 113 (10.6%)]) compared with 49 of 120 (40.8% [95% CI, 32.0%-49.6%]) in the ketamine group (most commonly emergence phenomenon [24 of 120 (20.0%)]). No adverse events required intervention.

CONCLUSIONS AND RELEVANCE: In the KETAMORPH study of patients with out-of-hospital traumatic pain, the use of intravenous ketamine compared with morphine showed noninferiority for pain reduction. In the ongoing opioid crisis, ketamine administered alone is an alternative to opioids in adults with out-of-hospital traumatic pain.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03236805.

Discipline Area Score
Emergency Medicine 7 / 7
Special Interest - Pain -- Physician 6 / 7
Comments from MORE raters

Emergency Medicine rater

In this study in France, low-dose ketamine (20 mg IV) was found to be as effective as morphine (4 mg IV) in prehospital trauma patients. Side effect frequency was comparable and as expected. This strategy is worth trialing in the US with paramedic services. We're already using this in the ED.

Emergency Medicine rater

The trial was designed to test whether ketamine provides non-inferior pain relief compared with morphine, based on an opioid-reduction rationale. Having demonstrated non-inferiority, the authors conclude that ketamine offers an opioid-reduction alternative to morphine. However, an alternative interpretation of the results could be that there was no difference in analgesic effect and ketamine was associated with more adverse effects (mostly emergence phenomenon). Useful results either way. The PACKMaN trial (https://sjtrem.biomedcentral.com/articles/10.1186/s13049-023-01146-1) has completed recruitment and addresses the same comparison, but is designed to test ketamine superiority. It will be interesting to compare the results when they are published.

Special Interest - Pain -- Physician rater

Ketamine is a drug with analgesic properties at low doses, has several routes of administration, preserves the upper airway reflexes, and has a lower risk for respiratory depression than opioids. According to this noninferiority trial, in adults with out-of-hospital traumatic pain, ketamine appears to be an effective analgesic with no increase in adverse outcomes compared with opioid analgesia and has a more favourable effect on vital signs. Ketamine is a safe and effective medication for managing pain in trauma patients during prehospital care. It could be considered a viable alternative to opioid analgesics.

Special Interest - Pain -- Physician rater

Rationale for using a non-opioid in this setting is shaky. However, there are other settings in which knowing that ketamine effectiveness and tolerability are equivalent to morphine could be important.
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