Paramedics in the United States often treat trauma patients’ pain with parenteral opioids, but many patients do not have optimal pain control.
Ketamine has analgesic and opioid-sparing effects with fewer negative impacts on respiratory or hemodynamic status. The intranasal route of administration of ketamine facilitates early initiation of treatment and may promote more rapid analgesia. However, there are few data evaluating the combination of fentanyl and ketamine in the management of pain in the out-of-hospital setting.
Recent recommendations for the treatment of pain in out-of-hospital settings do not mention intranasal ketamine which could provide an analgesic advantage to fentanyl in the management of post-traumatic pain during out-of-hospital care. However, the question arises of its effectiveness and safety when added to fentanyl.
A randomized trial with a small number of men only
Hence the interest in this randomized, placebo-controlled, blinded and parallel group US out-of-hospital clinical trial, conducted from October 2017 to December 2021. The participants were only men, aged 18 to 65, receiving fentanyl to treat acute traumatic pain prior to hospital admission, managed by emergency medical services, and transported to the region’s only adult Level I trauma center.
After randomization, participants received either 50 mg of intranasal ketamine or a placebo. The primary outcome was the proportion of trauma patients who achieved a reduction of at least 2 points in their pain on the Verbal Numerical Rating Scale 30 minutes after administration of the study drug, assessed by the overlap of the 95% confidence interval. Secondary outcomes were adverse events, pain assessment, and administration of other analgesic medications during the first three hours of care.
No clinically significant difference in analgesia
Of the 192 participants, 89 (46%) were White, their median age was 36 years (interquartile range, 27 to 53 years). Randomization assigned 103 of them to receive 50 mg of intranasal ketamine and 89 to receive a placebo. There was no difference in the proportion of participants who felt an improvement in pain 30 minutes after treatment: 46/103 (44.7%) on ketamine vs 32/89 (36.0%) on placebo (difference 8.7% [IC à 95 %, -5,1 % à 22,5 %] ; p = 0.22), or at any time up to 3 hours. There were no differences in secondary outcomes or adverse effects.
Limits to take into account
Given the small number of people, a large-scale study would be welcome in order to confirm or not the results of the present study. Intranasal administration of any drug requires skill, and poor technique can cause the drug to condense in the posterior part of the nasopharynx instead of distributing it along the nasal mucosa for rapid absorption.
At least 31 participants had received intranasal fentanyl as part of initial care, which may have saturated the nasal mucosa before ketamine administration, although the route of fentanyl administration was similar between groups.
Finally, this study could not include women, because ketamine is classified in pregnancy category N (unclassified) by the Food and Drug Administration and animal studies show a potential negative impact on brain development. Due to the lack of rapid pregnancy tests during treatment, the authors were unable to exclude pregnancies in order to facilitate the inclusion of women in this trial.
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