ESKetamine Low-dose vs Ketamine Low-dose for Severe Acute Pain in Emergency Units, Comparison of PsychodyslEptic Effects

Overview

Almost 30% of painful patients in emergency departments (ED) describe their pain as severe (i.e. a Verbal Numerical Rating Score VNRS ≥ 6 on a scale ranging from 0 to 10). The management of such severe pain needs to be rapid and safe, and for this purpose intravenous (IV) morphine titration is still the gold-standard. However, morphine titration takes up considerable caregiver time, as patients need to be monitored and treated progressively with small quantities of morphine every 5 minutes until analgesia. This is sometimes difficult to reconcile with a saturating flow of patients, and overcrowding in ED is proven to significantly delay time-to-analgesia, and even lead to deleterious under-treatment. Finally, the opioid crisis is a major concern, explaining why strategies are being advocated to develop other ways of managing severe acute pain in the ED and to limit the use of opioids. Recent studies show that ketamine administered in small IV doses ("low-dose" ketamine LDK: 0.2 to 0.3 mg/kg) possesses potent analgesic activity as well as interesting anti-hyperalgesic and anti-allodynic properties. Compared with morphine, LDK does not induce respiratory depression, but can sometimes induce disturbing psychodysleptic effects. These may include a sensation of unreality, fatigue, anxiety, dizziness or hallucinations. According to studies, 30-80% of LDK-treated patients experience psychodysleptic effects. However, two recent studies suggest that slow IV injections of LDK (over 10 minutes) may improve patient tolerance, although these slow infusions do not totally reduce this discomfort. Pharmacologically, ketamine is a racemic mixture of 2 isomers: esketamine S(+), which is dextrorotatory, and arketamine R(-), which is levorotatory. In recent years, a new formulation containing only esketamine has been made available to hospitals in some northern European countries, and more recently in France. Esketamine appears to have twice the analgesic efficacy of racemic ketamine, and studies on healthy volunteers or in peri-operative settings suggest that it is also better tolerated psychologically than ketamine. For the moment, however, scientific data are lacking, and no comparative trial has yet been conducted in the ED setting. The investigators plan to conduct in their ED a prospective, single-center, randomized, double-blind study aiming to compare the tolerance and efficacy of esketamine versus racemic LDK in patients presenting with severe acute pain (VNRS ≥ 6/10).

More than two-thirds of patients visiting emergency departments (ED) complain of acute pain, and of these, almost 30% describe their pain as severe (i.e. a Verbal Numerical Rating Score VNRS ≥ 6 on a scale ranging from 0 to 10). The management of such severe pain needs to be rapid, safe and adapted to the suspected underlying causative pathology. To achieve this, recommendations call for widespread use of intravenous (IV) morphine titration, which combines high analgesic efficacy with a good clinical safety profile (low risk of respiratory depression). However, the need to monitor patients and inject small quantities of morphine every 5 minutes until the patient is relieved takes up a considerable amount of caregiver time, which is sometimes difficult to reconcile with a saturating flow of patients. This growing problem of overcrowding in ED can lead to significant under-treatment and delays in analgesia. At the same time, the opioid crisis in the USA is beginning to affect other countries, which explains why certain strategies are being advocated to limit the use of opioids, and why researchers are attempting to develop other ways of managing severe acute pain in the ED. Recent studies show that ketamine administered in small IV doses ("low-dose" ketamine KLD: 0.2 to 0.3 mg/kg) possesses potent analgesic activity comparable to that of IV morphine. These analgesic qualities have been known for decades, and ketamine's unique non-competitive antagonism of the NMDA (N-methyl-D-aspartic) receptor also results in interesting anti-hyperalgesic and anti-allodynic properties. Compared with morphine, KLD does not induce the risk of respiratory depression, but can induce psychodysleptic effects that can sometimes be troublesome. These may include a sensation of unreality, fatigue, anxiety, dizziness or hallucinations. According to studies, 30 to 80% of patients treated with KLD experience a psychodysleptic effect. However, two recent studies suggest that slow IV injections of KLD (\>10 min) may improve patient tolerance, although this slow injection may not significantly reduce this discomfort. Pharmacologically, ketamine is a racemic mixture of 2 isomers: esketamine S(+), which is dextrorotatory, and arketamine R(-), which is laevorotatory. In recent years, a new formulation containing only esketamine has been made available to hospitals in some northern European countries, and more recently in France. Esketamine appears to have twice the analgesic efficacy of racemic ketamine, and studies on healthy volunteers or in peri-operative settings suggest that it is also better tolerated psychologically than ketamine. For the moment, however, scientific data are lacking, and to our knowledge no comparative trial has yet been conducted in the ED setting. The prospective, single-center, randomized, double-blind study the investigators plan to conduct in the ED will compare the tolerance and efficacy of esketamine versus racemic LDK in patients presenting with severe acute pain (VNRS ≥ 6/10).