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Karlow N, Schlaepfer CH, Stoll CRT, Doering M, Carpenter CR, Colditz GA et al. A Systematic Review and Meta-analysis of Ketamine as an Alternative to Opioids for Acute Pain in the Emergency Department. Acad Emerg Med. 2018;25:1086-1097.

Ghate G, Clark E, Vaillancourt C. Systematic review of the use of low-dose ketamine for analgesia in the emergency department. CJEM. 2018;20:36-45.

Study Population: A total of 870 adult patients who presented to the emergency department with acute pain from traumatic and non-traumatic causes, in two meta-analyses comprising a total of 11 trials

Efficacy Endpoints

Change in Visual Analog Scale (VAS) for pain

Harm Endpoints

Adverse events (hypoxia, neuropsychological effects such as agitation, hallucination, dysphoria, and confusion)

Narrative

Acute pain is one of the most common complaints in the emergency department. With recent efforts to find effective non-opioid analgesics, ketamine has surfaced as a potential option for ED analgesia.1^, 2^, 3 While ketamine is typically used as a sedative agent, several studies have shown that when it is administered in sub-dissociative doses, both as a stand-alone agent and as an adjunct to opioids, it may also provide analgesia.4 Two recently published meta-analyses compared ketamine with opioid analgesics in adult ED patients with acute pain.

The patient-level meta-analysis, by Karlow et al.,5 included randomized controlled trials that directly compared a single bolus, slow push or slow infusion of a sub-dissociative intravenous dose of ketamine with a single IV dose of opioid/opiate analgesia. This comprised three studies that included a total of 261 adult ED patients. The primary outcome studied was the change in patient-reported pain scores after administration of ketamine (dose range: 0.3-0.5 mg/kg IV) or morphine (dose: 0.1 mg/kg IV). The pooled estimate for the mean difference in reported pain score reduction between the ketamine and morphine groups was 0.42 (95% CI, -0.70 to 1.54). Because of heterogeneity in the methods and timing of pain assessment and in event assessment, adverse events were reported as raw data. Ketamine was associated with a higher rate of adverse events than morphine in all of the individual studies. However, the only reported acute life-threatening adverse event was decreased oxygen saturation, which was reported in a single patient in the opioid trial arms, and in none of the patients in the ketamine groups.

Ghate et al.6 performed a systematic review and meta-analysis comparing low-dose ketamine with opioids in adults with acute pain in the ED. The authors included eight studies (6 RCTs and 2 observational studies), with a total of 609 ED patients. The major outcome studied was change in patient-reported pain scores 30 minutes after treatment. Both low-dose ketamine (dose range: 0.1-0.6 mg/kg IV/SC/IM) and morphine (dose: 0.1 mg/kg IV or 0.5 mg hydromorphone IV) appeared to provide some level of analgesia in individual studies (compiled data was not reported), but no significant difference was demonstrated between the two agents. The study also reported rates of neuropsychological adverse events of 15.4% in the ketamine group and 4.4% in the opioid group (Relative risk [RR]: 3.44, 95% CI, 1.81-6.55; absolute risk difference [ARD]: 11%; Number-needed-to harm [NNH]: 9). Neuropsychological events were defined as agitation, hallucination, dysphoria, and confusion.

Caveats

The meta-analysis by Ghate et al. included more studies than the meta-analysis by Karlow et al., and a larger sample of patients (N=609). However, the former included two observational studies, raising concern about the validity of the results and the appropriateness of pooling the data. The studies included in Ghate et al. varied significantly in the dose (0.1-0.6 mg/kg) and route of administration (IV/SC/IM) of ketamine, as well as in the use of adjunctive analgesia (one study’s protocol included a dose of midazolam with ketamine). The incorporated studies also varied in the choice of the compared opioid, with one study utilizing 0.5 mg IV hydromorphone and the others 0.1 mg/kg IV morphine.

Regarding the meta-analysis by Karlow et al., the clinical heterogeneity among the included trials is a major limitation. One of the studies included only patients with long bone fractures, while the other two included patients with musculoskeletal pain and abdominal pain, raising the question of whether specific etiologies of pain may respond differently to specific analgesics. Patients receiving ketamine appeared to have more acute adverse events, but it was difficult to draw conclusions about harm endpoints because of the small sample size.

Neither of the two meta-analyses included data on the rate of administration of the medications, which has been shown to correlate with adverse side effects.7 It must also be noted that pain control commonly requires re-dosing and titration. Comparing a single dose of opioid analgesia to a single dose of ketamine thus might not be appropriate for determining the efficacy of either for pain control. In addition, this meta-analysis included only patients with acute pain; the efficacy of ketamine in patients with chronic pain (e.g., chronic back pain) is not addressed here. Finally, the small sample size of the included trials and the meta-analyses, limits the validity of the findings.

In summary, ketamine appears to be comparable to opioids for acute pain control. However, because of the small sample size of the meta-analyses and limitations of the included trials, we have assigned a color recommendation of Yellow (Unclear if benefits) to this intervention. Larger high-quality studies are needed to further support the routine use of ketamine for pain control in the emergency department.

The original manuscript was published in Academic Emergency Medicine as part of the partnership between TheNNT.com and AEM.

Author

Michael J. Duhaime, MD; Allan B. Wolfson, MD
Supervising Editor: Shahriar Zehtabchi

Published/Updated

April 2, 2020