Evaluation of analgesic effects of ketamine through sub-dissociative dosing in the ED.

Effectively managing pain is known to be problematic in the emergency department (ED) with up to 43% of patients with oligoanalgesia [1–3]. Opioids alone are commonly inadequate at controlling acute and acute on chronic pain in the ED [4–6]. Furthermore, using higher doses or more potent opioids may be challenging in some patients because of the risk of adverse effects such as somnolence, respiratory and hemodynamic depression, nausea, and vomiting [7–12]. An alternative approach may be to use the analgesic properties of ketamine (Ketalar; JHP Pharmaceuticals, LLC, Rochester, Michigan) at subdissociative doses (intravenous doses less than 1 mg/kg), which have been shown to induce analgesia, reduce hyperalgesia, and decrease the amount of morphine with minimal oxygen desaturation and respiratory depression [7,13–17]. Clinically, analgesia onset is approximately 1 and 3 minutes for intravenous and intramuscular administration, respectively, with an elimination half-life of approximately 10 to 15 minutes [15]. In addition, ketamine can be administered via intranasal route, and it has been shown to decrease pain (from 6.4 to 4.4 and from 6.6 to 4.1; P b 0.05) after 1 hour and for a duration of 2 to 3 hours [18,19]. A PubMed, Cochrane Library, and International Pharmaceutical Abstracts (1973 to present) search was performed using the primary key words of “ketamine” and “emergency department.” Articles were included if ketamine was administered to adult patients in the ED for analgesia. Eleven original published articles were included and are presented in Table 1. Most of the studies evaluating ketamine as an analgesic in the emergency setting used it as adjunctive therapy in addition to an opioid [7,16,17,20–26]. A few observational studies and one randomized controlled trial (RCT) evaluated the use of low-dose ketamine alone [19,27–29]. Miller et al [19] showed similar maximum decreases in pain scores with administration of morphine vs ketamine, but noted they occurred at different times (100 vs 5minutes after administration). Yeaman et al [27] concluded that ketamine use alone produced suboptimal results (56% of patients had a clinically significant decrease in pain) and that it should be used with other analgesics. A variety of doses were used in studies evaluating low-dose ketamine for analgesia, primarily 0.1 to 1 mg/kg of ketamine. There is a lack of RCTs evaluating the effectiveness of intranasal ketamine as an analgesic; the most common dosing regimen was 0.5 mg/kg [27–29]. There are conflicting results regarding adverse effects with sub-dissociative doses of ketamine. A study by Jennings et al. [20] (N = 135) found 5.7% of patients receiving intravenous ketamine experienced an emergence phenomenon and 11.4% experienced disorientation in the prehospital setting; this may be due to higher ketamine doses (10 to 120mgor 0.14-1.7mg/kg in a 70-kg patient). Galinski et al. [16] treated patients experiencing severe pain in mobile intensive care units in a double-blind RCT and found a statistically significant (P=0.002) increase in neuropsychological adverse effects (36% vs 3%) with administration of 0.2 mg/kg intravenous ketamine compared to morphine including hallucinations, dizziness, diplopia, and dysphoria. Gurnani et al. [17] showed less overall nausea, whereas Johansson et al. [21] showed more overall nausea in the morphine only group vs the ketamine plus morphine group. In an RCT by Weinbroum [10], intravenous ketamine (0.25 mg/kg, n = 131) plus morphine (0.015 mg/kg) vs morphine alone (0.030 mg/kg, n = 114) resulted in less postoperative nausea and