Journal Club: Are you hopping on the Ketamine Train?

maryhaasBy Mary Haas, MD PGY-II

Ketamine is undeniably a hot topic right now in the EM world, especially within the community of FOAMed enthusiasts. There are a small but growing number of articles evaluating the safety and efficacy of ketamine in the ED for pain management. We recently had a journal club on the topic, which fueled some excellent discussion among our residents and faculty.

First, let’s go over a little background on ketamine. The May 2015 episode of EM:RAP features a great segment entitled “Doc in the Bay – Ketamine” by Howard Mell, MD. We’ll recap some of the pearls provided in this segment. First, ketamine’s mechanism of action is to antagonize NMDA receptors and thereby serve to limit internal transmission of external stimuli.  Ketamine is dosed on a spectrum, with different effects at different dosing rages, and some overlap in these ranges that can make it difficult to reach your target effect without unintentionally over or undershooting.

0.1 – 0.3 mg/kg IV: Analgesic Dose (Usually 10- 20 mg IV bolus in the average sized person)Journal Club

0.2 – 0.5 mg/kg IV: Recreational dose

0.4-0.8 mg/kg IV: Partially dissociated dose (where emergence reactions tend to occur)

Greater than 0.9 mg/kg IV: Dissociative dose (procedural sedation, RSI, etc.)

Dr. Mell mentions that ketamine actually has a relatively good safety profile, given that increasing the dose serves to bind up more NMDA receptors, and once all of them are saturated, increasing the dose further simply prolongs the duration of the drug.

The anesthesia and surgery literature has shown ketamine to mitigate pain and reduce opioid consumption in patients with chronic pain, cancer pain and acute post-operative pain. Although a paucity of literature exists for evaluating the use of ketamine for analgesia in the ED specifically, the number of studies looking into this is expanding, especially as both poorly controlled pain and opioid overuse and addiction are both understood to be major public health issues.

In journal club this week, we reviewed a recent article entitled “Intravenous Subdissociative-Dose Ketamine Versus Morphine for Analgesia in the Emergency Department: A Randomized Controlled Trial.” The primary author of this study is Dr. Sergey Motov, an emergency physician out of Maimonides Medical Center who has a particular interest in pain management in the ED. See his awesome website “The Pain-Free ED” here, and a shout out he received on the EMCrit blog here.

This study was performed at a single center site as a prospective, randomized, double-blind trial evaluating ED patients between the ages of 18-55 who presented with acute pain (< 7 days duration) that was moderate to severe (defined as at least a 5 on the 0-10 point traditional pain scale). Eligible patients were randomized to either receive 0.1 mg/kg morphine by IV push versus ketamine 0.3 mg/kg IV. The study was powered to detect  a difference of at least 1.3 at 30 minutes by enrolling 90 total patients (45 in each treatment arm). The study found no statistically significant difference in its primary outcome, which was defined as reduction in pain at 30 minutes. No difference in the secondary outcome, which was defined as incidence of rescue analgesia with fentanyl at 30 or 60 minutes, was observed. There was an increase in minor adverse effects in the ketamine group relative to morphine 15 minutes post drug injection, including dizziness, disorientation, mood changes and nausea. However, there was no serious adverse effects in either group. The study concluded that subdissociative IV ketamine at 0.3 mg/kg  provides analgesic effectiveness and apparent safety comparable to that of IV morphine for short-term treatment of acute pain in the ED.

Ketamine

Overall, the conclusion was that this was a fairly well-designed study. The outcome measures were clearly defined. The study’s randomized design allowed it to directly compare IV morphine to IV ketamine individually. However, several limitations must be acknowledged – this was a relatively small study, with the sample size near minimum for adequate power. It was a single-center study, with potential for unblinding given some ketamine-specific effects (i.e. nystagmus). Using pain scales as a metric for pain improvement is also fraught with potential issues, although some would argue it’s the best metric we’ve got (see here for interesting commentary on the difficulty interpreting studies evaluating effects on pain such as this study and the Beaudoin study that also looked at ketamine use in the ED).

The main issues the majority of us had with this article came down to the data’s generalizability to our every day practice, and whether or not this study (or the other studies currently out there on the topic) is enough to be practice changing given the barrier’s that currently exist for the routine use of ketamine for acute pain.

The study exclusion criteria was quite extensive (pregnancy, breast-feeding, altered mental status, allergy to morphine or ketamine, weight less than 46 kg or greater than 115 kg, unstable vital signs, medical history of acute head or eye injury, seizure, intracranial hypertension, chronic pain, renal or hepatic insufficiency, alcohol or drug abuse, psychiatric illness, or recent opioid use – 4 hours before). Given the extensive exclusion criteria, some would argue that the study can’t be effectively applied to many of the particular patients in which ketamine may actually be uniquely useful over opioids: for instance, those patients who have been given initial doses of opioids but continue to have poor controlled pain, patients with chronic pain, and patients who are relatively hypotensive/unstable in which you may be concerned to use opioids due to the side effects of respiratory depression and hypotension, but still wish to administer something for acute pain management.

Several of our faculty also made the point that this study is most applicable to patients with an acute cause of their pain, such as a femur fracture, for whom most faculty already feel comfortable simply using IV opioids and questioned the need for an alternative method such as ketamine. In counterpoint, others expressed concern that introducing opioid-naive patients to opioids, even in the acute setting, could potentially increase that person’s future risk of addiction, and thus there is a real need to have a non-opioid alternative up front. Some cited the recent study by Hoppe et al, which suggested that opioid-naive patients prescribed oral opioids for acute pain are at increased risk for additional opioid use at 1 year (although note that this study did not evaluate the effect of giving IV opioids acutely in the ED on subsequent narcotic use).

Additionally, this study compares one time dosages of morphine and ketamine, when in reality the more appropriate way to manage pain is often to titrate repeating dosing of a given agent to the goal effect.

Another practical issue that arose in the discussion was nursing discomfort with ketamine use for acute pain given that it is relatively less established than IV opioid use and is traditionally understood by nursing staff as a medication used for procedural sedation. Defining protocols for dosage and clarifying the type and extent of monitoring necessary to ensure patient safety when IV ketamine is used for acute pain is a potential solution.

The take home point that can be drawn from this particular study is that ketamine is a relatively safe and similarly effective alternative to morphine for patients with acute pain in the ED, with a potential for increase in minor adverse effects with ketamine. This study does not prove whether ketamine is a better alternative to opioids in the ED for acute pain, either in general or for certain patient populations who remain to be fully defined. The more relevant question may be whether ketamine is safe and efficacious as an adjunct to opioids compared to opioids alone, which multiple other studies have explored, and may be the more relevant question (see the further reading section below, including the study by Beaudoin et al).

References and Further Reading

Journal Jam 4 – Low Dose Ketamine Analgesia 

 Mell, H. Doc in the Bay – Ketamine. EM:Rap May 2015

Beaudoin FL, Lin C, Guan W, Merchant RC. Low-dose ketamine improves pain relief in patients receiving intravenous opioids for acute pain in the emergency department: results of a randomized, double-blind, clinical trial. Acad Emerg Med. 2014;21(11):1193-202.

Lester LM, Braude DM, Niles CM, et al. Low-dose ketamine for analgesia in the ED: a retrospective case series. Am J Emerg Med. 2010;28:820-827.

Richards JM, Rockford RM. Low-dose ketamine analgesia: patient and physician experience in the ED. Am J Emerg Med. 2013;31:390-394.

Miller J, Schauer S, Ganem V, et al. Low-dose ketamine vs morphine for acute pain in the ED: a randomized controlled trial. Am J Emerg Med. 2015; http://dx.doi.org/10.1016/j.ajem.2014.12.058.

Ahern T, Herring A, Stone M, et al. Effective analgesia with low-dose ketamine and reduced dose hydromorphone in ED patients with severe pain. Am J Emerg Med. 2013;31:847-851.

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