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Date: October 10th , 2018

Reference: Karlow et al. A Systematic Review And Meta-Analysis of Ketamine as an Alternative to Opioids for Acute Pain in the Emergency Department. AEM Oct 2018.

Guest Skeptic: Dr. Corey Heitz is an emergency physician in Roanoke, Virginia. He is also the CME Editor for Academic Emergency Medicine.

Case: You are caring for a 38-year-old male (Larry) who presented to the emergency department with lower back pain. During your evaluation, he tells you he doesn’t want any narcotic pain medication. You wonder if there are alternative options, and a colleague reminds you that ketamine has recently gained a lot of exposure as a possible alternative.

Background: The amelioration of pain and suffering should be one of the top priorities of emergency physicians.  In 2001, JACHO made pain the 5th vital sign to address the issue of oligoanalgesia, which unfortunately created many problems.

Opiates became a very common treatment for acute pain in the ED setting after JACHO and the introduction of new and powerful opioids like oxycodone.

However, in recent years, an increased desire for alternatives has been prompted in an attempt to reduce opiate usage. The pendulum is swinging to opiophobia. This can leave the patient left in the middle with ineffective pain management.

One alternative or adjunct to limit the use of opioids in the ED is low dose ketamine (LDK). Several studies have been performed evaluating low dose ketamine (LDK) for acute pain, with a variety of methodological designs, time endpoints, and doses.

We have covered some of those papers and watched the literature develop over the years on the SGEM.

  • SGEM#111: Comfortably Numb – Low dose Ketamine as Adjunct for ED Pain Control

SGEM Bottom Line: High-quality published evidence to support the use of sub dissociative-dose ketamine to quickly reduce acute pain in emergency department settings is lacking, but lower quality studies inconsistently demonstrate effectiveness with uniformly low risk of adverse effects.

  • SGEM#130: Low Dose Ketamine for Acute Pain Control in the Emergency Department (reviewed two ketamine papers)

SGEM Bottom Line: For patients who have a contraindication to opioids such as allergy or hypotension, sub dissociative ketamine would be a reasonable option to consider for treating acute pain.

SGEM Bottom Line: While further validation in other settings is needed, this study suggests ketamine as a relatively safe option for patients who do not achieve analgesia with high doses of morphine or are unable to tolerate them.

  • SGEM#198: Better Slow Down – Push vs. Short Infusion of Low Dose Ketamine for Pain in the Emergency Department

SGEM Bottom Line: Slowing down the rate of low-dose IV ketamine infusion to 15 minutes significantly reduces rates of the feeling of unreality and sedation with no difference in analgesic efficacy when compared to IV push over 3 – 5 minutes. 

Clinical Question: Is ketamine, at a dose of <0.5mg/kg, as effective as opiates for the treatment of acute pain in the emergency department?

Reference: Karlow et al. A Systematic Review And Meta-Analysis of Ketamine as an Alternative to Opioids for Acute Pain in the Emergency Department. AEM Oct 2018.

  • Population: Randomized control trials (RCTs) with emergency department patients >18 years old receiving LDK for acute pain
    • Exclusions: Did not report visual analog scale (VAS) score or numeric rating scale (NRS) pain scale measurement, co-administration of pharmacologically active substance less than 20 min after IV ketamine/opioid administration, included a placebo group
  • Intervention: <5mg/kg ketamine IV (bolus, slow push or short infusion)
  • Comparison: IV opioids converted to morphine equivalents
  • Outcome:
    • Primary Outcome: Numeric Rating Scale or Visual Analog Scale at ten minutes
    • Secondary Outcomes: Adverse events and the requirement of additional dosing or analgesics

Nicholas Karlow is a 4th year medical student and a graduate of the Masters of Population Health Sciences (MPHS) program at Washington University School of Medicine in St. Louis.

We also have the “senior” author, Dr. Even Schwarz. Evan is an Associate Professor of Emergency Medicine and the Medical Toxicology Section Chief at Washington University School of Medicine in St. Louis.

Authors’ Conclusions: Ketamine is non-inferior to morphine for the control of acute pain, indicating that ketamine can be considered as an alternative to opioids for ED short-term pain control.

Quality Checklist for Therapeutic Systematic Reviews:

  1. The clinical question is sensible and answerable. Yes
  2. The search for studies was detailed and exhaustive. Unsure
  3. The primary studies were of high methodological quality. Yes
  4. The assessment of studies were reproducible. Yes
  5. The outcomes were clinically relevant. Yes
  6. There was low statistical heterogeneity for the primary outcomes. Unsure
  7. The treatment effect was large enough and precise enough to be clinically significant. Yes

Key Results: An extensive search of English language only publications found three RCTs for a total of 261 patients.

Low-dose ketamine was non-inferior to morphine as an analgesic.

  • Primary Outcome: NRS or VAS at 10 minutes
    • Pooled estimate of difference between ketamine and morphine equivalents was 0.42 (95% CI -0.70 to 1.54)
    • That -0.70 is less than the lower end of inferiority established of -1.4
  • Secondary Outcomes:
    • No severe adverse events were reported
    • Higher rates of non-severe adverse events were seen with ketamine

Listen to the podcast on iTunes to hear Nick’s and Evan’s responses to our ten (two sets of five) nerdy questions.

  1. Nicholas Karlow

    Strict Inclusion Criteria: Your inclusion criteria limited the studies to just three. Can you discuss your reasoning behind the strict selection of studies? Was there any search of unpublished abstracts or non-English language studies?

  2. Heterogeneity: The heterogeneity was fairly high with an I2 of 64.3%. How should we interpret the results given such differences between the three studies? Did you do anything to address the heterogeneity?
  3. Small Sample Size: The sample size of the included trials was fairly small, and the confidence interval of the primary outcome was wide. Do you think there is a possibility that with increased patient numbers, a benefit of one over the other could be uncovered?
  4. Individual Patient Data: You were able to get individual patient data from two of the three studies (Motov and Miller but not Majidinejad). Explain the advantage to having individual patient data when conducting a SRMA?

  5. Dr. Evan Schwarz

    Ten Minutes: You chose ten minutes as the primary outcome timeline. Is it possible that one of the treatments has a longer lasting effect, making it overall more effective? Can you discuss whether and how this was addressed?

  6. Adverse Events: As you discussed, the numbers of adverse events were small and not able to be analyzed statistically. Most of the adverse events from ketamine are short lived. Is it possible the adverse events from morphine, while potentially less numerous and not able to be quantified, could be worse overall?
  7. Additional Dosing or Analgesics: The requirement for additional dosing or analgesics was another secondary outcome mentioned in the methods but not in the results. Why did you not report or discuss this secondary outcome?
  8. Social Media: It was interesting to note you cited FOAMed in the discussion as a reason ketamine has been adopted by the EM world as an alternative to opioids. A merging of traditional and non-traditional publications for knowledge translation.
  9. What to do at Discharge? Can you comment on your thoughts about how to treat patients who improved with ketamine, after they are discharged?
  10. Anything Else: Is there anything else you would like to say about your SRMA or ketamine in general?

Comment on Authors’ Conclusion Compared to SGEM Conclusion:  We agree with the authors’ conclusions.

SGEM Bottom Line: Ketamine at a dose of <0.5mg/kg is non-inferior to opioid analgesics for acute pain in the ED. It is possible that over a longer time point, or with increased study of a greater number of patients, that one of the treatments would show benefit over the other.

Case Resolution: You discuss the possibility of using ketamine with your patient. He is interested in trying, and you give 0.3mg/kg intravenously with a decrease in the patient’s pain level.

Clinical Application: In this time of transition between oligoanalgesia and opiophobia, IV ketamine offers a potential solution. It can minimize or avoid opioids while at the same time providing relief to ED patients with acute pain.

What Do I Tell My Patient? Ketamine is a non-opiate analgesic that has been shown to be similarly effective to opiates such as morphine for acute pain. There are some potential side effects, but these are not severe. Giving it to you as a slow infusion over 10 minutes should reduce the chances of you having a serious side effect.

Keener Kontest: Last weeks’ winner was Brittany Misener, an emergency department nurse from London, Ontario. She knew the term triage originated in approximately 1792. It was taken from the French word “trier”, meaning “to sort” or “to select”. This process was used by Napoleon’s Surgeon in Chief. Initially, triage was mostly used in mass casualty situations to determine who needed immediate, urgent, and non-urgent care.

Listen to the SGEM podcast on iTunes to hear this the new keener question. If you know the answer send an email to TheSGEM@gmail.com with “keener” in the subject line. The first correct answer will receive a cool skeptical prize.

Other FOAMed Resources:

  • St. Emlyn’s – Journal Club Ketamine
  • EM Cases Journal Jam – Low Dose Ketamine Analgesia
  • REBEL Cast Ep53 – GeriKet – Ketamine Analgesia in Older Adults
  • REBEL EM – Low-Dose Ketamine for Acute Pain in the ED: IV Push vs Short Infusion?
  • TOTAL EM#83 – Recent Literature Updates on Opiate Alternatives
  • CORE EM – Infusion Versus IV Push Low-Dose Ketamine for Analgesia
  • PharmERToxGuy – How to Administer Low-Dose IV Ketamine for Pain in the ED

SGEMHOP: Now it is your turn SGEMers. What do you think of this episode? Tweet your comments using #SGEMHOP. What questions do you have for Nick and Evan and their team about low dose ketamine for pain control? Ask them on the SGEM blog. The best social media feedback will be published in AEM.

Also, don’t forget those of you who are subscribers to Academic Emergency Medicine can head over to the AEM home page to get CME credit for this podcast and article. We will put the process on the SGEM blog:

  • Go to the Wiley Health Learning website
  • Register and create a log in
  • Search for Academic Emergency Medicine – “October”
  • Complete the five questions and submit your answers
  • Please email Corey (coreyheitzmd@gmail.com) with any questions or difficulties.

Remember to be skeptical of anything you learn, even if you heard it on the Skeptics’ Guide to Emergency Medicine.