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Date: October 29, 2024

Reference: Galili et al. Low dose ketamine as an adjunct to morphine: a randomized controlled trial among patients with and without current opioid use. AEM Oct 2024.

Guest Skeptic: Dr. Neil Dasgupta is an emergency medicine physician and ED intensivist from Long Island, NY.  He is the Vice Chair of the Emergency Department and Program Director of the EM residency program at Nassau University Medical Center in East Meadow, NY, the safety net hospital for Nassau County.

Case: You are hitting the zone in your shift, a veritable disposition machine meeting the constant flow of patients through the emergency department (ED). As you finish a note on a complex critically ill patient, you hear howls of pain coming from the EMS triage desk.  A 38-year-old male patient in cycling gear is being brought in after colliding with a lamp post with an obvious upper extremity deformity.  He explains loudly to the triage nurse that he has chronic back pain from multiple prior cycling accidents, and regularly takes significant doses of extended-release oxycodone.  As you walk over to assess the patient, you take note of how distressed he is and consider how to get him comfortable enough to work him up in the ED.

Background:  Management of acute pain is an important activity of emergency physicians and can be challenging. Patients frequently come to the ED because they are in pain, and our ability to relieve that pain is central to the patient experience.  Alternatives to opiate pain medications have significant limitations with analgesic ceilings (NSAIDs) as well as side effects or toxicity potential that limit their use and efficacy. This issue is even more fraught with difficulty in a patient who chronically uses opioid medications and has developed a tolerance.

Within the House of Medicine, there has been a significant shift in the use of opioids as we are more fully understanding the patient consequences and societal effects of a previously more liberal pain management strategy.  Judicious use of medications became paramount, with physicians becoming wary of the over-aggressive treatment of acute pain, leaving many patients hurting and frustrated.  One effective strategy is a multi-modal approach to pain management, including using adjuvant non-opioid medications for better pain control while attempting to minimize the dose of opiates.

Enter ketamine. Ketamine is a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist that was most used as a dissociative anesthetic. It provides excellent sedation, analgesia and amnesia while having a favourable hemodynamic profile and preserving airway reflexes.  It has become a favourite medication in emergency departments for procedural sedation as well as a useful behavioural takedown medication.  More recently, sub-dissociative doses of ketamine have been used to treat acute pain.

We have covered the use of ketamine multiple times on the SGEM, and there will be a list of those episodes at the end of this podcast. The most recent episode was SGEM#457 looking at nebulized ketamine.

Clinical Question: Is ketamine an effective adjunct agent along with morphine for acute pain control in the ED?

Reference: Galili et al. Low dose ketamine as an adjunct to morphine: a randomized controlled trial among patients with and without current opioid use. AEM Oct 2024.

  • Population: Patients over 18 years old in a single center in Denmark presenting to the ED with acute pain rated ≥5 on a numeric rating scale (NRS) from 0–10 that the ED physician decided required intravenous opioids.
  • Intervention: Administration of low-dose ketamine (LDK) 0.1 mg/kg intravenous (IV) bolus in addition to morphine IV dosed by clinical practice guidelines and adjusted if the patient is currently on opioid medication.
  • Comparison: Administration of isotonic saline as placebo with morphine
  • Outcome:
    • Primary Outcome: Pain reduction as measured by patient-reported pain score at 10 minutes after administration of analgesics.
    • Secondary Outcomes: Pain reduction at 20, 30, 45, 60, 90 and 120 minutes after medication administration; need for rescue opioids, adverse effects; patient satisfaction; provider satisfaction.
  • Type of Study: Single-center randomized double-masked placebo-controlled trial.

Dr. Stine Galili

This is an SGEMHOP, and we are pleased to have the lead author, Dr. Stine Galili, on the show. She is a Medical Doctor from Aarhus University, Denmark, with ten years of experience in emergency medicine and anesthesiology. Dr. Galili is back to being a specialty trainee in anesthesiology at Aarhus University Hospital after finishing PhD fellowship at the Research Center for Emergency Medicine at Aarhus University Hospital.

Authors’ Conclusions: “Low dose ketamine may be effective as an adjunct analgesic to morphine for short-term pain relief in treatment of acute pain in the ED for both patients with and without current opioid use.”

Quality Checklist for Randomized Clinical Trials:

  1. The study population included or focused on those in the emergency department. Yes
  2. The patients were adequately randomized. Yes
  3. The randomization process was concealed. Yes
  4. The patients were analyzed in the groups to which they were randomized. Yes
  5. The study patients were recruited consecutively (i.e. no selection bias). Unsure
  6. The patients in both groups were similar with respect to prognostic factors. No
  7. All participants (patients, clinicians, and outcome assessors) were unaware of group allocation. Yes
  8. All groups were treated equally except for the intervention. Yes
  9. Follow-up was complete (i.e. at least 80% for both groups). Yes
  10. All patient-important outcomes were considered. Yes
  11. The treatment effect was large enough and precise enough to be clinically significant. Yes
  12. Financial conflicts of interest. The authors declare no conflicts of interest.

Results: They were able to recruit 116 patients into the trial. The median age of patients was 51 years; 58% were male; 36% with chronic opioid use.

Key Result: Adding low-dose ketamine to morphine was superior to morphine alone in reducing pain in the ED.

  • Primary Outcome: Median pain reduction at 10 min
    • Ketamine and morphine 4 (3-6) vs morphine alone 1 (0-2). When looking at patients with current opiate use, pain score reduction was 5 (4-6) versus 1 (0-2), while for patients not currently using opiates the reduction was 4 (3-6) versus 1.5 (0-3).
  • Secondary Outcomes: At the 20 and 30-minute evaluations, there were statistically significantly lower pain scores in the ketamine group, but this effect was not statistically significant at 45, 60 and 120 minutes. For adverse effects, at 10 minutes, the ketamine group had more occurrence of nausea, vomiting and dissociation than placebo.  Other adverse effects, as well as patient and provider satisfaction, were not significantly different between the two groups.

Listen to the SGEM podcast to hear Stine answer our five nerdy questions.

1. Risk of Selection Bias: Not all eligible patients were included during recruitment​. Nine hundred patients were assessed for eligibility. Only 116 patients were included in the analysis (31 with current opioid use and 85 without). The main reasons for exclusion were a numeric rating scale (NRS ) score of < 5 or the ED physician deeming that opioid treatment was not necessary. There is subjectivity to the NRS and the physician’s judgment. This lack of objective standards could result in some selection bias.

2. Sample Size: It is also important to note you did not achieve the desired sample size. You assumed a mean decrease of 2.5 points on the NRS in the treatment group and an alpha value of 0.05. You would need to recruit 74 patients (37 in each treatment arm) to detect a mean difference of 1.5 points on the NRS with 90% power for the primary outcome using a two-sample t-test (assuming that pain reduction is normally distributed). Why were you not able to recruit (select) more patients for your study?

3. Unequal Groups: Whether because of recruiting methods or small sample size, the placebo group appears to be significantly older than the study group, by almost 20 years. Was recruiting continuous, and how were the patients identified, consented, and enrolled?

4. Ten-Minute Primary End-Point: The kinetics of the study medications would likely have a significant treatment effect. The primary outcome measures the analgesia response at 10 minutes, which would likely favour the faster onset ketamine, with the secondary outcomes showing the effect tapers off after 20 minutes. This could result in a Strawman comparison. This can occur when the intervention being tested (ketamine) is compared to an unfairly weak or inappropriate control. Why did you pick 10 minutes for the primary outcome?

5. Single Centre: This study was performed in a single center in Denmark, with a study population that made it difficult to recruit patients currently on opioids with acute pain, a major factor in the early termination of the study. The location may also affect the choice of opioid medication when short-acting agents like fentanyl may be preferable for acute pain in the ED. How translatable are these results to populations in other parts of the world where chronic opiate use is more prevalent, and the patient expectations about pain relief may be different?

Comment on Authors’ Conclusion Compared to SGEM Conclusion: We agree that LDK may help treat acute pain in the ED, but this study does not significantly move the needle to support its use.  Further, insufficient data was presented to support ketamine as an effective co-analgesic for patients currently on opioid medications.

SGEM Bottom Line: Adjunct use of ketamine may be a useful part of the ED physician’s analgesia toolbox for acute pain, but further study is needed to establish its role and support protocols for its use.

Case Resolution: Our patient received weight-based doses of morphine and ketamine with reasonably good effect, providing enough analgesia to obtain imaging and diagnose his complex forearm fracture.  He is appreciative of better analgesia than he has experienced with his prior accidents and asks you when he might be able to get another “slug of the good stuff.”

Dr. Neil Gasgupta

Clinical Application: Expanding the toolset of analgesia in acute pain is always a boon to ED physicians.  We can consider adding LDK to our multi-modal analgesia strategy in the emergency department.

What Do I Tell the Patient?  I understand you are in a great deal of pain, and we are going to do our best to help you feel better.  We can try a combination of medications to work in different ways to get you as much out of pain as possible – but rest assured we will come back and check on you and change course if our plan is not working.

Keener Kontest: Last week’s winner was a nurse, Bill Stoltzfus. He knew that nystagmus may unmask the IV Ketamine administration.

Listen to the SGEM podcast for this week’s question. If you know, then send an email to thesgem@gmail.com with “keener” in the subject line. The first correct answer will receive a shoutout on the next episode.

SGEMHOP: Now it is your turn SGEMers. What do you think of this episode on the LDK? Tweet your comments using #SGEMHOP.  What questions do you have for Dr. Galili and her team, ask them on the SGEM blog. The best social media feedback will be published in AEM.

Previous SGEM Episodes Discussing Ketamine:

  • SGEM#93: Ketamine, A Bad Reputation?
  • SGEM#111: Comfortably Numb – Low dose Ketamine as Adjunct for ED Pain Control
  • SGEM#114: Ketofol – Does It Take Two to Make a Procedure Go Right?
  • SGEM#130: Low Dose Ketamine for Acute Pain Control in the Emergency Department
  • SGEM#198: Better Slow Down – Push vs. Short Infusion of Low Dose Ketamine for Pain in the Emergency Department
  • SGEM#233: Larry in the Den with Kiwis (LDK) – Low Dose Ketamine vs. Opioids for Acute Pain
  • SGEM#356: Drugs are Gonna Knock You Out – Etomidate vs. Ketamine for Emergency Endotracheal Intubation

REMEMBER TO BE SKEPTICAL OF ANYTHING YOU LEARN, EVEN IF YOU HEARD IT ON THE SKEPTICS’ GUIDE TO EMERGENCY MEDICINE.