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Date: September 22nd, 2015

Guest Skeptic: Dr. Marcel Emond is an Associate professor, Laval University. Emergency physician the level one trauma centre in Quebec City. Research Director of the Canadian Emergency Team Initiative (CETI). Marcel is also the lead for SGEM Global French.

If you are interested in evidence based medicine, shortening the KT window down to less than one year, speak another language and always wanted to podcast then contact me at TheSGEM@gmail.com with global in the subject line to discuss joining the SGEM Global Team.

Case: A 48-year-old man presents to the emergency department with acute lumbar pain after trying to lift a heavy garbage can. He says his pain is ten out of ten despite taking ibuprofen. He does not have any “red flags” and you are considering how to safely and effectively address his pain.

Background: Oligoanalgesia is defined as the lack of or inadequate pain control. There are many studies showing this is a big problem in the emergency department (Wilson and Pendleton, Motov and Khan) with some groups of patients being at greater risk for oligoanalgesia (elderly, women, mentally ill, certain ethnic groups, insurance status and children).

Screen Shot 2015-10-03 at 4.18.46 PM

Guitarist Nigel Tufnel

To raise awareness about oligoanalgeisa, the Joint Commission made pain the “fifth vital sign” in 2001. American physicians started being evaluated and compensated by means of patient satisfaction with emergency department pain control on factor. This provided misguided incentives for giving out opioids.

There are some disturbing trends reported by the Center for Disease Control (CDC) over the last few years. Between 1991 and 2010, prescriptions for opioid analgesics increased from about 75 million to 210 million according to the National Institute of Drug Abuse (NIDA).

This was followed by an increase in abuse and overdose. The CDC estimates that narcotic pain relievers now cause or contribute to nearly three out of four prescription drug overdoses and about 15,000 deaths per year

In October 2012, American College of Emergency Physicians (ACEP) published practice guidelines regarding opioid including these Level C recommendations:

  • Physicians should avoid the routine prescribing of outpatient opioids for a patient with an acute exacerbation of chronic non-cancer pain seen in the emergency department.
  • The Prescriber should consider the patient’s risk for opioid misuse, abuse or diversion.
  • If opioids are prescribed on discharge, the prescription should be for the lowest practical dose for a limited duration.

If you want to watch a YouTube video that combines ACEP recommendations with a Taylor Swift song then check out Michael Barton’s parody video called We are Never (Giving you Drugs in the ER).

Besides abuse, there are other well know limitations to using opioids including: allergy, respiratory depression, hypotension, nausea and vomiting.

generics-ketamine-lg-1Other options to manage acute pain in the emergency department are being explored. Ketamine is one of those options being actively studied. Ketamine is a NMDA receptor antagonist that exerts sedative, amnestic, and analgesic effects as a dissociative anesthetic. It has been used for rapid sequence and delayed sequence intubation.

However, ketamine has a historic bad reputation for raising intracranial pressure. We now know ketamine does not deserve this bad reputation (SGEM#93).

The use of Ketamine in the emergency department has been expanding lately. One area has been for procedural sedation. This was covered on SGEM#114: Ketofol – Does It Take Two to Make a Procedure Go Right?

SGEM-HOP-SAEM-logo-227x300A recent SGEMHOP covered a systematic review on sub dissociative-dose ketamine as an adjunct for pain control. There were only 4 studies included with just over 400 patients. The bottom line from SGEM#111 was that 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.

To address the lack of high-quality papers on ketamine for pain control in the emergency department we are going to cover two papers today.

Question#1: Is a sub dissociative dose of ketamine equivalent to a standard dose of morphine for control of moderate to severe pain in the emergency department?

Reference: Motov et al. Intravenous Subdissociative-Dose Ketamine Versus Morphine for Analgesia in the Emergency Department: A Randomized Controlled Trial. Ann Emerg Med 2015

  • Population: Patients aged 18 to 55 years who presented to emergency department of a single-center teaching hospital with acute abdominal, flank, back, or musculoskeletal pain score of five or more on a standard 11-point (0 to 10) numeric rating scale and required opioid analgesia, as determined by the treating attending physician.
    • Exclusions: Pregnancy, breast-feeding, altered mental status, allergy to morphine or ketamine, weight ≤46 kg or ≥115 kg, unstable vital signs (systolic blood pressure <90 or >180 mm Hg, pulse rate <50 or >150 beats/minute, and respiration rate <10 or >30 breaths/minute), and 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 (within 4 hours) opioid use.
  • Intervention: Ketamine at 0.3 mg/kg intravenously.
  • Comparison: Morphine at 0.1 mg/kg intravenously.
  • Outcome:
    • Primary: Comparative reduction of numeric rating scale pain scores at 30 minutes.
    • Secondary: Incidence of rescue analgesia at 30 and 60 minutes.

Authors’ Conclusions: “Subdissociative intravenous ketamine administered at 0.3 mg/kg provides analgesic effectiveness and apparent safety comparable to that of intravenous morphine for short-term treatment of acute pain in the ED.

checklist-cartoonQuality Checklist for Randomized Clinical Trials:

  1. The study population included or focused on those in the ED. 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). No
  6. The patients in both groups were similar with respect to prognostic factors. Yes
  7. All participants (patients, clinicians, 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

Key Results: Ninety patients (45 ketamine and 45 morphine) were enrolled in this study. The patients’ mean age was around 35 years of age and about two-thirds of patients were women. There were no differences between the groups in terms of demographic characteristics or baseline vital signs, pain scores, or chief complaint.

  • Primary Outcome: Change in mean pain scores was not significantly different in the ketamine and morphine groups: 8.6 versus 8.5 at baseline (mean difference 0.1; 95% CI: 0.46, 0.77) and 4.1 versus 3.9 at 30 minutes (mean difference 0.2; 95% CI: 1.19, 1.46; P=0.97). The 95% CI for the mean difference at 30 minutes according to the mixed-model regression SD was –0.77 to 1.05.
  • Secondary Outcomes: No difference in the incidence of rescue fentanyl analgesia at 30 or 60 minutes. No statistically significant or clinically concerning changes in vital signs were observed. No serious adverse events occurred in either group. However, patients in the ketamine group reported increased minor adverse effects (dizziness, disorientation) at 15 minutes post-drug administration.

Screen Shot 2015-04-25 at 3.11.12 PMNot all emergency department patients with moderate to severe pain respond to or even tolerate opioids at standard doses. While some patients with high opioid tolerance prefer higher than standard doses, emergency staff do not.

There are few analgesics we can offer our patients and this trial adds more to the accumulating evidence that ketamine at a sub dissociative dose is a safe and effective alternative. Here are some limitations with this article:

  1. Single Centre  This was a single center study done in New York so the results may not reflect your patient population.
  2. Consecutive Patients: This was a convenience sample with patients being enrolled at various times of the day when both a study investigator and an emergency department pharmacist were available for medication preparation. This has the potential to introduce selection bias that would move us away from the truth.
  3. Superior, Equivalence or Inferior? The author says it was an equivalence study. Equivalence trials are designed to confirm the absence of a significant clinical difference between treatments (Lesaffre E). To conclude that the two treatments are equivalent, then the two-sided 95% confidence interval should lie entirely within the interval −Δ to + Δ. They set the minimal clinically meaningful difference at 1.3 on the numeric rating scale. This was an equivalence study.
  4. Adverse Events: We cannot just consider potential benefit but we must also consider potential harm. There were statistically significant more adverse events in the ketamine group. This mainly consisted of dizziness, disorientation and mood changes. Remember that the study was powered to find a 1.3 difference on the numeric rating scale not for adverse events.
  5. Blinding: The study was possibly un-blinded due to some patients in the ketamine group exhibiting nystagmus, a ketamine-specific reaction.
Dr. Marcel Emond

Dr. Marcel Emond

Comment on Authors’ Conclusion Compared to the SGEM Conclusion: We agree that a sub dissociative dose of ketamine (0.3mg/kg) appears effective for treatment of acute pain in the emergency department and has a similar reduction in a numeric rating scale to morphine. However, we are not as confident in commenting on safety as the study was not powered for this result and there were more adverse reactions with ketamine.

 

 

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.

Clinical Application: I will consider sub dissociative dose ketamine as a second line agent for patients who cannot be treated with an opioid.

What Do I Tell My Patient? We are going to give you some morphine to see if it improves your back pain? 

Question#2: Is the addition of low-dose ketamine to morphine superior to morphine alone in the emergency department pain patients?

Reference: Beaudoin et al. Low-dose ketamine improves pain relief in patients’ receving intravenous opiods for acute pain in the emergency department: results of a randomized, double-blind, clinical trial. Acad Emerg Med Nov 2014

  • Population: English-speaking adults (18 to 65 years old), moderate to severe pain (NRS>5/10) for < seven days, deemed appropriate for IV opioid analgesia by ED physician.
    • Exclusions: Neurologic, respiratory or hemodynamic compromise; known or suspected allergy to ketamine or morphine; acute psych illness; history of stroke; renal insufficiency; liver failure; coronary artery disease; pregnant; breastfeeding; pain not moderate; severe with just IV opioids/other adjuncts; or unable to provide consent.
  • Intervention:
    • Group 1: Morphine 0.1mg/kg IV (max 10 mg) + ketamine 0.15mg/kg IV
    • Group 2: Morphine 0.1mg/kg IV (max 10mg) + ketamine 0.3mg/kg IV
  • Comparison: Morphine 0.1mg/kg IV (max 10mg) + normal saline
  • Outcome:
    • Primary: Summed pain-intensity difference (SPID) at two hours (measured q30min) of >33%. This is different from the numeric rating scale from 0-10 that most of us are familiar with and was used in the last study. The clinically important change on the NRS is 1.3. The SPID is another recognized method to quantify clinically important difference in pain (Farrar et al 2000). It has been previously established that a 33%SPID represent a clinically important measurement in pain outcomes (Farrar et 2003).
    • Secondary: Numeric rating scale (NRS) score at each time point (0-10), total pain relief (5-point scale), adverse events, amount of rescue analgesia needed, time to rescue analgesia and global analgesia effectiveness (Silverman integrated analgesic [SIA] assessment score = SPID + rescue analgesia usage).

Authors’ Conclusions: Low-dose ketamine is a viable analgesic adjunct to morphine for the treatment of moderate to severe acute pain. Dosing of 0.3 mg/kg is possibly more effective than 0.15 mg/kg, but may be associated with minor adverse events. Future studies should evaluate additional outcomes, optimum dosing, and use in specific populations.

checklist-cartoonQuality Checklist for Randomized Clinical Trials:

  1. The study population included or focused on those in the ED. 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. No
  5. The study patients were recruited consecutively (i.e. no selection bias). No 
  6. The patients in both groups were similar with respect to prognostic factors. Unsure. Demographics were the same but we do not know about non-opioid analgesics used prior to ED presentation.
  7. All participants (patients, clinicians, outcome assessors) were unaware of group allocation. Yes
  8. All groups were treated equally except for the intervention. Unsure. Rescue analgesia was left to the treating physician.
  9. Follow-up was complete (i.e. at least 80% for both groups). Yes. For the primary outcome at 30 mintues but they did lose some patients by 2hrs.
  10. All patient-important outcomes were considered. No. They did not specifically ask the patient if needed more medication.
  11. The treatment effect was large enough and precise enough to be clinically significant. Yes

Key Results: 78 patients enrolled, 69 were randomized and 60 completed the study (20 per group).

  • Primary Outcomes: Combo treatment with morphine plus ketamine was superior to morphine alone. There was no difference observed between the higher vs. lower dose ketamine groups.

Screen Shot 2015-09-22 at 8.58.15 PM

  • Secondary Outcomes: Similar numbers of patients received rescue analgesia: There were more adverse events in the ketamine groups.

Screen Shot 2015-04-25 at 3.11.12 PMCombining analgesics in the emergency department is not new and neither is the concept of low-dose ketamine (0.15 mg/kg) IV as an adjunct to morphine IV in treating acute pain. Here are five limitations with this article:

  1. Small/Single Centre/Many Exclusions: This was a small (20 in each group) single center study done in Rhode Island and therefore the results may not reflect your patient population. In addition, there were so many exclusion criteria it would be hard to find many patients that fit the strict study protocol
  2. Side Effects: There were more adverse events in the ketamine+morphine group than the morphine group alone. These small studies are not powered for safety; however, ketamine has a fairly long history of being a safe drug.
  3. Multiple Drugs: Going from monotherapy to combination therapy increases the risk of drug error. We need to be very careful when making systems more and more complex. Ketamine also comes in different concentrations that could compound the chance of error.
  4. What are we Trying to Treat? The right dose of morphine for the patient in pain is when they no longer request pain medication. We get fixated on the mg/kg rather than the looking at the patient.
  5. Now What? So after we have successfully treated the acute pain in the emergency department what do we use when discharging them home for pain control? How long will their treatment last? Will the combination treatment result in less pain medication needed in the near term. All of these questions and more remain unanswered.

Comment on Authors’ Conclusion Compared to the SGEM Conclusion: We generally agree with the author’s conclusions.

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.

Clinical Application: I am going to use morphine as my first line agent unless there is a contraindication to using an opioid.

Marcel Emond

Dr. Marcel Emond

What Do I Tell My Patient? If your back pain does not improve with morphine we can always try an additional medication called ketamine.

Case Resolution: The 48 year old man with acute lumbar pain after trying to lift a heavy garbage can is given 0.1mg/kg of morphine IV. His pain after 30 minutes is down to 3/10 and he wants to go home. You write a prescription for a short course of non-steroidal anti-inflammatories and opioids. He is instructed to follow-up with his primary care provider next week and return to the emergency department if he has increased pain, decreased function, red flags or is worried.

Screen Shot 2013-06-03 at 1.48.37 PMOther FOAMed Resources on Ketamine for Analgesia:

Keener Kontest: Winner last weeks’ was Dr. Steven Joseph from South Huron Hospital. He knew it was Dr. Joseph Giordano, Chief of Trauma Surgery at George Washington University Medical Center who put a chest tube into President Ronal Reagan after he was shot.

To play the keener contest listen to the podcast for the question. If you know the answer then send me an email to TheSGEM@gmail.com with “keener” in the subject line. The first person to correctly answer the question will receive a cool skeptical prize.

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

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