Intravenous Subdissociative-Dose Ketamine Versus Morphine for Analgesia in the Emergency Department: A Randomized Controlled Trial

doi:10.1016/j.annemergmed.2015.03.004

Annals of Emergency Medicine

Volume 66, Issue 3, September 2015, Pages 222-229.e1

Presented at the New York American College of Emergency Physicians conference, July 2014, Bolton Landing, NY; the Society for Academic Emergency Medicine national conference, May 2014, Dallas, TX; and the Society for Academic Emergency Medicine Mid-Atlantic regional conference, February 2014, Philadelphia, PA.

https://doi.org/10.1016/j.annemergmed.2015.03.004 Get rights and content

Study objective

We assess and compare the analgesic efficacy and safety of subdissociative intravenous-dose ketamine with morphine in emergency department (ED) patients.

Methods

This was a prospective, randomized, double-blind trial evaluating ED patients aged 18 to 55 years and experiencing moderate to severe acute abdominal, flank, or musculoskeletal pain, defined as a numeric rating scale score greater than or equal to 5. Patients were randomized to receive ketamine at 0.3 mg/kg or morphine at 0.1 mg/kg by intravenous push during 3 to 5 minutes. Evaluations occurred at 15, 30, 60, 90, and 120 minutes. Primary outcome was reduction in pain at 30 minutes. Secondary outcome was the incidence of rescue analgesia at 30 and 60 minutes.

Results

Forty-five patients per group were enrolled in the study. The primary 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% confidence interval −0.46 to 0.77) and 4.1 versus 3.9 at 30 minutes (mean difference 0.2; 95% confidence interval −1.19 to 1.46; P=.97). There was 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. Patients in the ketamine group reported increased minor adverse effects at 15 minutes post–drug administration.

Conclusion

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.

Introduction

The provision of adequate, safe, and timely analgesia is a core component of patient care in the emergency department (ED). Ketamine is a noncompetitive N-methyl-d-aspartate and glutamate receptor antagonist that decreases central sensitization, “wind-up” phenomena, and pain memory.1, 2 As a phencyclidine-like dissociative agent, ketamine possesses a number of pharmacologic characteristics useful to the emergency physician. At doses commonly used for procedural sedation (1 to 1.5 mg/kg), ketamine produces a trancelike cataleptic state, whereas at subdissociative doses (0.1 to 0.6 mg/kg; most commonly 0.3 mg/kg) it maintains potent analgesic and amnestic effects that are accompanied by preservation of protective airway reflexes, spontaneous respiration, and cardiopulmonary stability.3, 4, 5

Editor’s Capsule Summary

What is already known on this topic

Ketamine is a potent analgesic.

What question this study addressed

Is ketamine more or less effective than morphine in treating acute pain?

What this study adds to our knowledge

In this trial, 90 adults with acute pain were randomized in the emergency department in double-blind fashion to receive either ketamine at 0.3 mg/kg or morphine at 0.1 mg/kg intravenously. Pain score reductions and the proportion of patients with complete pain relief were statistically similar between groups, with reasonable power to exclude clinically important differences. There were no serious adverse events, although ketamine subjects more frequently experienced dizziness and disorientation.

How this is relevant to clinical practice

This small but well-designed trial suggests generally similar analgesic equivalence between ketamine at 0.3 mg/kg and morphine at 0.1 mg/kg intravenously.

In subdissociative doses, ketamine has been shown to confer potent, opioid-sparing effects and to be effective in providing analgesia for pain that is poorly controlled by opioids in a variety of settings outside of the ED.6, 7, 8, 9 Emerging data on the use of subdissociative-dose ketamine as a single agent in out-of-hospital and austere settings, where it has compared favorably to morphine, support a role for ketamine in the analgesic armamentarium of emergency physicians. Two retrospective studies demonstrated that subdissociative-dose ketamine in the dosing range of 0.1 to 0.6 mg/kg, when administered as an adjunct to opioid analgesics, significantly reduced pain reported by patients in the ED.10, 11

In our study, we hypothesize that a subdissociative dose of ketamine administered as a single agent at 0.3 mg/kg will provide relief similar to that of a standard dose of morphine at 0.1 mg/kg for acute moderate to severe pain in the ED setting. The primary outcome used to test our hypothesis is the comparative reduction in participants’ pain scores at 30 minutes from medication administration.

Section snippets

Study Design

This was a prospective, randomized, double-blind trial comparing the safety and efficacy of subdissociative intravenous-dose ketamine with intravenous morphine for acute pain in the ED. This study was approved by the Maimonides Medical Center institutional review board and registered with clinicaltrials.gov (NCT01835262). The study was conducted and is reported according to the Consolidated Standards of Reporting Trials Group.¹²

Study Setting and Selection of Participants

The study facility is a 711-bed community teaching hospital with an

Results

Ninety patients (45 ketamine and 45 morphine) were enrolled in the study. The patients’ mean age was 35 and 36 years, respectively (SD=10 for both groups); 67% and 62% were women, respectively. There were no differences between the groups in terms of demographic characteristics or baseline vital signs, pain scores, or chief complaint (Table 1). The patient flow diagram is illustrated in Figure 1.

As shown in Table 2, patients’ reported pain scores at time 0 were similar in the 2 groups: the mean

Limitations

This was a single-center study in which patients were enrolled as a convenience sample according to predetermined inclusion and exclusion criteria. Sample size was near minimum for adequate power (80%). There was a potential for unblinding because some participants exhibited ketamine-specific reactions such as nystagmus. Patient enrollment was restricted to time frames in which both a member of the research team and pharmacy team were available.

Discussion

Subdissociative ketamine has been shown to mitigate pain and reduce opioid consumption in patients with chronic pain (neuropathic pain), cancer pain, and acute postoperative pain, as demonstrated in the anesthesia and surgical literature.17, 18, 19, 20 There have been several published retrospective studies and prospective trials examining ketamine used for analgesia in ED patients. Lester et al¹⁰ evaluated 35 patients who received subdissociative ketamine for analgesia and reported that 19

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Cited by (100)

“Low-dose ketamine versus morphine in the treatment of acute pain in the emergency department: A meta-analysis of 15” randomized controlled trials
2024, American Journal of Emergency Medicine
To compare the effectiveness and safety of ketamine and morphine in adult patients with acute pain in emergency department (ED) by using a meta-analysis method.
This study was based on the Cochrane methodology for conducting a meta-analysis. Only randomized controlled trials (RCTs) were eligible for this study, with an experimental group that received low-dose ketamine and a control group that received morphine. The participants were adults who had acute pain in the ED. The primary outcome measures were the numeric rating scale (NRS) and visual analog scale (VAS). The secondary outcome measures were the complete resolution of pain, NRS reduction ≥3 points, NRS reduction ≥50% or 60%, change of NRS score, change of VAS score, rescue analgesia, satisfaction and adverse events. Subgroup analysis was performed for studies with intravenous and intranasal administration of ketamine. The Review Manager Database was used to analyze the included studies.
15 RCTs involving 1768 patients were included. The ketamine group had lower NRS scores than morphine group at 30 min (MD, −0.77 [95% CI, −0.93 to −0.61]; p < 0.00001), while the morphine had better analgesic effects at 120 min after treatment (MD, 0.33 [95% CI, 0.15 to 051]; p = 0.0003). The subjects of complete resolution of pain in the ketamine group performed better than those in the morphine group at 15 min (RR 3.18, 95% CI 1.75 to 5.78; p = 0.0001). Compared with the morphine group, the ketamine group had a lower incidence of adverse events requiring intervention (RR, 0.34 [95% CI, 0.18 to 0.66]; p = 0.001). Subgroup analysis of intravenous ketamine showed that ketamine had lower VAS score than the morphine group at 30 min. However, also on the 30-min VAS score, intranasal ketamine analgesia was less effective than morphine.
Ketamine had better analgesic effects in the early stages after treatment, while morphine maintained more durable effects. Compared with morphine, ketamine had a lower incidence of adverse events requiring intervention. The results of subgroup analysis showed that intravenous administration of ketamine was more effective than intranasal administration.
Efficacy of analgesic and sub-dissociative dose ketamine for acute pain in the emergency department
2023, American Journal of Emergency Medicine
Acute pain accounts for over 70% of Emergency Department (ED) visits. Sub-dissociative dose ketamine (0.1–0.6 mg/kg) is safe and effective for the management of acute pain in the ED. However, the optimal dose of intravenous ketamine that provides effective analgesia and minimizes the risk of adverse effects has yet to be identified. The objective of this study was to describe an effective analgesia dose range of IV ketamine for acute pain in the ED.
This multi-center, retrospective cohort study evaluated adult patients who received analgesic and sub-dissociative dose ketamine for the management of acute pain between May 5, 2018, and August 30, 2021, in 21 emergency departments at academic, community, and critical access hospitals across four states. Patients were excluded if they received ketamine for an indication other than pain, such as procedural sedation or intubation, or for whom there was incomplete documentation for the primary outcome. Patients who received a ketamine dose <0.3 mg/kg were stratified into the low-dose group, and those who received a dose of 0.3 mg/kg or higher to the high-dose group. The primary outcome was change in pain scores within 60 min using a standard 11-point numeric rating scale (NRS). Secondary outcomes included incidence of adverse effects and use of rescue analgesics. Continuous variables were compared between dose groups using student t-test or Wilcoxon Rank-Sum test. Linear regression was used to assess the association between the change in NRS pain scores within 60 min and dose after adjusting for baseline pain, requiring an additional dose of ketamine, and receiving an opioid.
From 3796 patient encounters screened for receipt of ketamine, 384 patients met inclusion criteria including 258 in the low-dose group, and 126 in the high-dose group. The primary reason for exclusion was incomplete documentation of pain scores, or ketamine used for sedation. Median baseline pain scores were 8.2 in the low-dose group and 7.8 in the high-dose group (difference 0.5; 95% CI 0 to 1, p = 0.04). Both groups demonstrated significant reductions in their mean NRS pain scores within 60 min following the first administration of IV ketamine. There were no differences in the change in pain scores between both groups (−2.2 vs −2.6, mean difference 0.4, 95% CI -0.4 to 1.1, p = 0.34). Use of rescue analgesics (40.7% vs 36.5%, p = 0.43) and adverse effects were similar between groups, including early discontinuation of the ketamine infusion (37.2% vs. 37.3%, p = 0.99). Overall, the most common adverse effects were agitation (7.3%) and nausea (7.0%).
The analgesic efficacy and safety of high-dose sub-dissociative ketamine (≥0.3 mg/kg) was not superior to low-dose (< 0.3 mg/kg) for the management of acute pain in the ED. Low-dose ketamine <0.3 mg/kg is an effective and safe pain management strategy in this population.
Oral Aspirin/ketamine versus oral ketamine for emergency department patients with acute musculoskeletal pain
2022, American Journal of Emergency Medicine
The purpose of this study is to investigate if an orally administered combination of aspirin and ketamine will provide better analgesia than a ketamine alone in adult patients presenting to the Emergency Department (ED) with acute musculoskeletal pain.
We conducted a prospective, randomized, open-label trial of ED patients aged 18 and older presenting with moderate to severe acute musculoskeletal pain as defined by an 11-point numeric rating scale (NRS) with an initial score of ≥5. Patients were randomized to receive either 324 mg of VTS-Aspirin™ and 0.5 mg/kg of oral ketamine (AOK) that is directly swallowed or 0.5 mg/kg of oral ketamine (OK) alone that is swished first and then swallowed. Patients were assessed at baseline, 30, 60, 90, and 120 min. The primary outcome was a difference in pain scores between the two groups at 60 min post-administration. Secondary outcomes included adverse events and the need for rescue analgesia.
We enrolled 60 patients in the study (30 per group). The difference in mean pain scores at 60 min between the AOK and OK groups was 2.6 [95% CI: 1.38–3.77] showing a lower mean pain score in the OK group. At 60 min, the AOK group had a change in mean pain score from 8.4 to 6.3 (difference 2.1; 95% CI: 1.35–3.00). The OK group had a change in mean pain score from 7.8 to 3.7 (difference 4.1, 95% CI: 3.25–4.90). No clinically concerning changes in vital signs were observed. No serious adverse events occurred in either group. The most commonly reported adverse effects were dizziness and fatigue. None of the participants required rescue analgesia at 60 min post-medications administration.
The administration of an oral combination of VTS-Aspirin ™ and ketamine resulted in less analgesia compared to oral ketamine alone, for the short-term treatment of moderate to severe acute musculoskeletal pain in the ED.
Clinicaltrials.gov Registration: NCT04860804
Acute pain management in the Emergency Department: Use of multimodal and non-opioid analgesic treatment strategies
2022, American Journal of Emergency Medicine
Pain is a common complaint precipitating emergency department (ED) visit, occurring in more than half of patient encounters. While opioids are effective for acute pain management in the Emergency Department (ED), the associated adverse effects, including respiratory and central nervous system depression, nausea, vomiting, and constipation, and physical manifestations of use, including tolerance, dependence and misuse leading to overdose and death, accentuate the need for non-opioid alternatives and/or multi-modal pain control. This review will provide examples of non-opioid pain management strategies and multimodal regimens for treatment of acute pain in the ED.
Analgesic Efficacy of Oral Aspirin/Ketamine Combination for Management of Acute Musculoskeletal Pain in the Emergency Department – A Proof of Concept Pilot Study
2022, Journal of Emergency Medicine
Musculoskeletal pain (MSK) affects one out of three adults and is the most common source of significant long-term pain, physical disability, and under-treatment in the emergency department (ED).
We aimed to assess the analgesic efficacy of a combination of oral VTS-Aspirin® (Vitalis Analgesics, New York, NY) and ketamine in managing acute MSK pain in adult ED patients.
This was a prospective, proof-of-concept, single-arm, pilot study evaluating the analgesic efficacy of a single dose of oral combination of VTS-Aspirin and ketamine in adult ED patients with acute moderate-to-severe MSK pain. The primary outcome included the difference in pain scores on an 11-point numeric pain rating scale at 60 min. Secondary outcomes included the need for rescue analgesia, the occurrence of adverse events at 60 min, and a change in pain scores at 120 min.
We enrolled 25 subjects in the study. The mean baseline pain score was 8.6 and the mean pain score at 60 min decreased to 4.8. The oral ketamine dose ranged from 24 mg to 50 mg, with a mean dose of 37.8 mg. No clinically concerning changes in vital signs were noted. No serious adverse events occurred in any of the subjects. Majority of adverse effects were transient and weak in intensity.
We demonstrated that administration of an oral combination of VTS-Aspirin and ketamine to adult ED patients with acute MSK pain resulted in clinically significant pain relief in 80% of enrolled subjects.
Sub dissociative dose of ketamine with haloperidol versus fentanyl on pain reduction in patients with acute pain in the emergency department; a randomized clinical trial
2022, American Journal of Emergency Medicine
Ketamine is known to be an effective factor in reducing pain without significant side effects.
One of the limited side effects of Ketamine is agitation. Due to the reduction of this symptom with Haloperidol, we decided to design a randomized clinical trial to compare the analgesic effect of Ketamine with Haloperidol and Fentanyl in reducing acute pain and its complications.
In this study, 200 adult patients who presented to the emergency department with acute pain are examined. They are randomly divided into two groups. One group received intravenous Ketamine with Haloperidol and the other group received intravenous Fentanyl. Patients are then compared for their pain score before and after administration of the drugs, as well as the side effects they experienced.
There was no significant difference between the mean scores of initial pain in the two groups, but at all intervals of 5, 10, 15 and 30 min after injection, the mean of pain scores of patients in the group receiving Ketamine and Haloperidol were lower. The need for injection of rescue analgesic was 9% in the Ketamine and Haloperidol group and 34% in the Fentanyl group. The mean agitation score did not differ between the two groups except in the tenth minute. At tenth minute, the mean agitation score of the Ketamine group was higher.
Ketamine works better than fentanyl in controlling acute pain, and limited side effect of agitation can be controlled if injected with haloperidol. Due to its better function and fewer side effects, it seems that in controlling acute pain, Ketamine along with Haloperidol can be a good alternative to opioids.

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: Please see page 223 for the Editor’s Capsule Summary of this article.

: Supervising editor: Steven M. Green, MD

: Author contributions: SM, VC, IP, AL, ES-Z, and CF conceived the study, designed the trial, and obtained research funding. SM, BR, AL, and CF supervised the conduct of the trial and data collection. BR, IP, CM, and VT undertook recruitment of patients and managed the data, including quality control. AL and PH provided statistical advice on study design and data analysis. BR drafted the article, and all authors contributed substantially to its revision. SM takes responsibility for the paper as a whole.

: Funding and support: By Annals policy, all authors are required to disclose any and all commercial, financial, and other relationships in any way related to the subject of this article as per ICMJE conflict of interest guidelines (see www.icmje.org). The authors have stated that no such relationships exist and provided the following details: This research was funded, in part, by an unrestricted grant from the New York Department of Health’s Empire Clinical Research Investigator Program.

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Pain management and sedation/original researchIntravenous Subdissociative-Dose Ketamine Versus Morphine for Analgesia in the Emergency Department: A Randomized Controlled Trial

Study objective

Methods

Results

Conclusion

Introduction

Editor’s Capsule Summary

Section snippets

Study Design

Study Setting and Selection of Participants

Results

Limitations

Discussion

Pain

Am J Emerg Med

Pain

Am J Emerg Med

Ann Emerg Med

Pain

Am J Emerg Med

Am J Emerg Med

Pain

J Pain

Am J Emerg Med

Am J Emerg Med

Pain management and sedation/original research
Intravenous Subdissociative-Dose Ketamine Versus Morphine for Analgesia in the Emergency Department: A Randomized Controlled Trial