Dose Finding Ketamine ED pain

In Review

Lovett S, et al. "A randomized, noninferiority, controlled trial of two doses of intravenous subdissociative ketamine for analgesia in the emergency department". Acad Emerg Med. 2021. 28(6):647-654.
PubMed • Full text

Clinical Question

In adult patients with moderate to severe pain in the ED that receive a sub-dissociative dose of ketamine, is a lower dose of 0.15 mg/kg non-inferior to 0.30 mg/kg?

Bottom Line

The lower dose of 0.15 mg/kg ketamine was non-inferior to the higher dose of 0.30 mg/kg

Major Points

A common complaint in the emergency department, attempting to manage the pain in the short term may be challenging. With the ongoing issues with opioid use, one alternative for short term analgesia is ketamine. In another study, low-dose ketamine has demonstrating similar analgesic effects to morphine at 60 minutes. Sub-dissociative doses of ketamine ranging between 0.1 to 0.6 mg/kg have been explored for acute pain management but the optimal dose has yet to be confirmed. It is also unclear if ketamine has an analgesic ceiling, similar to NSAIDs such as Ketorolac Analgesic Ceiling.

This trial, published in 2020, explored two non-dissociative doses of 0.15 mg/kg vs. 30 mg/kg of ketamine for analgesia. Enrolling 49 patients in both arm, this non-inferior met their margin for the primary outcome of change in numerical rating scale (NRS) at 30 minutes, where the low dose NRS of 5 compared to 4.7 for the high dose of ketamine (mean difference -0.3, 95% CI −1.6 to 1.0). The trial also hit non-inferiority at 60 minutes as well. Looking at adverse events, there was greater adverse events in the high dose group at 15 minutes, but the difference resolved by 30 minutes. Patient was satisfaction stated that 76% of patients who received the low dose would accept the therapy whereas only 62% of patients who received the high dose.

There were some challenges, in this was a single centre, fairly small trial. Overall it suggests that the lower dose may be an effective management for acute pain in the short term.

Guidelines

American Academy of Emergency Medicine White Paper on Acute Pain Management in the Emergency Department (adapted, 2017):

Non-opioid Pharmacological Management:

• Non-steroidal anti-inflammatory drugs (NSIAD) at lowest effective doses
  • Topical NSAIDs or other topical analgesics (eg. lidocaine patches) if systemic NSAID contraindicated
• Oral/rectal acetaminophen
• Sub-dissociative dose ketamine (SDK) used alone or as part of a multimodal analgesic approach
• consider intravenous lidocaine for specific conditions (renal colic, herpetic/post-herpetic neuralgia) in patients without contraindications
• trigger point injections with local anesthetics
• nitrous oxide, alone or as an adjunct

Design

• Randomized, prospective, double-blinded, noninferiority trial
• N=98
  • Low dose ketamine 0.15 mg/kg (n=49)
  • High dose ketamine 0.30 mg/kg (n=49)
• Setting: single centre in USA
• Enrollment: October 2018 - September 2019
• Follow-up: 60-minutes
• Primary Outcome: Change in 11-point numeric rating scale numerical rating scale (NRS) pain score at 30 minutes

Population

Inclusion Criteria

• age 18 to 59 years
• presenting to the ED
• acute moderate to severe pain

Exclusion Criteria

• pregnancy or breastfeeding,
• weight <45 or >115 kg
• altered mental status
• known allergy to study drug
• history of chronic pain (chronic opioid use or actively following with a pain specialist)
• currently taking opioid medication
• renal dysfunction (serum creatinine >1.5 mg/dL or 132.6 μmol/L)
• hepatic insufficiency (aspartate transaminase/alanine transaminase >3× upper limit of normal value or history of end-stage liver disease or cirrhosis)
• history of a seizure leading to or during ED presentation
• traumatic head or eye injury, unstable vital signs (systolic blood pressure <90 or >180 mm Hg; heart rate <50 or >150 beats/min)
• active alcohol or drug use disorder
• acute alcohol or drug intoxication
• acute psychiatric illness

Baseline Characteristics

Ketamine 0.15 mg/kg (low dose) group displayed

• Demographics: mean age 39 years, 61% female
• Pre-existing conditions: 27% diabetes, 27% hypertension, 2% cancer, 2% anxiety, 4% heart failure, 6% depression, 23% obesity
• Baseline NRS pain score: 8.8
• Location of pain: 12% flank, 8% back, 29% musculoskeletal, 4% headache, 47% abdominal
• Duration of pain: 43% <24h, 18% 2 days, 39% 3-7 days

Interventions

• "Low" dose ketamine of 0.15 mg/kg IV over 15 minutes
• "High" dose ketamine of 0.30 mg/kg IV over 15 minutes

Outcomes

Comparisons are 0.15 mg/kg ketamine vs. 0.30 mg/kg ketamine.

Primary Outcomes

mean NRS at 30 minutes

5 vs. 4.7 (mean difference -0.3, 95% CI −1.6 to 1.0)

Secondary Outcomes

Baseline-adjusted mean difference in NRS score at 15 minutes

−1.2 (95% CI −2.4- to 0.1)

Baseline-adjusted mean difference in NRS score at 30 minutes

0.4 (95% CI −0.8 to 1.5)

RASS was similar between groups at all time periods.

Baseline-adjusted mean difference in NRS score at 60 minutes

0 (95% CI = −1.2 to 1.2)

Subgroup Analysis

Participants would take student agent again

76% vs. 62% (difference −13.9, 95% CI −32.6 to 4.9)

Adverse Events

Hearing Changes at 15 minutes

0% vs. 13% (difference 14.3, 95% CI 3.2 to 25.4)

Mood alterations at 15 minutes

12% vs 29% (difference 18.4, 95% CI 2.5 to 34.2)

Hallucinations 15 minutes

0% vs. 13% (difference 14.3, 95% CI 4.5 to 24.1)

All other adverse events were similar and the above statistically different events resolved at 30 and 60 minutes. Request for rescue analgesia was similar between groups.

Criticisms

• single centre trial
• convenience sample, bias may be introduced by excluding patients that present at night or on weekends
• groups had different baseline characteristics
• study duration only 60 minutes

Funding

• stated no grant or funding but in acknowledgements stated the senior author obtained research funding