Ketamine vs Opiates for ED Pain

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Karlow N. "A Systematic Review and Meta-analysis of Ketamine as an Alternative to Opioids for Acute Pain in the Emergency Department.". Acad Emerg Med. 2018. 25(10):1086-1097.
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Clinical Question

In adult patients that present to the Emergency Department, how does ketamine compare to opioids for acute analgesia in terms of effectiveness and adverse effects

Bottom Line

Low dose ketamine is non-inferior to morphine and could be considered as an alternative or adjunct to opiates for analgesia.

Major Points

The ongoing opioid epidemic adds increased pressure to find alternatives for analgesia, including for in the acute setting in Emerg. Ketamine has been used in several settings and indications, including induction as part of rapid sequence intubation, as a component of procedural sedation, and here at low dose (LDK) or at a sub-dissociative dose (SDK) for analgesia. No medical therapy is without potential side effects and ketamine can be associated with euphoria, disassociation, increased intracranial pressure, nausea, vomiting, laryngospasm, hypotension, and potentially respiratory depression. This trial included three articles, one from Iran and two from America, totalling 261 patients. Including trials that compared LDK/SDK of 0.3-0.5 mg/kg of ketamine to morphine equivalents of 0.1 mg/kg. he primary outcome was the mean change in pain scale rating and they used a non-inferiority margin of clinical significance of 1.4 on the pain scales. For their primary outcome they favoured ketamine (0.42 (95% IC -0.70 to 1.54)) but their confidence interval crossed unity so could not demonstrate superiority to opiates. Pooling adverse events across the trials was not possible as different measures was used for each trial but overall for any adverse drug events, ketamine was associated with more events with 42% vs. 24% for opiates, driven by dissociation and emergence syndrome associated to ketamine. The use of SDK for analgesia is supported by the American College of Emergency Physicians. [1] This systematic review and meta-analysis supports that LDK/SDK could be used as an alternative to or in concert with opiates for acute pain. There are several limitations with this trial, including the small number increasing the chance of bias including publication bias.


American Academy of Emergency Medicine White Paper on Acute Pain Management in the Emergency Department (adapted, 2017): [2]

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


  • Systematic review and meta-analysis of RCTs
  • N=261 (three trials)
    • Ketamine (n=132)
    • Opioid (n=129)
  • Setting: Emergency Departments in Iran and America
  • Analysis: non-inferiority margin of clinical significance 1.4
  • Primary Outcome: change in either the visual analog scale (VAS) score or numeric rating scale (NRS) pain scale from baseline to a second pain score within 60 minutes of intervention


Inclusion Criteria

  • Trial inclusion criteria:
    • RCTs
    • Compared the analgesic effect of IV LDK (≤0.5 mg/kg/dose administered as a bolus, slow push, or short infusion) to IV opioids (converted to morphine equivalent dosing);
    • ED setting
    • Adult (≥ 18 years old)
    • Patients presenting with acute pain, and
    • Published in English.

Exclusion Criteria

  • Trial exclusion criteria:
    • Did not report VAS or NRS pain scores
    • Protocol contained a coadministration of a phamacologically active substance less than 20 minutes after IV ketamine/opioid administration, or
    • Included a placebo comparison group.

Baseline Characteristics

  • Demographics: 54% male, mean age 33 years,
  • analgesic indication: long bone fracture, acute abdominal/flank/musculoskeletal pain


  • IV Ketamine 0.5 mg/kg or 0.3 mg/kg
  • IV Morphine equivalents 0.1 mg/kg


Comparisons are Ketamine vs. Morphine.

Primary Outcomes

Mean change in pain scale scores
0.42 (95% IC -0.70 to 1.54), favouring ketamine

Secondary Outcomes

Sensitivity analysis removing most heterogenous trial, mean change in pain scale
1.04 (95% CI 0.09 to 1.99), favouring ketamine

Adverse Events

All included trails included different measures for adverse events and requests for rescue medications

Any adverse event
42% vs. 24%


  • small number of trials included
  • included trials only comparing ketamine to morphine
  • no inter-rater reliability was assessed


  • not stated in journal or PROSPERO

Further Reading

PROSPERO registration CRD42017065303:

  1. [1] "Sub-dissociative Dose Ketamine for Analgesia Policy Resource and Education Paper (PREP), ACEP”
  2. [2] " AAEM White Paper on Acute Pain Management in the Emergency Department”