Study Finds No Statistically Significant Difference in Efficacy, Safety Between Intranasal Ketamine and IV Morphine

Research findings published in Pain Medicine did not show a statistically significant difference in efficacy or safety between intranasal ketamine and intravenous (IV) morphine when managing acute pain in the emergency department (ED). Despite these results, the authors suggest ketamine may remain a viable and potentially superior alternative to IV morphine; however, additional research is needed to confirm their hypothesis.¹

Previous research has demonstrated that ketamine has some effects in the early stages of acute pain treatment. A meta-analysis of 15 randomized controlled trials that treated 1768 patients in the ED with acute pain with either low-dose ketamine or morphine showed ketamine had better analgesic effects shortly after administration. Specifically, patients who received ketamine had lower numeric rating scale (NRS) scores at 30 minutes than those who received morphine (MD, −0.77 [95% CI, −0.93 to −0.61]; p < .00001), whereas morphine maintained better durable effects (MD, 0.33 [95% CI, 0.15 to 051]; p = .0003).²

Regarding complete resolution of pain, the patients in the ketamine groups performed better than those in the morphine groups at 15 minutes (RR 3.18, 95% CI 1.75 to 5.78; p = .0001). Those receiving ketamine had a lower incidence of adverse events (AEs) that required intervention (RR, 0.34 [95% CI, 0.18 to 0.66]; p = .001). In addition, subgroup analysis of intravenous ketamine showed that ketamine had lower visual analog scale (VAS) score than the morphine group at 30 minutes; however, also on the 30-min VAS score, intranasal ketamine analgesia was less effective than morphine.²

For the current study, the researchers aimed to compare the efficacy and safety of intranasal ketamine to IV morphine in patients admitted to the ED. This was a triple-blinded, placebo-controlled, randomized trial that enrolled consenting adult patients with moderate-to-severe pain (≥70 mm on a VAS) who were given either 0.1 mg/kg IV morphine and intranasal placebo or 1 mg/kg intranasal ketamine and IV placebo. Patients were monitored for vital signs, pain levels, and AEs for a 120-minute duration. The trial’s primary end point was the efficacy of intranasal ketamine compared with intravenous morphine in reducing pain (defined as achieving a ≥ 15-mm decrease in VAS pain score). Secondary end points included AEs and overall patient satisfaction.¹

A total of 68 participants (mean age: 43.5 ± 12.2 years) were enrolled and randomized equally. Groups were similar at baseline in mean age, sex, and pretreatment median pain levels.¹

The investigators observed no significant differences between the IV morphine and intranasal ketamine groups in the median [Intra quartile range (IQR)] values of time to onset of significant pain reduction (10.0 [5.0–20.0] vs 10.0 [5.0–15.0] minutes, respectively; P = .92), maximal pain reduction (30.0 [10.0–57.0] vs 20.5 [4.2–39.5] mm VAS, respectively; P = .18), and time to maximal pain reduction (105.0 [63.7–120.0] vs 90.0 [45.0–120.0] minutes, respectively; P = .35). Notably, there were no significant differences in frequency of AEs at 0, 60, and 120 minutes after administration.¹

Although the study did not demonstrate a statistically significant difference in efficacy or safety, the authors wrote that their findings still indicate that intranasal ketamine may be a viable—and potentially superior—alternative to IV-administered treatments for acute pain in the ED.¹

REFERENCES

1. Shopen N, Cohen N, Mizrahi M, Aviv Mordechai R, Ritter O, Werthein J, Cohen LA, Zeltser D, Halpern P. Intra-Nasal Ketamine Compared to Intravenous Morphine for Acute Pain in the Emergency Department: A Prospective, Triple Blind, Controlled Study. Pain Med. 2026 Jan 20:pnag012. doi:10.1093/pm/pnag012. Epub ahead of print. PMID: 41559921.

2. Guo J, Zhao F, Bian J, Hu Y, Tan J. Low-dose ketamine versus morphine in the treatment of acute pain in the emergency department: A meta-analysis of 15 randomized controlled trials. Am J Emerg Med. 2024;76:140–149. doi:10.1016/j.ajem.2023.11.056