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Three Part Question

In [adult patients presenting to ED with acute severe pain] is [intranasal ketamine] as [effective as intravenous opiates for pain reduction]?

Clinical Scenario

A 24-year-old female has presented to the Emergency Department (ED) with a distal radius fracture. She refuses cannulation due to a needle phobia but remains in severe acute pain despite the use of oral analgesics. You are aware of the increasing off-license use of intranasal (IN) ketamine for acute severe pain and wonder if it provides as effective pain relief as intravenous (IV) opiates for this patient.

Search Strategy

OVID was used to search EMBASE and MEDLINE on the 24th of March 2025, with no language or date restrictions, with the following search terms:

([emergency department.mp. or exp emergency ward/] OR A&E.mp. OR ED.mp. OR ER m.p. OR exp Emergency Service, Hospital/) AND ([acute pain.mp. or exp pain/] OR severe pain.mp.) AND ([exp ketamine/ or ketamine.mp. AND exp intranasal drug administration/ or intranasal.mp.] OR [intranasal ketamine.mp.]) LIMIT to all adult (19 plus years)

The reference lists of relevant abstracts were also screened for further studies.

Search Outcome

This search strategy identified 56 relevant studies. Duplicates (n = 12) were removed. After reviewing titles and abstracts, 29 studies were excluded as they were not applicable to our research question. Fifteen studies progressed to full-text review, of which one was excluded due to participants being under 18, and nine for not fully addressing the three-part question.

A total of five randomised controlled trials (RCT’s) were included in the final analysis (Table 1). The primary outcome measured for all studies was change in patient reported pain scores measured through visual analogue scale (VAS) or numeric rating scale (NRS).

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Tongbua et al 2022 Thailand	ED patients aged ≥65 years presenting with chief complaint of musculoskeletal pain within 7 days of known injury or scoring ≥5 on an 11-point NRS N= 74 Mean age: 73.4 years Male: 21.6% Two intervention groups (A and B) A = ketamine 0.3mg/kg intranasally + 10ml of normal saline solution intravenously B = morphine 0.1mg/kg intravenously in up to 10ml of normal saline solution	RCT Level II	Subjective pain improvement, NRS	No significant difference in mean pain scores at baseline (p > 0.05) No significant difference in mean pain reduction scores at 30 minutes or at all other times (45, 60, 75, 90, 105 and 120 minutes) IN ketamine had faster acceptable pain reduction (>3 NRS points) faster than IV morphine (45 minutes as opposed to 75 minutes)	Wide exclusion criteria (<65 years, co-morbidities, suspected COVID-19) Small sample size (n = 74) Convenience sampling Short assessment period of two hours – cannot exclude delayed adverse events or monitor pain relief beyond
			Requirement for rescue analgesia	No significant difference in rescue analgesia requirements
			Adverse events, Side Effect Rating Scale for Dissociative Anaesthetics (SERSDA) and Richmond Agitation Sedation Scale (RASS)	No significant increase in adverse effects between groups
Shimonovich et al 2016 Israel	ED patients aged 18-70 years presenting with mild to moderate blunt trauma (sustained in road, workplace and home accidents) causing moderate to severe orthopaedic pain, defined as ≥80mm on a 100mm visual analogue scale (VAS) N = 90 Mean age: 39.4 years Male: 68% Three intervention groups (A, B and C) A = 1mg/kg ketamine intranasally (n=24) B = 0.15mg/kg morphine intramuscularly (27) C = 0.1 mg/kg morphine intravenously (n=24)	RCT Level II	Subjective pain improvement, VAS	No significant difference between baseline VAS (p = 0.698) No significant difference between time to onset between IV ketamine (A) and (C) IV morphine (p = 0.300) No significant difference in pain reduction IN ketamine (A) and IV morphine (C) (p = 0.300) No significant reduction between time to maximal pain reduction between IN ketamine (A) and IV morphine (C) (p = 0.386)	No blinding Convenience sampling Small sample size (n = 90) Short follow up – 1 hour Wide exclusion criteria (haemodynamic instability, confusion, extremes of body weight) Fifteen patients excluded, disproportionately from IN ketamine group (n = 10) Only included orthopaedic limb and spinal injuries
			Subjective patient self-reported satisfaction, on a 100mm VAS 1 hour after drug administration	No significant difference between patient satisfaction between groups (P = 0.259)
			Adverse effects, recorded one hour after administration utilising the “Opiate Related Symptom Distress Scale”	IN ketamine significantly greater level of difficulty concentrating and significantly lower levels of dry mouth when compared to IV morphine (p = 0.034 and p = 0.002 respectively)
Kampan et al 2024 Thailand	Patients aged ≥65 presenting to ED with chief complaint of musculoskeletal pain within the past seven days and a pain score of ≥5 on 11-point NRS N = 92 Mean age: not stated (median age = 73.5 years) Male: 28% Two intervention groups (A and B) A = 0.75 mg/kg of nebulised ketamine + 10ml of normal saline intravenously (n = 46) B = 0.1mg/kg of morphine in normal saline solution (up to 10ml) intravenously (n = 46)	RCT Level I	Subjective pain improvement, NRS	No significant difference between baseline NRS No significant mean difference in change in NRS between (A) and (B) at all time frames	Wide exclusion criteria (extremes of body weight, language barrier) Convenience sampling Small sample size (n = 92) No long term follow up during drug administration
			Incidence of adverse effects, via SERSDA and RASS	Reports higher incidence of adverse effects in (B) but no figures provided, or statistical analysis performed
			Rate of rescue therapy	No significant difference between the rate of rescue therapy (p = 0.1)
Ziaei and Abdolrazaghnejad 2022 Iran	ED patients with a known history of renal stone, acute renal pain ≥4 VAS and aged between 20-50 with no underlying diseases N = 100 Mean age: 34.15 years Male: 68% Two intervention groups (A and B): A = 1.5mg/kg ketamine intranasally + distilled water intravenously (n= 50) B = 0.1 mg/kg IV morphine + distilled water intranasally (n= 50)	Level II	Subjective pain improvement, VAS	No significant difference in baseline characteristics between group (age, weight, examination, sonography findings) Significantly lower starting VAS in (A) group (p = 0.001). At 5, 15 minutes no significant difference. At 30 minutes pain significantly lower in (B) group (p= 0.030). At 60 minutes no significant difference in VAS (p = 0.130).	No blinding Excluded patients with any underlying conditions Small sample size (n =100) Simple and convenience sampling Short follow up – 1 hour
			Incidence of adverse effects	No significant difference in side effects (p = 0.21)
			Need for re-administration	No significant difference in need for re-administration (p = 0.83)
Pouraghaei et al 2020 Iran	ED patients aged ≥18 with renal colic and radiologically proven (Computerised Tomography of the Kidneys, Ureters and Bladder) renal tract stones N = 184 Mean age: 40.30 years Two intervention groups (A and B): A = 1mg/kg ketamine intranasally + 1ml of normal saline intravenously (n = 95) B = 0.1 mg/kg morphine intravenously + 4 puffs of intranasal saline (n = 89)	RCT Level II	Subjective pain improvement, NRS	No significant difference in pre-treatment pain scores between groups (p = 0.489) No significant difference observed in the pain scores between two groups 15 (p = 0.204), 30 (p = 0.978) and 60 (0.648) minutes after administration	Single centre study with small sample size (n = 184) Short follow up – 1 hour Only included patients with CT confirmed nephrolithiasis

Comment(s)

The selected RCT’s compared the analgesic efficacy of IN ketamine to IV morphine for acute severe pain in adult ED patients, using standardised pain scores VAS or NRS over defined time intervals. The review concludes that IN ketamine provides as effective pain relief as IV morphine in this patient cohort. The World Health Organisation (WHO) three-step analgesic ladder guides analgesic prescribing, starting with non-opioids and progressing through weak and strong opioids - titrated to the patient’s reported pain (6, 7). For severe pain, morphine is recommended as the drug of choice (6). All trials used intravenous morphine as the comparator. Four of the five trials found no significant difference in pain reduction between IN ketamine and IV morphine, demonstrating equal efficacy. One study reported a lower pain score with IV morphine at 30 minutes, but no difference at all other time frames. Most studies also found no significant difference in adverse effects between groups. It is important to note the limitations of these studies, as well as flaws in study design, that may limit these findings. There was large variability in the dose of IN ketamine (0.3 mg/kg to 1.5 mg/kg) and differences in pain scoring scales used. Both factors make it somewhat difficult to ascertain IN ketamine’s non-inferiority to IV morphine. No studies followed up participants for more than two hours; making it difficult to determine long-term efficacy. Further, no studies utilised IV opiates other than morphine in the comparator group. Most studies had large exclusion criteria; centred around age, body weight, co-morbidities and haemodynamic instability. Convenience sampling was utilised in nearly all studies, sample sizes were generally small with the largest sample consisting of 184 participants. Patients presenting to ED are diverse, often with multiple comorbidities. These factors serve to reduce the generalisability of these findings. Overall, these findings suggest that IN ketamine is as effective as IV morphine for acute severe pain in adult patient’s presenting to ED. The generalisability of these results is subject to certain limitations given lack of uniformity in study methodologies, short-term follow up, large exclusion criteria, sampling techniques and small sample sizes. Large scale RCT’s, addressing the weaknesses described, are needed to confirm IN ketamine as a treatment modality in ED.

Clinical Bottom Line

Intranasal ketamine provides as effective analgesia when compared to IV morphine in adult patients presenting with acute severe pain to ED. The side effect profile is largely similar and should be considered in patients in whom IV morphine is contraindicated or those who lack IV access.

References

1. Tongbua S, Sri-on J, Thong-on K, Paksophis T Non-inferiority of intranasal ketamine compared to intravenous morphine for musculoskeletal pain relief among older adults in an emergency department: a randomised controlled trial Age and Ageing 2022;51
2. Shimonovich S, Gigi R, Shapira A, Sarig-Meth T, Nadav D, Rozenek M, et al Intranasal ketamine for acute traumatic pain in the Emergency Department: a prospective, randomized clinical trial of efficacy and safety. BMC Emerg Med 2016;16(1):43
3. Kampan S, Thong-on K, Sri-on J A non-inferiority randomized controlled trial comparing nebulized ketamine to intravenous morphine for older adults in the emergency department with acute musculoskeletal pain Age and Ageing 2024;53
4. Ziaei M, Abdolrazaghnejad A The analgesic effect of intranasal ketamine and intravenous morphine in patients with flank pain (renal colic) in the emergency department; a clinical trial study Immunopathol Persa
5. Pouraghaei M, Moharamzadeh P, Paknezhad SP, Rajabpour ZV, Soleimanpour H Intranasal ketamine versus intravenous morphine for pain management in patients with renal colic: a double-blind, randomized, controlled trial World Journal of Urology 2021;39(4):1263-7
6. World Health Organisation Cancer pain relief Geneva: World Health Organization 1986
7. Ballantyne JC, Kalso E, Stannard C WHO analgesic ladder: a good concept gone astray BMJ 2016;352:i20