Nebulized Ketamine in Emergency Medicine: Between Brilliant Idea and Unanswered Questions

Every now and then it happens: you read a title and a light bulb goes off. It happened to me while browsing PubMed-Insights the other night, when I came across a review in the Scandinavian Journal of Trauma, Resuscitation and Emergency Medicine: nebulized ketamine for analgesia.

It's not entirely new – it's been discussed "sporadically" for years – but now numbers and systematic syntheses are starting to appear that deserve attention.

The real question, though, isn't "does it work?"

It's: does it work well enough, is it safe enough and practical enough to consider real-world use – especially outside the hospital?

In an ambulance or a crowded Emergency Department, a non-invasive option for acute pain could really be a game-changer. But before we get excited, let's look at what the literature actually says.

Current Evidence: What Do the Reviews Say?

Two recent papers attempt to bring order:

Kirk et al. (2025) – Scandinavian Journal of Trauma, Resuscitation and Emergency Medicine

• 9 studies, 453 patients
• Setting mainly in Emergency Department (ED)
• Conclusion: nebulized ketamine can significantly reduce pain, but with heterogeneous evidence and often small samples

Cetin et al. (2025) – American Journal of Emergency Medicine

• 13 studies, 2496 participants (of which 722 treated with nebulized ketamine)
• Larger meta-analysis, but overall quality of evidence low/very low
• Limitations: high heterogeneity, different designs, non-uniform endpoints, single-center studies

In practice: the signal is consistent and promising, but we're not looking at "definitive" proof.

Why Is the Evidence Low?

Analgesic Efficacy: How Well Does It Really Work?

Studies report clinically relevant reductions in pain (NRS/VAS) at various timepoints:

• Onset: often within 15–30 minutes
• Peak: further improvement at follow-up (30-60 min)
• Duration: variable, some studies report effect up to 2 hours

Caution: these are averages across different populations and protocols. Useful for orientation, not for promising a "guaranteed" result in individual patients.

Dose: 0.75 vs 1 vs 1.5 mg/kg

In the trial by Dove et al. (2021) no clear difference in analgesic efficacy emerges between three dose regimens. This is interesting, but needs careful interpretation: "I don't see differences" doesn't automatically mean "the optimal dose is defined for everyone."

An important limitation: nebulization doesn't guarantee the dose actually delivered and deposited. It depends heavily on the device, the patient's breathing pattern, the interface (mask vs mouthpiece), and environmental losses.

Comparison with Alternatives: IV Ketamine and Morphine

Some RCTs in Emergency Departments suggest that:

Adverse Event Profile

There's no clear and stable signal of "safety" superiority for either, but ketamine has the theoretical advantage of not depressing respiratory drive.

Key Contexts: Where Could It Really Be Useful?

Nebulized ketamine could have a role when venous access is a problem or when you want to avoid an invasive procedure during high pain/anxiety.

1. Pediatrics

The rationale is strong: less trauma from venous access, better compliance, rapid onset.

But let's be honest about the data: "pure" analgesic pediatric data are few and mostly on adolescents (10–16 years) in case series. Extending the reasoning to young children is still hypothesis, not evidence. Pharmacokinetics and response can vary significantly with age.

2. Difficult Venous Access

Situations where every minute is a struggle:

• Burn patients
• Significant edema
• Severe obesity
• Agitated patient
• IV drug users with compromised venous access

An inhalation route could "buy time," reduce stress, and allow better scene management.

3. Prehospital with Long Times or Complicated Environment

In theory, it's one of the most "logical" contexts for a non-invasive route. In practice, however, the data are still limited (see below).

4. Opioid Tolerance or Complex Pain

The NMDA-antagonist rationale is interesting as an option or add-on in patients already "saturated" with opioids or with neuropathic pain.

Two Field Scenarios

Scenario 1: Trauma with Difficult Venous Access

45-year-old man, 130 kg, fall from 3 meters at construction site. Suspected femur fracture. Pain 9/10. Agitated patient, poor venous access, IO access contraindicated for the site.

In this scenario, ketamine nebulization could:

• Provide early analgesia during access attempts
• Reduce agitation allowing a safer approach
• "Buy time" to organize immobilization

Scenario 2: Pediatric Burn

8-year-old girl, boiling water burn on forearm and hand (estimated 15% TBSA). Severe pain, inconsolable crying, refuses any approach.

Here nebulized ketamine could:

• Avoid the additional trauma of venous access
• Allow dressing and cooling
• Reduce procedural anxiety

Note: these are illustrative scenarios, not therapeutic indications. Every clinical decision must respect local protocols.

Prehospital: High Potential, Fragile Evidence

Here we need to be honest: out-of-hospital evidence is less robust than that in the ED.

• A case series (few patients) suggests feasibility and benefit during transport
• A large retrospective EMS study (McArthur et al., 2025) compares fentanyl vs nebulized ketamine and shows comparable pain reductions

But caution: it remains an observational design, with all the limitations (selection, confounders, non-uniform protocols).

Practical translation: it's plausible that it works, but it's not yet "ready to become standard" in EMS based solely on these data.

The Point That Interests Me Most: Operator Safety

Here, for me, is the real "elephant in the room."

Ketamine is a psychoactive drug. If you nebulize it in an enclosed environment (ambulance, helicopter, ED bay), a portion of aerosol can disperse into the air that operators breathe.

What We Know

Breath-actuated devices reduce dispersion compared to continuous nebulizers. But to date, what's almost universally missing is the part that would really let us sleep soundly:

• Measurements of environmental concentration during real-world use in ambulance/ED
• Biomonitoring (even just pilot) of operators
• Assessment of psychomotor performance (attention, reaction times) in high-risk contexts like driving

An Important Clarification

There is pharmacokinetic data on inhaled esketamine (Jonkman et al., 2017) in healthy volunteers, useful as a "starting point" to understand that absorption via inhalation is real.

But caution: intranasal esketamine (Spravato®, used for depression) is a different formulation from nebulized racemic ketamine for analgesia. They have different indications, dosages, and contexts of use. They are not interchangeable as a reference.

What Can We Do While Awaiting Evidence?

These are reasonable precautions, not validated guidelines:

The point remains: until we have data, this part remains a legitimate brake on routine implementation, not a detail.

And in Italy?

Today, nebulized ketamine for analgesia remains effectively an off-label use and not "codified" in standard Italian prehospital protocols.

This doesn't mean "prohibited a priori," but it means it cannot be improvised: clinical governance is needed.

If the Path Opens, How Should It Happen?

1. Controlled experimentation (ideally multicenter) in contexts where monitoring and teams are solid
2. Clear definition of:
3. Indications and exclusions
4. Standardized dose and device
5. Minimum required monitoring (serial NRS, sedation/agitation, BP/HR/SpO₂)
6. Adverse event management
7. Measures and procedures for environmental and personnel safety

My Take-Away (Practical and Prudent)

My position:

• Yes, it "probably" works – the signal is consistent
• No, it's not yet "standard" – heterogeneous evidence, low certainty
• Prehospital is where it could make a difference... but it's also where we have the least data
• Operator safety is the priority – without real measurements, it's difficult to justify widespread adoption

For now I'd put it in this category: promising technique, to be followed with attention, to be experimented with methodically where possible, but not to be "launched" in the field just because the idea is elegant.

So, Operationally?

Fundamental premise: nebulized ketamine is not yet a standard of care and there are no Italian national protocols recommending its routine use. Any implementation should occur within approved local protocols, pilot studies with adequate supervision, and specific personnel training.

That said, here are some reflections by context:

My advice: if the topic interests you, discuss it with your clinical supervisor or local ethics committee. Proposing an observational study or internal audit could be the first step to generating data in your context.

The keyword, in any case, is method. Not improvisation.

Doses and Technique: What We Know (Practical Box)

Caution: this is not a prescriptive protocol, but a descriptive synthesis of what is reported in the literature.

Most reported adverse events:

• Dizziness
• Mild dysphoria
• Nausea
• Transient BP/HR increase
• Serious events: rare in studied samples (but limited samples!)

Critical limitation: nebulization doesn't guarantee the dose actually deposited at the pulmonary level. It depends on device, breathing pattern, patient compliance, environmental losses.

📚 Essential References

1. Kirk D, Whiles E, Jones A, Edmunds C. Breathing new life into pain management: a systematic review of nebulised ketamine for analgesia. Scand J Trauma Resusc Emerg Med. 2025;33:196. doi:10.1186/s13049-025-01501-4
2. Cetin M, Brown CS, Bellolio F, et al. Nebulized ketamine for acute pain management in the Emergency Department: A systematic review and meta-analysis. Am J Emerg Med. 2025;94:110–118. doi:10.1016/j.ajem.2025.04.051
3. Dove D, Fassassi C, Davis A, et al. Comparison of nebulized ketamine at three different dosing regimens for treating painful conditions in the emergency department. Ann Emerg Med. 2021;78(6):779–787. doi:10.1016/j.annemergmed.2021.07.003
4. Nguyen T, Mai M, Choudhary A, et al. Comparison of nebulized ketamine to intravenous subdissociative dose ketamine for treating acute painful conditions in the emergency department. Ann Emerg Med. 2024. doi:10.1016/j.annemergmed.2024.03.024
5. 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 Ageing. 2024;53(1):255. doi:10.1093/ageing/afaa271
6. Rhodes AJ, Fagan M, Motov S. Nebulized ketamine for managing acute pain in the pediatric emergency department: a case series. Turk J Emerg Med. 2021;21(2):75–78. doi:10.1016/j.tjem.2021.03.001
7. Patrick C, Smith M, Rafique Z, et al. Nebulized Ketamine for Analgesia in the Prehospital Setting: A Case Series. Prehosp Emerg Care. 2023;27(2):269–274. doi:10.1080/10903127.2022.2099602
8. McArthur R, Cash RE, Anderson J, et al. Fentanyl versus nebulized ketamine for prehospital analgesia: A retrospective data review. Am J Emerg Med. 2025;89:124–128. doi:10.1016/j.ajem.2024.12.033
9. Jonkman K, Duma A, Olofsen E, et al. Pharmacokinetics and Bioavailability of Inhaled Esketamine in Healthy Volunteers. Anesthesiology. 2017;127(4):675–683. doi:10.1097/ALN.0000000000001798