Published March 2, 2026 | 9 min read

 

For most of EMS history, pain management in the field has been the domain of opioids. Morphine. Fentanyl. Start a line, push the drug, document the response, move on. The system worked until it didn’t. Between opioid diversion, respiratory depression in already-compromised trauma patients, and a growing opioid epidemic that EMS helped fuel one morphine push at a time, the field has been quietly searching for a better answer.

That answer has been sitting in paramedic drug bags for years. And the research to back it up has finally arrived.

Ketamine, the dissociative anesthetic that has been used in operating rooms, on battlefields, and in emergency departments for decades, is now at the center of a wave of prehospital research that is challenging everything we thought we knew about how paramedics should manage acute pain in trauma. The question is no longer whether ketamine works in the field. The question is why it isn’t being used more.

What the Latest Research Actually Says

The most significant piece of evidence to land in recent years is the PACKMaN trial, or Paramedic Analgesia Comparing Ketamine and Morphine in Trauma, a randomized, double-blind, Phase 3 clinical trial published in The Lancet Regional Health: Europe in April 2025.

This is not another observational study. This is the first fully blinded, randomized trial comparing prehospital ketamine to morphine administered by paramedics for severe traumatic pain. Participants had to report a pain score of 7 or higher on a 0-10 numeric rating scale and, in the attending paramedic’s clinical judgment, would normally require parenteral morphine. Patients receiving ketamine were managed with routine monitoring: no end-tidal CO2, no two-clinician airway requirement, and the same basic setup most ALS units run every day.

The findings confirmed what observational data had been suggesting for years: ketamine is not inferior to morphine for prehospital trauma analgesia, and it demonstrated a favorable side-effect profile in a real-world paramedic-led environment. Importantly, patients did not experience an increased rate of adverse events despite operating under a lower monitoring standard than previous physician-led studies had used.

The Lancet research team’s own literature review, conducted through January 2025, identified 6 randomized trials, 22 observational studies, and 4 systematic reviews on ketamine versus other agents in the emergency setting. Across those 22 observational studies, the conclusion was that ketamine performs as well as or better than morphine, while the 4 systematic reviews found ketamine to be at least as effective with fewer concerning side effects.

That’s a robust body of evidence. And it keeps growing.

Why Morphine Has Always Been a Compromise

To understand why ketamine matters, you have to understand why morphine has always been a flawed default.

Morphine lowers blood pressure. In a trauma patient who may be bleeding, even occultly, that’s not a neutral pharmacological event. It depresses respiration. In a patient with chest trauma, rib fractures, or a compromised airway, that’s a problem you’re adding to the call, not solving. And it carries a real risk of dependency. You’re delivering an opioid to a patient who may be predisposed, who is in acute distress, and who will likely receive more opioids in the ED and during any surgical intervention. You’re contributing to a pipeline, and EMS has known this for years.

JEMS has covered prehospital pain management extensively, noting that while opioids remain the most commonly administered strong analgesics by paramedics, their side-effect profile and the scope of the opioid epidemic have created genuine pressure to find alternatives. Ketamine, one JEMS overview noted, is a drug with over 60 years of clinical history, synthesized in 1962, that has been used across veterinary medicine, operating rooms, battlefield hospitals, and emergency departments, and that brings a remarkably broad therapeutic window to the table.

The pharmacology is the key. At sub-dissociative doses, roughly 0.1 to 0.5 mg/kg IV, ketamine blocks NMDA receptors to blunt pain perception without producing full dissociation. It maintains airway reflexes. It doesn’t drop blood pressure; its sympathomimetic properties tend to support it. It works fast. And because it doesn’t hit the same receptor pathways as opioids, it sidesteps the respiratory depression concern that makes every morphine push in a compromised patient a calculated risk.

The Route Question: IV, IM, IN, or Nebulized?

One of the most practical shifts in prehospital ketamine use is the expanding discussion around non-IV routes, a development with major implications for field care.

A 2025 retrospective study out of Harris County EMS in Texas, published in the American Journal of Emergency Medicine, compared fentanyl against ketamine delivered via breath-actuated nebulizer (BAN) across 1,480 patients. In the overall population, there was no statistically significant difference in pain reduction between the two drugs. But in the subgroup of patients with traumatic pain specifically, ketamine via BAN produced significantly greater analgesia than fentanyl, and it required no IV access to deliver.

That last detail matters more than it might seem. IV access in the prehospital environment is not always fast, clean, or simple. A patient with blast injuries, burns, or severe trauma may have no viable peripheral vein. A pediatric patient in pain may require IO access just to get a line. The ability to deliver meaningful analgesia through a nebulizer, with no needle, no line, and no delay, changes the calculus of pain management on a complex scene.

Intranasal ketamine has also been studied in the prehospital context, with the PAIN-K trial (Andolfatto et al., 2019) demonstrating effectiveness via the IN route in adults. And intramuscular ketamine remains widely used, particularly for agitation management, with a faster onset than IV in some presentations due to the ability to deliver a larger bolus quickly.

JEMS has covered the expanding use of these non-IV routes as part of a broader push toward more flexible, patient-centered prehospital analgesia, one that doesn’t make pain relief contingent on IV access.

The Side Effect Conversation: What Paramedics Actually Need to Know

Every time ketamine comes up in protocol discussions, the same concerns surface: emergence phenomena, dysphoria, hallucinations, agitation on the back end. These are real, but they are also contextual, and the research increasingly puts them in perspective.

A 2025 systematic review published in the International Journal of Paramedicine (Barnes and Gander) looked specifically at side effects and adverse events from prehospital ketamine analgesia in trauma. The review found that at sub-dissociative analgesic doses, adverse events are documented but generally mild and self-limiting. The most common side effects, including dizziness, nausea, and dissociative symptoms, occurred at a frequency that was not dramatically different from the opioid comparators, and serious airway complications were rare in the analgesic dosing range.

The PACKMaN trial reinforced this in its real-world paramedic context: patients in the ketamine arm did not experience elevated adverse event rates, even without advanced airway monitoring in place.

There is also an emerging conversation about ketamine’s potential benefits that extend beyond the scene. Research cited in JEMS has noted that prehospital analgesia in trauma has a measurable effect on long-term PTSD outcomes, and that ketamine, in particular, may have an advantage over opioids in reducing post-traumatic stress in non-TBI trauma patients. A 2022 military medicine study found ketamine’s early administration was associated with improved PTSD prognosis in that population. The implications for civilian EMS, where trauma calls are common and long-term patient outcomes are rarely tracked, are worth sitting with.

The one area where caution remains warranted is ketamine for agitation, where the dosing is fundamentally different (dissociative, not analgesic doses), the population is different, and the intubation-rate data is more mixed. Analgesic ketamine and sedative ketamine are not the same clinical conversation. A 2024 study comparing ketamine versus midazolam for acute severe agitation in the prehospital setting, published in the International Journal of Paramedicine, found that while ketamine produced faster and deeper initial sedation, it was also associated with higher re-sedation rates in hospital, likely from re-emergence, and did not outperform midazolam at achieving the target RASS score of -1, 0, or 1. That nuance matters.

What’s Holding Adoption Back?

If the evidence is this strong, why isn’t ketamine on every ALS unit as a first-line analgesic right now?

There are a few honest answers.

Protocol inertia. Medical directors are cautious, and updating standing orders takes time, politics, and sometimes a legal review. Morphine and fentanyl are known quantities. Ketamine still carries a stigma in some systems, as the word “dissociative” makes some administrators nervous, even when the dosing in question is nowhere near dissociative territory.

Training gaps. Ketamine requires paramedics to understand dosing tiers. The analgesic dose (0.1-0.5 mg/kg IV) is meaningfully different from the sedative dose (1-2 mg/kg IV) and the induction dose (>2 mg/kg IV). Getting that dose range wrong in either direction changes the clinical picture significantly. That requires training, and training costs time and money.

Monitoring concerns. Some state protocols and medical directors have historically required EtCO2 monitoring and dual-clinician airway capability for ketamine administration, a standard the PACKMaN trial has now directly challenged by demonstrating safety without those requirements at analgesic doses.

Documentation culture. In some EMS systems, controlled substances require such onerous documentation that providers default to simpler agents. Reducing administrative barriers is as important as updating the drug protocol.

The Practical Takeaway for Paramedics and Medical Directors

If you are a paramedic working in a system that still defaults to morphine or fentanyl as the first-line analgesic for severe traumatic pain, here is what the current evidence supports:

Ketamine at sub-dissociative doses (0.1-0.5 mg/kg IV) is a clinically appropriate, evidence-backed alternative to opioids for prehospital trauma analgesia. It does not require a higher level of airway monitoring than standard ALS care at analgesic doses. Its side-effect profile is comparable to opioids and arguably more favorable in hemodynamically sensitive patients.

For patients without IV access, nebulized ketamine via BAN has demonstrated effectiveness in traumatic pain specifically and represents a practical option that should be in more protocol discussions.

The conversation about ketamine is no longer whether it belongs in EMS. It already does, in systems that have made the evidence-based move. The conversation now is about making that access consistent and protocol-driven across the country, so that the patient with a traumatic femur fracture in rural Oklahoma gets the same quality of prehospital analgesia as the patient in a Houston metro system.

Pain is a vital sign. It deserves a first-line treatment with a 60-year safety record, a growing body of Phase 3 trial evidence, and a pharmacological profile that doesn’t add respiratory compromise to an already injured patient.

That drug is sitting in your drug bag. The research says it’s time to use it more.

Sources & Further Reading

• Smyth MA, Noordali H, Starr K, et al. “Paramedic Analgesia Comparing Ketamine and Morphine in Trauma (PACKMaN): A Randomised, Double-Blind, Phase 3 Trial.” The Lancet Regional Health: Europe. Published April 5, 2025. DOI: 10.1016/j.lanepe.2025.101265. https://www.thelancet.com/journals/lanepe/article/PIIS2666-7762(25)00057-2/fulltext
• McArthur R, Cash RE, Anderson J, et al. “Fentanyl versus Nebulized Ketamine for Prehospital Analgesia: A Retrospective Data Review.” American Journal of Emergency Medicine. 2025 Mar;89:124-128. DOI: 10.1016/j.ajem.2024.12.033.
• Barnes L, Gander B. “Side Effects and Adverse Events in Prehospital Ketamine Analgesia for Trauma: A Systematic Review.” International Journal of Paramedicine. No. 12 (Oct-Dec 2025): 141-155. DOI: 10.56068/YVZO4619.
• Johndro C, Caffyn S, Chen J, et al. “Prehospital Use of Ketamine Versus Midazolam for Sedation in Acute Severe Agitation.” International Journal of Paramedicine. No. 7 (Jul-Sep 2024): 23-30. DOI: 10.56068/RHLT6550.
• JEMS. “Ketamine Considerations for Prehospital Use.” October 2024. https://www.jems.com/patient-care/ketamine-considerations-for-prehospital-use/
• JEMS. “Prehospital Pain Management.” https://www.jems.com/ems-management/prehospital-pain-management/
• JEMS / International Prehospital Medicine Institute. “Literature Review, October 2024.” https://www.jems.com/patient-care/international-prehospital-medicine-institute-literature-review-october-2024/
• Morgan MM, Perina DG, Acquisto NM, et al. “Ketamine Use in Prehospital and Hospital Treatment of the Acute Trauma Patient: A Joint Position Statement.” Prehospital Emergency Care. 2021;25(4):588-592. DOI: 10.1080/10903127.2020.1801920.

This post is for EMS continuing education and clinical discussion purposes. Always follow your agency’s protocols and the guidance of your medical director.