Inhaled analgesia is as effective as morphine for early pain relief, study shows

by Vibeke Buan, Julie Nybakk Kvaal, University of Oslo

edited by Gaby Clark, reviewed by Robert Egan

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Treating pain while in the field can be very demanding. Researchers have finally identified an effective alternative for providing pain relief during the earliest phase of prehospital care, when establishing intravenous access can be difficult. The study is published in The Lancet journal.

In emergency medical services (or ambulance services), it is common to treat severe pain by administering morphine and similar substances intravenously. This is achieved by inserting an intravenous cannula into a vein.

"This is a good treatment, but in some situations, it can be challenging to insert a cannula, particularly when it's dark, cold or windy at the scene. Some patients are also afraid of needles. In that case, it can take some time before patients receive satisfactory pain relief," Fridtjof Heyerdahl, researcher at the Institute of Clinical Medicine at the University of Oslo (UiO), says.

He is also a senior researcher affiliated with the Norwegian Air Ambulance Foundation (SNLA) and Oslo University Hospital (OUS), and is the head of the Air Ambulance Department at OUS.

Injured in a car wreck

Typical patients include those who have sustained injuries while skiing, fallen from a ladder or at a construction site, or been injured in a traffic collision. It could be a patient with a broken leg, acute back pain or chest pain.

The patient often needs to be moved downstairs, across difficult terrain and into an ambulance or helicopter before being transported to a hospital.

"Many of the patients who need an ambulance have injuries or conditions causing a lot of pain. In many instances, we are unable to relieve their pain well enough immediately. Acute pain is extremely distressing, and patients are often frightened and vulnerable," Heyerdahl explains.

"The fact that we now, to a greater extent, can do something about this is of huge importance to the patients," he says.

Pain relief without needles

In the PreMeFen study, he and his colleagues compared three treatment options for pain management in an ambulance situation.

"There are other ways to provide pain relief than through a needle. We wanted to investigate whether these function as well as intravenous morphine does," he explains.

They had three groups of patients. The first group received morphine via a cannula, the standard treatment that has been used for decades.

The second group received the medication methoxyflurane, which was administered using a handheld inhaler. Although this treatment has been used for a long time in some parts of the world, it is quite new in Norway and the rest of Europe.

The last group received a nasal spray with the medication fentanyl, a synthetic opioid that has been used for many years. However, administering fentanyl as a nasal spray for acute pain is relatively new.

More tools in the toolbox

Now the results are clear:

"Inhaling methoxyflurane through a handheld inhaler provides pain relief as good as intravenous morphine in the early treatment of acute, moderate to severe pain," Randi Simensen says. She is a Ph.D. candidate at the Norwegian Air Ambulance Foundation and Innlandet Hospital, and a paramedic at OUS.

"The drug is easy to administer, does not require access to a vein, and is therefore an effective and practical alternative to morphine," she points out.

Simensen has more than 20 years of experience working in the ambulance service.

"It's difficult to provide pain relief in the field, often under demanding conditions. The initial phase of patient care, when the patient is in pain, is the most challenging. Often, we must move them before we can provide optimal pain relief. That's horrible for both the patients and the ambulance personnel," she says.

Now, more tools are available in their toolbox.

"We can now provide effective pain relief for patients in whom intravenous access is difficult or not immediately available. This does not mean that every patient with acute pain should receive inhaled pain reliever, but it does mean that we now have an additional treatment option," Simensen says.

Receiving pain patients in the ambulance every day

"Providing effective pain relief as early as possible is important for the patient's overall experience during a medical emergency. For example, it can provide rapid relief for a patient with a hip fracture who has been lying on the ground for a prolonged period," Simensen explains.

She is supported by paramedic Joakim Kolstad at Innlandet Hospital, one of the ambulance workers who has participated in the PreMeFen study.

"Every day we transport patients who need pain relief in the ambulance, and this is one of our main focuses. When pain is relieved, patients regain a sense of control over their situation," Kolstad says.

The first study of its kind in the world

The PreMeFen study is the first randomized controlled study in the world to directly compare these three analgesic—pain-relieving—strategies. And it is done in the ambulance service, where the patients are.

"When it comes to prehospital emergency care, we largely rely on research that is done inside hospitals and laboratories. This does not reflect the reality we work in. We need research that shows what's effective in our setting," Heyerdahl says, and adds,

"This is the first study in the world that demonstrates that methoxyflurane has an important role in the earliest phase of prehospital emergency care. It is groundbreaking work to be able to establish this type of safe knowledge about new treatment."

"Our job is to have the right medications available and to provide the best possible pain relief for our patients. Decisions about which medications should be used in different parts of the health care system are made elsewhere," Simensen says.

"Our focus is simple: There is no reason for patients to experience more pain than necessary."

Publication details

Randi Simensen et al, Comparison of inhalational methoxyflurane, intranasal fentanyl, and intravenous morphine for treatment of prehospital acute pain in Norway (PreMeFen): a randomised, non-inferiority, three-arm, phase 3 trial, The Lancet (2025). DOI: 10.1016/s0140-6736(25)01575-2

Journal information: The Lancet

Key medical concepts

MorphineFentanylRandomized Controlled Trial

Clinical categories

Emergency medicineClinical pharmacology Provided by University of Oslo Who's behind this story?

Gaby Clark

MA in English, copy editor since 2021 with experience in higher education and health content. Dedicated to trustworthy science news. Full profile →

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Bachelor's in mathematical biology, Master's in creative writing. Well-traveled with unique perspectives on science and language. Full profile →

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