Study: Inhaled pain relief is as effective as morphine

In emergency medical services, severe pain is often treated with morphine or similar substances. The medicine is administered directly into a vein through a small tube called an intravenous cannula.

“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," says Fridtjof Heyerdahl, a researcher at the Univeristy of Oslo's Institute of Clinical Medicine.

Some patients are also afraid of needles.

"In that case, it can take some time before patients receive satisfactory pain relief,” he adds.

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

Injured in a car accident

Typical patients include those who have been injured while skiing, fallen from a ladder or construction site, or been hurt in a traffic accident. They may have a broken leg, severe back pain, or chest pain.

The patient often needs to be moved down stairs or across difficult terrain before reaching an ambulance or helicopter and being taken to 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," says Heyerdahl.

He explains that acute pain can be extremely distressing, and patients are often scared and vulnerable.

“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, Heyerdahl and his colleagues compared three treatment options for pain management in an ambulance.

“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.

The patients were divided into three groups. The first group received morphine through a cannula. This is the standard treatment that has been used for decades.

The second group received methoxyflurane through a handheld inhaler. This treatment has been used for a long time in some parts of the world, but it is still quite new in Norway and the rest of Europe.

The third group were given a nasal spray with fentanyl. Fentanyl is a synthetic opioid that has been used as pain relief for many years. But administrating it as a nasal spray for acute pain is relatively new.

More tools in the toolbox

The results of the study are now 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,” says Randi Simensen.

She is a researcher 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 worked in the ambulance service for more than 20 years.

“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.

Ambulance workers now have another option for treating pain.

“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,” she says.

Treating patients in pain every day

“Providing effective pain relief as early as possible is important for the patient's overall experience during a medical emergency," says Simensen.

She explains that it can, for example, provide rapid relief for a patient with a hip fracture who has been lying on the ground for a long time.

Paramedic Joakim Kolstad at Innlandet Hospital agrees. He was one of the ambulance workers who took part 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,” he says.

The first study of its kind in the world

The PreMeFen study is the first randomised controlled study in the world to directly compare these three methods of pain relief. The research was carried out in ambulances, where patients actually receive emergency treatment.

“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,” says Heyerdahl.

He adds that this is the first study to show that methoxyflurane can play an important role in the earliest phase of emergency care before a patient reaches hospital.

“It's groundbreaking work to be able to establish this type of safe knowledge about new treatment,” he says.

“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 healthcare system are made elsewhere,” says Simensen.

She adds that their goal is simple: patients should not have to experience more pain than necessary.

Reference:

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

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