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Neuropathic pain was classified in a way that stymied research. Not anymore

EUROPAIN’s evidence that neuropathic pain patients should be grouped by their pain perception and not the event that sparked it convinced the European regulator to change its guidelines

Amytriptiline by Juan Gaertner via Shutterstock
Image by Juan Gaertner via Shutterstock


The EUROPAIN project was able to help break a research impasse by bringing forward new biomarkers for stratifying and diagnosing neuropathic pain. They showed medicine regulators that better therapeutics could be developed by grouping neuropathic pain patients by phenotype, meaning the sensory phenomena that they experience, as opposed to what set off their pain in the first place, such as surgery or diabetes. The evidence they collected was so compelling that the regulators not only green-lit two biomarkers but also adapted their current guidelines for pain drug development to reflect the project’s findings. This helped spark renewed interest among big and small drug developers to restart the search for new pain treatments after decades of stalled efforts.

Märta Segerdahl, MD, PhD, Assoc. Prof, is an alumni of the Karolinska Institute, where she also received her board certifications in Anesthesia and Intensive Care and in Pain Medicine, as well as scientific training. She was the coordinator of the IMI Europain consortium (as part of AstraZeneca CNS R&D). We asked Dr Segerdahl to explain what the project was able to achieve. 

Q. Broadly, what was EUROPAIN about?

Dr Märta Segerdahl: The idea behind the project was to get a better grip on how to differentiate neuropathic pain from chronic pain in general, going beyond just pain intensity. This would lead to better diagnosis and better treatments. It has been difficult for companies to develop new treatments, and the research had largely stopped. This is a problem because opioids have a potential for abuse liability but also gabapentinoids and antidepressants have a lot of side effects, so new drugs are really needed.

Q. What was the problem with the regulatory guidelines as they existed?

Dr Märta Segerdahl: Regulators want pharma companies to demonstrate that a new drug is safe, but also that it is effective. The problem is that they define what constitutes a disorder, i.e. what group of patients to study. A pharma company might have a target population such as people who experience cold as pain (cold allodynia), which is linked then to a specific disturbance in nerve function. But the regulators were saying that they can’t differentiate patients according to this phenomenology, but rather they have to differentiate them based on whether their neuropathic pain is due to diabetes, or post-herpetic neuralgia, or nerve injury due to some other disease.

In other words, they wanted drug developers to associate the pain with disease history, not by pain mechanism or pain type. This means that their studies must include anyone who has neuropathic pain linked to a certain etiology - and that’s a huge amount of people. If you know that your drug doesn’t work for the whole group, then you probably don’t have a drug. Pharma companies had to hope that among the large number of people in their studies there were enough patients with the right phenotype to demonstrate the efficacy of the drug.

They might start off knowing, for example, that only 40% of the people are likely to respond to the drug. They had to demonstrate a valid difference between active and placebo patients, even though they knew that there will be 60% of patients who will not respond.

Q. How did you demonstrate that there was a better way to go about this?

Dr Märta Segerdahl: We collected a large database of patients with neuropathic pain and we stratified them. We did this by carrying out a very systematic and detailed profiling by defining the sensory phenomena in all these patients - the phenotype. We were able to draw conclusions as to how many patients were in each population or subpopulation.

We demonstrated that patients whose pain is elicited by close-to-normal temperatures and mechanical stimuli like needle pricking for instance, this phenomena also known as hyperphenomena, would be more likely to respond to a drug called a sodium channel blocker, and that patients with these hyperphenomena were significantly more responsive to treatment than the patients without hyperphenomena.

For regulators to understand that there is a difference between these patients, we couldn’t just hypothesise, we had to be able to demonstrate it with data. So we went to them with all the data and we were able to show them that the principle holds.

I should note that it is overall extremely rare for academics go to the regulators for scientific advice, and for pharma as well, when the key point is not to discuss a drug but to discuss a scientific principle. At the time, the EMA were updating their guidelines on the development of new drugs for the treatment of pain in general and they waited for our scientific advice to have been conducted, and they included many of our points in the final draft.

Q. What was the outcome?

Dr Märta Segerdahl: They gave a positive opinion on two biomarkers. Biomarkers can be diagnostic, they can be useful for stratification in clinical trials, and they can also be used as endpoints. The EMA said that it’s clear that QST, or quantitative sensory testing biomarker, could be used for stratification at least up to phase two trials, which is a huge step forward.

The other was a tool that can measure pain activity and various sensory nerve fibres (microneurography) which we also brought for scientific advice. The regulators were very convinced that that would also be useful as an endpoint tool.

Q. How has this affected research in this area?

Dr Märta Segerdahl:  We changed the game in the sense that before, the EMA wouldn't have accepted stratification by phenotype as opposed to disease history, but now they do. That's a pretty big achievement.

This has been a research area priority for many years for all of the clinical researchers that were part of the EUROPAIN consortium. On the academic side, they couldn’t see things from the company perspective. They couldn't understand why industry couldn't just do it this way. On the industry side, they weren't allowed to stratify populations in this way and as a result there was no more pain research being done. That's one huge achievement with these IMI projects really, is that we can understand the other side in a much better way.

Q. What has happened since?

Dr Märta Segerdahl: Of course, it takes time because companies need to restart their research from square one, but there are more biotech companies and pain research companies looking into these new targets. I have been talking to small and large companies and the interest has really increased in the last five years. I think one can hypothesise that the efforts of EUROPAIN and the change in the guidelines, combined with increased awareness of the opioid epidemic, have really contributed to the increased interest.   


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