Finding the treatments of the future for pain relief

Routine pain treatments could soon include virtual reality, and harnessing the body’s ability to generate its own pain relief.

Finding the treatments of the future, is one driving force behind NUI Galway's Centre for Pain Research. Founded in 2007 by professor of pharmacology and therapeutics, David Finn, and professor of clinical psychology, Brian McGuire, it brings together academics and researchers from across the health sciences.

Prof Finn's background is in biotechnology and neuroscience, while Dr Michelle Roche, a member of the centre since its inception and co-director since 2020, has a background in physiology and neuropharmacology. There are also collaborations with clinical colleagues, in particular those at University Hospital Galway's Pain Clinic, where Prof McGuire works as a psychologist.

Sensors for a virtual reality device are attached to the stump, and the patient sees an image of their missing limb, their virtual arm or leg, on the screen

Much of their work is driven by the search to understand and alleviate pain. “About 20 per cent of the population suffers from chronic pain,” says Prof Finn. “But if you asked that cohort how they’re doing on their medications, about 70 per cent say that it is inadequate some of the time, and about 40 per cent say it’s inadequate all of the time. So there’s this massive unmet clinical need, first of all for better drugs that are more effective against pain, but also because a lot of existing drugs have very substantial side effects.

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“Like addiction – we can see the problems of the opioid crisis in the US. Even non-addictive painkillers, such as non-steroidal anti inflammatory drugs like aspirin and ibuprofen, are very hard on people when taken over a long period of time, because they cause stomach ulcers and have other effects.”

In addition to new therapies, novel ways of delivering drugs are being investigated. Delivery systems that allow the administration of pharmacological treatments directly to the site of injury are of a particular interest, and may avoid adverse side effects associated with pain medication taken orally or intravenously, explains Dr Roche.

Prof Finn describes some current delivery projects. "One, for osteoarthritis, is an injection into the inflamed knee joint. Another for chronic wound pain – like venous ulcers – incorporates some therapy into the dressing. CÚRAM, the Science Foundation Ireland Research Centre for Medical Devices is involved in that research. And there is a commercial collaboration with Relivium Medical, a spin-out company from NUIG, on a hydrogel for chronic pain."

Another new approach to pain management uses virtual reality. McGuire has just completed part of an international clinical trial for phantom limb pain, where amputees still experience pain as if the limb was still there.

“Sensors for a virtual reality device are attached to the stump, and the patient sees an image of their missing limb, their virtual arm or leg, on the screen. They’re taught to move the muscles through the sensors, and to execute movement. This is thought to reorganise some brain pathways, and seems to reduce pain outcomes. This would be great because phantom limb pain is really hard to treat, and medications and procedures don’t work well.”

Much of the CPR’s current research centres around endogenous cannabinoids, pain-relieving marijuana-like substances in our own bodies. “We produce them in our brains, and in other cells and tissues,” explains Finn, “and they change during pain and stress and other factors. We’re interested in looking at whether, and how, the levels change, and whether they might be useful in predicting pain outcomes, and as potential biomarkers. The body’s cannabinoid system might also be a useful therapeutic target.

“There are drugs – enzyme inhibitors, for example – that can boost the levels of the body’s own cannabinoid molecules. We’re investigating the endocannabinoid system both at the basic science, laboratory level, and clinically in patients, and in the future we aim to start patient trials for those kinds of drugs.”

Medicinal cannabis

The CPR has also found itself at the heart of the debate over medicinal cannabis. “It’s probably fair to say that the medical community, particularly many pain consultants, would be hesitant to embrace medical cannabis or cannabinoids,” says Prof Finn. “And then you have people like us, working on the basic science aspects of the pharmacology of cannabinoids and how they work, and whether they work. We’re trying to inform the debate from an evidence-based perspective.”

Prof Finn sat on two recent international task forces considering its use, and the controversy, as he sees it, is that experts can’t agree. “I’m not a clinician, I’m a scientist, but I would endorse the recommendation of the European Pain Federation’s Presidential Task Force that cannabis-based medicines could reasonably be considered by consultant doctors for the right type of patient and the right type of pain, particularly neuropathic pain.”

Other research focuses on better ways to diagnose and assess pain. “Measuring pain is very difficult,” Prof Finn stresses. “In the past, it’s been done fairly crudely, with visual analogue or numerical rating scales – where a patient is asked to indicate their perceived pain intensity along a 100mm horizontal line or on a scale from 1 to 10 – and asking people to describe their pain. People describe pain very differently.

“Unfortunately, there’s no biomarker yet for pain. It’s not like other conditions, where there might be something you can measure in blood or saliva, and it tells you the level of disease, or the extent to which it is present. Part of our research is trying to search for biomarkers.”

In the meantime, they are examining new ways to assess pain in children. “Up to 10 per cent of five- to 12-year-olds have chronic pain, which is astounding,” notes Dr Roche. There are, of course, other patients who find it difficult to communicate or describe symptoms.

“Recently we’ve been doing some research with people with intellectual disability and autism,” says Prof McGuire, “looking at whether we can pick up on the presence of pain based on their facial expressions, looking for cues that tend to be present when they are experiencing pain.”

“So we’re looking to get better diagnostic tools, and to understand the underlying biology,” adds Dr Roche. “Autistic children and adults are quite sensitive to the sensory environment. And even gentle touch can be perceived quite adversely.”

In addition to studying the intersections between intellectual or cognitive impairment and pain, all three CPR co-directors have an interest in trying to unravel how, and why, mood disorders and pain are so interlinked.

“Depression and chronic pain, for example, can co-occur in up to 70 per cent of patients,” says Dr Roche. “Chronic pain conditions occur more frequently in those with psychiatric disorders such as anxiety and depression, and conversely chronic pain patients frequently experience psychiatric disorders such as anxiety and depression.”

A very simplified summary of their conclusions to date would be that: “The combination of depression and pain is associated with dysregulation in the central nervous system.”

Chronic pain

Dr Roche and Prof Finn are Ireland’s principal investigators on a new multi-million euro EU Horizon 2020-HaPpY-project, involving universities from nine countries (eight European and one from Canada). “This project brings together both basic science and clinicians to try and understand this interaction between psychiatric conditions and chronic pain in more detail,” explains Dr Roche. “It’s bi-directional. In some cases, we’re looking at the impact of depression on chronic pain, and sometimes we’re looking at the impact of chronic pain and it’s comorbidity with depression and anxiety.”

Chronic pain is more prevalent in females, who are disproportionately affected by pain syndromes such as arthritis

Five PhD students will be recruited in Galway to “look at the different brain areas that might be involved in this comorbidity. They’ll be looking at different targets like the cannabinoid system, and the role of immune markers in the interaction between depression and pain, and hopefully identifying novel treatment targets.”

One objective of the project, another interest of both Dr Roche and Prof Finn, will be to determine the impact of sex differences on pain conditions and responses. “We know,” says Dr Roche, that “chronic pain is more prevalent in females, who are disproportionately affected by pain syndromes such as arthritis, temporomandibular disorder, migraine, and fibromyalgia.”

“The main issue,” adds Prof Finn, “is that females have been under-studied over the years, the focus has been on males, particularly in basic science research, so we’re trying to redress the balance there”.

Psychological interventions are also under scrutiny as scientists look for answers.

“The experience of pain is not just to do with an injury or tissue damage,” explains Prof McGuire. “The intensity of pain is also influenced by things like people’s expectations, or their previous experiences of something as being painful, or not painful. And other things can magnify or reduce their perception of pain, such as a person’s mood, or anxiety, or fear.

“Personal beliefs also have an influence. For example some people have a trait called catastrophising, a tendency to make things seem worse than they really are. People who have that way of thinking about their symptoms tend to do worse, and take longer to recover.”

The most common pain conditions Prof McGuire sees at the Pain Clinic are headaches and low back or spinal pain, but chronic pain – pain that persists for three months or longer – can afflict patients anywhere from face to feet. Treatment approaches include Cognitive Behavioural Therapy (CBT), relaxation techniques, physical activity, meditation, mindfulness, physical activity, even hypnosis. With Acceptance and Commitment Therapy (ACT), “patients learn to accept and live with pain and still get on with the things they want to do”.

Many of these interventions are being studied and adapted. CPR teams have had good results converting CBT and ACT therapies into online formats or apps for adults, and are currently trialling an app with pain management strategies for children undergoing scoliosis or leg lengthening surgeries. Online interventions for teenagers with juvenile arthritis are also being evaluated. And “Feeling Better”, a gamefied online pain management programme for very young children, has been simplified for people with Intellectual Disability to trial.

Virtual distraction techniques have also been used to relieve acute pain.”We have found that children attending to have blood taken report less pain and less distress when they are playing games,” said Prof McGuire. “If you have something that takes your attention away from pain, then you don’t experience it as much.”

Pain treatment

And what about the future of pain treatment?

Prof McGuire sees digital and online pain management programmes as a way to tackle a national shortage of pain psychologists, and also address problems of distance and cost. “If you have a chronic back problem it can be hard to get from Roscommon or Mayo to Galway, sit in a clinic waiting room, and then get back in your car again. If you can do something from home that’s effective, then that’s very appealing. One of the few upsides to Covid is that it has normalised virtual clinics and online programmes.”

For Prof Finn, “the holy grail might be personalised medicine. That you get to a point where you can tailor pain treatments individually to patients.”

The focus of these programmes is to help people to be less reliant on medication and procedures and to learn their own coping skills

What would make pain treatments better in the shorter term, says Dr Roche, is stratifying patients. “So, rather than grouping chronic pain patients solely by pain condition, grouping them by the phenotype and characteristics of their pain could identify patients that respond better to certain classes of medications. Getting better at diagnosing the pain in different groups, and the more we learn about pain mechanisms, the closer we may get to developing more effective, and more personalised, pain treatments.”

But first, insists Prof McGuire, what’s needed is a national pain management strategy and more resources. “We have strategies for other illnesses such as cancer, but we don’t have one for pain, which is surprising given how common chronic pain is. Because it’s so prevalent, chronic pain is much more expensive than cancer, or diabetes, or cardiovascular disease. There are currently very few multidisciplinary, fully staffed pain management programmes around the country, even though they’re the gold standard, and all the international evidence is that they are what works best.

“The focus of these programmes is to help people to be less reliant on medication and procedures and to learn their own coping skills. But it’s almost impossible to get them funded, because they’re heavily staffed and appear expensive. However, if you get even one person back to work, they are cost effective. It’s economically – and humanely – the way to go.”

The CPR is currently recruiting people for a range of pain studies. More details can be found on nuigalway.ie/centre-for-pain-research