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Painstaking research – tackling chronic pain

13 Nov, 2009
Composite artwork illustrating the severe pain of a migraine or sinus problems.Pain is an important warning system in our bodies, but what if it never stops? It is estimated that one in five Europeans suffer from chronic pain, yet there are few effective treatments that offer adequate relief. Mun-Keat Looi talks to researchers from the London Pain Consortium, whose discoveries are prompting a surge in promising drug targets.
Janet Mahar drops into the waiting room chair. She slips off her sandals and lets out a huge sigh of relief. “Have you ever walked on the beach when it’s burning hot?” she asks. “That’s what my feet are like 24 hours a day, even when it’s bitter cold.”

Janet has erythermalgia, a rare condition where even the slightest change in temperature triggers excruciating pain in her feet.

“It’s like first degree burns. Your feet are not warm, not sweaty, not hot, but on fire. You can’t go to sleep with even a sheet over your feet, even in the winter.”

“You limp while you’re walking. If I try to wear socks, tights, boots trainers, they start burning and aching. You think your health is just deteriorating. It affects your whole life.”

Janet is one of a surprisingly large proportion of people around the world who suffer from chronic pain. A 2002-03 survey by the Pain in Europe group estimated that as many as one in five Europeans is affected, with conditions commonly affecting the back and joints and arthritis/osteoarthritis the most frequent cause.

The survey found that almost two-thirds of people with chronic pain polled felt that their treatment was inadequate for managing their pain. Moreover, some treatments are subject to severe side effects.

“There is an astonishing burden of pain in the community, unremarked upon, probably because people tolerate it,” says Professor Steve McMahon, Sherrington Professor of Physiology at King’s College London.

Professor McMahon is one of the principal investigators of the London Pain Consortium (LPC), made up of some of the world’s leading pain experts.

Combining genetics, laboratory studies, animal models and clinical work, the LPC is revealing more about the way our bodies process pain and developing better treatments that, it is hoped, will one day bring relief to people like Janet.

Chronic pain

“People understand pain as a sensation whereby there is a relationship between the degree of injury and the level of pain, but in chronic pain you lose that relationship,” says Dr David Bennett, a member of the LPC, Janet’s neurologist and a Wellcome Clinical Scientist at King’s College Hospital in London.

“With acute pain, you can rationalise it: I’ve cut myself, it will heal, the pain will go away. But with chronic pain it is a life-long condition and there is an element of lack of control.”

“With most of these conditions it is not a constant phenomena but one that is triggered by certain things. It makes a big difference to your life if you have this unpredictable thing that has a massive impact on you.”

“It’s hard to live with because you can’t see it and people don’t understand it,” says Janet. “People think you’re either a hypochondriac or you’re lazy.”

Not so Dr Bennett. Upon meeting Janet, he recognised her symptoms – onset in her early teenage years, colour change to red or purple in the feet, constant burning pain exacerbated by any increase in temperature and partially relieved by cold – as characteristic of inherited erythermalgia. And if so, the root cause would be a small genetic malfunction uncovered by LPC researchers just a few years earlier.

Running time: 4 min 19 s
Read the transcript [PDF 144KB]

From patient to lab

Professor John Wood of University College London uses molecular genetics to understand more about pain. It is this technology that has lead to one of the biggest breakthroughs relevant to understanding Janet’s ongoing pain.

In 2004, Dr Mohammad Nassar, then a LPC postdoctoral student, conducted a series of experiments with a transgenic mouse created at University College. His aim was to find out more about the signalling pathways involved in peripheral sensory nerve cells (such as those found in the skin) that detect an injury and send pain signals to the nervous system.

He found a single protein that has a radical affect on the pain system. Nav1.7 is a sodium channel. It opens when it receives a stimulus, allowing the nerve cell to activate and transmit a signal to the spinal cord and the brain, causing pain.

Dr Nassar demonstrated that mice genetically engineered to lose the gene for Nav1.7 have major deficits in pain sensing – they were essentially pain-free. And as this work was being published, researchers in China found the first evidence that the same channel was responsible for chronic pain in erythermalgia patients. They discovered that a variety of mutations render the Nav1.7 channel easier to activate, causing the condition.

Back in Dr Woods’ laboratory, researchers found that mutations in Nav1.7 cause another pain syndrome, Paroxysmal Extreme Pain Disorder (previously known as Familial Rectal Pain Syndrome), a condition where the sodium channel doesn’t switch off when activated, causing a constant burning pain.

With an increasing understanding of how Nav1.7 is involved in the pain system, the researchers tested samples from Dr Bennett’s patients, including Janet. Tests by LPC student Alva Chen revealed a novel mutation in Janet’s Nav1.7 gene – the likely cause of her erythermalgia.

Hope for the future

There is a further remarkable finding that offers tremendous promise for developing drugs to treat erythermalgia or Paroxysmal Extreme Pain Disorder.

At Cambridge University, Professor Geoffrey Woods found a family in Pakistan who were immune to pain, including a firewalker. Like Dr Nassar’s pain-free mice, the family had a mutation that completely knocked out the Nav1.7 channel. But unlike people with other inherited pain-free conditions – usually associated with major cognitive disabilities – the family were otherwise completely normal.

“It suggests that if you can block this channel selectively you can do so without side effects,” says Professor Wood.

“It’s potentially one of the biggest pain advances in the last few years, an exciting new pain target that could help a lot of people with mechanical pain, cancer pain, osteoarthritic pain. All could potentially be treated with selective Nav1.7 blockers.”

Professor Woods’ lab along with several pharmaceutical companies are now looking at a variety of such compounds, which could generate promising drugs for clinical trials within a few years.

A world without pain?

There is still a way to go before any of these compounds are available to patients. But the explosion in pain research over the last 20 years is now generating more promising targets than in the previous 50 years – much needed given the lack of adequate analgesic drugs on the market at present.

“The last decade has seen a dramatic advance in our understanding of pain systems, providing a plethora of analgesic targets,” says Professor Wood. “The chances of improved treatment for chronic pain within the next 5-10 years are looking good.”

“Previously, you could have counted the number of molecular targets on one hand, now there are dozens” says Professor McMahon.

“At some point our increased understanding of pain pathways has to allow for opportunities to intervene and we will start to see novel classes of drugs appearing.”

And this is going to be needed, says Professor McMahon, as the burden of chronic pain is only going to become greater.

“The epidemiological evidence is clear for a huge amount of pain in the population – probably largely age-related. And it is going to get worse as the ageing population increases and the survival age increases.”

“There will always be chronic pain. It’s a battle that can never be won but one that’s worth fighting. While the burden of chronic pain won’t go away, I am optimistic that it will diminish.”

Reference

Cox JJ et al. An SCN9A channelopathy causes congenital inability to experience pain. Nature 2006;444(7121):894-8.

Image credit: Darren Hopes.

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