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Chronic pain: the search for a killer

Millions of desperate people live with chronic pain, but medicine has had little luck finding cures. Could a new range of analgesics offer them hope at last?

Every day of her life, Jayne Nelson has suffered severe pain in her feet and legs. “It’s as if I have plunged them into scalding water,” she says. In an attempt to counter the constant discomfort, the 32-year-old marketing executive takes powerful painkillers but admits these are only partially successful.

“The drugs help me to live as normal a life as possible but I still suffer severe pain several times a day,” she says. “I have to keep electric fans on in my office and over my bed, and have the air-conditioning on in my car virtually all the time in order to try to control the burning that I feel in my feet and legs.”

Jayne suffers from erythromelalgia, a disease that causes blood vessels in sufferers’ limbs to become blocked and inflamed. The condition triggers intense feelings of burning – sensations that are only made worse by exercise or stress. The causes of erythromelalgia are complex – in Jayne’s case, it was inherited – and the subject of considerable medical success recently. However, this new understanding has yet to be translated into effective treatment and doctors’ efforts, when confronted with cases, are still mainly confined to trying to limit patients’ discomfort. The disease is uncommon, however, and its overall impact on the general health of the nation is limited.

Yet Jayne’s condition, for all its rarity, does raise widespread concerns and connects her to a far wider problem than the one posed by erythromelalgia itself – her illness is just one of several dozen ailments that inflict chronic pain, according to neuroscientist Professor Stephen McMahon.

Several million people in Britain suffer from chronic pain, he says. Sometimes the cause is unusual and rare, as with erythromelalgia. In other cases, the trigger is a widespread one, as is the case with osteoarthritis, a degradation of patients’ joints that is associated with burning spasms and other symptoms, and which affects large numbers of men and women in the UK. Other causes include cancer, irritable bowel syndrome, spinal accidents, damage to nerves and the nauseous headaches associated with migraines.

“Overall, one in five people in this country suffers from chronic pain,” says McMahon, who is director of the London Pain Consortium, a physiological research centre based at King’s College, London, which has been set up to study and treat chronic pain. “That means there are more than 10m individuals in this country who are affected with regular, frequent bouts of intense physical distress. It represents a colossal level of suffering that receives very little publicity.”

Chronic pain is defined as pain that persists for more than three to six months, for at least three times a week, and is rated as severe. At its mildest, it causes extreme discomfort. At its worst, it can have a devastating impact on the sufferer, and their family, and it is associated with high rates of depression and serious loss of sleep, says Dr David Bennett, a consultant neurologist with the consortium.

“Apart from the suffering involved, chronic pain is also a colossal problem in terms of days lost from work. One estimate suggests that it costs around £5bn a year to the UK economy,” adds Bennett.

This point is backed by McMahon. “Chronic pain can be triggered by a rare condition like erythromelalgia or by a widespread one like osteoarthritis. Either way, the effects are often debilitating. Of those 10m individuals afflicted by chronic pain, about 20% – around 2m people – have suffered from it for 20 years or more. This is an insidious problem and it has yet to be tackled satisfactorily by modern medicine.”

Hence the establishment of the London Pain Consortium in 2002. Backed by funds from the Wellcome Trust, its researchers are investigating the mechanisms that trigger pain in order to find ways to alleviate and control it. McMahon works from tiny office, in a small cluster of rooms at Guy’s Hospital near London Bridge which he shares with a sizeable collection of old bicycles and spare wheels that he keeps there. During my visit, Bennett was wearing a dark blue shirt and dark trousers while McMahon had on a T-shirt and trainers. Both were clear about the urgent need to find ways to tackle the pain suffered by so many members of the population.

“It may take many years for medicine to find cures or vaccines for some of the illnesses that trigger chronic pain,” says McMahon. “But if, in the meantime, we can counter the discomfort provoked by these conditions, we will go a long way to allowing lots of people to lead happy, comfortable lives again. The trouble is that the physiological mechanisms that transmit and trigger pain are difficult to study – though we are beginning to make headway.”

Pain is an important and useful sensation, even if it is an unpleasant one. “It stops us doing silly things,” says Bennett. “It tells us that something is amiss so we can take action to avoid the cause. If your hand is near a dangerously hot object, the heat you feel will tell you to move away before your body is badly damaged. Pain serves a real purpose. You only have to look at people who cannot feel it to realise that.”

One person in a million is unable to feel pain, it is estimated. Intriguingly such individuals also have no sense of smell. The cause of the condition, known as congenital analgesia, is a rare recessive gene that only expresses itself when two carrier adults meet and have a child who inherits one copy of that gene from each parent. These individuals then fail to develop an ability to feel pain – or to have a sense of smell.

In many cases, the condition appears in remote societies where there are high levels of interbreeding. For example, in the village of Vittangi, in northern Sweden, more than 40 cases of congenital analgesia have been reported. The crucial point is that individuals affected by the condition are placed in continual mortal danger because they cannot spot when harm is being done to them. They might only realise they are being scorched by an electric fire when someone smells their burning flesh, for instance.

“Pain has real biological usefulness,” says Bennett. “It tells you that something is amiss so you can take action. However it is not always a help. Kidney stones can cause extreme distress but that pain serves no purpose. You still have to wait until the stones have passed through your system. There is nothing you can do about them. Yet you are made to suffer considerably by your body when you get them.”

Painkillers such as paracetamol and aspirin can help to alleviate discomfort but are associated with serious side-effects, particularly those of the gut. “If you are dealing with cancer, certain drugs that may have side-effects are tolerated because the condition is considered to be so serious,” adds McMahon. “But this is not accepted when dealing with the issue of pain. Because it does not kill, regulatory authorities set very high standards for safety. No side-effects are tolerated and that makes it very difficult to come up with new types of painkillers. However, there is now a lot of optimism in the field that we may soon make progress.”

A key feature about pain, scientists have discovered, is that it acts unlike any other sense in our nervous system which usually disregards repeated stimulations. For example, you quickly stop feeling the pressure of your socks after you put them on. The brain ignores the input because it is no longer novel. The exception to this rule is pain. “It is special,” says McMahon. “It has a positive feedback effect.”

Research has shown that damage to tissue will change nerve terminals in surrounding tissue to make it more responsive to pain. “If you have a small burn on the palm of your hand, it will be quickly subsumed by a larger area of hyper-sensitivity to pain,” says Bennett. “Or consider what happens when someone has a heart attack. The pain affects their chest before spreading down an arm.”

In fact, two processes are now thought to be involved when tissue is damaged. First, the area near it becomes highly sensitised to pain. In addition, the brain turns up its receptivity to pain signals.

Essentially, it amplifies an already increased input from its pain receptors. “It’s a double whammy, in effect,” says McMahon. “You get more pain sensors being switched on and you get more brain sensitivity to the signals sent by those sensors. The trick is to try to find ways to desensitise the brain or halt the spread of those new pain receptors.”

And this goal could soon be achieved, the scientists believe. Recent research has shown that the spread of pain receptors near the site of tissue damage is controlled by a chemical known as nerve growth factor (NGF).

“NGF does what its names suggest it does,” says Bennett. “It promotes the growth of nerve and pain pathways. That’s good for the growing body but in the case of chronic pain, it can have highly unwelcome side-effects.”

The crucial point is that several pharmaceutical companies are now developing medicines that counter the effects of nerve growth factor and have reported highly encouraging results. These drugs operate by attaching themselfs to NGF so that it can operate properly and interact the cell-surface receptors as it normally does. Of these medicines, the most advanced is Pfizer’s Tanezumab although the drug giants Johnson & Johnson and Amgen are also known to be working on versions.

In the case of Tanezumab, trials have reached phase three with a large number of osteoarthritis patients reporting considerable easing of their pain. “People on the drug went from having very limited activity to practically being on the dance floor. No medication available today has such dramatic results,” said Professor Nancy Lane, of the University College of Davis, California, and the co-author of a study on the drug, published in the New England Journal of Medicine.

However, trials on Tanezumab were halted last year because a small number of patients reported a worsening of their condition. The decision is a blow for patients who are desperate for any kind of alleviation from their chronic pain. In fact, says Lane, the drug could be a victim of its own success.

“I believe that the apparent worsening of certain patients’ conditions may be due to the fact that Tanezumab works so well. People feel so much better that they become more active, putting increased stress on their already badly diseased joints,” she has said.

The drug and its effects are now being investigated by the US Food and Drug Administration, which is due to give a ruling this month. Essentially, it will decide its fate.

“We are waiting eagerly to see what happens,” says Bennett. “It would be a real boon if it was given the go-ahead. We desperately need a new range of painkillers to help the millions who suffer not just from osteoarthritis but from all those other debilitating illnesses, from nerve damage to rare conditions like erythromelalgia. It has taken a long time to unravel the science of pain. Now we need to turn that knowledge into something that helps as soon as possible.” © Guardian News & Media Limited 2011 | Use of this content is subject to our Terms & Conditions | More Feeds