Turn the clock back a couple of decades and people who suffered ongoing pain without any obvious medical cause were sometimes dismissed by their doctors.
Rather than realise that the person was genuinely suffering, some clinicians believed the problem was simply in the mind.
It piled on the misery for many patients left with no answer to their anguish.
“If you had pain without a discernible cause in the body, if there wasn’t all-singing, all-dancing inflammation, a doctor might say, ‘It’s probably in your head,’” says Dr Franziska Denk, a senior lecturer at King’s College London who researches the peripheral nervous system.
“And women are more likely to suffer from chronic pain, so you might have been labelled a hysterical woman, who should go see her therapist. When we cannot see pain, we arrogantly assume the body is not dysfunctional, rather than maybe we just don’t have the tools with the right sensitivity to detect the dysfunction.”
Scientific findings change attitudes
As science has advanced, there is greater acknowledgement that chronic pain is real and that it does have a biological cause. While real, this cause may not be obvious, and it may not directly involve the nerves.
“There’s a lot of abnormality in the body still that we as neuroscientists haven’t fully clocked on to yet, so we tend to blame the nervous system. [We think] the brain is going wrong,” says Dr Denk.
“I’m not saying the brain isn’t important, but maybe it is going wrong because there’s still a lot of low-grade inflammation and connective tissue cells sitting there constantly yelling at the nerves, ‘I’m not happy, I’m not happy.’”
A key area of interest in the chronic pain field are glia, which are various types of cell that are linked to or support the nerves or neurones, which are the cells that actually transmit impulses from the body to the brain or the spinal cord, and back again.
With many conditions, including chronic pain and neurodegenerative illnesses such as Alzheimer’s, research has typically focused on the neurones and what their role in disease might be.
But for quite a number of years, many scientists have thought that the pathology may not be in the nerves, but in the glial cells associated with them.
Discovered in the middle of the 19th century and found in invertebrates and vertebrates, they exist in various forms.
These include astroglia, which are homeostatic cells of the central nervous system, carrying out actions such as dealing with waste. There are also oligodendroglia, which support and insulate axons, the long parts of neurones that conduct impulses from the cell body, and microglia, which have a role in immunity.
“As long as these glial cells are doing everything fine, there’s no disease whatsoever. They are taking care, they are restoring homeostasis, they are restoring whatever mini-trauma, they are fighting pathogens,” says Prof Alexei Verkhratsky, a professor of neurophysiology at the University of Manchester in the UK.
If, in addition to these supportive functions, glia are responsible for what has been described as the “silent epidemic” of chronic pain, then their actions are affecting hundreds of millions of people around the world.
Figures from the US suggest as many as one in five people has chronic pain, while estimates from the UK, published by The British Pain Society, indicate that about one in seven has “moderately or severely disabling” chronic pain, with elderly people worst hit.
Glial cells could prove a fault in pain chain
Glia could be the reason why, for example, people who have suffered accidents continue to feel pain long after their injuries have healed. It is a case of pain that once had a biological function – to indicate an injury – becoming a pathology in itself.
“You can strain your leg for example,” says Prof Verkhratsky.
“You have this pain sensation and you have sciatica for a week or two. Then it’s gone. But in certain conditions, the very same thing in a different person will trigger something where this pain will continue for months and months.”
Chronic pain can involve problems at three levels. The first involves peripheral sensory neurones, which are nerves located outside the central nervous system and whose role is to respond to external stimuli and inflammation.
There may also be an abnormality at the spinal cord, where neural circuits may amplify the input from the peripheral nervous system. The third level involves the brain itself, which could be perceiving pain because it is, in a sense, expecting it.
“There’s evidence that the brain in someone who has chronic pain is maladjusted,” says Dr Denk.
“The brain keeps expecting pain because it happens a lot, so it sometimes sees it even when it’s not there.”
Since as far back as the early 2000s, it has become apparent that glia can become in some way remodelled and that this causes continuous stimulation of the central nervous system.
No easy solution to conundrum
They may be affecting the complex handover of impulses from the peripheral to the central nervous system, causing constant stimulation.
Understanding the causes and finding drug treatments that can alleviate this has proved incredibly difficult, mirroring the challenges of dealing with other neurological diseases, such as Alzheimer’s.
One difficulty, says Prof Verkhratsky, is translating results from animal trials into humans. There is no guarantee, he says, that research findings in mice will be applicable to human beings.
“How to translate what we found in mice, to the human? In many cases the translation is impossible. We are studying human diseases in non-humans. That clearly triggers some errors,” he says.
“The second [problem] is even more difficult because clearly it’s probably a multifaceted pathology. So there could be different pathophysiological mechanisms which could converge on the very same clinical outcome.”
Because glia regulate the activity of neurones in myriad complex ways, it is very difficult to target their effects on chronic pain, because dealing with one form of communication may leave others unaffected.
All of this has contributed to the difficulty scientists have had in finding drugs to treat the condition or other neurological disorders.
No clinical trial has found a drug that can specifically target glial cells and show benefits in chronic pain, according to Dr Thiago Cunha, an associate professor of pharmacology at Ribeirao Preto Medical School, part of the University of Sao Paulo.
“I believe we have to understand better the molecular mechanisms in each of these types of pain,” he says.
“We need to understand each type of chronic pain and try to understand deeply the molecular mechanisms. Then we could plan the clinical trials better.”
“Depending on the type of chronic pain, glial cells can contribute in a different intensity. Maybe [they are] involved more in some type of chronic pain than in other ones.
Progress can be made
Despite the hurdles, Dr Denk believes progress is being made in understanding chronic pain and the role played by glial cells.
“I’m quite optimistic,” she says.
“I think you can have a lot of near misses. In the pain field there was a drug that made it all the way to Phase 3 [clinical trials]. It was a humanised antibody [called tanezumab]. Pfizer developed this compound.
“They tried it in osteoarthritis. It failed because of some dose-limiting side effects and was terrible for the company, but personally I think that whole pathway would be a pathway that would be analgesic [pain relieving] and so there are other ways to tap into that pathway.
“There are similar examples … I do feel that our understanding has advanced a lot. We’re close but not quite there yet.”
