Chronic pain is one of the least understood conditions in medicine, but scientists from Massachusetts General Hospital in Boston have developed a new brain-scanning method that could have implications for more effective therapy for the disorder. Dr Marco Loggia, assistant professor of radiology, explains more.
Though unpleasant, pain serves us well most of the time. A sharp reminder when we touch a hot pot, for instance, prompts us to protect ourselves from further injury. We wouldn’t want to be without that recognition. For instance, a rare disorder called congenital analgesia results in patients who don’t feel any pain at all. It’s certainly more a curse than a blessing, leading to an accumulation of wounds, broken bones and other health issues due to sufferers inadvertently putting themselves in dangerous situations.
However, as helpful as pain can be, it is nothing short of cruel when there is no actual disease or injury to detect, or the feeling persists for far longer than it should. It is estimated that around 7.8 million people in the UK suffer from moderate to severe pain that has lasted for more than six months. Studies suggest it is more commonly reported by women and those from socially or financially disadvantaged groups.
Traditionally, chronic pain has been poorly treated, with patients told the uncomfortable sensations are all in their head but, in recent years, the medical community has begun to understand that if pain is no longer there to signal disease or underlying injury, then the chronic pain itself becomes the problem and needs to be treated as the primary pathology.
It’s something Dr Marco Loggia, assistant professor at Harvard Medical School, knows only too well. He works at the Martinos Center for Biomedical Imaging in Massachusetts General Hospital where he conducts research on the role of the brain in disorders such as chronic lower-back pain, fibromyalgia and rheumatoid arthritis. He became fascinated with the topic during his PhD, when he worked under the supervision of Catherine Bushnell, a renowned scientist and expert on the brain’s role in chronic pain, who is now scientific director at the National Center for Complementary and Integrative Health, US National Institutes of Health.
Loggia says the prevalence of chronic pain is enormous, quoting a report from the Institute of Medicine that suggests around 100 million Americans suffer from the disorder – a figure higher than diabetes, heart disease and cancer combined. "I think one of the main reasons why chronic pain is so challenging to treat is that, as is now increasingly being recognised, the central nervous system plays an important role in its establishment and maintenance," he says.
Prior to this way of thinking, it was assumed chronic pain arose from dysfunction in nociceptors, the nerve cells that sense and respond to damaged parts of the body. Current research, however, suggests that sometimes, after an initial injury has occurred in the body, the effect of the event can propagate throughout the nervous system, from the spinal cord to the brain.
"When this happens, merely treating the original source of the pain is no longer enough because the central nervous system itself now contributes to the pain," explains Loggia. "This is problematic because, while surgically fixing a peripheral problem may be straightforward, fixing a nervous system that has changed and rewired can be challenging."
A possible source?
Loggia’s research, however, may reveal cause for optimism when it comes to working out what is going on in this situation and consequently identifying treatment options that might prove effective.
Loggia and his team look into the role of brain inflammation in pain disorders. In the past two decades, studies have shown that when an animal receives an injury, glial cells – non-neuronal components that provide support and the protection to the nervous system – react. Their name is derived from the Greek word for ‘glue’, and these components surround brain cells, holding them in place while supplying them with nutrients and oxygen.
Glial cells respond to pathological events in the CNS, such as stroke, trauma or neurodegenerative disease by undergoing a series of responses collectively known as ‘glial activation’. This reaction includes proliferation, morphological changes and the production of inflammatory substances. Activation is usually an adaptive, defensive mechanism that contributes to handling acute stress, limiting tissue damage and maintaining homeostasis, but it is thought the process can sometimes malfunction and thus have deleterious effects. Several animal studies have established that this activation is a key contributing factor in persistent pain.
"These animal studies are very exciting because they suggest glial cells may be a therapeutic target for pain," says Loggia. "Unfortunately, however, evidence showing glial activation in humans with chronic pain has so far been very scarce. As a result, the attempts to develop glial-based therapies for pain have been less aggressive than they probably should have been."
So Loggia and his team set out to observe this phenomenon in humans. In a recent study, the researchers demonstrated for the first time that patients with chronic lower-back pain have heightened levels of a protein called ‘translocator protein’, or TPSO, in the brain. TSPO is normally expressed at very low levels in the CNS, but its concentration increases dramatically when glial cells become activated.
The researchers recruited 19 individuals diagnosed with chronic lower-back pain and 25 healthy volunteers. Using a PET/MRI scanner and employing a recently developed radioactive tracer called 11CPBR28 that binds to TSPO, the team could identify how much and where in the brain the radioligand accumulates in order to make inferences about the levels and distribution of the protein, and hence, whether glial cells were being activated.
Strong signs
The results were interesting to say the least. It was the first time scientists have found evidence of neuroinflammation in key regions of the brain in humans with chronic pain. Loggia and colleagues discovered that levels of TPSO in the thalamus and other brain regions were significantly higher in patients than in controls. The PET signal increases were so remarkably consistent across participants that it was possible to spot which were patients and which were healthy controls just by looking at the individual images produced from the machine, prior to any statistical analysis.
Loggia says: "I was surprised by the consistency of the TPSO signals in a specific region: the thalamus, which is the gateway to the brain for most sensory signals coming from the body. In this region, just by looking at the individual data, we could pinpoint who was a patient and who was a pain-free control, which is really quite remarkable given there are currently no known biomarkers to diagnose a pain condition."
Intriguingly, among the patient participants who had been asked to report their current levels of pain during the imaging session, those with the highest levels of TPSO reported the lowest levels of pain.
Loggia explains: "While upregulation of TSPO is a marker of glial activation, which is an inflammatory state, animal studies have suggested that the protein actually limits the magnitude of glial response after its initiation and promotes the return to a pain-free, pre-injury status. This means that what we are imaging may be the process of glial cells trying to ‘calm down’ after being activated by the pain.
"Those participants with less pain-related upregulation of TSPO may have a more exaggerated neuroinflammatory response that ultimately leads to more inflammation and pain."
He says that while larger studies would be needed to further support this interpretation, the findings provide a rationale for exploring the role of glia as a therapeutic target for chronic pain. For example, TSPO agonists, which intensify the action of TSPO, may benefit pain patients by helping to limit glial activation. Certainly in animal studies, drugs that reduce glial activation, such as propentofylline and minicycline, have been shown to suppress the development of neuropathic pain. Some of these molecules are already FDA approved to treat other conditions; therefore, testing for new chronic- pain-related indications would be immediately possible.
Two recent clinical trials have indicated that low-dose naltrexone, an opioid antagonist, may be effective for patients with fibromyalgia. As the drug is thought to antagonise the activity of glial cells, it is possible naltrexone and related modulators may be beneficial for chronic pain patients. However, it must also be pointed out that some studies testing similar compounds have had negative results, although Loggia reckons there are methodological concerns with these. For instance, longer trial durations might be needed to properly assess the efficacy of such compounds in pain conditions.
As for the next steps for Loggia and his team, they are already working on further studies to determine whether different populations present differences in the spatial distribution of glial activation. It is hoped this might lead to the identification of imaging markers that could be used to help with diagnosis. Additionally, the researchers believe measuring glial activation might one day allow early identification of individuals at risk of transitioning from acute to chronic pain, thus optimising treatment strategy and ensuring pain only occurs when it is actually required.
