Chronic pain can be treated — so why are millions still suffering?

Pain often seems like a simple experience: grab a hot pan, and a harm alarm will sound. But in many cases where pain persists, the relationship between pain and harm is anything but simple.

In 1996, when Kass was 28, he was working as an acrobatics instructor with a travel and tourism company in the Bahamas. One morning, after a day of catching people on the flying trapeze, he was awoken by excruciating pain in his lower back.

He quit his job and flew back to the United States, where magnetic resonance imaging (MRI) revealed damage to a cartilaginous disc in his lower back, between his L5 and S1 vertebrae.

It’s impossible to know exactly what was going on in Kass’s body in the first hours and days after his injury. The specialists he saw in the United States told him that fragments of material from the damaged disc were probably pressing on his spinal nerves. But assuming Kass had experienced some kind of tissue damage, inflammation resulting from that would almost certainly have altered his pain-processing machinery.

Researchers have known for decades that tissue damage can alter the sensitivity of neurons in the peripheral nervous system (all of the nerves that exist outside the spinal cord, brainstem and brain), as well as how the central nervous system interprets signals.

After a sunburn, for instance, warm water that felt pleasant the day before might seem scalding. This happens because the inflammation caused by the sunburn alters the sensitivity of nerves in the peripheral nervous system known as nociceptors, which recognize noxious stimuli — a phenomenon called peripheral sensitization. Similarly, days after surgery, well away from the site of the incision where there is no inflammation, a light touch of the skin might hurt. That’s thanks to changes in the central nervous system. Multiple mechanisms drive this process, known as central sensitization, but in this case, firing from sensory neurons activated by innocuous stimuli is now perceived as pain.

In most people, most of the time, peripheral and central sensitization are temporary and adaptive. They prevent people from doing more harm to damaged tissues. But what if that amplified sensitivity persists after wounds have healed, or even in the absence of any detectable tissue damage?

Various studies, mainly in animals, have identified dozens of pathways and cell types involved in peripheral and central sensitization. Following damage — the cutting or crushing of a rat’s sciatic nerve, say — a menagerie of cells get activated around the nociceptors, and release factors that make the neurons more sensitive. These include macrophages, neutrophils, T cells and B cells, as well as glial cells, which are non-neuronal cells that support and protect neurons.

It’s a remarkably complex set of interactions, says Jeffrey Mogil, a neuroscientist at McGill University in Montreal, Canada. “Evolution took a piece of string and randomly — because it had millions of years — knotted it into a hellacious ball of yarn,” he says.

And the communication between nociceptors and immune cells goes both ways. In certain contexts, pain-triggering neurons can block or ramp up the activities of neutrophils and other types of immune cell². “The nervous system doesn’t even have to go via the brain; it just signals directly to the immune system in the periphery,” says Isaac Chiu, a neuroimmunologist at Harvard Medical School in Boston, Massachusetts.

In people with skin conditions such as eczema, where there is ongoing inflammation, these reciprocal interactions between the immune system and nociceptors might help to drive persistent inflammation, and with that, persistent pain.

Even a person’s microbiome, which interacts with both the immune and nervous systems, could play a part in certain pain conditions. Several groups, for example, are exploring the use of probiotics to treat people with irritable bowel syndrome (which causes abdominal pain)³.

Another emerging idea is that some immune-system processes that drive sensitization might also be important in driving pain away. Last year, scientists at McGill University published an analysis of gene-expression patterns in people with lower-back pain. Although clinical trials are needed to verify the results, their data indicate that if inflammation is blocked by drugs, neutrophils don’t do what they are supposed to do to resolve pain⁴.

This flies in the face of expectation, says Clifford Woolf, a neuroscientist also at Harvard Medical School — and the first to demonstrate central sensitization⁵. Physicians have long prescribed anti-inflammatory drugs on the premise that if pain is allowed to persist, it might become chronic. “This paper suggests the complete unexpected opposite, which is that the inflammation is actually helping,” Woolf says.