Inflammation is a core component of pain. But early inflammatory responses may protect against acute pain becoming chronic, according to an intriguing study of nearly 100 patients with low back pain.

At first glance, the study, which also included mouse models of persistent pain and a population-level analysis of painkiller use, seemingly goes against mounds of evidence indicating that inflammation drives widespread chronic pain.

But its focus is on acute inflammation – the first wave of immune cells led by neutrophils, a type of white blood cell deployed to damaged tissues.

Led by computational biologist Marc Parisien of McGill University in Canada, the study points to the role inflammation plays as acute pain transforms into persistent chronic pain (the latter lasts six months or more).

Despite immediate pain relief from anti-inflammatory drugs, a current mainstay of pain treatment, the findings also hint that these drugs may be counterproductive for long-term outcomes for people with low back pain. Longer, more diverse studies are needed though, because this one only followed participants (all White adults) for three months.

"Despite advances in the understanding of social, psychological, and genetic factors, as well as brain processes associated with chronic [low back pain], we understand very little of the molecular mechanisms underlying the acute-to-chronic pain transition that might lead to more efficacious analgesic strategies," Parisien and colleagues write in their paper.

Clearly, the global need for better pain relief is huge. Low back pain ranks the highest of all chronic conditions in terms of years lived with disability, followed by headache disorders and depression.

To treat it, we also need to better understand how chronic pain initially develops, and why the acute pain which resolves in some patients persists as chronic pain in others.

Technically, acute pain is sharp, sudden pain which persists for less than three months. Long-lasting chronic pain involves a complex interplay between the body's immune and nervous systems, and can manifest in many forms: autoimmune diseases such as rheumatoid arthritis, and musculoskeletal conditions, such as back pain.

In this study, Parisien and colleagues looked at gene expression levels in the immune cells of 98 patients with acute low back pain, comparing data from people whose pain resolved after three months with those from patients whose pain persisted.

People whose acute low back pain resolved had highly active inflammatory responses driven by neutrophils, the study found. Dynamic changes in several thousand genes were observed in their immune cells, but none in people with persistent pain.

These acute and possibly protective inflammatory responses are short-lived, "which is probably the main reason why they were previously overlooked," Parisien and colleagues write. But they also note their analysis lacked control subjects who never experienced pain in the first place.

In the mouse studies, early treatment with anti-inflammatory drugs prolonged pain despite relieving it in the short term, whereas no such effect was seen with painkillers that don't act on inflammation, such as lidocaine.

In other experiments, mice depleted of neutrophils took longer to resolve pain signals, while mice injected with neutrophils or the proteins neutrophils produce, did not develop long-lasting pain when treated with anti-inflammatory drugs.

But it almost goes without saying that mice are only rough models; in this case, these animal studies provide mechanistic insights into pain processes.

Using data from the UK Biobank, a large population-level database, the team also analyzed painkiller usage among people with low back pain.

They found people who used non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen and aspirin, had a 1.76-fold higher risk of reporting back pain 2 to 6 years later than those taking pain-relieving but not anti-inflammatory drugs such as acetaminophen.

The data did not capture measures of pain intensity or psychological distress, two major risk factors for the development of chronic pain.

That said, the researchers did account for age, sex, and ethnicity in the analysis, and when they factored in antidepressant use as a proxy for psychological distress, the findings did not change.

Altogether, the results led Parisien and colleagues to conclude that acute inflammatory responses, regulated by neutrophils and inhibited by anti-inflammatory drugs, could underlie pain resolution, a process which they think is impaired in people whose pain becomes chronic.

"We always think of pain as some active pathological process happening to us," says study author and pain scientist Luda Diatchenko also of McGill University in a podcast discussing the study's results.

"But looking now at the data, it's the opposite: it's an active adaptational process that's happening in people who resolve pain, and having chronic pain is the absence of it."

While this study provides some intriguing biological insights, painkillers are just one part of the pain management picture, and there are many types of chronic pain.

For those who do unfortunately develop chronic low back pain, recent research shows that the key to managing their persistent pain is psychotherapy, which can help to reduce pain intensity and improve physical function by tackling the mental aspects of pain alongside physical remedies.

The study was published in Science Translational Medicine.