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Pain transition from acute to chronic – inflammation matters

Updated: May 17, 2023

For our latest pain update, Matt reviews this paper entitled; ‘Acute inflammatory response via neutrophil activation protects against the development of chronic pain’

It is widely recognised that chronic pain can develop from an acute pain state. The holy grail here is when does acute pain become chronic and how does it happen? These authors start with the understanding that these mechanisms remain to be elucidated. In this work, the researchers examined changes in immune cells from subjects with low back pain (LBP) using a technique known as transcriptomic analysis.

In short, the work showed neutrophil activation-dependent upregulation of genes in subjects with resolved pain, which did not occur in people with persistent pain. Studies in rodents showed that the use of anti-inflammatory treatments actually prolonged the duration of pain.

Sounds converse, right? Controlling inflammation in the acute stages actually makes pain worse long term? Do anti-inflammatory treatments have a negative effect on pain duration?

That transition from acute to chronic pain is not well understood, hence the drive for research such as this. The pathophysiology is now recognised to involve a complex interplay between the nervous and immune systems and we can think of chronic pain as a neuroinflammatory disorder mediated by neuronal and non-neuronal cells. Immune cells become activated in the periphery at the site of inflammation. These cells also enter the peripheral and central nervous systems where they express a variety of inflammatory mediators which then act on the nervous system to influence pain transmission and thus the transition from acute to chronic pain.

This particular study used people with LBP as the subjects. With genetic analysis of peripheral immune cells they set out to identify changes in those cells in people where the pain resolved within 3 months versus people whose pain was ongoing. The analysis identified thousands of dynamic transcriptional changes in the group where the pain resolved, but not in the group with persistent pain. So, there is evidence here that the body is adapting to the painful stimulus to prevent chronic pain. In those patients that develop persistent pain, those systems are maladaptive – a term you will hear used with chronic pain – which makes a little more sense, as a result of this research.

‘By the time of the second visit, more than 1700 differentially expressed genes were detected at the genome-wide scale between resolved and persistent patients’

Transient neutrophil-driven upregulation of inflammatory responses was protective against the transition to chronic pain. So, our neutrophil response is important. However our treatment over the past 30 plus years has been to reduce inflammation. Do you feel in a quandary now? That’s understandable. In the mouse studies, early treatment with a steroid or NSAID was analgesic in the short term but led to prolonged pain.

‘Subjects who resolved pain over time have an abundance of active biological processes underlying recovery and these processes are partially driven by changes in blood cell composition’.

At this point it’s important to step back and consider this. So, before you stop using NSAIDs for your acute pain cases, let’s regroup. The bigger picture question is ‘do we see chronic pain in our veterinary patients following the use of NSAIDs to manage acute pain?’ This paper raises the important aspect of translational research. Whilst this work has human and rodent studies, can we draw firm parallels to dogs and cats? And if we stop using NSAIDs, given the body of literature that supports their use for acute pain, what will we use instead? The authors of the paper state that the prolongation of pain seen after anti-inflammatories was not seen with other analgesics – but which other analgesics? This work involved people with low back pain. How does that translate to our use of NSAIDs in dogs and cats?

The statement the authors use is ‘despite analgesic efficacy at early time points, the management of acute inflammation may be counterproductive for long-term outcomes of LBP sufferers’ – which I think we agree is an appropriate conclusion from the data presented.

Do the models used in the rodent study really replicate the type of pain we see in our veterinary patients? Those models were chronic constriction of the sciatic nerve (a model for neuropathic pain), injection of nerve growth factor into back muscles (inflammatory muscular pain) or injection of complete Freund’s adjuvant – a cell-mediated immunity stimulator. This is one of the big reasons we should carefully consider how this research translates to our day-to-day practice.

To investigate further, these authors selected another pain condition to examine – temporomandibular disorder, and drew similar conclusions – there is a shared pathophysiology at play here so these findings are thought to be applicable to other pain conditions.

Drug effects were evident from the different experiments within this publication. In the rodent studies, the use of diclofenac and dexamethasone caused a prolongation of allodynia. This was not seen when morphine, gabapentin or lidocaine were trialled. In human subjects suffering LBP treated with NSAIDs, there was an increased risk of still reporting back pain at 2-6 years later. Other drugs examined that were not associated with this transition to chronic pain were anti-depressants – despite the fact that people taking these drugs generally have higher pain reports and higher psychological distress.

Lessons to consider

Resolution of pain is an active biological process

This process is impaired in subjects with persistent pain

The inflammatory process is beneficial to healing and resolution of pain

Higher percentages of neutrophils at the acute pain stage protects against chronic pain

In their discussion the authors state that ‘active biological processes protect from transitioning to chronic pain after an acute pain episode’. These findings are perhaps a turning point in our understanding of that transition from acute to chronic pain. I would like to see some of this research examined closer with our patient population and common pain conditions. It’s a topic worth staying close to.


Parisien M, Lima LV, Dagostino C, El-Hachem N, Drury GL, Grant AV, Huising J, Verma V, Meloto CB, Silva JR, Dutra GGS, Markova T, Dang H, Tessier PA, Slade GD, Nackley AG, Ghasemlou N, Mogil JS, Allegri M, Diatchenko L. Acute inflammatory response via neutrophil activation protects against the development of chronic pain. Sci Transl Med. 2022 May 11;14(644):eabj9954. doi: 10.1126/scitranslmed.abj9954. Epub 2022 May 11. PMID: 35544595.

This post was written by Matt Gurney.

Matt sees referrals in the pain clinic at Anderson Moores Veterinary Specialists. You can also receive telemedicine advice from us here if you have a pain case where you need a helping hand.

Matt & Carl established Zero Pain Philosophy to provide educational resources & telemedicine to veterinary professionals enabling optimal management of pain.

Matt Gurney is an RCVS & European Specialist in Veterinary Anaesthesia & Analgesia and works at Anderson Moores Veterinary Specialists. Matt is President of the European College of Veterinary Anaesthesia & Analgesia.

Carl Bradbrook is an RCVS & European Specialist in Veterinary Anaesthesia & Analgesia and is President of the Association of Veterinary Anaesthetists. Carl works at Anderson Moores Veterinary Specialists.

The intended audience for this pain update is veterinary professionals. This pain update is based on clinical experience and independent opinion.

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