Chronic Pain and the Immune System: What We Know & What We Do Not

The immune and nervous systems communicate continuously. Following injury or infection, immune signals can temporarily make pain-sensing nerves more sensitive. This is usually protective: it encourages us to rest an injured area while tissues recover.

In some conditions, continuing inflammation, nerve injury or altered communication between immune cells and the nervous system may contribute to persistent pain. However, chronic pain does not necessarily mean that inflammation is continuing, and chronic pain by itself is not evidence of an autoimmune or inflammatory disease.

Neuroimmune mechanisms are an important area of pain research. Much of the detailed evidence, however, comes from laboratory and animal studies, and many proposed immune tests and treatments are not yet part of routine clinical care.[1–3]

HOW THE IMMUNE SYSTEM CONTRIBUTES TO NORMAL PAIN

When tissue is injured, damaged cells and immune cells release chemical messengers including prostaglandins, cytokines and growth factors. Immune cells involved may include neutrophils, macrophages and mast cells.

These chemical signals can sensitise nociceptors—specialised nerve endings that detect actual or potential tissue damage. As a result:

• an injured area may become tender;

• movement or pressure may hurt more than usual;

• normally painful stimuli may feel more intense, known as hyperalgesia; and

• in some circumstances, normally non-painful contact may become painful, known as allodynia.

This short-term increase in sensitivity can protect an injured area. Immune cells also participate in tissue repair and release substances that help resolve inflammation and reduce pain as healing progresses.

Persistent pain is more complicated. In some people, inflammation remains active because of continuing tissue disease, infection or an immune-mediated illness. In others, pain persists after the original inflammation has settled because nerves and pain-processing pathways have become sensitised. These processes may overlap, but they are not the same.[1,2]

WHAT IS NEUROINFLAMMATION?

Neuroinflammation is a broad research term describing immune and inflammatory activity within or around the nervous system. It does not automatically mean that there is an infection of the nervous system or an autoimmune disease.

Neuroinflammation may occur in the peripheral nerves, spinal cord or brain. Its role varies considerably between different pain conditions.

Peripheral neuroimmune activity

After damage to a nerve or nearby tissue, macrophages and other immune cells can accumulate around the affected area. Schwann cells, which support peripheral nerves, and satellite glial cells surrounding nerve-cell bodies can also participate in immune signalling.

The resulting chemical signals may:

• lower the activation threshold of pain-sensing nerves;

• increase spontaneous or exaggerated nerve activity;

• recruit additional immune cells; and

• contribute to burning pain, hypersensitivity, allodynia or hyperalgesia.

These processes are particularly relevant to inflammatory and neuropathic pain, although their contribution differs between conditions and individuals.[1,2]

Central neuroimmune activity

Within the spinal cord and brain, support cells called glial cells - for example microglia and astrocytes - can influence how pain signals are processed. In animal models of nerve injury and inflammation, activation of these cells can increase excitability in pain pathways and reduce normal inhibitory signalling.

This may interact with central sensitisation, in which the central nervous system becomes more responsive to incoming signals. Neuroinflammation and central sensitisation are related concepts, but they are not interchangeable: central sensitisation can involve several neural mechanisms and does not necessarily prove that significant inflammation is present.

Importantly, most direct evidence linking particular glial cells or cytokines to ongoing pain comes from experimental studies. Fatigue, poor concentration, sleep disturbance or “brain fog” may accompany chronic pain, but these symptoms do not demonstrate microglial activation or “brain inflammation” in an individual patient.[1–3]

IS CHRONIC PAIN AN AUTOIMMUNE DISEASE?

An autoimmune disease occurs when the immune system mistakenly targets the body’s own cells or tissues. Examples include rheumatoid arthritis, systemic lupus erythematosus (SLE) and some forms of vasculitis (blood vessel inflammation disorders).

In these conditions, inflammation may cause pain through swelling, tissue injury or damage to nerves. Controlling the underlying immune-mediated disease may reduce pain. However, pain can sometimes continue despite good control of inflammation because of joint damage, nerve injury, altered pain processing or other coexisting pain mechanisms.

Most chronic pain conditions are not currently classified as autoimmune diseases. Research into autoantibodies and immune dysregulation in CRPS, fibromyalgia and some neuropathic pain conditions is scientifically important, but it has not yet produced validated diagnostic tests or established immune treatments for patients.

Complex regional pain syndrome

CRPS is a heterogeneous condition involving variable combinations of sensory, inflammatory, autonomic, vascular, movement and tissue changes. Peripheral and central sensitisation can also contribute.

Studies have identified immune abnormalities and potentially functional autoantibodies (antibodies targeting the body’s own cells or tissues) in some people with CRPS. These findings support the possibility that immune mechanisms contribute in at least some patients or at particular stages of the condition. They do not establish that all cases of CRPS are autoimmune or that a specific antibody causes the condition in every patient.[6,8]

There is currently no routinely validated blood test for autoimmune CRPS. Immune treatments such as intravenous immunoglobulin (IVIG) are not standard CRPS therapy. Although early small studies suggested possible benefit, a subsequent larger randomised controlled trial found that low-dose IVIG was no more effective than placebo for pain in longstanding CRPS.[7]

Fibromyalgia

Fibromyalgia is generally understood as a condition involving altered pain and sensory processing, often described using the term nociplastic pain. Immune abnormalities have also been reported, but findings are not sufficiently consistent or specific to establish fibromyalgia as an autoimmune disease.

One important study found that transferring immunoglobulin G antibodies from people with fibromyalgia to mice produced pain-related hypersensitivity and other changes in the animals. This provides evidence that antibodies may influence pain mechanisms in at least some circumstances. However, a mouse-transfer experiment does not establish that fibromyalgia is universally autoimmune in humans, identify a validated diagnostic antibody, or demonstrate that immune treatment is safe and effective for patients.[4,5]

There is therefore no established autoimmune blood test or routinely recommended immunotherapy for fibromyalgia. The question remains the subject of active scientific debate.

IMMUNE INVOLVEMENT IN DIFFERENT PAIN CONDITIONS

Immune involvement in different pain conditions

1. Inflammatory arthritis and established autoimmune disease: Immune-mediated inflammation is an established cause of tissue injury and pain. Disease-specific immune treatment may reduce pain by controlling the underlying illness.\

2. Osteoarthritis: Local inflammation of the joint lining and immune-cell activity can contribute, but osteoarthritis is not simply a systemic autoimmune disease. Structural, mechanical and nervous-system factors also influence pain.[9]

3. Neuropathic pain: Immune and glial signalling can contribute after nerve injury. The evidence is strong in experimental models, but individual treatment is generally based on the cause and clinical features rather than cytokine testing.[1,2]

4. CRPS: Inflammatory, neuroimmune, autonomic, sensory and motor mechanisms may all contribute. Their relative importance may change over time and between patients.[6,8]

5. Fibromyalgia: Immune findings are under investigation, but altered sensory processing remains central to current clinical understanding. Autoimmunity is not established for all patients.[4,5]

6. Post-infectious pain: Some infections can injure nerves, provoke inflammation or trigger longer-lasting sensitisation. Persistent pain after infection does not necessarily mean that an active infection remains.[10]

Osteoarthritis, neuropathic pain, CRPS and fibromyalgia can also involve more than one pain mechanism at the same time. This is one reason a single inflammatory marker or medication rarely explains or treats every aspect of a person’s pain.

WHY MIGHT IMMUNE-RELATED PAIN PERSIST?

Several processes may contribute.

• Continuing disease or tissue injury: Active inflammatory arthritis, infection, repeated injury or another unresolved medical condition may continue to generate inflammatory signals.

• Nerve sensitisation: After an injury, pain-sensing nerves and spinal pain pathways may remain more responsive even when the original tissue inflammation has reduced.

• Impaired resolution: The immune system not only initiates inflammation; it also has mechanisms that actively resolve it and support recovery. Disruption of these processes is being investigated as a contributor to persistent pain.

• Interaction with general health: Sleep disturbance, prolonged stress, mood symptoms, smoking, reduced physical activity and metabolic illness can influence both immune regulation and pain sensitivity. These relationships are bidirectional. They do not mean that pain is imagined, self-inflicted or solely psychological.

The gut microbiome is also being studied as a possible influence on immune and nervous-system signalling. At present, however, there is no validated microbiome profile, stool test or probiotic regimen that diagnoses or treats chronic pain in routine practice.

Can neuroinflammation be tested?

There is currently no single blood test, scan or cytokine panel that can determine whether neuroinflammation is causing an individual person’s chronic pain.

Blood tests such as C-reactive protein, erythrocyte sedimentation rate and specific autoantibodies may help identify particular inflammatory or autoimmune diseases when the history and examination suggest one. These tests are not general tests for chronic pain, and abnormal results can be nonspecific.

Specialised imaging, immune profiling and biomarker studies are being used in research, but more research is still required before they can reliably guide diagnosis or treatment.[11] Pain remains a subjective experience that must be assessed through the person’s reported experiences, together with clinical history, examination and relevant investigations.

Features such as persistent joint swelling, prolonged morning stiffness, unexplained fevers, rashes, weight loss or new neurological symptoms may warrant assessment for an inflammatory, autoimmune, infectious or neurological condition.

What does this mean for treatment?

Treat an established underlying disease

When pain is caused by a diagnosed inflammatory or autoimmune illness, treating that condition is important. Depending on the diagnosis, treatment may include anti-inflammatory medicines, disease-modifying antirheumatic drugs, biologic medicines or other immune therapies.

These treatments are directed at particular diseases. They are not general chronic pain treatments and can cause significant adverse effects, including increased susceptibility to infection. Their use requires an appropriate diagnosis, individual risk assessment and medical monitoring.

Use anti-inflammatory medicines selectively

NSAIDs or corticosteroids may help selected inflammatory conditions or short-term flares. They are not suitable for every type of pain or every patient, and corticosteroids are generally not a long-term solution for non-inflammatory chronic pain.

Whether they are appropriate depends on factors such as kidney, gastrointestinal, cardiovascular, bone and metabolic health, as well as other medications.

Address the other contributors to persistent pain

Even when inflammation is present, pain may also be influenced by nerve injury, sensitisation, loss of physical conditioning, poor sleep, reduced activity, distress and disruption of work or valued activities.

Treatment may therefore include:

• education about the condition and its pain mechanisms;

• appropriately paced physical activity and rehabilitation;

• treatment of sleep or mood disorders where present;

• medicines selected for the likely pain mechanism and to target specific symptoms;

• psychological strategies for managing distress, fear, activity avoidance or pain-related disruption; and

• selected procedures where there is a clear clinical indication.

Psychological therapies are not offered because pain is “all in the mind”. They can help people improve sleep, manage stress, resume activity, and reduce the impact of pain on daily life. It would, however, be misleading to claim that psychotherapy treats chronic pain by reliably lowering a particular cytokine.

Exercise, diet and general health

Regular, appropriately graded exercise can improve function and symptoms in many pain conditions. Exercise may also affect immune and metabolic regulation, but it should not be promoted as “resetting” the immune system or curing neuroinflammation.

A balanced dietary pattern—such as a Mediterranean-style diet—may support cardiovascular, metabolic and general health. Evidence that a particular diet, supplement, omega-3 product or probiotic directly treats neuroinflammation-related chronic pain remains limited. Dietary interventions should not replace assessment or treatment of a diagnosed medical condition.

Which immune treatments remain experimental?

Researchers are investigating treatments that influence glial cells, cytokines, antibodies and the biological processes that normally resolve inflammation. It is possible that future research will identify subgroups of patients who benefit from more targeted treatment.

At present, however:

• biologics and JAK inhibitors should not be presented as treatments for fibromyalgia or undifferentiated chronic pain;

• IVIG and plasma exchange are not established routine treatments for CRPS;

• minocycline is not a validated “microglial treatment” for chronic pain;

• probiotics are not established treatments for neuroinflammation; and

• although ketamine has several proposed cellular and anti-inflammatory effects, its selected clinical use in pain medicine should not be described as an established immune-modulating treatment.

Promising laboratory mechanisms do not necessarily translate into safe or effective treatment in humans. Deliberately altering immune function can also produce significant harm, so immune therapy should not be undertaken without a recognised clinical indication.[1,3,7]

The key message

The immune system is an important participant in pain, not merely a bystander. It helps generate protective pain after injury, contributes directly to pain in inflammatory and autoimmune diseases, interacts with injured nerves, and can also help resolve inflammation and pain.

However, immune involvement is not the same in every chronic pain condition. Persistent pain does not automatically indicate continuing inflammation, hidden infection or autoimmune disease. For CRPS, fibromyalgia and several other chronic pain conditions, immune findings are scientifically important but have not yet produced routine immune tests or proven immunotherapies.

Current care is therefore based on identifying any underlying disease, considering the different pain mechanisms that may be operating, and developing an individual treatment plan that addresses function, physical health, sleep, emotional wellbeing and participation in daily life.

General information disclaimer

This article provides general educational information and is not a substitute for individual medical assessment, diagnosis or treatment. It does not recommend any specific investigation, medicine, procedure or immune therapy. Treatment suitability varies according to the diagnosis, medical history, other medications and individual circumstances. Concerns about persistent pain, inflammation or possible autoimmune disease should be discussed with an appropriately qualified health practitioner.

References

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3. Paolini L, Sigaux J, Boissier MC, Rivière E. Immune control of pain. Joint Bone Spine. 2026;93(3):105999. doi:10.1016/j.jbspin.2025.105999.

4. Clauw D, Sarzi-Puttini P, Pellegrino G, Shoenfeld Y. Is fibromyalgia an autoimmune disorder? Autoimmun Rev. 2024;23(1):103424. doi:10.1016/j.autrev.2023.103424.

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7. Goebel A, Bisla J, Carganillo R, et al. Low-dose intravenous immunoglobulin treatment for long-standing complex regional pain syndrome: a randomized trial. Ann Intern Med. 2017;167(7):476–483. doi:10.7326/M17-0509.

8. Harden RN, McCabe CS, Goebel A, et al. Complex regional pain syndrome: practical diagnostic and treatment guidelines, 5th edition. Pain Med. 2022;23(Suppl 1):S1–S53. doi:10.1093/pm/pnac046.

9. Mukherjee A, Das B. The role of inflammatory mediators and matrix metalloproteinases in the progression of osteoarthritis. Biomater Biosyst. 2024;13:100090. doi:10.1016/j.bbiosy.2024.100090.

10. Cohen SP, Wang EJ, Doshi TL, Vase L, Cawcutt KA, Tontisirin N. Chronic pain and infection: mechanisms, causes, conditions, treatments, and controversies. BMJ Med. 2022;1(1):e000108. doi:10.1136/bmjmed-2021-000108.

11. Davis KD, Aghaeepour N, Ahn AH, et al. Discovery and validation of biomarkers to aid the development of safe and effective pain therapeutics: challenges and opportunities. Nat Rev Neurol. 2020;16:381–400. doi:10.1038/s41582-020-0362-2.