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Pain Biomarkers: What They Are and What They Can Show

Blood sample tubes in a clinical laboratory

A pain biomarker is an objectively measured biological signal that tracks with pain, such as an inflammatory protein in your blood, a pattern on a brain scan or a change in heart rate during sleep. For chronic pain, the signals with the most consistent research behind them are immune and inflammatory markers, and blood is the most accessible place to measure them. That is the idea behind The Pain Signal Test™, which looks at immune system markers linked to pain through a single blood draw, so that you and your clinician have measured data to work from.

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TL;DR

  • A biomarker is a measured biological characteristic. Your own description of your pain is a different thing: it stays the gold standard, and a biomarker adds objective context to it.
  • Researchers study blood, imaging, nerve and sensory signals. Blood markers are comparatively accessible and low-cost to collect.
  • Inflammatory markers (CRP, IL-6 and TNF-α) show the most consistent associations with chronic musculoskeletal pain in a 2026 umbrella review.
  • Blood-based pain testing gives you something concrete to bring to a doctor. It works alongside your history, exam and imaging.
  • The Pain Signal Test™ is a blood test built on peer-reviewed DNA research from a leading U.S. university. Patients covered by Medicare or PPO insurance typically pay nothing out of pocket.

Table of Contents

What a pain biomarker is, and what it is not

Pain is personal. Nobody can feel it for you, so for decades doctors have relied on what patients say: where it hurts, how much, how often, what makes it worse. The U.S. FDA and NIH define a biomarker differently. In their BEST glossary, it is an objectively measured characteristic that indicates normal biology, a disease process or a response to a treatment. A 2019 review of neuroimaging-based pain biomarkers points out that this is not the same as a patient’s report of pain, function or survival, which counts as a clinical endpoint.

The two work together. A 2026 Nature Neuroscience commentary says self-report remains the gold standard for measuring pain. A biomarker does not replace your account. It adds a measured layer that can help explain mechanisms behind it.

That layer matters because of how chronic pain is usually assessed today. A 2021 review of laboratory biomarkers describes standard assessment as a mix of history, physical examination, imaging, response to earlier treatments, clinical judgment and subjective criteria. Routine chronic-pain care has not had an established laboratory marker to sit beside those inputs. That gap is why so many people with long-term pain hear “your scans look normal” and are left without a biological explanation.

What a pain biomarker is, and what it is not

The kinds of signals researchers study

Pain biomarker research is broad. A 2025 review of acute and chronic pain biomarkers lists cellular, genetic, proteomic, metabolomic, microbiome, epigenetic, neurochemical and inflammatory signals. Samples include blood, urine, cerebrospinal fluid (the fluid around the brain and spinal cord) and stool. Other approaches use imaging, electrical recordings of the brain, sensory testing and activity trackers.

Here is how the main families break down for a non-specialist.

Type of biomarker What is measured Practical notes
Blood molecules Cytokines (immune signaling proteins), other proteins, metabolites, genetic and epigenetic markers Blood is comparatively accessible and low-cost to collect, according to the 2025 review
Brain and body imaging Structural and functional MRI, PET, CT, ultrasound PET can measure metabolism and neurochemistry, according to a 2020 Nature Reviews Neurology review
Electrical recordings EEG, MEG, microneurography (recording from single nerve fibers) Typically done in specialized research or clinic settings
Sensory testing Responses to heat, pressure and other stimuli (quantitative sensory testing) Earlier versions were described as costly and technically complex in a 2012 study
Wearables and behavior Activity, sleep, heart rate Can track pain patterns day to day

Most researchers expect that combining several of these, along with psychological and social factors, will describe pain better than any single measure. For a person living with pain, the practical question is which signal is easy to collect, repeatable, and connected to something a clinician can act on. Blood checks those boxes better than most.

What studies have found in chronic pain

Immune and inflammatory markers

The strongest recurring theme is inflammation. A 2026 umbrella review (a review of reviews, covering 49 systematic reviews and meta-analyses) found consistent associations between three blood markers and chronic musculoskeletal pain: CRP (C-reactive protein), IL-6 (interleukin-6) and TNF-α (tumor necrosis factor alpha). The same review reported exploratory diagnostic potential for protein panels in fibromyalgia.

The pattern shows up in specific conditions too. According to that umbrella review, elevated CRP, IL-6 and TNF-α have been associated with pain or severity in chronic low-back pain and osteoarthritis, and training-related reductions in these markers have been reported in painful osteoarthritis.

In fibromyalgia, researchers have long suspected that inflammation in the nervous system, called neuroinflammation, plays a part in making pain persist. A 2023 review of fibromyalgia biomarkers is not the source for that point, so the more direct reading is this: the consistent immune associations above are why immune factors have become a focus for chronic pain research.

Chemical signals in muscle

A 2014 review of chronic musculoskeletal pain found elevated serotonin, glutamate, lactate and pyruvate in muscles with localized chronic pain, and described them as potential biomarkers. It also noted that more research was needed for fibromyalgia and widespread pain.

Small RNA molecules in blood

A 2025 exploratory study of 13 people with hip osteoarthritis, 11 with chronic primary pain and 7 healthy controls found that three circulating microRNAs (let-7a, miR-26a and miR-16) contributed to a model that separated the groups with an AUC above 0.94. The sample was small and the design exploratory, so this is a direction for further work. It does show that blood carries pain-related information beyond the familiar inflammation proteins.

Sleep and heart rate

A 2024 observational study followed 66 people with chronic pain for an average of 81 days. Sleeping heart rate predicted next-day pain intensity, even after accounting for previous-day pain and painkiller use. The relationship was the same in fibromyalgia and in primary chronic back pain, which suggests a shared mechanism involving the autonomic nervous system, the part that regulates heart rate and other automatic functions.

Sensory testing

A 2012 study of people with fibromyalgia, people with local musculoskeletal pain and healthy controls found that combining heat or pressure pain ratings, tender-point counts and negative affect estimated up to 49.4% of the variance in clinical pain intensity. Pain involves the body and the mind together, and the best-performing measures tend to reflect both.

Why immune markers are a practical place to start

Many people with chronic pain have been through the same cycle: a medication helps briefly or not at all, imaging shows little, and the next step is another medication. Pain relief that is not working is rarely a sign that the pain is imaginary. More often it means the cause has not been identified. Our guide on why pain relief stops working covers that cycle in detail.

Immune markers address a part of the picture that standard exams and scans do not capture. An X-ray or MRI shows structure. Blood can show biology: how active your immune system is, and whether signals associated with pain are elevated. That is why this is a sensible first biological layer to look at, and why it fits a clinical conversation.

The approach also has a practical advantage. A blood draw is routine, takes minutes at a standard lab and can be repeated. Brain imaging and specialized nerve recordings need equipment and expertise most clinics do not have.

How to use biomarker information well

Whatever signal is measured, a few principles make the result useful.

  1. Treat it as one input. Researchers describe a biomarker as a complement to self-report, not a verdict on whether pain is real. A 2026 perspective in Nature Neuroscience is blunt that biomarkers cannot prove or disprove another person’s pain, and that they do not have to be dismissed as reductionist either. Your experience and the measurement belong together.
  2. Bring it to your clinician. Results are most useful when a doctor reads them with your history, exam and imaging. Interpretation depends on your conditions, medications and other lab values.
  3. Ask what it changes. Researchers separate three questions: is the test analytically sound, does it say something clinically valid, and does it change care? The 2021 laboratory review frames those as distinct steps. A good conversation with your provider asks which treatment options your results open up or narrow.
  4. Track over time. A single value is a snapshot. Pain changes with sleep, activity, weight, stress and medication. Repeated measures, plus a simple pain diary, give a clearer pattern.
  5. Do not stop treatment on your own. If you take pain medication, change it only with your prescriber. New severe pain, numbness or weakness, loss of bladder or bowel control, fever with pain, or pain after an injury needs prompt medical attention, not a lab test first.

Reading the common lab results you may already have

If you have had routine bloodwork, you may have seen CRP or a sedimentation rate. Those are general inflammation markers, and they are not specific to pain. Our overview of joint pain blood tests explains what the common ones show, and our piece on blood testing for pain explains where a pain-focused panel fits.

What clinicians and researchers say comes next

For healthcare providers, the field’s direction is clear. A 2026 review of translational barriers says progress depends on prospective studies in representative populations, external validation, clinically meaningful endpoints, reproducibility and transparent methods. It names small selected cohorts and overfitting as problems to be solved by larger, better-designed studies.

What clinicians and researchers say comes next

A 2017 IMMPACT consensus review identified sensory testing, skin punch biopsy and brain imaging as promising research biomarkers and called for standardization and replication. A diagnostic marker is judged on its sensitivity, specificity and predictive value in large populations, as the 2019 review explains.

For a clinician, that translates into a clear way to evaluate any pain test: look at the peer-reviewed science behind it, understand what it measures, and use the result together with the clinical picture.

What we think about pain biomarkers

We built The Pain Signal Test™ around one observation: the immune system is often left out of chronic pain workups. Patients get history, exam and imaging, and when those come back unremarkable, the conversation can stall.

We believe objective biological information changes that conversation. Our test is developed from peer-reviewed DNA research at a leading U.S. university, and it uses a simple blood draw to look at immune system factors linked to pain. The aim is not to replace what you tell your doctor. It is to put measured data next to it, so the next step comes from information instead of guesswork.

The research literature supports looking at immune and inflammatory signals, and blood is an accessible way to do it. We want that accessibility to be real in practice, which is why we verify coverage for eligible patients, and why patients covered by Medicare or PPO insurance typically pay nothing out of pocket.

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Getting tested with The Pain Signal Test™

If you are living with chronic pain and want a measured look at the immune side of it, The Pain Signal Test™ is built for that. It is a blood test that evaluates immune system markers linked to pain and is based on peer-reviewed DNA research from a leading U.S. university. You can order it directly or through your healthcare provider, and the results are designed to help you and your provider discuss next steps.

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Patients covered by Medicare or PPO insurance typically pay nothing out of pocket, and we check coverage for eligible patients. FSA and HSA funds can also be used. To see how it works or to start an order, visit The Pain Signal Test™. If you want to understand how Medicare handles lab tests first, read our guide to Medicare lab test coverage.

FAQ

What are pain biomarkers?

Pain biomarkers are objectively measured biological characteristics that relate to pain, such as inflammatory proteins in blood, imaging patterns or nerve responses. They are different from your own report of how much you hurt, which remains the gold standard. They add measured information that can help explain mechanisms behind that report.

Which chronic pain biomarkers have the most research behind them?

Inflammatory markers lead. A 2026 umbrella review found consistent associations between CRP, IL-6 and TNF-α and chronic musculoskeletal pain. The same review reported exploratory potential for protein panels in fibromyalgia. Research also covers imaging, sensory testing and heart-rate measures.

What is a pain biomarker test, and what does it involve?

Research approaches include blood, urine or spinal fluid assays, imaging, brain recordings and sensory testing. Blood is the most accessible, and a draw takes minutes at a lab. The Pain Signal Test™ uses a blood draw to look at immune system markers linked to pain.

Will my insurance cover biomarker testing for pain?

Patients with Medicare or PPO coverage typically pay nothing out of pocket for The Pain Signal Test™, and we verify coverage for eligible patients. Where insurance does not pay, FSA or HSA pre-tax funds can be used. Your plan’s details decide the final answer, so coverage verification is the first step.

Can a pain biomarker replace a doctor’s evaluation?

No. Results are meant to be read by your clinician alongside your history, exam and imaging. Their purpose is to give you and your provider objective information for deciding next steps together.

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