When Tests Are Normal but the Pain Is Not.

Many people with fibromyalgia hear the same confusing message from doctors: your tests are normal.
Bloodwork looks fine. Imaging shows nothing unusual. Yet the pain is persistent, widespread, and often severe.
This disconnect has led to decades of misunderstanding about fibromyalgia. But research in pain neuroscience has begun to clarify what is happening.
The issue is often not in the muscles or joints.
The issue is how the nervous system processes pain.

Researchers refer to this phenomenon as central sensitization—a biological process in which the brain and spinal cord become overly responsive to sensory signals.
Instead of filtering incoming information, the nervous system amplifies it. Signals that should feel mild begin to feel painful, and existing pain signals become stronger.
Central sensitization helps explain why fibromyalgia pain can be widespread, persistent, and difficult to treat with traditional pain medications.

What Is Central Sensitization?
Central sensitization refers to increased responsiveness of neurons within the central nervous system, particularly in the spinal cord and brain regions involved in pain processing (Jo Nijs, Lotte Lahousse, Efthymios Kapreli, Panagiota Bilika, İbrahim Saraçoğlu, Anneleen Malfliet, Iris Coppieters, and Mira Meeus, 2021).
Under normal conditions, the nervous system filters sensory information. Signals travel from peripheral nerves through the spinal cord to the brain, where they are interpreted.
When central sensitization develops, that filtering system becomes disrupted.
The nervous system essentially turns up the volume on incoming signals.

Two common features of this process include:
Hyperalgesia – an exaggerated response to painful stimuli
Allodynia – pain triggered by sensations that normally would not cause pain, such as light touch or mild pressure
For someone living with fibromyalgia, something as simple as clothing pressing against the skin or sitting for too long can trigger pain.
How Central Sensitization Changes Pain Processing
Researchers have identified several biological changes that contribute to central sensitization.
One key factor involves glutamate, a neurotransmitter responsible for excitatory signaling in the brain. Elevated glutamate levels have been observed in brain regions associated with pain processing in individuals with fibromyalgia (Kathleen Sluka and Daniel Clauw, 2023).

Glutamate increases neuronal activity. When glutamate levels rise, neurons become easier to activate and more responsive to incoming signals.
At the same time, the nervous system loses some of its natural braking system.
The brain normally relies on descending inhibitory pain pathways that help regulate pain signals before they reach conscious awareness. Evidence suggests that these pathways function less effectively in fibromyalgia (Winfried Häuser, Mary-Ann Fitzcharles, and Claudia Sommer, 2022).

When excitatory signaling increases and inhibitory control decreases, the nervous system becomes primed to amplify pain.
The Role of the Spinal Cord in Chronic Pain
The spinal cord plays an important role in central sensitization.
Sensory nerves transmit signals to neurons in the dorsal horn of the spinal cord, which then relay those signals to the brain.
When central sensitization occurs, these spinal neurons become more responsive.
Researchers often describe this process as wind-up.
Wind-up occurs when repeated stimulation causes spinal neurons to respond more strongly each time they are activated.

Over time, the system becomes increasingly reactive.
This heightened sensitivity can allow pain to persist long after the original trigger has resolved.
Brain Imaging Evidence in Fibromyalgia
Brain imaging studies provide strong evidence that central sensitization occurs in fibromyalgia.
Functional MRI research shows that individuals with fibromyalgia demonstrate greater activity in brain regions responsible for pain processing, even when exposed to sensory stimuli that healthy individuals would not perceive as painful (Kathleen Sluka and Daniel Clauw, 2023).
These regions include:
the insula
the anterior cingulate cortex
the somatosensory cortex

Together, these structures form part of the brain’s pain processing network, sometimes referred to as the pain matrix.
Researchers have also observed changes in how these regions communicate with each other. These changes may contribute to symptoms such as fatigue, sensory sensitivity, and cognitive difficulties.
Why Fibromyalgia Pain Is Widespread
Fibromyalgia pain rarely stays in one place. Instead, it often affects multiple regions of the body.
Central sensitization helps explain why this happens.
When the nervous system becomes hypersensitive, neurons begin responding to signals from multiple parts of the body rather than a single injury site. The entire system becomes more reactive.

As a result, pain can migrate between body regions or occur simultaneously in several areas.
This is why fibromyalgia is often described as a disorder of pain processing rather than tissue damage.

Common Triggers That May Lead to Central Sensitization
Researchers believe central sensitization can develop after different types of physiological stress.
Common triggers reported by patients include:
physical injury or trauma
infections or viral illness
autoimmune diseases
chronic psychological stress
disrupted sleep
For many individuals with fibromyalgia, symptoms begin after a significant physiological event such as surgery, illness, or prolonged stress (Winfried Häuser, Mary-Ann Fitzcharles, and Claudia Sommer, 2022).
Genetic susceptibility may also influence how easily central sensitization develops.

Why Traditional Pain Medications Often Do Not Work
Central sensitization also explains why many traditional pain treatments are ineffective for fibromyalgia.
Medications such as nonsteroidal anti-inflammatory drugs primarily target inflammation in tissues. However, fibromyalgia is classified as a nociplastic pain condition, meaning the main issue lies in the nervous system’s processing of pain signals rather than tissue inflammation.
For this reason, medications that affect neurotransmitters involved in pain signaling are sometimes more effective.
Examples include:
duloxetine
milnacipran
pregabalin
These medications work by influencing neurotransmitters involved in pain modulation.
Other Conditions Linked to Central Sensitization
Central sensitization is not unique to fibromyalgia. Similar mechanisms have been identified in several other chronic pain disorders.

These include:
chronic migraine
irritable bowel syndrome
temporomandibular disorder
chronic fatigue syndrome
complex regional pain syndrome
Because these conditions share similar neurological mechanisms, researchers sometimes refer to them collectively as central sensitivity syndromes (Jo Nijs, Lotte Lahousse, Efthymios Kapreli, Panagiota Bilika, İbrahim Saraçoğlu, Anneleen Malfliet, Iris Coppieters, and Mira Meeus, 2021).

Why Understanding Central Sensitization Matters

Central sensitization reflects real biological changes in the nervous system.
For people living with fibromyalgia, understanding this concept can help explain why pain persists even when laboratory tests or imaging appear normal.
Fibromyalgia is not simply stress or emotional distress. It involves measurable differences in how the nervous system processes sensory signals.
As research continues to evolve, a deeper understanding of central sensitization may lead to more targeted therapies for chronic pain.

References

Häuser, Winfried, Fitzcharles, Mary-Ann, and Sommer, Claudia. (2022). Fibromyalgia syndrome: Underlying mechanisms and clinical implications. The Lancet Rheumatology, 4(9), e629–e637. https://doi.org/10.1016/S2665-9913(22)00159-8⁠.

Nijs, Jo, Lahousse, Lotte, Kapreli, Efthymios, Bilika, Panagiota, Saraçoğlu, İbrahim, Malfliet, Anneleen, Coppieters, Iris, and Meeus, Mira. (2021). Nociplastic pain criteria or recognition of central sensitization? Pain Physician, 24(6), E891–E899.

Paroli, Massimo, Gioia, Claudio, Accapezzato, Daniele, and Caccavale, Riccardo. (2024). Inflammation, autoimmunity, and infection in fibromyalgia: A narrative review. International Journal of Molecular Sciences, 25(11), 5922. https://doi.org/10.3390/ijms25115922⁠.

Sluka, Kathleen, and Clauw, Daniel. (2023). Neurobiology of fibromyalgia and chronic widespread pain. Nature Reviews Rheumatology, 19(5), 293–304. https://doi.org/10.1038/s41584-023-00917-6⁠.