Introduction

Chronic pain syndromes are pain disorders in which pain persists beyond three months and are classified on the basis of physiological function and anatomical origin of pain: central, peripheral, or mixed.¹ In the case of central pain syndrome (CPS), lesions occur in the brain and spinal cord, amplifying the pain processing, whereas peripheral neuropathies (PN) arise from damage to peripheral nerves, which leads to localised sensory loss, resulting in the neuropathy.² Moreover, peripheral nerve injury and overresponsiveness of the central nervous system (CNS) to little stimuli or noxious stimuli, such as inflammation or infection, cause widespread musculoskeletal pain. This condition is called fibromyalgia.^1,2

Peripheral neuropathy feeds painful stimuli to the CNS, which in turn produces an exaggerated pain sensation called hyperalgesia.^1,2 When this hyperresponsiveness to pain persists for a longer period, the body begins responding to subthreshold painful stimuli, leading to the condition called allodynia.^1,2 As a result, this allodynic condition causes unnecessary musculoskeletal pain throughout the body: fibromyalgia. This is how central pain syndrome, PN, and fibromyalgia are interrelated to each other.^1,2

Pathophysiological mechanisms: How do PN, CPS, and fibromyalgia occur?

Multiple causes are responsible for inducing peripheral neuropathy, central pain syndrome, and fibromyalgia:

• In the case of CPS, substance P and glutamate N-methyl-D-aspartate receptors (NMDARs) induced hyperexcitability in the spinal cord dorsal horn (DH), more expression of potassium, sodium, and calcium ion channels, more activation of acid-sensing ion channels (ASICs) and purinergic P2X receptors, and neuroglial-triggered neuroinflammation, causing hyperexcitation and increasing pain sensations in the body. Diseases such as stroke and epileptic conditions may be predisposing factors to CPS^3,4
• Peripheral neuropathy results from myelin degeneration and axonal injury. These both occur due to mutations in myelin proteins such as connexin-32 and Po protein, more expression of the transient receptor potential (TRPV1) receptor, enhanced outbursts of substance P, and a higher rate of pro-inflammatory cytokines (TNF-α, IL-1β, and COX-2) through microglial cells in the periphery^5,6
• Fibromyalgia is the outcome of both central pain syndrome and peripheral neuropathy. Oxidative stress-triggered neuroinflammation, hyperexcitation of glutamate neurons, reduced GABAergic transmission, and changes in genes of the serotonin receptor (HTR2A) and dopamine receptors are behind the pathogenesis of both CPS and PN, which ultimately lead to musculoskeletal pain of fibromyalgia⁷

Symptoms of chronic pain syndromes

Central pain syndrome: How does it manifest?

Persistent shooting pain, numbness, and paraesthesia in peripheral parts of the body are the prominent signs in the clinical setup. This is worsened by little touch, stress, and changes in temperature.^3,4

Symptoms of PN

Throbbing pain, lightheadedness, muscle convulsions, and excessive sweating are the most common signs/ symptoms of peripheral neuropathy.^5,6

Clinical signs in fibromyalgia

Persistent pain on both sides of the body, higher sensitivity to lighted rooms and noisy stimuli, stabbing pain, cognitive problems, sleep disturbances, and muscle stiffness are signs of fibromyalgia.⁷

Differentiating between the clinical signs of CPS, PN, and fibromyalgia

In PN, sharp burning pain is associated with the periphery, such as hands and feet, whereas CPS is a constant, widespread pain sensation. In fibromyalgia, there is a diffuse dull pain that is widespread in the musculoskeletal region. Whilst in PN, the allodynic and hyperalgesic effects are related to only affected peripheral areas, they are more prominent and generalised in CPS. In addition, loss of sensory nerves is strongly observed in PN, unlike CPS and fibromyalgia.⁸

How to diagnose CPS, PN, and fibromyalgia?

For the differential diagnosis of central pain syndrome, peripheral neuropathy, and fibromyalgia, there are many different assessments and laboratory techniques, such as:^9,10,11

• The first step is assessment of pain processing characteristics, such as burning and stabbing pain in CPS, feet/ hand numbness in peripheral neuropathy, and musculoskeletal pain for over 3 months in the case of fibromyalgia
• The second step is neurological testing. For example, sensory testing such as touch, temperature, position, and pain; checking reflexes such as knee or ankle jerks; and motor tests such as muscle strength or tone
• Additionally, neuroimaging scans such as magnetic resonance imaging (MRI) and computed tomography (CT) evaluate structural abnormalities such as brain lesions in CPS and nerve compression in PN. In addition, Functional Magnetic Resonance Imaging (fMRI), Positron Emission Tomography (PET), and Single-Photon Emission Computed Tomography (SPECT) are used to evaluate functional loss, such as pain processing and sensitivities, in both CPS and PN

In fibromyalgia, fMRI detects changes in blood flow, structural MRI measures white matter abnormalities, and PET is used for metabolic changes or neuroinflammation.

How to mitigate CPS, PN, and fibromyalgia?

Interventions for pain disorders combine both non-pharmacological and pharmacological treatment. 

• Anticonvulsants, such as gabapentin, and antidepressants, such as amitriptyline, duloxetine, and lidocaine, for symptomatic treatments¹²
• Cognitive behavioural therapy (CBT) facilitates the intervention of CPS, PN and fibromyalgia¹³
• Regular exercises with low impact are part and parcel of treatment strategies¹⁴
• Education and counselling
• Consume a healthy diet¹⁵
• Follow stress reduction programmes
• Avoid smoking¹⁶

Lifestyle modifications, physical therapy and psychological intervention are part of the non-pharmacological treatment, whilst medicines administered are part of the pharmacological intervention.

FAQs

How is fibromyalgia diagnosed?

 In order to confirm the fibromyalgia diagnosis and exclude other diseases, doctors assess clinical symptoms and take blood samples for blood tests for thyroid and inflammatory markers.

Are you familiar with the stages present in fibromyalgia?

Four stages of fibromyalgia are present, which encompass everything from localised lesion-induced symptoms to widespread manifestations, as described below:^17,18

• Regional fibromyalgia, associated with muscle strain in the peripheries, such as the neck and shoulder regions
• Generalised fibromyalgia, when regional pain extends beyond other body regions, such as arms, legs and trunk, then fatigue, cognitive problems and increased sensitivity to light stimuli such as touch and temperature changes
• Advanced stage of fibromyalgia, when the generalised effect leads to further complications such as severe fatigue, anxiety, depressive moods and disrupted sleep cycles
• Secondary fibromyalgia, when this advanced fibromyalgia accompanies secondary disorders such as rheumatoid arthritis and autoimmune diseases

Are there any stages for central pain syndrome and peripheral neuropathy, just like for fibromyalgia?

Unlike fibromyalgia, the central pain syndrome and peripheral neuropathy do not have progression stages. However, based upon the disease duration, they have acute, subacute and chronic stages:^17,18

• Acute: >3 months
• Subacute: 3-6 months
• chronic: >6 months

Summary

Whenever we talk about CPS, the lesions found in different parts of the brain and spinal cord are the ones causing alterations in the basic processing of central pain. PN results from damage to the peripheral nerves due to causes such as diabetes or toxins. Fibromyalgia is a central sensitisation disorder, causing widespread musculoskeletal pain without nerve damage. 

CPS presents with burning, stabbing pain, plus neurological deficits such as weakness and spasticity. PN symptoms include numbness, tingling, muscle weakness, and reduced reflexes, often in a glove-and-stocking pattern. Fibromyalgia features chronic widespread pain, fatigue, sleep issues, and cognitive problems ("fibro fog") with normal neurological exams. 

CPS diagnosis relies on clinical history of CNS injury, neurological exam, and MRI/ CT detecting CNS lesions. Diagnosis of peripheral neuropathy uses clinical evaluation, blood tests, nerve conduction studies, electromyography, and sometimes nerve imaging. A fibromyalgia diagnosis includes clinical symptom criteria for excluding other diseases. There is no definitive test for it. Neuroimaging for CPS detects CNS damage; for PN, it assesses peripheral nerves, whilst in fibromyalgia, imaging is mainly research-based on brain function.