Central Neuropathic Pain

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Central neuropathic pain (CNP) is defined by the International Association for the Study of Pain (IASP) as “pain caused by a lesion or disease of the central somatosensory nervous system” – that is, the brain or spinal cord. This distinguishes it from peripheral neuropathic pain, which affects the peripheral nerves. The term CNP also encompasses and replaces previous terminologies such as "thalamic pain syndrome," "Dejerine-Roussy syndrome," "deafferentation syndrome," "dysaesthetic pain," and "anaesthesia dolorosa".  

Causes

Common Causes of CNP include a variety of neurological conditions that damage central sensory pathways:

• Central post-stroke pain (CPSP): This is the most prevalent form of CNP worldwide, occurring after ischemic or hemorrhagic stroke affecting sensory processing areas like the thalamus or somatosensory cortex. The pooled prevalence is estimated at 11% among stroke survivors, but up to 50% in specific types of strokes like medullary, thalamic, and operculo-insular strokes.
• Spinal Cord Injury (SCI): Trauma or disease affecting the spinal cord can lead to CNP, often experienced at or below the level of the lesion. About 53% of individuals with SCI experience neuropathic pain.
• Multiple Sclerosis (MS): Demyelinating lesions in the brain or spinal cord can cause various types of neuropathic pain, including CNP.
• Traumatic Brain Injury (TBI): Damage to central pain pathways can result in CNP.
• Brain Tumors or Abscesses: Lesions impinging on or infiltrating central sensory structures.
• Neuroinflammatory conditions: Such as neuromyelitis optica spectrum disorders (NMOSDs).
• Syringomyelia/Syringobulbia: Fluid-filled cavities within the spinal cord or brainstem.

Pathophysiology

The underlying mechanisms of CNP are multifaceted and intricate, leading to neuronal hyperexcitability and altered pain processing within the CNS. This hyperexcitability is considered the primary electrophysiological basis for both spontaneous and evoked pain experienced by individuals with CNP. Much of our current understanding is derived from animal models of neuropathic pain.  

Damage to Sensory Pathways: Damage to critical sensory pathways, especially lesions impacting the spinothalamic tract (a major pain and temperature pathway) and the thalamocortical projections (connections between the thalamus and the brain's cortex), is a frequent underlying issue.

Deafferentation & Ectopic Activity: The loss of normal sensory input from such lesions (deafferentation) can provoke spontaneous, abnormal electrical discharges in deafferented central neurons, for instance, in the thalamus or cortex. Such ectopic activity can also originate from deafferented thalamic or other supraspinal neurons more broadly. Indeed, a 'central pattern generating process' has been implicated, where abnormal neuronal activity in specific brain sites, like the operculo-insular cortex (as seen in some painful epileptic seizures or with tumors in this region), is sufficient to generate pain. Direct electrical stimulation of areas like the posterior insula in humans has also been shown to elicit pain.  

Ion Channel Dysfunction: Alterations in the function or expression of ion channels—specifically voltage-gated sodium, potassium, and calcium channels—within central neurons can heighten their responsiveness and contribute significantly to this state of hyperexcitability. For example, Nav1.5 upregulation in astrocytes in MS lesions,, potassium, and calcium channels (e.g., a2​δ−1 subunit upregulation ) in central neurons increase their responsiveness and contribute to hyperexcitability.

Neuro-immune Interactions & Central Inflammation: Following an injury to the CNS, neuro-immune interactions and central inflammation become key players. The activation of glial cells like microglia and astrocytes triggers the release of pro-inflammatory cytokines (such as IL-1β, IL-6, and TNF-α) and other mediators that can sensitize neurons and perpetuate the pain. More specifically, bidirectional interactions occur between neurons and glial cells, and reciprocal interactions with immune cells like T cells and macrophages contribute to CNP pathogenesis. For instance, the chemokine CX3CL1 (fractalkine), released by neurons, can bind to its receptor CX3CR1 (which is upregulated on microglia after injury), fueling inflammatory processes.  

Imbalance of Excitatory & Inhibitory Neurotransmission: This can manifest as a diminished inhibitory tone (for instance, reduced GABAergic or glycinergic inhibition) or an augmented excitatory transmission (often involving glutamate and its NMDA and AMPA receptors). For example, brain-derived neurotrophic factor (BDNF), released after CNS injury, can lead to the downregulation of the potassium chloride co-transporter KCC2. KCC2 is vital for establishing the correct chloride gradient in neurons; its downregulation diminishes the efficacy of GABA-mediated inhibitory signals, thereby contributing to disinhibition.  

Increased Neuronal Responsiveness: Increased neuronal responsiveness along the nociceptive pathways to preserved afferent input is thought to underlie evoked pain phenomena like allodynia and hyperalgesia, and may even contribute to spontaneous pain if there's an abnormally heightened response to continuous, otherwise normal, peripheral sensory input. Supporting this, some patients with CPSP have experienced complete pain relief following peripheral anaesthetic nerve blocks. There may be a spectrum of neuronal hyperexcitability, where early sensory hypersensitivity (evoked pain or dysaesthesia) reflects increased neuronal responsiveness, which, over time and with ongoing central neuroplastic changes, can escalate to or develop into spontaneous neuronal activity that manifests as chronic, ongoing pain.  

Thalamocortical Dysrhythmia: Thalamocortical dysrhythmia, characterized by altered oscillatory activity (often in α and θ brainwave bands, and potentially high γ) and firing patterns between the thalamus and the cortex, has also been proposed as a significant mechanism. Thalamic deafferentation can change the firing properties of thalamic neurons, which in turn alters these crucial thalamocortical oscillations. Microstimulation studies in the sensory thalamus have provided evidence of these altered pain pathways following damage to the spinothalamic system.  

Maladaptive Structural & Functional Plasticity: Furthermore, maladaptive structural and functional plasticity leads to changes in synaptic strength, neuronal connectivity, and the organization of sensory maps within the brain. Neuroimaging studies have revealed alterations in opioid receptor-binding capacity and evidence of glial activation in CNP. In individuals with SCI-induced CNP, biochemical shifts in the thalamus, such as decreased N-acetylaspartate and GABA content, alongside structural changes, point to an imbalance between excitatory and inhibitory mechanisms. Progressive damage within the spinothalamic tract itself has been suggested as a time-dependent factor in the development of CNP after SCI.

Altered Descending Modulation: Additionally, alterations in conditioned pain modulation (the body's own pain-dampening systems) have been reported, suggesting impaired descending inhibitory control.  

Complex Network Interactions: Ultimately, pain in CNP is thought to arise from complex, dynamic interactions of activity across widespread brain networks—not from a single "pain spot." The "dynamic pain connectome" model highlights that the experience of pain involves coordinated activity within and between central ascending (sensory) pathways, descending (modulatory) pathways, and brain networks crucial for attention, salience, cognition, and other functions that shape the overall pain experience.  

Altered Sensory Coding: The traditional concept of sensory information traveling along "labelled lines" (dedicated pathways for each sense) is being expanded to include notions of cross-modality interactions and "population coding," where multiple sensory inputs might be conveyed via shared circuits and distinguished by differing neural coding properties like firing intensity. The thermal grill illusion, where a sensation of painful burning cold is elicited by touching interlaced warm and cool bars, serves as a compelling human model for some of these complex central integrative mechanisms that might be at play in CNP.  

Clinical Features

Symptoms of CNP are diverse and often severe:

• Spontaneous pain: This is a hallmark and can be ongoing or intermittent. Patients often use descriptors like burning, pricking, squeezing, freezing, aching, or electric shock-like sensations.
• Evoked pain:
  • Allodynia: Pain in response to normally non-painful stimuli (e.g., light touch, temperature changes). Thermal allodynia (especially to cold) is common.
  • Hyperalgesia: Increased sensitivity to painful stimuli.

• Dysaesthesias and Paresthesias: Unpleasant abnormal sensations or abnormal sensations like tingling or prickling may also be present.

The pain is typically located in body regions where sensation is already altered (e.g., experiencing numbness or reduced temperature sensation) due to the underlying CNS lesion. Sometimes, a proximal-to-distal gradient of pain intensity is observed, with pain being more intense in the more distant parts of a limb.

A perplexing aspect of CNP development is the paradox it presents: damage to sensory pathways like the spinothalamic tract, which are responsible for transmitting pain and temperature signals, paradoxically leads to the generation of pain. This highlights that CNP is not simply a consequence of "too much" normal sensory input from the periphery. Instead, it is a pathological state arising from dysfunction within the CNS itself. The injury doesn't just block signals; it can trigger abnormal activity and maladaptive processing in the remaining or connected parts of the pain system. This results in the positive symptom of pain emerging from a loss of normal structure or function.

Diagnostic Considerations

Classification

Neuropathic pain, including CNP, is often diagnosed according to levels of certainty:  

Possible CNP: Based on a history suggestive of a relevant CNS lesion or disease, along with a pain distribution that is neuroanatomically plausible (i.e., located in body areas corresponding to the likely site of CNS damage).  

Probable CNP: In addition to the criteria for 'possible' CNP, a clinical examination reveals sensory signs (e.g., sensory loss, allodynia, hyperalgesia) in the same neuroanatomically plausible distribution. At this stage, it is crucial to consider and exclude other potential causes of pain.  

Definite CNP: Requires confirmation of a CNS lesion or disease through diagnostic tests (e.g., neuroimaging) that explains the spatial distribution of the pain, in conjunction with the above criteria, and after other causes of pain have been reasonably excluded.  

Diagnostic Steps

History: A detailed history is crucial, focusing on the onset of pain in relation to the CNS lesion/disease, and the characteristics and distribution of the pain. Pain descriptors such as burning, pricking, squeezing, freezing, or electric shock-like are common in neuropathic pain, although some may also occur in non-neuropathic conditions.  

Clinical Examination: A thorough neurological examination is needed to identify positive and negative sensory signs (e.g., allodynia, hyperalgesia, hypoaesthesia, thermal sensory loss) within the painful area and ensure they are consistent with the suspected CNS lesion.  

Neuroanatomically Plausible Distribution: The pain must be in an area that makes sense given the location of the CNS lesion (e.g., contralateral to a stroke, at or below the level of an SCI).  

Differential Diagnosis: This is a critical step. CNP must be distinguished from other types of pain that can occur following a CNS injury, such as:

• Nociceptive pain: Musculoskeletal pain (e.g., from joint contractures, immobility, or spasticity-related muscle strain) is common after conditions like stroke or SCI and can occur in the same body regions affected by sensory loss.  
• Pain related to spasticity: Pain directly driven by nociceptor activation in muscles and joints due to involuntary muscle contractions is a form of nociceptive pain, even if indirectly related to the CNS damage.  
• Other pre-existing pain conditions.

Confirmatory Tests:

• Neuroimaging: Structural MRI and CT scans are standard for detecting lesions in the brain and spinal cord (e.g., stroke, MS plaques, SCI, tumors) that could cause CNP.  
• Neurophysiological Tests: While not always required for diagnosis if clear anatomical evidence exists, pain-related cortical evoked potentials can help assess the functional integrity of nociceptive pathways from the periphery to the cortex and may reveal abnormalities consistent with a central lesion. However, neuroimaging often remains the gold standard for lesion localization.  

Prognosis

Central neuropathic pain is typically a chronic and persistent condition. It is also notoriously challenging to achieve even minimal improvements in pain levels.

Resources

Central Neuropathic Pain - Rosner 2023.pdf - 1.65 MB (f)

Chronic Neuropathic Pain - IASP 2019.pdf - 459 KB (f)