Peripheral Neuropathic Pain

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Peripheral neuropathic pain (PNP) is, by IASP definition, “pain caused by a lesion or disease of the peripheral somatosensory nervous system”. This encompasses damage or dysfunction affecting peripheral nerves, plexuses, or dorsal root ganglia, up to the point where nerve roots enter the spinal cord.

Causes

Common Causes of PNP are diverse and include:

• Metabolic disorders: Diabetic peripheral neuropathy is one of the most common causes.
• Infections: Postherpetic neuralgia (following shingles), HIV-associated neuropathy.
• Trauma: Direct injury to nerves from accidents, surgery (post-surgical neuropathic pain), or compression/entrapment syndromes (e.g., carpal tunnel syndrome, meralgia paresthetica).
• Toxic exposure: Chemotherapy-induced peripheral neuropathy, alcohol-related neuropathy.
• Hereditary neuropathies: e.g., Charcot-Marie-Tooth disease.
• Inflammatory/Immune-mediated conditions: Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP).
• Nutritional deficiencies: e.g., Vitamin B12 deficiency.
• Cancer-related neuropathy: Due to direct tumor invasion of nerves or paraneoplastic syndromes.
• Complex Regional Pain Syndrome (CRPS) Type II (formerly Causalgia): This involves neuropathic pain following a distinct nerve injury

Pathophysiology

The diverse array of positive sensory phenomena reflects the aberrant and ectopic firing patterns originating from damaged nerve fibers, as well as altered central processing of these abnormal signals. Different types of nerve fiber damage (e.g., to A-beta, A-delta, or C fibers) and the specific ion channel dysfunctions can contribute to the varied qualities of pain experienced by patients. This is quite different from nociceptive pain, which results from the physiological activation of specific nociceptors by tissue injury.

Mechanisms primarily involve peripheral changes such as ectopic impulse generation from AIGS in damaged axons or neuromas, and alterations in ion channel expression and function leading to hyperexcitability. However, with persistent PNP, central sensitization mechanisms in the spinal cord and brain often become engaged, contributing to the maintenance and amplification of pain, as well as the spread of hypersensitivity.

Subtypes

Based on sensory profiles, PNP can be categorized into distinct subtypes, which may reflect different underlying neurobiological mechanisms:

• Sensory Loss: This subtype is characterized by a loss of both small and large nerve fiber function. Patients often experience paradoxical heat sensations (PHS), where a cold stimulus is perceived as hot. Generally, these patients do not report sensory gain, although some may experience mild dynamic mechanical allodynia (DMA), which is pain evoked by light stroking of the skin.  
• Thermal Hyperalgesia: Patients in this group have relatively preserved sensory nerve function. Their defining characteristics are hyperalgesia (increased sensitivity to pain) in response to both heat and cold stimuli. Dynamic mechanical allodynia, if present, is typically of low intensity.  
• Mechanical Hyperalgesia: This subtype is distinguished by a predominant loss of small nerve fiber function, affecting the perception of cold and heat. However, these patients exhibit significant mechanical hyperalgesia, including increased sensitivity to pinprick and blunt pressure. Marked and more frequent dynamic mechanical allodynia is also a common feature.  

These subtypes can occur across various causes of PNP, although their frequencies may differ depending on the underlying aetiology. Understanding these sensory profiles may be useful in tailoring pain management strategies.  

Clinical Features

Symptoms of PNP are often characterized by a combination of positive and negative sensory phenomena, typically in the distribution of the affected nerve(s):

Positive Symptoms (gain of abnormal sensation):

• Spontaneous pain: Often described as burning, shooting, stabbing, lancinating, electric shock-like, or aching.
• Paresthesias: Abnormal, non-painful sensations like tingling, prickling, "pins and needles," or crawling.
• Dysesthesias: Unpleasant abnormal sensations, which can be spontaneous or evoked.
• Allodynia: Pain evoked by a stimulus that does not normally cause pain (e.g., light touch of clothing, gentle breeze).
• Hyperalgesia: An exaggerated pain response to a normally painful stimulus.
• Summation: Progressive worsening of pain with repetitive stimulation.

Negative Symptoms (loss of normal sensation/function):

• Hypoesthesia or anesthesia: Reduced or complete loss of sensation (e.g., to touch, pinprick, temperature) in the affected area.
• Weakness or paralysis: If motor fibers are involved.
• Decreased or absent reflexes.

Resources

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

Peripheral neuropathic pain - mechanism related organizing principle based on sensory profiles - Baron 2016.pdf - 832 KB (f)

Mechanism based diagnosis - Vardeh 2016.pdf - 974 KB (f)

Pain mechanism categories - Shaim 2021.pdf - 9.85 MB (f)

Precision Pain Treatments - Edwards 2023.pdf - 900 KB (f)