Definition and classification of neuropathic pain

Neuropathic pain is a complex and debilitating condition that occurs following an injury or disease affecting the somatosensory system. This system, responsible for sensory perception, when damaged, can generate abnormal and persistent pain signals. According to the definition provided by the International Association for the Study of Pain (IASP), recognized worldwide, neuropathic pain can be classified into two main categories:

• Central Neuropathic Pain: This type of pain results from damage occurring at the level of the central nervous system, specifically involving the cortical structures of the brain or the spinal cord. Lesions in these areas can cause a wide range of painful symptoms that manifest in different parts of the body.

• Peripheral neuropathic pain: This form of pain arises from lesions affecting the peripheral nervous system. It may involve peripheral nerves, nerve plexuses (complex networks of intertwined nerves), dorsal root ganglia (groups of sensory neurons), or the nerve roots themselves. The resulting pain may be localized or diffuse, depending on the extent and location of the nerve damage.

The causes of neuropathic pain are many and varied, reflecting the complexity of the nervous system itself. Among the most common causes are:

• Trauma: Direct physical injuries to nerves, such as cuts, compressions, or strains
• Ischemia: reduction of blood flow to nerves, depriving them of oxygen and essential nutrients
• Neurotoxic conditions: Exposure to chemicals or drugs that damage nerves
• Neurodegenerative processes: diseases such as multiple sclerosis or Parkinson's disease
• Neoplastic conditions: tumors that compress or infiltrate nerves
• Metabolic disorders: such as diabetes, which can cause peripheral neuropathy
• Vitamin deficiencies: especially B vitamins, essential for nervous health

Pathophysiological mechanisms of neuropathic pain

In neuropathic pain, tissue damage directly affects the nervous system, triggering a series of complex changes at the cellular and molecular levels. These pathophysiological mechanisms underlie the persistence and intensity of neuropathic pain:

• Ectopic discharge generation: Damaged nerves can develop sites of abnormal electrical activity, generating painful impulses in the absence of actual stimuli. These "ectopic discharges" can manifest as spontaneous or intermittent pain.
• Post-stimulus residual activity: Even after a painful stimulus has ceased, damaged nerves can continue to send pain signals to the brain, prolonging the painful sensation well beyond the duration of the original stimulus.
• Changes in Ion Channel Expression: Sodium, calcium, and potassium channels in neuronal membranes undergo significant changes. For example, increased sodium channels can make nerves hyperexcitable, lowering the threshold for pain activation.
• Changes in gene expression: Nerve damage can induce changes in the expression of hundreds of genes, affecting nerve excitability, synaptic transmission, and sensitivity to stimuli. These changes can lead to a "reprogramming" of the nervous system, making it more responsive to painful stimuli.

Characteristic symptoms of neuropathic pain

Neuropathic pain is characterized by its high intensity and a constellation of peculiar sensations that make it unique compared to other forms of pain. Patients often describe their pain using vivid and metaphorical terms:

• Intense burning: a persistent and painful sensation of heat, as if the skin were in contact with a flame
• Burning, stabbing pain: sharp, piercing pains that shoot through the affected area
• "Pulling" sensation: as if the nerves were constantly under tension or being pulled
• Constrictive pain: Likened to a vice squeezing the affected area or a deep, persistent bite
• "Stinging" sensation: sharp, localized pain, as if a sharp object were penetrating the skin
• Random electric shocks: sudden bursts of intense pain, similar to an electric shock, that may occur without warning

A distinctive feature of neuropathic pain is its precise location. Patients often report a clear dermatomal demarcation of pain, that is, a distribution of pain that follows the path of specific nerves or nerve roots. This feature can help clinicians in identifying and diagnosing neuropathic pain.

Clinical signs and alterations associated with neuropathic pain

Neuropathic pain is not limited to the painful sensation alone, but is often accompanied by a series of sensory alterations that contribute to the patient's overall discomfort:

• Paresthesias: Abnormal, non-painful sensations such as tingling, numbness, or a "walking skin" sensation. These sensations may be constant or intermittent and often precede or accompany pain.
• Dysesthesias: Unpleasant and abnormal sensations, often described as uncomfortable or disturbing. They may include sensations of intense itching, "water running under the skin," or "bugs crawling" on the skin's surface.
• Hypoesthesia or hyperesthesia: alterations in tactile sensitivity. Hypoesthesia manifests itself as a reduction in sensitivity to touch, while hyperesthesia is an increased sensitivity, where even mild stimuli can be perceived as intense or annoying.
• Allodynia: A condition in which normally painless stimuli, such as light touch or contact with clothing, cause pain. Allodynia is particularly disabling, as it can make simple daily activities difficult.
• Hyperalgesia: An exaggerated response to painful stimuli. In this case, pain that would normally be perceived as mild or moderate is felt as intense or unbearable.