Peripheral Neuropathic Pain: From Mechanisms to Symptoms

Several independent pathophysiological mechanisms in both the peripheral and central nervous system are responsible for sensory symptoms as well as spontaneous and evoked pains in peripheral neuropathies: (1) Pathologic active or sensitized nociceptors can induce secondary changes in central processing, leading to spinal cord hyperexcitability that causes input from mechanoreceptive Aβ-fibers (light touching) to be perceived as pain. These patients characteristically have spontaneous pain, heat hyperalgesia, static mechanical allodynia, and and severe dynamic mechanical allodynia. (2) Nociceptor function may be selectively impaired within the allodynic skin. Pain and temperature sensation are profoundly impaired but light moving mechanical stimuli can often produce severe pain (dynamic mechanical allodynia). Anatomic reorganization in the dorsal horn resulting from C-fiber degeneration may lead to Aβ-fiber-mediated allodynia. (3) Persistent inflammatory reactions of the nerve trunk can induce ectopic activity in primary afferent nociceptors and thus is a potential cause of spontaneous pain and allodynia. This effect is mediated by the cytokine tumor necrosis factor-α produced by activated macrophages. (4) After nerve lesion the sympathetic nervous system might interact with afferent neurons. Activity in sympathetic fibers can induce further activity in sensitized nociceptors and, therefore, enhance pain and allodynia (sympathetically maintained pain). This pathologic interaction acts via noradrenaline released from sympathetic terminals and newly expressed receptors on the afferent neuron membrane. These mechanisms can operate in concert in a single disease entity (e.g., postherpetic neuralgia) and also in a single patient. Distinct pathophysiological mechanisms lead to specific sensory symptoms (e.g., dynamic mechanical allodynia, cold hyperalgesia). It is also possible that the pain-generating mechanism and the symptoms change during the course of the disease. A thorough analysis of sensory symptoms may reveal the underlying mechanisms that are mainly active in a particular patient. The treatment of neuropathic pain is currently unsatisfactory. In the future, drugs will be developed that address specifically the relevant combination of mechanisms.