NEUROPATHIC PAIN: DEFINITIONS AND CLINICAL CONSIDERATIONS Although neuropathic pain might accurately be considered a disease state, it is more generally thought of as a collection of chronic pain syndromes with a common feature, that being dysfunction of peripheral sensory nerves or nerves within the CNS. The definition of peripheral neuropathic pain, according to the International Association for the Study of Pain (IASP) is “Pain initiated or caused by a primary lesion or dysfunction in the peripheral nervous system.” 1 Neuropathic pain of peripheral origin is not merely a condition arising from a single event that diminishes as healing from the original insult progresses, but rather is an abnormal pain state that it is maintained long after the initiating event has resolved. 1Of the neuropathic pain conditions, those associated with nerve trauma have received the lion's share of clinical investigation and consequently are the best described. 2 In fact, abnormal chronic pain states along with changes suggestive of trophic and autonomic alterations were described during the American Civil War. Weir Mitchell described trophic signs, glossy skin, and burning pain that developed in large numbers of soldiers with bullet wounds as causalgia. 3–5 Some soldiers with bullet wounds and nerve damage developed a syndrome of burning pain, hyperesthesia, glossy skin, rubor, edema, and skin that would appear colder than the uninjured parts of the body. This term causalgia arose from the Greek term for burning pain. Causalgia was initially thought of as a unique class of neuropathic pain caused by nerve trauma delivered by a high-velocity missile impact. Such pain was characterized by persistent burning sensations of the hands and/or feet after a high-velocity missile impact (i.e., bullet wound) involving peripheral nerves of the arms or legs, and might be accompanied by red, glossy, and edematous skin. 6 Causalgia was considered to be a subset of reflex sympathetic dystrophy, or sympathetically maintained pain. This neuropathic pain syndrome is indicated by spontaneous burning sensation and/or the presence of allodynia or hyperpathia to light touch. 6 It has been reported that sympathetic blockade, including complete surgical sympathectomy, permanent chemical sympathectomy with phenol, or systemic sympatholytics abolish both the adverse pain condition and the trophic changes, especially when performed soon after the insult. 6,7 Although previously expressed as an independent form of neuropathic pain, it is now recognized that sympathetically maintained pain may be a component of neuropathic pain in some, but not all, patients, regardless of the initiating factor. A sympathetic component has been described in neuralgias including postherptic neuralgia (PHN), metabolic neuropathies, and phantom limb pain. 8 Based on our growing understanding of the symptomology of these chronic pain states, conditions earlier classified as causalgia, reflex sympathetic dystrophy, and sympathetically maintained pain have been grouped as complex regional pain syndrome (CRPS), which is indicated clinically by hyperalgesia and allodynia, pain disproportionate to the injury, dyesthesias and hyperesthesias, or hyperalgesia that extends beyond the territory of the injury, along with autonomic, trophic and motor changes. 8–10 CRPS includes sympathetically maintained or sympathetic-independent pain, with undefined underlying mechanisms and many treatment options with unpredictable outcomes. 9,10 It is now suggested that perhaps 3–5% of CRPS is sympathetically maintained. 11,12 Furthermore, CRPS is subdivided into CRPS-I and CPRS-II. 8 CPRS-II is defined by spontaneous pain and hyperalgesia or allodynia, along with the presence, or evidence of previously present, edema, abnormal blood flow, and autonomic, trophic, or sudomotor abnormalities, and is distinguished from type I by the clear indication of nerve trauma. 1,7,8,13 The signs and symptoms of CPRS-I are the same as those of CPRS-II, except that there is no verifiable damage to a peripheral nerve. 1,7,9,10 By definition, it is precipitated by a noxious event that might include fractures, joint sprains, strains, thoracic surgery, soft tissue injury, and cardiac ischemia. 5–7,14 Idiopathic CRPS-I has been described as sequella to noxious events so trivial patients may not remember the occurrence, and include venipuncture, lacerations, and other types of minor trauma. 6,7 Because of the absence of verified injury, the inclusion of CPRS-I as a neuropathic pain state has been challenged. 15 However, it has been strongly argued that the symptomology is consistent with neuropathic pain, and that the signs and symptoms, and not the etiology of the condition, should drive the therapeutic options. 16–18Diabetic peripheral neuropathy (DPN) and PHN are two important clinical neuropathic pain syndromes that have been extensively studied with regard to establishing treatment regimens for neuropathic pain. 19 Like the traumatic pain syndromes described above, DPN and PHN are associated with spontaneous, episodic pain and evoked pain, including allodynia in response to touch, cold, or heated tactile stimuli, and light brush (dynamic allodynia). 19 DPN has been defined as including “symptoms and/or signs of peripheral nerve dysfunction in people with diabetes after the exclusion of other causes.” 20,21 The causes of DPN are not clearly understood but are believed to include release of toxic metabolites, alterations in growth factors, a compromised microvasculature, and possible inflammatory events. 22 Pathological changes are observed in Aβ, Aδ, and C-fibers, which help explain the fact that diabetic patients present with varying signs and symptoms that range from complete nonpainful anesthesia of the feet to severe neuropathic pain (see Table 1). 20 Although DPN usually involves the extremities, it may also involve thoracic or cranial regions where it presents either symmetrically or asymmetrically, and may occur from ischemia or nerve entrapment in addition to the progression of the disease. 22 PHN is a very painful neuropathic condition that is still present between 1 and 6 months after the herpes zoster (shingles) has cleared, representing a transition from acute herpes zoster to PHN. 23–25 It has been described as an intermittent pain or can present as a persistent, but fluctuating, pain. 24,25 Patients with PHN describe it as burning, itching, throbbing or a shooting pain, and dyesthesias may be present. 24,25 Like DPN, PHN has been associated with neuroinflammation and a loss of large and small sensory fibers. 26 The etiology of neuropathic pain states encompasses many other conditions, including prolonged treatment with chemotherapeutic agents, infections such as HIV, and from idiopathic and genetic sources. The common causes of neuropathic pain are listed in Table 2. ![TABLE 2. TABLE 2.](corehtml/pmc/pmcgifs/table-icon.gif) | TABLE 2. Etiologies and Neuronal Dysfunctions Associated with Neuropathic Pain |
It has been suggested that changes in innervation of the hypersensitized skin area along with changes in spinal processing may contribute to neuropathic pain in PHN. 27,28 The examination of skin biopsies taken from regions affected by PHN demonstrated that the severity of allodynia was inversely correlated with the loss of sensory nerve endings in the skin. 27 Punch skin biopsies were taken from patients with shingles and with or without PHN and immunostained with the axonal marker anti-PGP9.5. 29 Those with neuropathic pain showed an epidermal neurite density of only 339 ± 97 epidermal neurites/mm 2 of skin surface area compared with a density of 1661 ± 262 neurites/mm 2 of skin surface area from the pain-free patients. 29 Because nearly all epidermal neurites are sensitive to capsaicin, these observations indicate a loss of nociception innervation. 29 It is suggested that allodynia and hyperalgesia after PHN may be due to hypersensitivity of the remaining nociceptors along with abnormal spinal processing of the afferent inputs. 28–30 In a recent study, the neurite density of skin punches taken from the most painful region from patients with PHN and from analogous regions in pain-free patients with shingles was evaluated and it was determined that minimum of approximately 650 neurites/mm 2 was needed to prevent the development of PHN. 28 Because the degeneration of the peripheral branch of a primary afferent fiber leads ultimately to the degeneration of its central projection as well, it is suggested that the loss of these primary afferents cause a compensatory hyperactivity of the second-order projection neurons. 28 Accordingly, dorsal horn atrophy was reported in patients with PHN after shingles. 31,32 Furthermore, MRI studies performed on the spinal cord of patients after a herpes zoster outbreak showed abnormal deafferentation only in those that developed PHN. 26Neuropathic pain is best considered as a complex set of abnormal physiologic processes incited by trauma, a noxious event or a disease state. 22,33 Accordingly, it should not be considered as a syndrome in and of itself, but as a symptom of other neurologic dysfunctions. It presents in various ways in different patients, and the presentation and susceptibility to treatment of neuropathic pain is widely recognized by clinicians as being quite unpredictable. 33,34 Taken together, these factors suggest that an organic basis, possibly driven by genetic factors, may underlie a patient's susceptibility to the development of neuropathic pain. The challenge before us is to determine the mechanisms that drive neuropathic pain in humans. Moreover, it is imperative to learn why only a small group of people develop neuropathic pain after events that leave a much larger population unaffected. More adequately controlled clinical studies are needed to move us beyond the era of “trial and error” and into physiologically based rational therapeutic protocols. For all of these reasons, “effective new strategies are desperately needed.” 2 |
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