POSTINJURY NEUROPATHIC PAIN SYNDROMES

Robert J. Schwartzman; Jahangir Maleki

doi:10.1016/S0025-7125(05)70126-7

Pain is the sensory modality that signals tissue-destructive stimuli to the organism and initiates protective reflexes to limit further damage. If roots, plexi, nerves, or central pain pathways are damaged, pain may be persistently generated with no benefit to the organism and is termed neuropathic pain. 28 Pain is caused by the activation of A-δ (1- to 4-μ thinly myelinated fibers) or C-fibers (1-μ unmyelinated nociceptor units). 65,106 A-δ fibers entrain sharp, lancinating, well-localized first pain, whereas C-fibers encode slow, poorly localized, diffuse, burning second pain. 1,19 Natural and tissue-destructive stimuli coactivate different pain and somatosensory tissue receptors, whose summated activity results in a blended sensation. Thus, burning or cold pain is a combination of activation of specific A-δ cold receptors and C-fiber nociceptors. At the site of nerve injury, there is the production and release of algesiogenic substances, cytokines, inflammatory mediators, and products of wallerian degeneration that produce inhomogeneous receptor sensitization and activation of polymodal C-nociceptors. 38,76 Patients with postinjury neuropathic pain syndromes frequently demonstrate three specific aspects of pain sensation: (1) mechanoallodynia and thermal allodynia, (2) mechanohyperalgesia and thermal hyperalgesia, and (3) hyperpathia. 19,98 Allodynia refers to pain provoked by an innocuous mechanical or thermal stimulus. Hyperalgesia signifies a lowered threshold to a normally painful stimulus and enhanced pain perception. Hyperpathia is a reflection of disordered central pain processing in which there is an increased pain threshold, but once exceeded pain reaches maximal intensity too rapidly, is more severe than expected, and is not stimulus bound. 93 Dynamic mechanoallodynia and hyperalgesia refers to a gentle moving stimulus over the skin surface that elicits pain (A-β fiber mediated), whereas static mechanoallodynia and hyperalgesia is pain produced by a stationary pressure stimulus (sensitized C-fiber mediated). 21,33 These qualities of pain are expressed differentially in specific neuropathic pain states. The state of the peripheral polymodal C-fiber and A-δ receptor is important in determining the type and quality of neuropathic pain after specific injury. Some neuropathic pain patients with thermal and mechanical hyperalgesia after peripheral tissue injury have C-nociceptor sensitization. 102 In other patients, A-δ nociceptors may be sensitized to heat and cause thermal hyperalgesia. 11 Some neuropathic pain patients demonstrate cross-modality threshold sensitization at the receptor level such that their polymodal C-nociceptors discharge to touch when the skin is warm and not when it is cold, whereas others suffer pain when their skin is cold. 64 Microneurographic stimulation studies in human sensory nerves reveal that the localization quality and magnitude of a sensation can be determined from the afferent input of a single primary somatosensory unit. 36,37 The intensity of perceived pain is related to the frequency of discharge in specific groups of nociceptors such that in the area of injury the state of the receptor may determine if hypoalgesia (receptor fatigue) or hyperalgesia (receptor sensitization and activation) occurs after a specific stimulus. 51 In chronic neuropathic pain states, disordered processing of nociceptor impulses at the dorsal horn is the dominant mechanism that underlies neuropathic pain. 73,93 Differential nerve blocks in controls and patients with neuropathic pain have provided insights into which fiber types are responsible for particular sensations. A pressure block of a peripheral nerve in a normal person causes specific perceptual loss related to axon size. The first sensation lost is touch, followed by cold, warmth, and pain. 58 After release of a pressure block in two neuropathic pain patients (chronic regional pain syndrome type I [CRPS I]), allodynia to cold and tactile stimuli returned concomitantly with touch and cold sensibility (A-β and A-δ fibers), whereas allodynia to heat persisted during the block and therefore must have been mediated by C-fibers that were still conducting. 98,101 In control subjects, postischemic paresthesias are caused by ectopic firing of myelinated fibers and are described as tingling, pricking, or squeezing sensations. 66 In two neuropathic pain patients (CRPS I) in whom postischemic paresthesias were induced, these paresthesias were reported as extremely painful and must have been transmitted by A-β (large myelinated) fiber. 101 Intraneural microstimulation studies of the median nerve in subjects elicits a tactile sensation at the threshold of perception in 80% and pain in 20%. 83 In two neuropathic pain patients, who suffered mechanoallodynia and touch allodynia, intraneural microstimulation induced pain at the threshold of perceived sensation. 98 Once induced in these patients, the pain increased with high frequencies of stimulation and decayed slowly; this pattern was in contrast to normal subjects, in whom a rapid decrement of pain after high-frequency stimulation occurs, which is characteristic of unmyelinated axons. 102 Because only myelinated large fibers can follow high-frequency stimulation, these A-β fibers must have transmitted the pain experienced by these patients. 98 Patient experience and experimental studies in neuropathic animal pain models strongly support the involvement of the sympathetic innervation and primarily the α 2-adrenoreceptor in many types of neuropathic pains. 84 The strongest evidence for this is the relief of pain by sympathetic blockade both in patients and in sympathetically maintained neuropathic pain models. 8,13,47,89,111 The role of the α 2-adrenoreceptor in the pain of CRPS I and II (neuropathic pain syndromes) is supported by the use of the intravenous phentolamine test (α-receptor antagonist), which has been shown to correlate experienced pain with adrenoreceptor activation. 103 If a patient's pain is significantly reduced by α-receptor blockade, it is sympathetically maintained. 103 Further support for the role of the adrenoreceptor in the neuropathic pain of CRPS I and II patients is the demonstration in a large group of patients that cutaneous application of noradrenaline can aggravate the pain in some but not all sympathetically maintained patients. 100 Injection of noradrenaline into the asymptomatic limb of a former CRPS I patient (cured by sympathectomy) reproduced the original pain within 30 minutes. 110 Another feature of neuropathic pain, particularly common in CRPS I and II patients, is extraterritorial pain. These pains are spontaneous, are stimulus evoked, and are regional and thus do not respect dermatomal, nerve, or plexus distributions. 41,93 These extraterritorial pains are secondary to dynamically rearranged dorsal horn, thalamic and cortical, and somatotopic maps. 60,93,112 The spinal cord, nerve roots, plexi, and peripheral nerves move with different body postures. These neural structures can be trapped at the level of the foraminal exit canals (nerve roots), in the thoracic inlet or outlet (brachial plexus), or in tendinous canals or tunnels (peripheral nerve). These anatomic entrapments form the basis of each position of comfort assumed by patients in pain as well as the various maneuvers and stretch tests that irritate sensitized nerves. The nerve roots, plexi, and peripheral nerves have their own nerve and blood supply. Irritation by mechanical stimuli, inflammatory mediators, cytokines, prostanoids, and kinins sensitizes these roots, nerves, and plexi and usually causes mechanoallodynia and hyperalgesia when they are compressed (Tinel's sign.)

POSTINJURY NEUROPATHIC PAIN SYNDROMES

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POSTINJURY NEUROPATHIC PAIN SYNDROMES

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