Neurogenic hyperalgesia versus painful hypoalgesia: two distinct mechanisms of neuropathic pain

Abstract

Patients with sensory disturbances of painful and non-painful character show distinct changes in touch and/or pain sensitivity. The patterns of sensory changes were compared to those of human surrogate models of neuropathic pain to assess the underlying mechanisms. We investigated 30 consecutive in-patients with dysaesthesia of various origins (peripheral, spinal, and brainstem lesions) and 15 healthy subjects. Tactile thresholds were determined with calibrated von Frey hairs (1.1mm). Thresholds and stimulus-response functions for pricking pain were determined with a series of calibrated punctate mechanical stimulators (0.2mm). Allodynia was tested by light stroking with a brush, Q-tip, and cotton wisp. Perceptual wind-up was tested by trains of punctate stimuli at 0.2 or 1Hz. Intradermal injection of capsaicin (n=7) and A-fiber conduction blockade (n=8) served as human surrogate models for neurogenic hyperalgesia and partial nociceptive deafferentation, respectively. Patients without pain (18/30) showed a continuous distribution of threshold shifts in the dysaesthetic skin area with a low to moderate increase in pain threshold (by 1.52+/-0.45 log2 units). Patients with painful dysaesthesia presented as two separate groups (six patients each): one showing lowered pain thresholds (by -1.94+/-0.46 log2 units, hyperalgesia) and the other elevated pain thresholds (by 3.02+/-0.48 log2 units, hypoalgesia). The human surrogate model of neurogenic hyperalgesia revealed nearly identical leftward shifts in stimulus-response function for pricking pain as patients with spontaneous pain and hyperalgesia (by a factor of about 5 each). The sensory changes in the human surrogate model of deafferentation were similar to patients with hypoalgesia and spontaneous pain (rightward shift of the stimulus-response function with a decrease in slope). Perceptual wind-up did not differ between symptomatic and control areas. There was no exclusive association of any parameter obtained by quantitative sensory testing with a particular disease (of either peripheral or central origin). Our findings suggest that neuropathic pain is based on two distinct mechanisms: (I) central sensitization (neurogenic hyperalgesia; in patients with minor sensory impairment) and (II) partial nociceptive deafferentation (painful hypoalgesia; in patients with major sensory deficit). This distinction as previously postulated for postherpetic neuralgia, is obviously valid also for other conditions. Our findings emphasize the significance of a mechanism-based classification of neuropathic pain.

Pharmacological modulation of pain-related brain activity during normal and central sensitization states in humans

“…Accordingly, patients with pain and hyperalgesia exhibit a nearly identical shift of stimulus-response function and incidence of hyperalgesia to stroking as normal subjects after capsaicin injection (9). These findings indicate that capsaicin-induced experimental hyperalgesia is a valid human surrogate model for neurogenic hyperalgesia, and support the view that central sensitization in neurogenic hyperalgesia is a feature of one group of neuropathic pain states (8,10).…”

“…It is characterized by two different clinical features: neurogenic hyperalgesia in patients with minor sensory impairment and painful hypoalgesia in patients with major sensory deficits (8). Central sensitization of nociceptive neurons in the spinal cord by primary nociceptive afferent input is the mechanism underlying neurogenic hyperalgesia during neuropatic pain.…”

Low back related leg pain: An investigation of construct validity of a new classification system

“…Additionally, secondary 12 changes in cortical and subcortical brain regions, triggered by cognitions, emotions 13 and attention may further add to central sensitization and development of spontaneous 14 activity and pain [40,41]. Another mechanism potentially contributing to 15 augmentation of central pain processing is deafferentation: Clinical and QST 16 examinations revealed deficits in large fibre function not only in group Denervation 17 but also in group Neuropathic Sensitization, indicating nerve fibre damage that for the 18 latter group may have induced secondary sensitization of higher order nociceptive 19 neurons [42]. QST findings from patients with other conditions thought to involve 20 central sensitization such as whiplash associated disorders [43], LBP [44] or 21 fibromyalgia [45] have also shown increased sensitivity to thermal and mechanical 22 pain stimuli consistent with findings in the present study.…”

Functional Imaging of Central Nervous System Involvement in Complex Regional Pain Syndrome

“…In another study, Maihöfner et al 35 used fMRI to examine the cortical network involved in the processing of pin-prick hyperalgesia in patients with CRPS I, because pin-pricking is known to activate A␦ fibers. 36,37 Compared with nonpainful mechanical stimulation, during pin-prick hyperalgesia, there was a significantly increased activation of the S1 cortex contralaterally, S2 cortex bilaterally, insular cortex bilaterally, parietal association cortex (PA) contralaterally, inferior parietal lobule (IPL) bilater-ally, superior, middle, and inferior frontal cortex bilaterally, and the anterior cingulate cortex bilaterally. It was concluded that the cortical network underlying pin-prick hyperalgesia comprises areas involved in nociceptive, motor, and attention processing, which might account for a number of clinical symptoms occurring in CRPS.…”