Mechanism-based Symptoms
At the bedside examination, neuropathic pain can been distinguished from spontaneous pain, (i.e., stimulus independent) and provoked pain.[70] Spontaneous pain can have several different qualities. The most typical spontaneous pains are ongoing pain (usually superficial burning or deep pressing pain, or both), and paroxysmal pain (electrical shock-like, stabbing pain).[79,91] Provoked pain includes allodynia, pain in response to a normally nonpainful stimulus, and hyperalgesia, an increased response to a normally painful stimulus. Unfortunately, unlike animal studies, neuropathic pain mechanisms in humans remain largely unclear; current clinical and neurophysiological research has proposed various mechanisms for each type of pain.
A useful way to draw parallels between symptom and mechanism is to combine patients' sensory profiles, obtained by specific questionnaires such as the Neuropathic Pain Symptom Inventory (NPSI), using data obtained with neurophysiological tools (blink reflex, nerve conduction studies and laser-evoked potentials).
Patients with neuropathic pain syndromes typically describe their pain as constant and burning. In a group of 150 patients with various types of polyneuropathy (68 with neuropathic pain) approximately 90% complained of burning pain.[92] Previous neurophysiological studies demonstrated that in patients with various neuropathic pain conditions (postherpetic neuralgia, carpal tunnel syndrome and polyneuropathy) burning pain is associated with nociceptive pathway damage as assessed by laser-evoked potential recordings (Figure 3).[92–94] Microneurographic studies demonstrated that in patients with peripheral neuropathies the spontaneous burning pain was associated with the ongoing spontaneous firing of C fibers.[65–67] Skin biopsy studies described reduced intraepidermal nociceptive terminals in patients with ongoing pain related to peripheral neuropathy.[95,96] These data suggest that ongoing burning pain is probably due to the abnormal spontaneous activity originating in damaged nociceptive fiber axons that have lost their intraepidermal endings. Although the spontaneous activity causing burning pain presumably originates from axonal sprouts, a concurrent mechanism might include long-term CNS changes provoked by nociceptive pathway damage, such as hyperactivity in the second-order neurons (central sensitization).[22,97] A recent microneurographic study provided new evidence of a specific C-fiber set that have a bimodal thermoreceptive properties and are activated by cooling, heating and menthol.[98] Activity of this specific set of C-fibers could be responsible for the stinging, hot and burning sensations evoked by innocuous cold stimuli.[99] Ongoing burning pain might also be related to the central hyperactivity resulting from deafferentation. In patients with postherpetic neuralgia, the ongoing burning pain is associated with a severe heat pain deficit, thus suggesting a severe C-afferent-fiber loss. A previous study used the C-fiber-mediated histamine axon reflex in patients with postherpetic neuralgia to determine C-fiber activity, demonstrating an abolished response in the area of maximum pain.[16] Ongoing burning pain frequently manifest as sequelae related to deafferentation, produced by a brachial plexus avulsion. Direct recordings of spinal neuron activity in a patient with injury to the dorsal roots of the cauda equina disclosed high-frequency, regular and paroxysmal bursting discharges.[16] The patient suffered from spontaneous burning pain in a region where the lesion had caused anesthesia (anaesthesia dolorosa).
Figure 3.
Correlations between the severity of ongoing burning pain and laser-evoked potential abnormalities in various neuropathic pain conditions. (A) 41 patients with ophthalmic postherpetic neuralgia. LEPs elicited from supraorbital stimulation. (B) 40 patients (75 hands) with carpal tunnel syndrome. LEPs elicited from the hand (median nerve territory). (C) 150 patients with polyneuropathy. LEPs elicited from the foot. The more severe the burning pain, the more abnormal the LEPs, changes that reflect nociceptive pathway damage.
LEP: Laser-evoked potential.
Previous neurophysiological studies in patients with postherpetic neuralgia and carpal tunnel syndrome demonstrated that paroxysmal pain is associated with abnormalities involving non-nociceptive Aβ-fibers.[93,94] More specifically, in patients with postherpetic neuralgia and carpal tunnel syndrome, the correlation between the blink reflex delay and median-nerve sensory conduction velocity slowing, suggests that this type of pain is related to focal Aβ-fiber demyelination. In accordance with previous studies in animals describing spontaneous ectopic discharges recorded in large myelinated Aβ-fiber axons after nerve injuries,[9,100,101] paroxysmal pain may be related to high-frequency bursts generated in demyelinated Aβ-fibers. It is still unclear whether these high-frequency bursts in demyelinated Aβ-fibers are sufficient to provoke pain per se or do so only after ephaptic transmission to the neighbouring unmyelinated C-fibers, or by involving wide dynamic range neurons.[94] Although most investigators consider paroxysms as peripheral phenomena related to spontaneous firing, a clinical study provided evidence that paroxysmal pain is associated with decreased small-fiber function, thus raising the possibility that paroxysms originate centrally in the second-order neurons.[102]
No general agreement exists regarding the pathophysiological mechanism underlying allodynia.[18] Two opposing views currently exist, one peripheral[67,103] and the other central.[104] According to some investigators, allodynia reflects peripheral sensitization.[105] Over the past decades, a possible role for hyperexcitable peripheral nociceptors as primary determinants of pain in humans has received ample support. Microneurographic recordings in patients with painful neuropathy demonstrated that allodynia was related to C nociceptor firing.[67] A recent study in patients with polyneuropathy found that allodynia was associated with a relative sparing of nociceptive fibers, as assessed with laser-evoked potentials.[92] These findings suggest that allodynia reflects an abnormal reduction in the mechanical threshold in sensitized peripheral nociceptors.[79,92,106]
According to many investigators, allodynia is generated at a central level.[16,18] The spontaneous firing in damaged nociceptive afferents may evoke ongoing pain and, as a secondary effect, sensitize central nociceptive neurons.[68,107–109] As a result, a large skin area surrounding the initial lesion site may become hypersensitive to light touch (i.e., allodynia). Microneurographic studies demonstrated that allodynia is mediated by large myelinated Aβ-fiber low-threshold mechanoreceptors.[110] In chronic neuropathic pain, differential nerve blocks demonstrate that allodynia is abolished concomitantly with loss of innocuous tactile sensation at a time when Aδ- and C-fiber mediated modalities are unaffected.[107,111] In patients with neuropathic pain, a selective Aβ-fiber block eliminates allodynia[107,112] but ongoing burning pain persists, indicating that it is mediated by C-nociceptors.[16] Central sensitization as the main mechanism underlying allodynia also receives support from the link between this pain symptom and abnormal pain summation on repetitive mechanical stimulation, a sign of central sensitization.[16] Future research efforts, designed to translate mechanisms into symptoms, should therefore seek more information to clarify the peripheral mechanisms underlying neuropathic pain.
Sensory Profiles
Patients experiencing neuropathic pain suffer from sensory deficits, as well as various types and different combinations of pain. Neuropathic pain may be ongoing (e.g., burning and pressing), paroxysmal pain (e.g., stabbing and electric shock-like sensations) or pain provoked by various stimuli (e.g., gentle brushing [allodynia] or cold water [cold allodynia]). Specific types of pain may predominate in some neuropathic pain conditions but none of them are etiologic specific.[113,114] Thus, patients suffering from the same disease may present with a heterogeneous profile of symptoms and sensory signs. Therefore, the aim of diagnostic workup should be to define specific sensory profiles through clinical examination, questionnaires dedicated to neuropathic pain and laboratory tools.
Current research findings strongly indicate that the different profile of sensory signs and symptoms, (including provoked pain and spontaneous pain) arise through different pathophysiological mechanisms. Clinical, neurophysiological and neuropathological investigations show that in patients with peripheral neuropathy of various etiologies, spontaneous burning pain is invariably related to the nociceptive pathway damage.[92–95] By contrast, recent neurophysiological studies suggest that spontaneous paroxysmal pain reflects demyelination of non-nociceptive, large-myelinated fibers (as described previously).[93,94] Overall, these findings suggest that neuropathic pain can be classified by sensory profiles (quality of pain) rather than etiology, as the recent European guidelines recommend.[115] Classifying neuropathic pain according to a mechanism-based rather than an etiology-based approach might minimize pathophysiological heterogeneity within the groups under study and thus help in targeting therapy to the individual patient.
Future Neurology. 2011;6(4):497-509. © 2011 Future Medicine Ltd.
Cite this: Pathophysiological Mechanisms of Neuropathic Pain - Medscape - Jul 01, 2011.
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