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Microneurographic studies were performed using cutaneous nerves of 8 patients with documented peripheral neuropathy who expressed positive sensory symptoms. Intraneural recordings in single myelinated fibers revealed: (i) ectopic generation of bursts of spontaneous action potentials; (ii) ectopic generation of ongoing repetitive discharges transiently interrupted by natural stimulation of the receptive field; and (iii) repetitive discharges triggered by a preceding action potential. These results provide direct evidence of a peripheral pathophysiological basis for spontaneous and stimulus-induced paresthesias and dysesthesias in patients with peripheral neuropathy.

Current opinion on "neuropathic" pain is chaotic and divided. This review is a summary attempt at describing the principal hypotheses that are currently entertained and at interpreting the basic underlying mechanisms of these pains. Rather than relying preferentially on rigorous data generated from neurophysiological animal experimentation, reasonable priority is given to evidence derived from rigorous neurophysiological and psychophysical studies in human volunteers and patients. Issues such as the concept of "centralization" of neuropathic pain mechanisms, which dwell excessively upon extrapolation from animal experiment to human clinical reality, are highlighted as questionable. Psychogenic pseudoneuropathy, an entity of high clinical prevalence and low appreciation by basic scientists and the reflex sympathetic dystrophy establishment, is also given the emphasis it deserves.

To test for the presence of "sympathetically maintained pain" (SMP), we administered placebo-controlled phentolamine sympathetic blocks to 14 patients with painful polyneuropathies. Six received i.v. infusion of saline for 30 minutes, followed by phentolamine (35 mg). In eight patients, the saline phase was followed by double-blind infusion of phentolamine or phenylephrine (500 micrograms), a second saline phase, and then the other active drug. We measured magnitudes of spontaneous pain and mechanical hyperalgesias on a 0-to-10 pain scale every 5 minutes and monitored sensory and sympathetic effects clinically and through quantitative thermotest and thermography. Five patients reported significant diminution of pain (> 50%), all in response to placebo. Neither phentolamine nor phenylephrine provided relief, although all patients had signs of physiologic abnormalities reputed to be determinants or predictors of SMP. These results complement previous studies demonstrating the nonexistence of SMP among "reflex sympathetic dystrophy" patients and further question the concept of SMP.

A syndrome of cold hyperalgesia associated with cold hypoaesthesia is described in 28 patients with peripheral polyneuropathy or mononeuropathy of various aetiologies. A mechanism of sensory disinhibition, where diminished cold-specific A delta input releases cold pain input carried by C nociceptors, is proposed to explain the hyperalgesia. In most patients, the symptomatic skin is abnormally cold. This is a likely consequence of vasospasm, due to sympathetic denervation supersensitivity, caused by dropout of sympathetic efferents as part of the small caliber nerve fibre insult. The term 'triple cold syndrome' is coined to describe this specific pathophysiological condition. Descriptively it is a mirror image of erythralgia, as described by Sir Thomas Lewis (1936) and updated by one of the present authors, a human condition also centred around anomalous primary nociceptor input, in which there is heat hyperalgesia and hot symptomatic skin due to C nociceptor sensitization and vasodilatation from antidromic discharge. Thus, like the latter condition, the triple cold syndrome emerges as an independent clinical entity with definable abnormal mechanisms which should be retrieved out of the all-embracing, descriptive, diagnostic category 'reflex sympathetic dystrophy--causalgia'.

Two behavioral kinds of mechanical hyperalgesia can be clearly discerned by clinical criteria in patients with neuropathic syndromes, i.e., a dynamic type, elicitable by lightly stroking the symptomatic skin, and a static type, elicitable by steadily applying gentle pressure on it. Of 28 patients studied, 19 had dynamic and 18 had static type mechanical hyperalgesia (9 expressed both types). Experimental compression-ischemia nerve block totally abolished the dynamic hyperalgesia in all patients except in 2, in whom it was markedly diminished. Disappearance of dynamic hyperalgesia occurred contemporaneously with block of myelinated A fibers, as expressed by abolition of the sensations of touch and cold, monitored quantitatively. Static hyperalgesia, however, outlasted A-fiber block in 15 of 18 patients; the phenomenon persisted during the stage when only unmyelinated fibers were available for impulse conduction. It is thus concluded that, at the primary afferent level, dynamic hyperalgesia is mediated by myelinated fibers, whereas static hyperalgesia depends on unmyelinated afferents. These two kinds of hyperalgesia represent discrete pathophysiological entities with distinct clinical connotations.