S. La Cesa

Transcutaneous spinal direct current stimulation inhibits nociceptive spinal pathway conduction and increases pain tolerance in humans

Despite concerted efforts from pharmacologic research into neuropathic pain, many patients fail to achieve sufficient pain relief with medication alone. For this reason, increasing interest centres on neurostimulation techniques. We assessed whether transcutaneous spinal direct current stimulation (tsDCS) modulates conduction in ascending nociceptive spinal pathways. We measured changes induced by anodal and cathodal tsDCS over the thoracic spinal cord on face‐ and foot‐laser evoked potentials (LEPs) and foot‐cold pressor test responses in 20 healthy subjects. Whereas anodal tsDCS reduced the amplitude of the N1 and N2 components of foot‐LEPs (P < 0.05) neither anodal nor cathodal tsDCS changed LEPs evoked by face stimulation. Pain tolerance to the cold pressor test was significantly higher after anodal than after cathodal tsDCS (P < 0.05). Conversely, no difference was found in the pain threshold or pain ratings to the cold pressor test between the two polarity conditions.

Mechanisms of pain in distal symmetric polyneuropathy: A combined clinical and neurophysiological study

&NA; In patients with distal symmetric polyneuropathy we assessed non‐nociceptive A&bgr;‐ and nociceptive A&dgr;‐afferents to investigate their role in the development of neuropathic pain. We screened 2240 consecutive patients with sensory disturbances and collected 150 patients with distal symmetric polyneuropathy (68 with pain and 82 without). All patients underwent the Neuropathic Pain Symptom Inventory to rate ongoing, paroxysmal and provoked pains, a standard nerve conduction study (NCS) to assess A&bgr;‐fibre function, and laser‐evoked potentials (LEPs) to assess A&dgr;‐fibre function. Patients with pain had the same age (P > 0.50), but a longer delay since symptom onset than those without (P < 0.01). Whereas the LEP amplitude was significantly lower in patients with pain than in those without (P < 0.0001), NCS data did not differ between groups (P > 0.50). LEPs were more severely affected in patients with ongoing pain than in those with provoked pain (P < 0.0001). Our findings indicate that the impairment of A&bgr;‐fibres has no role in the development of ongoing or provoked pain. In patients with ongoing pain the severe LEP suppression and the correlation between pain intensity and LEP attenuation may indicate that this type of pain reflects damage to nociceptive axons. The partially preserved LEPs in patients with provoked pain suggest that this type of pain is related to the abnormal activity arising from partially spared and sensitised nociceptive terminals. Because clinical and neurophysiological abnormalities followed similar patterns regardless of aetiology, pain should be classified and treated on mechanism‐based grounds.

Palmitoylethanolamide Restores Myelinated-Fibre Function in Patients with Chemotherapy-Induced Painful Neuropathy

We assessed the effect of palmitoylethanolamide (PEA) on pain and nerve function in patients with chemotherapy-induced painful neuropathy, in 20 patients undergoing thalidomide and bortezomib treatment for multiple myeloma. All patients were evaluated before and after a two-month treatment with PEA 300 mg BID using pain and warmth thresholds; blinded examiners measured motor and sensory nerve fibre function and laser-evoked potentials. Although no variables returned to normal values, pain and all neurophysiological measures � assessing Aα, Aβ, and Aδ fibres � significantly improved (P < 0.05). In contrast, warmth thresholds, assessing unmyelinated afferents, remained unchanged (P > 0.50). Although a placebo effect might play a role in the reported pain relief, the changes in neurophysiological measures indicate that PEA exerted a positive action on myelinated fibre groups. PEA, possibly by moderating mast cell hyperactivity, relieved conduction blocks secondary to endoneural edema. In a severe condition such as painful neuropathy associated with multiple myeloma and chemotherapy, a safe substance such as PEA provides significant restoration of nerve function.

Small-fibre neuropathy related to bulbar and spinal-onset in patients with ALS

AbstractWe aimed at seeking more precise diagnostic information on the sensory nervous system involvement described in patients with amyotrophic lateral sclerosis (ALS). We investigated large myelinated nerve fibres with nerve conduction study and small-nerve fibres with Quantitative Sensory Testing (QST) (assessing thermal-pain perceptive thresholds) and skin biopsy (assessing intraepidermal nerve fibre density) in 24 consecutive patients with ALS, 11 with bulbar-onset and 13 with spinal-onset. In 23 of the 24 patients, regardless of ALS onset, nerve conduction study invariably showed large myelinated fibre sparing. In patients with bulbar-onset ALS, QST found normal thermal-pain perceptive thresholds and skin biopsy disclosed normal intraepidermal nerve fibre density. Conversely, in patients with spinal-onset, thermal-pain thresholds were abnormal and distal intraepidermal nerve fibre density was reduced. Sensory nervous system involvement in ALS differs according to disease onset. Patients with spinal-onset but not those with bulbar-onset ALS have concomitant distal small-fibre neuropathy. Neurologists should therefore seek this ALS-related non-motor feature to improve its diagnosis and treatment.

Does the epidermal nerve fibre density measured by skin biopsy in patients with peripheral neuropathies correlate with neuropathic pain

Summary In patients with peripheral neuropathy, epidermal innervation and axonal abnormalities, as assessed with skin biopsy, are associated with provoked but not ongoing burning pain. ABSTRACT The different neuropathic pain types (eg, ongoing burning pain and allodynia) are frequent and disabling complaints in patients with peripheral neuropathies. Although the reference standard technique for diagnosing painful small‐fibre neuropathies is nerve fibre density assessment by skin biopsy, the relationship between the epidermal nerve fibre (ENF) density and neuropathic pain is still unclear. In a clinical and skin biopsy study designed to investigate whether changes in ENF density are directly related to pain, we enrolled 139 consecutive patients with distal symmetric peripheral neuropathy. All patients underwent clinical examination. The Neuropathic Pain Symptom Inventory was used to distinguish the different neuropathic pain types. A skin biopsy was conducted, and ENFs were immunostained with the antiprotein gene product 9.5, and their linear density was quantified with bright‐field microscopy. No difference was found in ENF density between patients with and without neuropathic pain, nor between patients with and without ongoing burning pain. Conversely, ENF density was higher in patients with provoked pains (including mechanical dynamic allodynia) than in those without. The variable association between ENF density and symptoms of neuropathic pain supports the idea that neuropathic pain symptoms arise through distinct underlying mechanisms. The lack of relationship between ongoing burning pain and ENF density suggests that this type of pain reflects factors other than loss of nociceptive afferents. The association between ENF density and provoked pain (including mechanical dynamic allodynia) suggests that this type of pain might be mediated by spared and sensitised nociceptive afferents.

Heat-Evoked Experimental Pain Induces Long-Term Potentiation-Like Plasticity in Human Primary Motor Cortex

We designed a new paired associative stimulation (PAS) protocol that combines experimental pain evoked by laser stimuli and transcranial magnetic stimulation (TMS) (Laser-PAS) to primary motor cortex (M1). We tested in healthy subjects whether Laser-PAS elicits cortical plasticity as reflected by long-term changes in motor-evoked potentials (MEPs) (after-effects). In separate experiments, we examined numerous variables including changes induced by varying the interstimulus intervals (ISIs) and Laser-PAS-induced changes in target and non-target muscle MEPs. We measured MEPs after repetitive laser or TMS (rTMS) pulses, and compared magnetic- and electric (TES)-induced MEPs. We tested MEPs after applying Laser-PAS with laser pulses ipsilaterally to M1. Finally, we studied subjects receiving an N-methyl-D-aspartate (NMDA) receptor antagonist (memantine) or placebo (α-lipoic acid). During Laser-PAS at the 50 ms ISI MEPs decreased, thereafter they increased for 60 min; other ISIs induced no after-effects. The after-effects remained restricted to the target muscle. Repetitive laser pulses and rTMS induced no after-effects. After Laser-PAS, TMS-induced MEPs increased, whereas TES-induced MEPs did not. Laser-PAS with laser pulses ipsilaterally to M1 left MEPs unchanged. Memantine, but not α-lipoic acid, abolished the after-effects. In conclusion, Laser-PAS elicits NMDA-dependent cortical plasticity and provides new insights into human pain-motor integration.

How to diagnose neuropathic pain? The contribution from clinical examination, pain questionnaires and diagnostic tests

Patients with peripheral and central nervous system diseases may suffer from different types of pain, namely nociceptive, neuropathic and mixed pain. Although in some cases, the distinction between these types of pain is clinically evident, yet in some patients an accurate differential diagnosis requires dedicated clinical examination, screening questionnaires and diagnostic techniques some of which are available only in specialized pain centres. This review briefly addresses the currently agreed definitions of the different types of pain and shows how clinical examination, pain questionnaires and diagnostic tests can help the clinicians in identifying neuropathic pain.

Central sensitization as the mechanism underlying pain in joint hypermobility syndrome/Ehlers–Danlos syndrome, hypermobility type

Patients with joint hypermobility syndrome/Ehlers–Danlos syndrome, hypermobility type (JHS/EDS‐HT) commonly suffer from pain. How this hereditary connective tissue disorder causes pain remains unclear although previous studies suggested it shares similar mechanisms with neuropathic pain and fibromyalgia.

fMRI pain activation in the periaqueductal gray in healthy volunteers during the cold pressor test

The periaqueductal gray (PAG), a brain area belonging to the descending pain modulatory system, plays a crucial role in pain perception. Little information is available on the relationship between PAG activation and perceived pain intensity. In this study, we acquired functional magnetic resonance imaging (fMRI) scans from the PAG during the cold pressor test, a model for tonic pain, in 12 healthy volunteers. fMRI data were acquired with a 12-channel head-coil and a 3-Tesla scanner and analyzed with Statistical Parametric Mapping (SPM8) software. During the cold pressor test, fMRI showed significant activation clusters in pain-related brain areas: bilateral middle and superior frontal gyrus, anterior cingulate cortex and thalamus, left insula, right inferior frontal gyrus, left inferior temporal gyrus and in the bilateral PAG (cluster level corrected threshold p<0.05). PAG activation correlated directly with the pain threshold and inversely with the participants perceived pain intensity (cluster level corrected threshold (p<0.05). The cold pressor test consistently activated the PAG as well as other pain-related areas in the brain. Our study, showing that the greater the PAG activation the higher the pain threshold and the weaker the pain intensity perceived, highlights the key role of the PAG in inhibiting the pain afferent pathway function. Our findings might be useful for neuroimaging studies investigating PAG activation in patients with chronic idiopathic pain conditions possibly related to dysfunction in the descending pain modulatory system.

Topographical distribution of warmth, burning and itch sensations in healthy humans

To gain information on the topographical distribution of warmth, burning and itch sensations in healthy humans, we delivered laser stimuli to elicit sensations of warmth, applied capsaicin cream for burning, and pricked histamine for itch on the skin of the face, shoulder, hand, thigh and foot in 12 healthy subjects. We found that whereas warm and burning sensations progressively increased from foot to face, itch sensation increased from face to foot (P<0.0001). Hence our findings indicate that unlike thermal and pain receptors, itch receptors are denser at distal than at proximal body sites. Our psychophysical study provides new information supporting the idea that specific unmyelinated neuronal pathways mediate sensations of warmth, burning and itch.