Clinical criteria and diagnostic assessment of fibromyalgia: position statement of the Italian Society of Neurology-Neuropathic Pain Study Group.

BACKGROUND: The role of central and/or peripheral nervous system dysfunction is basically fundamental in fibromyalgia. AIM: The aim of this position statement on behalf of the Neuropathic Pain Study Group of the Italian Society of Neurology is to give practical guidelines for the clinical and instrumental assessment of fibromyalgia (FM) in the neurological clinical practice, taking into consideration recent studies. METHODS: Criteria for study selection and consideration were original studies, case-controls design, use of standardized methodologies for clinical practice, and FM diagnosis with ACR criteria (2010, 2011, 2016). RESULTS: ACR criteria were revised. For diagnostic procedure of small-fiber pathology, 47 studies were totally considered. Recent diagnostic criteria should be applied (ACR, 2016). A rheumatologic visit seems mandatory. The involvement of small fibers should request at least 2 among HRV + SSR and/or laser-evoked responses and/or skin biopsy and/or corneal confocal microscopy, eventually followed by monitoring of metabolic and/or immunological/ and or/paraneoplastic basis, to be repeated at 1-year follow-up. CONCLUSIONS: The correct diagnostic approach to FM could promote the exclusion of the known causes of small-fiber impairment. The research toward common genetic factors would be useful to promote a more specific therapeutic approach.

Hydrokinetic pancreatic function and insulin secretion are moduled by Cl- uniporter Slc26a9 in mice.

AIM: Slc26a9 is a member of the Slc26 multifunctional anion transporter family. Polymorphisms in Slc26a9 are associated with an increased incidence of meconium ileus and diabetes in cystic fibrosis patients. We investigated the expression of Slc26a9 in the murine pancreatic ducts, islets and parenchyma, and elucidated its role in pancreatic ductal electrolyte and fluid secretion and endocrine function. METHODS: Pancreatic Slc26a9 and CFTR mRNA expression, fluid and bicarbonate secretion were assessed in slc26a9-/- mice and their age- and sex-matched wild-type (wt) littermates. Glucose and insulin tolerance tests were performed. RESULTS: Compared with stomach, the mRNA expression of Slc26a9 was low in pancreatic parenchyma, 20-fold higher in microdissected pancreatic ducts than parenchyma, and very low in islets. CFTR mRNA was ~10 fold higher than Slc26a9 mRNA expression in each pancreatic cell type. Significantly reduced pancreatic fluid secretory rates and impaired glucose tolerance were observed in female slc26a9-/- mice, whereas alterations in male mice did not reach statistical significance. No significant difference was observed in peripheral insulin resistance in slc26a9-/- compared to sex- and aged-matched wt controls. In contrast, isolated slc26a9-/- islets in short term culture displayed no difference in insulin content, but a significantly reduced glucose-stimulated insulin secretion compared to age- and sex-matched wt islets, suggesting that the impaired glucose tolerance in the absence of Slc26a9 expression these is a pancreatic defect. CONCLUSIONS: Deletion of Slc26a9 is associated with a reduction in pancreatic fluid secretion and impaired glucose tolerance in female mice. The results underline the importance of Slc26a9 in pancreatic physiology.

European Academy of Neurology guideline on trigeminal neuralgia.

BACKGROUND AND PURPOSE: Trigeminal neuralgia (TN) is an extremely painful condition which can be difficult to diagnose and treat. In Europe, TN patients are managed by many different specialities. Therefore, there is a great need for comprehensive European guidelines for the management of TN. The European Academy of Neurology asked an expert panel to develop recommendations for a series of questions that are essential for daily clinical management of patients with TN. METHODS: A systematic review of the literature was performed and recommendations was developed based on GRADE, where feasible; if not, a good practice statement was given. RESULTS: The use of the most recent classification system is recommended, which diagnoses TN as primary TN, either classical or idiopathic depending on the degree of neurovascular contact, or as secondary TN caused by pathology other than neurovascular contact. Magnetic resonance imaging (MRI), using a combination of three high-resolution sequences, should be performed as part of the work-up in TN patients, because no clinical characteristics can exclude secondary TN. If MRI is not possible, trigeminal reflexes can be used. Neurovascular contact plays an important role in primary TN, but demonstration of a neurovascular contact should not be used to confirm the diagnosis of TN. Rather, it may help to decide if and when a patient should be referred for microvascular decompression. In acute exacerbations of pain, intravenous infusion of fosphenytoin or lidocaine can be used. For long-term treatment, carbamazepine or oxcarbazepine are recommended as drugs of first choice. Lamotrigine, gabapentin, botulinum toxin type A, pregabalin, baclofen and phenytoin may be used either alone or as add-on therapy. It is recommended that patients should be offered surgery if pain is not sufficiently controlled medically or if medical treatment is poorly tolerated. Microvascular decompression is recommended as first-line surgery in patients with classical TN. No recommendation can be given for choice between any neuroablative treatments or between them and microvascular decompression in patients with idiopathic TN. Neuroablative treatments should be the preferred choice if MRI does not demonstrate any neurovascular contact. Treatment for patients with secondary TN should in general follow the same principles as for primary TN. In addition to medical and surgical management, it is recommended that patients are offered psychological and nursing support. CONCLUSIONS: Compared with previous TN guidelines, there are important changes regarding diagnosis and imaging. These allow better characterization of patients and help in decision making regarding the planning of medical and surgical management. Recommendations on pharmacological and surgical management have been updated. There is a great need for future research on all aspects of TN, including pathophysiology and management.

A pain in the skin. Regenerating nerve sprouts are distinctly associated with ongoing burning pain in patients with diabetes.

BACKGROUNDS: Patients with diabetic polyneuropathy commonly suffer from ongoing burning pain and dynamic mechanical allodynia. In this clinical and skin biopsy study, we aimed at assessing how intraepidermal regenerating nerve sprouts are associated with these two types of pain. METHODS: We consecutively enrolled 85 patients with diabetic polyneuropathy. All patients underwent skin biopsy at the distal leg. Intraepidermal nerve fibres were immunostained with the anti-protein gene product 9.5 (PGP9.5) to quantify all intraepidermal nerve fibres, and the growth-associated protein 43 (GAP43) to quantify regenerating nerve sprouts. RESULTS: We found that the GAP43-stained intraepidermal nerve fibre density and the ratio GAP43/PGP9.5 were significantly higher in patients with ongoing burning pain than in those without. The area of receiver operating characteristic (ROC) curve for the ratio GAP43/PGP9.5 was 0.74 and yielded a sensitivity and specificity for identifying ongoing burning pain of 72% and 71%, respectively. Conversely, although the density of PGP9.5 and GAP43 intraepidermal nerve fibre was higher in patients with dynamic mechanical allodynia than in those without, this difference was statistically weak and the ROC curve analysis of skin biopsy variables for this type of pain failed to reach the statistical significance. CONCLUSION: Our clinical and skin biopsy study showed that ongoing burning pain was strongly associated with regenerating sprouts, as assessed with GAP43 immunostaining. This finding improves our understanding on the mechanisms underlying neuropathic pain in patients with diabetic polyneuropathy and suggests that the GAP43/PGP 9.5 ratio might be used as an objective marker for ongoing burning pain due to regenerating sprouts. SIGNIFICANCE: Our skin biopsy study showing that regenerating sprouts, as assessed with GAP43-staining, were strongly associated with ongoing burning pain, improves our knowledge on the mechanisms underlying neuropathic pain in patients with diabetes.

Skin denervation does not alter cortical potentials to surface concentric electrode stimulation: A comparison with laser evoked potentials and contact heat evoked potentials.

BACKGROUND: In the neurophysiological assessment of patients with neuropathic pain, laser evoked potentials (LEPs), contact heat evoked potentials (CHEPs) and the evoked potentials by the intraepidermal electrical stimulation via concentric needle electrode are widely agreed as nociceptive specific responses; conversely, the nociceptive specificity of evoked potentials by surface concentric electrode (SE-PREPs) is still debated. METHODS: In this neurophysiological study we aimed at verifying the nociceptive specificity of SE-PREPs. We recorded LEPs, CHEPs and SE-PREPs in eleven healthy participants, before and after epidermal denervation produced by prolonged capsaicin application. We also used skin biopsy to verify the capsaicin-induced nociceptive nerve fibre loss in the epidermis. RESULTS: We found that whereas LEPs and CHEPs were suppressed after capsaicin-induced epidermal denervation, the surface concentric electrode stimulation of the same denervated skin area yielded unchanged SE-PREPs. CONCLUSION: The suppression of LEPs and CHEPs after nociceptive nerve fibre loss in the epidermis indicates that these techniques are selectively mediated by nociceptive system. Conversely, the lack of SE-PREP changes suggests that SE-PREPs do not provide selective information on nociceptive system function. SIGNIFICANCE: Capsaicin-induced epidermal denervation abolishes laser evoked potentials (LEPs) and contact heat evoked potentials (CHEPs), but leaves unaffected pain-related evoked potentials by surface concentric electrode (SE-PREPs). These findings suggest that unlike LEPs and CHEPs, SE-PREPs are not selectively mediated by nociceptive system.

Genetic deletion of the bacterial sensor NOD2 improves murine Crohn's disease-like ileitis independent of functional dysbiosis.

Although genetic polymorphisms in NOD2 (nucleotide-binding oligomerization domain-containing 2) have been associated with the pathogenesis of Crohn's disease (CD), little is known regarding the role of wild-type (WT) NOD2 in the gut. To date, most murine studies addressing the role of WT Nod2 have been conducted using healthy (ileitis/colitis-free) mouse strains. Here, we evaluated the effects of Nod2 deletion in a murine model of spontaneous ileitis, i.e., the SAMP1Yit/Fc (SAMP) strain, which closely resembles CD. Remarkably, Nod2 deletion improved both chronic cobblestone ileitis (by 50% assessed, as the % of abnormal mucosa at 24 wks of age), as well as acute dextran sodium sulfate (DSS) colitis. Mechanistically, Th2 cytokine production and Th2-transcription factor activation (i.e., STAT6 phosphorylation) were reduced. Microbiologically, the effects of Nod2 deletion appeared independent of fecal microbiota composition and function, assessed by 16S rRNA and metatranscriptomics. Our findings indicate that pharmacological blockade of NOD2 signaling in humans could improve health in Th2-driven chronic intestinal inflammation.

Vitamin D3 inhibits TNFα-induced latent HIV reactivation in J-LAT cells.

1,25-Dihydroxyvitamin D3 (1,25(OH)2D3) is known to suppress NF-kB activity by interfering with its pathways. The aim of this study was to investigate the ability of 1,25(OH)2D3 in reducing the reactivation of the HIV virus J-LAT cells, an established model of latently infected cells, which were treated with TNFalpha (100 ng/ml) for 2 h with or without 24 h 1,25(OH)2D3 (100 nM) pretreatment. Reactivation of HIV RNA in J-LAT was evaluated in terms of green fluorescent protein (GFP) expression. The same experimental setting was repeated on T cells from HIV-infected patients. Treatment with TNFalpha was associated with a 16 % increase in GFP+ cells and a five-fold increase in unspliced HIV RNA expression (p < 0.04). Pretreatment of J-LAT cells with 1,25(OH)2D3 for 24 h followed by TNFalpha (100 ng/ml) for 2 h reduced the percentage of GFP+ cells by 8 %; moreover, a 2.4-fold decrease in unspliced HIV RNA expression was observed (p < 0.002). In T cells from patients, treatment with TNFalpha significantly increased unspliced HIV RNA expression (sixfold increase, p < 0.02), whereas prestimulation with 1,25(OH)2D3 reduced its expression (2.5-fold decrease, p < 0.02) compared to controls.1,25(OH)2D3 is able to reduce the ability of TNFalpha to upregulate the transcription of HIV RNA from latently infected cells. These data provide further understanding of the pathogenic mechanisms regulating viral reactivation from latent reservoirs, along with new insight in viral internalization.

An observational study assessing peripheral neuropathy related to multiple myeloma.

We aimed at assessing the prevalence of peripheral neuropathy in newly diagnosed, treatment-naïve patients with multiple myeloma. We enrolled 153 patients with multiple myeloma at initial diagnosis. All patients underwent neurological examination and nerve conduction study. Patients with suspected pure small fiber neuropathy underwent skin biopsy. Of the 153 patients included in this study, 7.2 % had a multiple myeloma-related neuropathy. All patients suffered from a distal symmetric sensory peripheral neuropathy, associated with age (P = 0.04). Our study on prevalence rate of multiple myeloma-related peripheral neuropathy might provide a basis for improving the clinical management of this condition.

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

BACKGROUND: 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. METHODS: In this prospective study seeking information on the mechanisms underlying pain in patients with JHS/EDS-HT, we enrolled 27 consecutive patients with this connective tissue disorder. Patients underwent a detailed clinical examination, including the neuropathic pain questionnaire DN4 and the fibromyalgia rapid screening tool. As quantitative sensory testing methods, we included thermal-pain perceptive thresholds and the wind-up ratio and recorded a standard nerve conduction study to assess non-nociceptive fibres and laser-evoked potentials, assessing nociceptive fibres. RESULTS: Clinical examination and diagnostic tests disclosed no somatosensory nervous system damage. Conversely, most patients suffered from widespread pain, the fibromyalgia rapid screening tool elicited positive findings, and quantitative sensory testing showed lowered cold and heat pain thresholds and an increased wind-up ratio. CONCLUSIONS: While the lack of somatosensory nervous system damage is incompatible with neuropathic pain as the mechanism underlying pain in JHS/EDS-HT, the lowered cold and heat pain thresholds and increased wind-up ratio imply that pain in JHS/EDS-HT might arise through central sensitization. Hence, this connective tissue disorder and fibromyalgia share similar pain mechanisms. WHAT DOES THIS STUDY ADD?: In patients with JHS/EDS-HT, the persistent nociceptive input due to joint abnormalities probably triggers central sensitization in the dorsal horn neurons and causes widespread pain.

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

We 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?

The different neuropathic pain types (e.g., 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.

Clinical, neurophysiological, and skin biopsy findings in peripheral neuropathy associated with hepatitis C virus-related cryoglobulinemia.

Hepatitis C virus (HCV)-related cryoglobulinemia commonly causes disabling complications including peripheral neuropathy and neuropathic pain. In this prospective clinical, neurophysiological, and skin biopsy study we aimed at assessing clinical characteristics and risk factors of peripheral neuropathy and neuropathic pain in patients with HCV-related cryoglobulinemia. We enrolled 69 consecutive patients with HCV-related cryoglobulinemia. We diagnosed neuropathic pain with the DN4 (Neuropathic Pain Diagnostic) questionnaire, and rated the various neuropathic pains with the Neuropathic Pain Symptom Inventory (NPSI). All patients underwent a standard nerve conduction study to assess Aß-fiber function, laser-evoked potentials to assess Aδ-fiber function, and skin biopsy to assess C-fiber terminals. Of the 69 patients studied, 47 had a peripheral neuropathy, and 29 had neuropathic pain. Patients with peripheral neuropathy were older than those without (P < 0.0001). While peripheral neuropathy was significantly associated with the duration of HCV infection (P < 0.01), it was unrelated to the duration of cryoglobulinemia and cryocrit (P > 0.5). The severity of peripheral neuropathy significantly correlated with the duration of HCV infection (P < 0.05). Laser-evoked potential amplitudes were significantly lower in patients with than in those without neuropathic pain (P < 0.05). Conversely, no difference was found in nerve conduction study and skin biopsy findings (P > 0.05). Our findings show that peripheral neuropathy is related to age and HCV infection, rather than to cryoglobulinemia, and neuropathic pain is associated with damage to nociceptive pathways as assessed with laser-evoked potentials; this might be useful for designing more effective clinical interventions for these common HCV related-cryoglobulinemia complications.

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 participant's 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.

Breast cancer and sentinel lymph node micrometastases: indications for lymphadenectomy and literature review.

An increasingly early diagnosis for discovering breast cancer, an improvement of surgical procedures with refining techniques for research and study of sentinel node, currently allow a more conservative surgical approach. Association with suitable chemo-radiotherapy allows a good control of breast disease. Our study, although modest, was carried out on 63 patients suffering from breast cancer, who underwent surgical treatment with assessment of sentinel lymph node. Aim of study was to establish the most correct strategy in the presence of isolated tumor cells (ITC) and/or micro-metastases of sentinel lymph node. Many studies have been carried out to find which was the most appropriate treatment, nevertheless, in the absence of univocal guidelines, we prefer to proceed to axillary dissection, though the topic is very debated and controversial. Following this strategy we obtained quite satisfactory results.

Incisional hernia in day surgery: our personal experience.

Incisional hernia is one of the most common complications of laparotomy. Its repair with prosthesis has enabled a considerable improvement in the outcome, significantly reducing recurrences. This study analyses the results of open hernioplasty with mesh performed as a Day Surgery procedure in 42 patients between November 2008 and October 2010. The results were good, with low postoperative morbidity and recurrences (2.4%).

Galloflavin, a new lactate dehydrogenase inhibitor, induces the death of human breast cancer cells with different glycolytic attitude by affecting distinct signaling pathways.

Galloflavin (GF), a recently identified lactate dehydrogenase inhibitor, hinders the proliferation of cancer cells by blocking glycolysis and ATP production. The aim of the present experiments was to study the effect of this compound on breast cancer cell lines reproducing different pathological subtypes of this tumor: MCF-7 (the well differentiated form), MDA-MB-231 (the aggressive triple negative tumor) and MCF-Tam (a sub-line of MCF-7 with acquired tamoxifen resistance). We observed marked differences in the energetic metabolism of these cell lines. Compared to MCF-7 cells, both MDA-MB-231 and MCF-Tam cells exhibited higher LDH levels and glucose uptake and showed lower capacity of oxygen consumption. In spite of these differences, GF exerted similar growth inhibitory effects. This result was explained by the finding of a constitutively activated stress response in MDA-MB-231 and MCF-Tam cells, which reproduce the poor prognosis tumor forms. As a further proof, different signaling pathways were found to be involved in the antiproliferative action of GF. In MCF-7 cells we observed a down regulation of the ERα-mediated signaling needed for cell survival. On the contrary, in MCF-Tam and MDA-MB-231 cells growth inhibition appeared to be contributed by an oxidative stress condition. The prevalent mechanism of cell death was found to be apoptosis induction. Because of the clinical relevance of breast cancer forms having the triple negative and/or chemoresistant phenotype, our results showing comparable effects of GF even on aggressively growing cells encourage further studies to verify the potential of this compound in improving the chemotherapy of breast cancer.

The role of laparoscopy and intraoperative ultrasound in the diagnosis and staging of lymphomas.

Laparoscopic surgery plays today an important role in the diagnosis and staging of abdominal lymphomas; in fact it provides adequate lymph node sampling for histological typing and immunophenotyping. The mini-invasive procedure is safe and effective. Intra-operative ultrasound permits to study the parenchimal organs in addition to intra-abdominal lymph node and/or masses.

Laparoscopic surgery in acute small bowel obstruction: our experience.

Small bowel obstruction (SBO) is a very common condition, in the vast majority of cases caused by post-operative adhesions. It often requires surgical treatment. Traditionally, this consisted of a laparotomy, but nowadays a laparoscopic approach is also possible. This study discusses 24 cases of SBO and compares them with literature data. Successful complete laparoscopic treatment was feasible in 9 patients, while conversion to laparoscopically-assisted surgery or laparotomy was required for the others.

[Gastrointestinal stromal tumors: diagnosis and treatment. Our experience]. / Tumori stromali gastro-intestinali: diagnosi e trattamento. Contributo casistico.

The incidence of GIST is estimated to be 1,5/100.000 per year; nevertheless they represent the most common mesenchimal tumours of gastrointestinal tract. Endoscopy, endoscopic ultrasonography and CT are the most used diagnostic tools. Complete surgical resection of localized GIST is the gold standard therapy, with possibility of laparoscopic approch in selected cases. Imatinib represents the recommended treatment of recurrent or metastatic disease. Diameter, mitotic count and surgical margins appear to be the main prognostic factors. In this paper we present ten cases of gastric or intestinal GIST and surgically treated.

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, Aß, 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.