Painful Polyneuropathy Research Articles

Painful polyneuropathy in people with diabetes: An overview of the updated guideline.

In 2022, the American Academy of Neurology (AAN) released an updated clinical practice guideline for the treatment of painful diabetic polyneuropathy. This article synthesizes the AAN recommendations, providing rationales and implementation considerations for them for primary care NP practice.

Painful polyneuropathy in people with diabetes: An overview of the updated guideline.

Painful polyneuropathy in people with diabetes: An overview of the updated guideline.

Differences in corneal nerve fiber density and fiber length in patients with painful chronic idiopathic axonal polyneuropathy and diabetic polyneuropathy.

Corneal confocal microscopy (CCM) detects small nerve fiber loss and correlates with skin biopsy findings in diabetic neuropathy. In chronic idiopathic axonal polyneuropathy (CIAP) this correlation is unknown. Therefore, we compared CCM and skin biopsy in patients with CIAP to healthy controls, patients with painful diabetic neuropathy (PDN) and diabetics without overt neuropathy (DM). Participants with CIAP and suspected small fiber neuropathy (n = 15), PDN (n = 16), DM (n = 15), and healthy controls (n = 16) underwent skin biopsy and CCM testing. Inter-center intraclass correlation coefficients (ICC) were calculated for CCM parameters. Compared with healthy controls, patients with CIAP and PDN had significantly fewer nerve fibers in the skin (IENFD: 5.7 ± 2.3, 3.0 ± 1.8, 3.9 ± 1.5 fibers/mm, all p < .05). Corneal nerve parameters in CIAP (fiber density 23.8 ± 4.9 no./mm2, branch density 16.0 ± 8.8 no./mm2, fiber length 13.1 ± 2.6 mm/mm2) were not different from healthy controls (24.0 ± 6.8 no./mm2, 22.1 ± 9.7 no./mm2, 13.5 ± 3.5 mm/mm2, all p > .05). In patients with PDN, corneal nerve fiber density (17.8 ± 5.7 no./mm2) and fiber length (10.5 ± 2.7 mm/mm2) were reduced compared with healthy controls (p < .05). CCM results did not correlate with IENFD in CIAP patients. Inter-center ICC was 0.77 for fiber density and 0.87 for fiber length. In contrast to patients with PDN, corneal nerve parameters were not decreased in patients with CIAP and small nerve fiber damage. Therefore, CCM is not a good biomarker for small nerve fiber loss in CIAP patients.

Idiopathic Distal Sensory Polyneuropathy and Fibromyalgia Syndrome: A Comparative Phenotyping Study.

Painful idiopathic distal sensory polyneuropathy (IDSP) and fibromyalgia syndrome (FMS) are cryptogenic chronic pain syndromes. The contribution of small fibre pathology (SFP) in FMS remains controversial. This study aims to quantify small nerve pathology in participants with IDSP and FMS and identify relationships of SFP with sensory phenotypes. In this study, 73 individuals (FMS: 25, IDSP: 23, healthy volunteers: 25) underwent comprehensive assessment, including neurological exams, questionnaires, sensory tests, and corneal confocal microscopy. IDSP participants displayed lower wind-up ratio (WUR) relative to FMS (p<0.001), loss of function to thermal and mechanical stimuli and elevated neuropathy disability scores compared to FMS and healthy volunteers (all p<0.001). FMS participants demonstrated gain of function to heat and blunt pressure pain responses relative to IDSP, and healthy volunteers (heat: p=0.002 and p=0.003; pressure: both p<0.001) and WUR (both p<0.001). FMS participants exhibited reduced corneal nerve fibre density (p=0.02), while IDSP participants had lower global corneal nerve measures (density, branch density, and length) relative to healthy volunteers (all p<0.001). Utilising corneal nerve fibre length, SFP was demonstrated in 66.6% of participants (FMS: 13/25; IDSP: 22/23). Participants with SFP,in both FMS and IDSP, reported symptoms indicative of small nerve fibre disease. Although distinctions in pain distributions are evident between individuals with FMS and IDSP, over 50% of participants between the two conditions displayed both a loss and gain of thermal and mechanical function suggestive of shared mechanisms. However, sensory phenotypes were associated with the presence of SFP in IDSP but not in FMS.

Effects of Monochromatic Infrared Light on Painful Diabetic Polyneuropathy: Randomized Controlled Trial

Purpose: To evaluate the effect of 890 nm Monochromatic Infrared Light (MIR) associated with a physical therapy protocol on pain in individuals with diabetic Distal Symmetric Polyneuropathy.Methods: Randomized, parallel, double-blind controlled trial conducted with individuals randomly allocated into two groups: an experimental group (EG) with the application of 890 nm MIR associated with physical therapy and a control group that received the same treatment protocol without MIR application. Both groups underwent 18 treatment sessions and were followed up for 10 weeks. Pain assessment took place at four times using the instruments: Leeds Assessment of Neuropathic Symptoms and Signs, Douleur Neuropathique 4, and Brief Pain Inventory. Descriptive, inferential statistics and probabilistic estimates of the magnitude of the intervention's effect on neuropathic pain were used in data analysis (5% significance level).Results: A total of 144 patients were allocated to groups. Lower levels of pain were observed for the EG after 6 weeks of intervention (p < .001) and 30 days after the intervention ended (p < .001). Pain intensity was lower and sleep quality improved (p < .001) for the experiment group, especially in people with severe pain.Conclusions: 890 nm MIR associated with a physical therapy protocol alleviated pain in people with Diabetic Painful Polyneuropathy after 6 weeks of follow-up, showing to be a promising alternative for the control of neuropathic pain due to diabetes mellitus.Clinical Implications: 890 nm MIR improves Painful Diabetic Polyneuropathy patient care due to relief of neuropathic pain.

Factors influencing timely diagnosis in neurolymphomatosis.

Neurolymphomatosis refers to infiltration of the peripheral nervous system (PNS) by non-Hodgkin lymphoma (NHL). Diagnostic intervals in neurolymphomatosis and factors delaying diagnosis have not been evaluated. We therefore aimed to analyze diagnostic intervals in a large cohort. The quality control database at Yale Cancer Center, Section of Neuro-Oncology, was searched for neurolymphomatosis cases diagnosed between 2001 and 2021. Univariate analyses were performed to identify parameters influencing diagnostic intervals. We identified 22 neurolymphomatosis cases including 7 with primary and 15 with secondary disease, which occurred a median (range: 4-144) of 16 months after initial NHL diagnosis. Patients typically presented with painful polyneuropathy (73%), that was asymmetrical and rapidly progressive. Diagnosis was based on PNS biopsy (50%) or integration of neuroimaging findings (50%) with NHL history and diagnostic cerebrospinal fluid examinations. Median interval from symptom onset to diagnosis was 3 months (range: 1-12). Secondary neurolymphomatosis compared to primary disease (median 2 vs. 6 months, p = 0.02), and cases with rapidly-progressive asymmetrical neuropathy as opposed to other presentations (median 2 vs. 6 months; p < 0.001) were diagnosed earlier. Upfront conventional CT compared to other modalities (median 2 vs. 5 months p = 0.04) and nerve root localization as opposed to other disease sites (median 1.5 vs. 4 months; p = 0.04) delayed diagnosis. NL type and localization, neuropathy course and distribution, and imaging modality selected for initial evaluation influence diagnostic intervals in neurolymphomatosis. Knowledge of this rare entity is critical for early suspicion, and diagnosis.

What is associated with painful polyneuropathy? A cross-sectional analysis of symptoms and signs in patients with painful and painless polyneuropathy.

It is still unclear how and why some patients develop painful and others painless polyneuropathy. The aim of this study was to identify multiple factors associated with painful polyneuropathies (NeuP). A total of 1181 patients of the multicenter DOLORISK database with painful (probable or definite NeuP) or painless (unlikely NeuP) probable or confirmed neuropathy were investigated clinically, with questionnaires and quantitative sensory testing. Multivariate logistic regression including all variables (demographics, medical history, psychological symptoms, personality items, pain-related worrying, life-style factors, as well as results from clinical examination and quantitative sensory testing) and machine learning was used for the identification of predictors and final risk prediction of painful neuropathy. Multivariate logistic regression demonstrated that severity and idiopathic etiology of neuropathy, presence of chronic pain in family, Patient-Reported Outcomes Measurement Information System Fatigue and Depression T-Score, as well as Pain Catastrophizing Scale total score are the most important features associated with the presence of pain in neuropathy. Machine learning (random forest) identified the same variables. Multivariate logistic regression archived an accuracy above 78%, random forest of 76%; thus, almost 4 out of 5 subjects can be classified correctly. This multicenter analysis shows that pain-related worrying, emotional well-being, and clinical phenotype are factors associated with painful (vs painless) neuropathy. Results may help in the future to identify patients at risk of developing painful neuropathy and identify consequences of pain in longitudinal studies.

Perceived Stress and its Association with Sleep Quality in Patients with Neuropathic Pain and Distal Symmetric Polyneuropathy (P3-11.020)

Perceived Stress and its Association with Sleep Quality in Patients with Neuropathic Pain and Distal Symmetric Polyneuropathy (P3-11.020)

The role of cytokines and chemokines in the maintenance of chronic pain-a pilot study.

The immune system is believed to be important in the initiation and maintenance of chronic pain. The aim was to investigate whether patients with chronic painful polyneuropathy (PP) differ in cytokine profiles of serum and/or cerebrospinal fluid (CSF) compared with pain-free controls. Thirty-nine patients (16 women and 23 men, mean age, 69.2 ± 12.7 years, range 41-92 years) with PP (mean duration 43 ± 48.3 months) were phenotyped with quantitative sensory testing and electroneurography, and serum and CSF samples were analyzed by 40-multiplexed, bead-based cytokine immunoassays. Results were compared with 36 age- and gender-matched patients with normal pressure hydrocephalus and absence of abnormal CSF findings. Compared with controls, patients with PP had lower concentrations of several proinflammatory and anti-inflammatory chemokines and cytokines in CSF, and others showed the same tendency, among these were tumor necrosis factor-α (14.1 ± 10.0 vs 23.9 ± 16.4 pg/mL, P < 0.005), interleukin (IL)-2 (0.6 ± 0.4 vs 1.2 ± 0.6 pg/mL, P < 0.0001), IL-6 (4.7 ± 6.8 vs 7.3 ± 9 pg/mL, P = 0.001), and IL-10 (7.5 ± 6.8 vs 16.8 ± 19.2 pg/mL, P < 0.01), whereas no differences were observed in serum. Results suggest that (1) inflammatory mediators play a minor role in the maintenance of chronic pain in contrast to initiation of acute pain, (2) chemokines/cytokines are downregulated in chronic pain, or (3) chemokines/cytokines have a protective role for nerve regeneration that is disturbed in patients with chronic pain.

Диабетическая дорсопатия: от теории к практике

ABSRTACT INTRODUCTION. Currently, in the scientific literature, the problem of the relationship between pain in the lower back and diabetes mellitus is given great attention, and therefore the term diabetic dorsopathy has appeared. CONCLUSION. The treatment strategy for a patient with back pain depends on the age of presentation, the severity of disc degeneration associated with nerve compression, the stability of the functional spine, and the overall balance of the spinal column (ie, sagittal balance). Therapy for diabetic dorsopathy is based on the general principles of treating nonspecific back pain. The drugs of choice for acute back pain are non-steroidal anti-inflammatory drugs, when choosing which you need to take into account their pharmacodynamics and pharmacokinetics. Artoxan (tenoxicam) according to these parameters demonstrates proper efficiency and safety. In a patient with a polyneuropathic component of back pain and diabetic polyneuropathy, it is advisable to include the drug Cocarnit in complex therapy. The quadro-effect of Cocarnit components is able to influence different points of formation of complications of diabetes and significantly improve the quality of life of such patients, restoring neurometabolic processes, reducing pain, the drug increases patient adherence to therapy. KEYWORDS: comorbidity, pain, diabetes, diabetic dorsopathy

Hypersensitivity of myelinated A-fibers via toll-like receptor 5 promotes mechanical allodynia in tenascin-X-deficient mice associated with Ehlers–Danlos syndrome

Deficiency of an extracellular matrix glycoprotein tenascin-X (TNX) leads to a human heritable disorder Ehlers–Danlos syndrome, and TNX-deficient patients complain of chronic joint pain, myalgia, paresthesia, and axonal polyneuropathy. We previously reported that TNX-deficient (Tnxb−/−) mice exhibit mechanical allodynia and hypersensitivity to myelinated A-fibers. Here, we investigated the pain response of Tnxb−/− mice using pharmacological silencing of A-fibers with co-injection of N-(2,6-Dimethylphenylcarbamoylmethyl) triethylammonium bromide (QX-314), a membrane-impermeable lidocaine analog, plus flagellin, a toll-like receptor 5 (TLR5) ligand. Intraplantar co-injection of QX-314 and flagellin significantly increased the paw withdrawal threshold to transcutaneous sine wave stimuli at frequencies of 250 Hz (Aδ fiber responses) and 2000 Hz (Aβ fiber responses), but not 5 Hz (C fiber responses) in wild-type mice. The QX-314 plus flagellin-induced silencing of Aδ- and Aβ-fibers was also observed in Tnxb−/− mice. Co-injection of QX-314 and flagellin significantly inhibited the mechanical allodynia and neuronal activation of the spinal dorsal horn in Tnxb−/− mice. Interestingly, QX-314 alone inhibited the mechanical allodynia in Tnxb−/− mice, and it increased the paw withdrawal threshold to stimuli at frequencies of 250 Hz and 2000 Hz in Tnxb−/− mice, but not in wild-type mice. The inhibition of mechanical allodynia induced by QX-314 alone was blocked by intraplantar injection of a TLR5 antagonist TH1020 in Tnxb−/− mice. These results suggest that mechanical allodynia due to TNX deficiency is caused by the hypersensitivity of Aδ- and Aβ-fibers, and it is induced by constitutive activation of TLR5.

EFFECTS OF MLS-LASER ON NEUROPATHIC PAIN IN DIABETIC SENSОMOTOR NEUROPATHY

About 20-50 % of patients with diabetes and about 60 % of those with diabetic neuropathy develop neuropathic pain, which is characterized by tingling, burning, sharp, shooting, or stabbing sensations, and even electric shock-like sensations. Painful diabetic neuropathy can significantly affect the quality of life of patients with diabetes, the ability to perform daily activities and negatively affect mood. According to the 2021 consensus of an international panel of experts regarding the treatment of painful distal symmetric polyneuropathy, non-pharmacological forms of treatment should also be considered due to unsatisfactory pharmacotherapy. A number of studies have demonstrated the role of photobiomodulation as a non-pharmacological method of treating painful diabetic neuropathy. The purpose of this placebo-controlled, longitudinal study was to investigate the effect of high-energy MLS-laser therapy on neuropathic pain. Material and methods: A total of 69 cases of patients with type 2 diabetes and painful diabetic neuropathy of the lower extremities were followed, divided into two groups: an experimental - 41 patients received high-energy laser radiation and a control (placebo) group - 28 patients, with a "mock" laser treatment. For objectification of pain, the Bulgarian version of the short form of the McGill pain questionnaire, version SF-MPQ-2, which includes the visual analog scale (VAS), was used. Comparisons between groups were performed with parametric or non parametric tests depending on the distribution of the variables, the number of the compared groups and the study pre test – post test design. Results: The pain index, reported by the McGill questionnaire, in the experimental group, decreased by - 63.2 % at the end of the nine-day treatment and by - 56.1 % at the 90th day after the start of treatment compared to the value before therapy. In the control group, there was a minimal change at the end of treatment (day 21), which did not persist until the end of the observation period (day 90). Conclusions: MLS laser therapy significantly increases the pain threshold and should be considered a safe, non-pharmacological adjunct to standard therapy in patients with painful diabetic peripheral neuropathy.

Local Inflammatory Mediators Involved in Neuropathic Pain.

Polyneuropathy (PNP) is a term to describe diseases of the peripheral nervous system, 50% of which present with neuropathic pain. In some types of PNP, pain is restricted to the skin distally in the leg, suggesting a local regulatory process leading to pain. In this study, we proposed a pro-inflammatory pathway mediated by NF-κB that might be involved in the development of pain in patients with painful PNP. To test this hypothesis, we have collected nerve and skin samples from patients with different etiologies and levels of pain. We performed RT-qPCR to analyze the gene expression of the proposed inflammatory pathway components in sural nerve and in distal and proximal skin samples. In sural nerve, we showed a correlation of TLR4 and TNFα to neuropathic pain, and an upregulation of TNFα in patients with severe pain. Patients with an inflammatory PNP also presented a lower expression of TRPV1 and SIRT1. In distal skin, we found a reduced expression of TLR4 and miR-146-5p, in comparison to proximal skin. Our findings thus support our hypothesis of local inflammatory processes involved in pain in PNP, and further show disturbed anti-inflammatory pathways involving TRPV1 and SIRT1 in inflammatory PNP.

Use of plasma rich in growth factors for symptoms of diabetic neuropathy.

Painful peripheral polyneuropathy is a common complication of diabetes mellitus (DM) and is a significant source of chronic disability and remains a challenging condition with no available disease-modifying treatment. In the present case report, we describe the treatment of a patient featuring painful diabetic neuropathy with perineural injections of autologous plasma rich in growth factors (PRGF). At one-year post-procedure, the patient exhibited improved scores on the neuropathic pain scale and improvement in the activity level. Plasma rich in growth factors (PRGF) is an autologous product that can be prepared and administered in a physician's office. PRGF can be infiltrated as a liquid, creating a three-dimensional gel scaffold in the body. PRGF releases growth factors involved in nerve healing. PRGF may be established as a potent alternative treatment of painful diabetic polyneuropathy.

Differential Expression of microRNAs in Serum of Patients with Chronic Painful Polyneuropathy and Healthy Age-Matched Controls

Polyneuropathies (PNP) are the most common type of disorder of the peripheral nervous system in adults. However, information on microRNA expression in PNP is lacking. Following microRNA sequencing, we compared the expression of microRNAs in the serum of patients experiencing chronic painful PNP with healthy age-matched controls. We have been able to identify four microRNAs (hsa-miR-3135b, hsa-miR-584-5p, hsa-miR-12136, and hsa-miR-550a-3p) that provide possible molecular links between degenerative processes, blood flow regulation, and signal transduction, that eventually lead to PNP. In addition, these microRNAs are discussed regarding the targeting of proteins that are involved in high blood flow/pressure and neural activity dysregulations/disbalances, presumably resulting in PNP-typical symptoms such as chronical numbness/pain. Within our study, we have identified four microRNAs that may serve as potential novel biomarkers of chronic painful PNP, and that may potentially bear therapeutic implications.

Effect of Transcutaneous Spinal Direct Current Stimulation in Patients with Painful Polyneuropathy and Influence of Possible Predictors of Efficacy including BDNF Polymorphism: A Randomized, Sham-Controlled Crossover Study.

Introduction: The neuromodulating effects of transcutaneous-spinal Direct Current Stimulation (tsDCS) have been reported to block pain signaling. For patients with chronic pain, tsDCS could be a potential treatment option. To approach this, we studied the effect of anodal tsDCS on patients with neuropathic pain approaching an optimal paradigm including the investigation of different outcome predictors. Methods: In this randomized, double-blinded, sham-controlled crossover study we recruited twenty patients with neurophysiologically evaluated neuropathic pain due to polyneuropathy (PNP). Variables (VAS; pain and sleep quality) were reported daily, one week prior to, and one week after the stimulation/sham period. Anodal tsDCS (2.5 mA, 20 min) was given once daily for three days during one week. BDNF-polymorphism, pharmacological treatment, and body mass index (BMI) of all the patients were investigated. Results: Comparing the effects of sham and real stimulation at the group level, there was a tendency towards reduced pain, but no significant effects were found. However, for sleep quality a significant improvement was seen. At the individual level, 30 and 35% of the subjects had a clinically significant improvement of pain level and sleep quality, respectively, the first day after the stimulation. Both effects were reduced over the coming week and these changes were negatively correlated. The BDNF polymorphism Val66Met was carried by 35% of the patients and this group was found to have a lower general level of pain but there was no significant difference in the tsDCS response effect. Neither pharmacologic treatment or BMI influenced the treatment effect. Conclusions: Short-term and sparse anodal thoracic tsDCS reduces pain and improves sleep with large inter-individual differences. Roughly 30% will benefit in a clinically meaningful way. The BDNF genotype seems to influence the level of pain that PNP produces. Individualized and intensified tsDCS may be a treatment option for neuropathic pain due to PNP.

Neurolymphomatosis in Recrudescent Diffuse Large B-cell Lymphoma.

Neurolymphomatosis is an uncommon manifestation of lymphoma, often presenting with painful polyneuropathy or polyradiculopathy and concomitant distal extremity weakness. Differentiation from other etiologies resulting in similar neuropathic symptoms such as compressive or inflammatory pathologies can be difficult and often results in delayed diagnosis. Here we describe a case of neurolymphomatosis affecting a 64-year-old man with a history of diffuse large B-cell lymphoma (DLBCL) in remission presenting with a right-sided foot drop following a gunshot wound. MRI at that time demonstrated thickening and enhancement of the cauda equina nerve roots. Over the course of the subsequent eight months, he developed left lower extremity sensory symptoms, left-sided foot drop and signs of upper motor neuron involvement, including left facial weakness, dysphonia, and dysphagia. 18F-FDG PET/CT revealed intensely avid left lumbosacral nerve roots, bilateral lower extremity and left upper extremity neurovascular bundles. Left sural nerve biopsies showed infiltration of DLBCL and confirmed neurolymphomatosis. We highlight the role of 18F-FDG PET/CT, with histological verification, for the diagnosis of an extended course of neurolymphomatosis occurring in the absence of typical painful neuropathy but with cranial and peripheral neuropathies.

The pandemic’s effect on a patient cohort with painful polyneuropathy in 2020: A longitudinal study on pain, mood, and everyday life

In the early phase of the COVID pandemic 2020, we demonstrated how patients with painful polyneuropathy, against our expectations, did not experience a deterioration of their neuropathic pain. We hypothesized that our assessed measures, that is, pain intensity and characteristics, emotional wellbeing, and everyday life, would deteriorate in the further course of the pandemic according to the phases of disaster management. Thus, the aim of our study was to investigate patients repeatedly under varying pandemic conditions from March until December 2020. Sixty-three patients were investigated with validated questionnaires (brief pain inventory [BPI], neuropathic pain symptom inventory [NPSI], pain catastrophizing scale [PCS], patient-reported outcomes measurement information system [PROMIS] pain interference/sleep disturbance/fatigue/ depression/anxiety, EuroQol 5 dimensions 5 level version [EQ-5D-5L]) and a pandemic-specific, self-designed questionnaire. The data from the beginning of the pandemic with severe restrictions, during summer with loosened regulations and from December 2020 with reinstalled, severe restrictions were compared with an observational design. Patients reported higher pain severity when restrictions were lower. Sleep, mood, and quality of life did not change in the course of the pandemic in the validated measures. Pain interference significantly decreased during the study independent from restrictions. Patients who reported medical disadvantages had a lower quality of life upon EuroQol 5 dimension (EQ-5D) and were significantly more worried about their health. The perception of pain intensity was dependent on pandemic severity. Sleep, mood, and quality of life did not change significantly in validated measures. Continued medical care seems decisive to prevent worsening of pain and quality of life.

Electroencephalography functional connectivity-A biomarker for painful polyneuropathy.

Advanced analysis of electroencephalography (EEG) data has become an essential tool in brain research. Based solely on resting state EEG signals, a data-driven, predictive and explanatory approach is presented to discriminate painful from non-painful diabetic polyneuropathy (DPN) patients. Three minutes long, 64 electrode resting-state recordings were obtained from 180 DPN patients. The analysis consisted of a mixture of traditional, explanatory and machine learning analyses. First, the 10 functional bivariate connections best differentiating between painful and non-painful patients in each EEG band were identified and the relevant receiver operating characteristic was calculated. Later, those connections were correlated with selected clinical parameters. Predictive analysis indicated that theta and beta bands contain most of the information required for discrimination between painful and non-painful polyneuropathy patients, with area under the receiver operating characteristic curve values of 0.93 for theta and 0.89 for beta bands. Assessing statistical differences between the average magnitude of functional connectivity values and clinical pain parameters revealed that painful DPN patients had significantly higher cortical functional connectivity than non-painful ones (p= 0.008 for theta and p= 0.001 for alpha bands). Moreover, intra-band analysis of individual significant functional connections revealed a positive correlation with average reported pain in the previous 3months in all frequency bands. Resting state EEG functional connectivity can serve as a highly accurate biomarker for the presence or absence of pain in DPN patients. This highlights the importance of the brain, in addition to the peripheral lesions, in generating the clinical pain picture. This tool can probably be extended to other pain syndromes.

Enriched enrollment randomized double-blind placebo-controlled cross-over trial with phenytoin cream in painful chronic idiopathic axonal polyneuropathy (EPHENE): a study protocol

BackgroundPatients with chronic idiopathic axonal polyneuropathy (CIAP) can have neuropathic pain that significantly impacts quality of life. Oral neuropathic pain medication often has insufficient pain relief and side effects. Topical phenytoin cream could circumvent these limitations.The primary objectives of this trial are to evaluate (1) efficacy in pain reduction and (2) safety of phenytoin cream in patients with painful CIAP. The main secondary objective is to explore the usefulness of a double-blind placebo-controlled response test (DOBRET) to identify responders to sustained pain relief with phenytoin cream.MethodsThis 6-week, enriched enrollment randomized double-blind, placebo-controlled triple cross-over trial compares phenytoin 20%, 10% and placebo cream in 48 participants with painful CIAP. Enriched enrollment is based on a positive DOBRET in 48 participants who experience within 30 minutes ≥2 points pain reduction on the 11-point numerical rating scale (NRS) in the phenytoin 10% cream applied area and ≥1 point difference in pain reduction on the NRS between phenytoin 10% and placebo cream applied area, in favour of the former. To explore whether DOBRET has predictive value for sustained pain relief, 24 DOBRET-negative participants will be included.An open-label extension phase is offered with phenytoin 20% cream for up to one year, to study long-term safety.The main inclusion criteria are a diagnosis of CIAP and symmetrical neuropathic pain with a mean weekly pain score of ≥4 and <10 on the NRS.The primary outcome is the mean difference between phenytoin 20% versus placebo cream in 7-day average pain intensity, as measured by the NRS, over week 2 in DOBRET positive participants.Key secondary outcomes include the mean difference in pain intensity between phenytoin 10% and phenytoin 20% cream, and between phenytoin 10% and placebo cream. Furthermore, differences between the 3 interventions will be evaluated on the Neuropathic Pain Symptom Inventory, EuroQol EQ5-5D-5L, and evaluation of adverse events.DiscussionThis study will provide evidence on the efficacy and safety of phenytoin cream in patients with painful CIAP and will give insight into the usefulness of DOBRET as a way of personalized medicine to identify responders to sustained pain relief with phenytoin cream.Trial registrationClinicalTrials.gov NCT04647877. Registered on 1 December 2020.