Degenerative and regenerative peripheral processes are associated with persistent painful chemotherapy-induced neuropathies in males and females.

This study investigated the time course of gene expression changes during the progression of persistent painful neuropathy caused by paclitaxel (PTX) in male and female mouse hindpaws and dorsal root ganglia (DRG). Bulk RNA-seq was used to examine these gene expression changes at 1, 16, and 31 days post-last PTX. At these time points, differentially expressed genes (DEGs) were predominantly related to the reduction or increase in epithelial, skin, bone, and muscle development and to angiogenesis, myelination, axonogenesis, and neurogenesis. These processes are accompanied by the regulation of DEGs related to the cytoskeleton, extracellular matrix organization, and cellular energy production. This gene plasticity during the progression of persistent painful neuropathy could be interpreted as a biological process linked to tissue regeneration/degeneration. In contrast, gene plasticity related to immune processes was minimal at 1-31 days after PTX. It was also noted that despite similarities in biological processes and pain chronicity between males and females, specific DEGs differed dramatically according to sex. The main conclusions of this study are that gene expression plasticity in hindpaw and DRG during PTX neuropathy progression similar to tissue regeneration and degeneration, minimally affects immune system processes and is heavily sex-dependent at the individual gene level.

Contemporary prevalence of diabetic neuropathies in individuals with type 1 and type 2 diabetes in a Danish tertiary outpatient clinic.

BACKGROUND: Population-based prevalence estimates of distal symmetric polyneuropathy (DPN) and diabetic autonomic neuropathy (DAN) are scares. Here we present neuropathy estimates and describe their overlap in a large cohort of people with type 1 and type 2 diabetes. METHODS: In a large population of outpatient participants, DPN was assessed using vibration perception threshold, sural nerve function, touch, pain and thermal sensation. Definite DPN was defined by the Toronto Consensus Criteria. Painful DPN was defined by Douleur Neuropathique 4 Questions. DAN measures were: cardiovascular reflex tests, electrochemical skin conductance, and gastroparesis cardinal symptom index. RESULTS: We included 822 individuals with type 1 (mean age (±SD) 54 ± 16 years, median [IQR] diabetes duration 26 [15-40] years) and 899 with type 2 diabetes (mean age 67 ± 11 years, median diabetes duration 16 [11-22] years). Definite DPN was prevalent in 54 % and 68 %, and painful DPN was in 5 % and 15 % of type 1 and type 2 participants, respectively. The prevalence of DAN varied between 6 and 39 % for type 1 and 9-49 % for type 2 diabetes. DPN without other neuropathy was present in 45 % with T1D and 50 % with T2D. CONCLUSION: The prevalence of DPN and DAN was high. DPN and DAN co-existed in only 50 % of cases.

Diabetic Neuropathy: Pathophysiology Review.

PURPOSE OF REVIEW: Diabetic neuropathy is a debilitating complication of diabetes mellitus that affects millions of individuals worldwide. It is characterized by nerve damage resulting from prolonged exposure to high blood glucose levels. Diabetic neuropathy may cause a range of symptoms, including pain, numbness, muscle weakness, autonomic dysfunction, and foot ulcers, potentially causing significant impairment to the quality of life for those affected. This review article aims to provide a comprehensive overview of the pathophysiology of diabetic neuropathy. The etiology of diabetic neuropathy will be discussed, including risk factors, predisposing conditions, and an overview of the complex interplay between hyperglycemia, metabolic dysregulation, and nerve damage. Additionally, we will explore the molecular mechanisms and pathways of diabetic neuropathy, including the impact of hyperglycemia on nerve function, abnormalities in glucose metabolism, the role of advanced glycation end products (AGEs), and inflammatory and immune-mediated processes. We will provide an overview of the various nerve fibers affected by diabetic neuropathy and explore the common symptoms and complications associated with diabetic neuropathy in the pain medicine field. RECENT FINDINGS: This review highlights advances in understanding the pathophysiology of diabetic neuropathy as well as reviews potential novel therapeutic strategies and promising areas for future research. In conclusion, this review article aims to shed light on the pathophysiology of diabetic neuropathy, its far-reaching consequences, and the evolving strategies for prevention and management. In understanding the mechanisms of diabetic neuropathy and the ongoing research in this area, healthcare professionals can better serve patients with diabetes, ultimately improving well-being and reducing complications.

Brachial Plexus Injury Secondary to Spontaneous Upper Limb Haematoma.

Spontaneous upper limb muscle haematomas are rare clinical phenomenons, which often go under- or misdiagnosed. They can present management challenges in the context of anticoagulant therapy, especially in the presence of other medical conditions. We present the case of a 52-year-old male with an initially missed presentation of a spontaneous muscle haematoma that progressed and re-presented to the emergency department (ED) with signs of mixed upper limb neuropathy requiring surgical evacuation and an emergency fasciotomy. This case highlights the importance of prompt diagnosis and intervention. While brachial plexus injuries from haematoma compression are uncommon, in our case, we discuss the need for surgical intervention to relieve pressure and optimise patient outcomes when clinically concerned about compartment syndrome or progressive neuropathy.

Female sex is a risk factor for painful diabetic peripheral neuropathy: the EURODIAB prospective diabetes complications study.

AIMS/HYPOTHESIS: While the risk factors for diabetic peripheral neuropathy (DPN) are now well recognised, the risk factors for painful DPN remain unknown. We performed analysis of the EURODIAB Prospective Complications Study data to elucidate the incidence and risk factors of painful DPN. METHODS: The EURODIAB Prospective Complications Study recruited 3250 participants with type 1 diabetes who were followed up for 7.3±0.6 (mean ± SD) years. To evaluate DPN, a standardised protocol was used, including clinical assessment, quantitative sensory testing and autonomic function tests. Painful DPN (defined as painful neuropathic symptoms in the legs in participants with confirmed DPN) was assessed at baseline and follow-up. RESULTS: At baseline, 234 (25.2%) out of 927 participants with DPN had painful DPN. At follow-up, incident DPN developed in 276 (23.5%) of 1172 participants. Of these, 41 (14.9%) had incident painful DPN. Most of the participants who developed incident painful DPN were female (73% vs 48% painless DPN p=0.003) and this remained significant after adjustment for duration of diabetes and HbA1c (OR 2.69 [95% CI 1.41, 6.23], p=0.004). The proportion of participants with macro- or microalbuminuria was lower in those with painful DPN compared with painless DPN (15% vs 34%, p=0.02), and this association remained after adjusting for HbA1c, diabetes duration and sex (p=0.03). CONCLUSIONS/INTERPRETATION: In this first prospective study to investigate the risk factors for painful DPN, we definitively demonstrate that female sex is a risk factor for painful DPN. Additionally, there is less evidence of diabetic nephropathy in incident painful, compared with painless, DPN. Thus, painful DPN is not driven by cardiometabolic factors traditionally associated with microvascular disease. Sex differences may therefore play an important role in the pathophysiology of neuropathic pain in diabetes. Future studies need to look at psychosocial, genetic and other factors in the development of painful DPN.

Cooled Radiofrequency Treatment for Radicular Pain Related to Lumbar Disc Herniation.

BACKGROUND: Lower back and radicular pain are leading causes of disability and loss of quality of life, especially due to its high prevalence in the general population. Cooled radiofrequency treatment (CRT) has emerged as a novel non-invasive technique for the management of discogenic pain with safe and effective results. The aim of this study was to evaluate the effectiveness of CRT in the treatment of radicular pain secondary to a lumbar hernia in patients with chronic neuropathic pain after receiving conservative treatment that did not achieve adequate pain management. METHODS: A prospective study of patients undergoing CRT for the management of discogenic low back pain was carried out. When attending the first evaluation and corroborating the lumbar hernias by magnetic resonance imaging (MRI), treatment was offered one month of physiotherapy before CRT. To assess the evolution of the patients, measurements were taken before and after the intervention with the visual analog scale (VAS) and the Oswestry low back pain disability scale (OLBPDS) scores. RESULTS: A total of 74 patients (mean age: 48.42 ± 14.32 years, 66.11% female) were included, who were undergoing a total of 134 herniated intervertebral lumbar discs. When comparing the initial perception of low back pain and after finding a non-significant partial improvement with one month of physiotherapy treatment, it was observed that the patients who were offered CRT showed an average improvement in discogenic pain of 79.92% (p = <0.0001, 95% CI: -7.010 to -6.379) in 98.64% of cases. This was accompanied by an increase in their functionality of daily living activities, as measured by OLBPDS. No patients presented significant adverse events, and in the only case where the desired pain management was not obtained, the patient's discomfort did not worsen. CONCLUSIONS: Intradiscal biacuplasty by CRT is a considerable treatment for lumbar radiculopathy. Postoperative results demonstrated its effectiveness and safety in the management of radicular pain without the presence of significant adverse effects.

Gabapentin-Induced Myoclonus in a Patient With Chronic Kidney Disease.

Gabapentin contains a cyclohexyl group and is a form of gamma-aminobutyric acid (GABA). Despite its name, gabapentin does not affect the inhibitory neurotransmitter GABA or its receptors. Instead, it acts as a ligand, binding strongly to the α2δ (Ca) channel subunit and interfering with its regulatory function and the release of excitatory neurotransmitters. Gabapentin is approved by the FDA for treating seizure disorders and neuropathic pain, except for trigeminal neuralgia. However, it is frequently used off-label to treat other pain conditions and psychological disorders, such as anxiety. Unlike other drugs, gabapentin is not metabolized in the liver and is solely excreted by the kidneys. Therefore, it is crucial to adjust the dosage in patients with renal insufficiency to avoid severe adverse effects. In this case report, we present a patient with chronic renal impairment who experienced devastating myoclonic jerky movements shortly after increasing his gabapentin dose.

Diabetes-Induced Amplification of Nociceptive DRG Neuron Output by Upregulation of Somatic T-Type Ca2+ Channels.

The development of pain symptoms in peripheral diabetic neuropathy (PDN) is associated with the upregulation of T-type Ca2+ channels (T-channels) in the soma of nociceptive DRG neurons. Moreover, a block of these channels in DRG neurons effectively reversed mechanical and thermal hyperalgesia in animal diabetic models, indicating that T-channel functioning in these neurons is causally linked to PDN. However, no particular mechanisms relating the upregulation of T-channels in the soma of nociceptive DRG neurons to the pathological pain processing in PDN have been suggested. Here we have electrophysiologically identified voltage-gated currents expressed in nociceptive DRG neurons and developed a computation model of the neurons, including peripheral and central axons. Simulations showed substantially stronger sensitivity of neuronal excitability to diabetes-induced T-channel upregulation at the normal body temperature compared to the ambient one. We also found that upregulation of somatic T-channels, observed in these neurons under diabetic conditions, amplifies a single action potential invading the soma from the periphery into a burst of multiple action potentials further propagated to the end of the central axon. We have concluded that the somatic T-channel-dependent amplification of the peripheral nociceptive input to the spinal cord demonstrated in this work may underlie abnormal nociception at different stages of diabetes development.

Efficacy and safety of vixotrigine in idiopathic or diabetes-associated painful small fibre neuropathy (CONVEY): a phase 2 placebo-controlled enriched-enrolment randomised withdrawal study.

Background: No pharmacological treatments are specifically indicated for painful small fibre neuropathy (SFN). CONVEY, a phase 2 enriched-enrolment study, evaluated the efficacy and safety of vixotrigine, a voltage- and use-dependent sodium channel blocker, in participants with idiopathic or diabetes-associated painful SFN. Methods: CONVEY was a phase 2, multicentre, placebo-controlled, double-blind (DB), enriched-enrolment, randomised withdrawal study. The study was conducted at 68 sites in 13 countries (Europe and Canada) between May 17, 2018, and April 12, 2021. Following a 4-week open-label period in which 265 adults with painful SFN (a mixture of large and small fibre neuropathy was not exclusionary) received oral vixotrigine 350 mg twice daily (BID), 123 participants (with a ≥30% reduction from baseline in average daily pain [ADP] score during the open-label period) were randomised 1:1:1 to receive 200 mg BID, 350 mg BID or placebo for a 12-week double-blind (DB) period. Primary endpoint was change from baseline in ADP at DB Week 12. Secondary endpoints included the proportion of participants with a ≥30% reduction from baseline in ADP and the proportion of Patient Global Impression of Pain (PGIC) responders at DB Week 12. Treatment-emergent adverse events (AEs) were monitored. Statistical significance was set at 0.10 (2-sided). The trial was registered on ClinicalTrials.gov (NCT03339336) and on ClinicalTrialsregister.eu (2017-000991-27). Findings: A statistically significant difference from placebo in least squares mean reduction in ADP score from baseline to DB Week 12 was observed with vixotrigine 200 mg BID (-0.85; SE, 0.43; 95% CI, -1.71 to 0.00; p = 0.050) but not 350 mg BID (-0.17; SE, 0.43; 95% CI, -1.01 to 0.68; p = 0.70). Numerically, but not statistically significantly, more participants who received vixotrigine vs placebo experienced a ≥30% ADP reduction from baseline (68.3-72.5% vs 52.5%), and only the 350 mg BID group had significantly more PGIC responders vs placebo (48.8% vs 30.0%; odds ratio = 2.60; 95% CI, 0.97-6.99; p = 0.058) at DB Week 12. AEs were mostly mild to moderate in the vixotrigine groups. The most common AEs (≥5% of vixotrigine-treated participants) in the DB 200 mg BID and 350 mg BID vixotrigine groups were falls, nasopharyngitis, muscle spasm, and urinary tract infection. Interpretation: In our study, vixotrigine 200 mg BID, but not 350 mg BID, met the primary endpoint; more vixotrigine-treated participants experienced a ≥30% reduction from baseline in ADP at DB Week 12. Vixotrigine (at both dosages) was well tolerated in participants with SFN. Funding: Biogen, Inc.

Interosseous Membrane Stimulation: A Treatment for Painful Peripheral Neuropathy.

Background: Painful peripheral neuropathy is a condition that may be associated with diabetes as well as other causes of neuropathy. Common treatments for the pain include topical application of capsaicin as well as using oral medications, typically gabapentin. The results are variable and rarely provide substantial lasting relief. Cases: This report describes how a simple and easy to perform acupuncture technique-interosseous membrane stimulation-was used to treat painful neuropathy in 3 patients: 1 with painful diabetic neuropathy; 1 with idiopathic painful neuropathy; and 1 with painful neuropathy caused by exposure to Agent Orange while serving in Vietnam. Results: The 3 patients had much relief from the pain associated with their neuropathy for several weeks at a time. With regular treatments, sustained relief was obtained any without the addition of new medication. Conclusions: Interosseous membrane stimulation is safe, simple, and effective for treatment of painful neuropathy. This treatment should be considered for patients who are suffering with painful neuropathy.

Neurolymphomatosis: involvement of peripheral nervous system revealing hematologic malignancy, a report of nine cases.

BACKGROUND AND AIM: Neurolymphomatosis is defined as an infiltration of the peripheral nervous system (PNS) by malignant lymphoma cells. It is a rare entity and diagnosis is complicated especially when PNS involvement is the initial and leading symptom. To improve knowledge of the disorder and shorten the time to diagnosis, we report a series of nine patients without a history of hematologic malignancy, who were diagnosed with neurolymphomatosis after evaluation and workup of peripheral neuropathy. METHODS: The patients were included from the Department of Clinical Neurophysiology at Pitié Salpêtrière and Nancy Hospitals over a period of 15 years. Diagnosis of neurolymphomatosis was confirmed by histopathologic examination for each patient. We characterized their clinical, electrophysiological, biological, imaging, and histopathologic features. RESULTS: The neuropathy was characterized by pain (78%), proximal involvement (44%) or of all four limbs (67%), asymmetrical or with multifocal distribution (78%), abundant fibrillation (78%), a tendency to worsen rapidly, and significant associated weight loss (67%). Neurolymphomatosis was diagnosed principally on nerve biopsy (89%) identifying infiltration of lymphoid cells, atypical cells (78%), a monoclonal population (78%), and supported by fluorodeoxyglucose-positron emission tomography, spine or plexus MRI, cerebrospinal fluid analysis, and blood lymphocyte immunophenotyping. Six patients had systemic disease and three impairment limited to the PNS. In the latter case, progression could be unpredictable and may be diffuse and explosive, sometimes occurring years after a seemingly indolent course. INTERPRETATION: This study provides better knowledge and understanding of neurolymphomatosis when neuropathy is the initial presentation.

Do Magnetic Fields Have a Place in Treating Vascular Complications in Diabetes?

The use of electromagnetic field therapy (EMFT) is a non-invasive, potential alternative or complementary choice in the treatment of wounds, chronic pain, neuropathy, and other medical conditions, including tissue repair and cell proliferation. Static magnetic fields (SMFs) have been reported to increase microcirculatory blood flow by mediating vasodilation via nitric oxide. Studies report that SMF exposure causes homeostatic, normalizing effects on the vascular tone that may have beneficial effects in situations where tissue perfusion is limited, such as may be present in diabetes. Pulsed electromagnetic fields (PEMFs) have also shown promise in treating diabetic wounds by improving wound healing rates and other attributes. Our purpose was to critically review prior applications of EMFT for relevancy and effectiveness in treating diabetic complications. The goal was to provide information to allow for informed decisions on the possible use of these modalities in the treatment of persons with diabetic complications. The focus was on the following major areas: wound healing, neuropathy, blood glucose control, blood flow, inflammation and oxidative stress.

Interleukin-6 Levels in Patients With Diabetic Polyneuropathy.

Introduction Diabetic polyneuropathy (DPN) is a common chronic complication of type 2 diabetes. The pathogenesis of DPN is still debated, but proinflammatory cytokine mediators like interleukin-6 (IL-6) are possibly involved. We conducted this cross-sectional observational study to assess whether IL-6 levels increase in patients with DPN. Materials and methods This study was conducted at the Institute of Post Graduate Medical Education and Research Hospital in Kolkata, India, from 2016 to 2017. The study included 57 patients aged 30 to 60 years diagnosed with type 2 diabetes with neuropathy on clinical examination and nerve conduction study. Patients with neuropathy due to other causes were excluded. The study participants were assigned into one of four groups. Group 1 (n=15) served as healthy control patients, Group 2 (n=12) contained patients with type 2 diabetes without neuropathy, Group 3 (n=20) contained patients with type 2 diabetes with painful neuropathy, and Group 4 (n=10) contained patients with type 2 diabetes with painless neuropathy. We compared IL-6 levels between each group.  Results There was no significant difference in serum IL-6 levels between healthy controls (Group 1) and patients with type 2 diabetes without neuropathy (Group 2). However, we noted a significant increase in serum IL-6 levels among patients with painful DPN (Group 3) compared to control groups. Interestingly, serum IL-6 levels were higher in patients with painful DPN (Group 3) than patients with painless DPN (Group 4). Conclusions IL-6 increases significantly in painful diabetic neuropathy patients compared to patients with diabetes with painless neuropathy and thus may have a role in the pathogenesis of pain in DPN. Serum IL6 level can be a potential noninvasive marker of painful DPN, and it can help distinguish painful DPN from other causes of pain in patients with diabetes.

A Rare Case of Spinal Cord Injury Following Thoracic Radiofrequency Ablation.

Medial branch radiofrequency ablation (RFA) has become a common treatment for facet-related back pain. While this procedure is often performed in the lumbar and cervical spinal segments, it can also be applied to the thoracic spine. Complications of spinal RFA at any level are scarce in the literature and are often mild. The patient is a 37-year-old male with a family history of multiple sclerosis in his siblings who underwent thoracic RFA at the T2-T5 nerve root levels. Within one week of the procedure, the patient experienced paresthesias below the nipple line and progressive lower-extremity weakness. He was also found to exhibit urinary retention on presentation to our facility one month later. MRI showed focal cord short T1 inversion recovery (STIR) signal abnormality at the T3-T4 level, favored to represent myelomalacia. An extensive laboratory and imaging workup was otherwise unrevealing. The patient was treated with neuromodulators and a short course of inpatient rehabilitation. One year later, he used knee-ankle-foot orthoses for ambulating short distances and a manual wheelchair for longer distances, and he no longer required intermittent catheterization for bladder management. This case presents a rare and unusual timeline of symptom evolution, laboratory findings, and imaging results that do not unveil a clear pathophysiological mechanism, which led to the patient's spinal cord injury. The clinical level of injury based on the patient's symptoms and location of myelomalacia on MRI, however, strongly support a causative contribution by the thoracic RFA procedure.

Efficacy and safety of low-dose naltrexone in painful diabetic neuropathy: A randomized, double-blind, active-control, crossover clinical trial.

BACKGROUND: There is a need for newer therapies for chronic painful diabetic neuropathy as the existing drugs have their own limitations. Clinical trials on low-dose naltrexone (1-5 mg/d) showed efficacy and safety in certain chronic painful conditions, but not in painful diabetic neuropathy. Hence the present study was planned. METHODS: Sixty-seven participants with painful diabetic neuropathy were randomized to receive either 2 mg naltrexone or 10 mg amitriptyline daily following a 2-week run-in period. The participants were followed up every 2 weeks for a total of 6 weeks. Up-titration was done (to 4 mg naltrexone or 25/50 mg amitriptyline) if the pain reduction was less than 20% on the visual analog scale (VAS) during the next follow-up visit. Efficacy was assessed using the change in VAS score at the end of 6 weeks from baseline. Safety was evaluated at each follow-up visit. After 2 weeks of washout period, the participants were crossed over to receive the comparator drug for another 6 weeks with similar evaluations. RESULTS: The difference (confidence interval) in the change in VAS score between groups from baseline was 1.64 (-0.92 to 4.20) in per-protocol analysis and 1.5 (-1.11 to 4.13) in intention-to-treat analysis. Eight and fifty-two adverse events were reported in the naltrexone and amitriptyline groups, respectively (P < .001). The most common adverse events were mild diarrhea with naltrexone and somnolence with amitriptyline. CONCLUSIONS: Low-dose naltrexone exhibited similar efficacy and a superior safety profile compared with amitriptyline in painful diabetic neuropathy.

Increased thalamo-cortical functional connectivity in patients with diabetic painful neuropathy: A resting-state functional MRI study.

Functional changes in the brain of patients with painful diabetic neuropathy (PDN) have remained largely elusive. The aim of the present study was to explore changes in thalamo-cortical functional connectivity (FC) of patients with PDN using resting-state functional MRI. A total of 20 patients with type 2 diabetes mellitus (T2DM) with non-painful diabetic neuropathy (Group NDN), 19 patients with T2DM with PDN (Group-PDN) and 13 age-, sex- and education-matched healthy controls were recruited. The differences in thalamo-cortical FC among the three groups were compared. Patients in Group PDN had increased FC in the left thalamus, the right angular gyrus and the occipital gyrus as compared to those in Group NDN. Furthermore, patients in Group PDN had increased FC in the right thalamus and angular gyrus as compared to those in Group NDN. In conclusion, the present results suggested that the thalamo-cortical FC is increased in patients with T2DM and PDN. Furthermore, the increased FC in the thalamic-parietal-occipital connectivity may be a central pathophysiological mechanism for PDN. The study was retrospectively registered at ClinicalTrials.gov on 3 October 2018 (identifier no. NCT03700502).

Death and Rebirth of the Thalidomide Molecule: A Case of Thalidomide-Induced Sensory Neuropathy.

The thalidomide molecule is a remarkable molecule that exists in a racemic mixture of optical isomers. In the 1950s, due to its teratogenicity, the levorotatory isomer led to its dramatic downfall. However, the molecule with its panoramic mechanisms of action and its uncanny ability to intercalate within the geometry of deoxyribonucleic acid (DNA), led to its remarkable renaissance; thalidomide being United States Food and Drug Administration (FDA)-approved for at least 13 different indications ranging from multiple myeloma to leprosy to glioblastoma. Thalidomide-induced polyneuropathy is usually reversible and is the rate-limiting step in its long-term use. The development of a polyneuropathy is invariably associated with a cumulative dose exceeding 20 grams. However, the polyneuropathy is almost always a sensory neuropathy. Asymmetry, bona fide weakness such as difficulty standing on the heels, a poly-ganglioneuropathy pattern with widespread or patchy numbness and sensory ataxia should raise a red flag and an alternative diagnosis should be considered. We present a typical case of a thalidomide-induced sensory neuropathy in order to highlight the resurgence of thalidomide use in clinical practice. We review the literature and outline the molecular biology of the thalidomide molecule.

Pharmacological Modulation of Rate-Dependent Depression of the Spinal H-Reflex Predicts Therapeutic Efficacy against Painful Diabetic Neuropathy.

Impaired rate-dependent depression (RDD) of the spinal H-reflex occurs in diabetic rodents and a sub-set of patients with painful diabetic neuropathy. RDD is unaffected in animal models of painful neuropathy associated with peripheral pain mechanisms and diabetic patients with painless neuropathy, suggesting RDD could serve as a biomarker for individuals in whom spinal disinhibition contributes to painful neuropathy and help identify therapies that target impaired spinal inhibitory function. The spinal pharmacology of RDD was investigated in normal rats and rats after 4 and 8 weeks of streptozotocin-induced diabetes. In normal rats, dependence of RDD on spinal GABAergic inhibitory function encompassed both GABAA and GABAB receptor sub-types. The time-dependent emergence of impaired RDD in diabetic rats was preceded by depletion of potassium-chloride co-transporter 2 (KCC2) protein in the dorsal, but not ventral, spinal cord and by dysfunction of GABAA receptor-mediated inhibition. GABAB receptor-mediated spinal inhibition remained functional and initially compensated for loss of GABAA receptor-mediated inhibition. Administration of the GABAB receptor agonist baclofen restored RDD and alleviated indices of neuropathic pain in diabetic rats, as did spinal delivery of the carbonic anhydrase inhibitor acetazolamide. Pharmacological manipulation of RDD can be used to identify potential therapies that act against neuropathic pain arising from spinal disinhibition.

Relative Efficacy and Safety of Pharmacotherapeutic Interventions for Diabetic Peripheral Neuropathy: A Systematic Review and Bayesian Network Meta-Analysis.

BACKGROUND: Diabetic peripheral neuropathy (DPN) is a most common devitalizing complication of diabetes mellitus, which is primarily characterized by sensory loss, paresthesia, prickling, pain, or allodynia. OBJECTIVES: To evaluate the relative efficacy and safety of the interventions used in the DPN pain management and rank their order. STUDY DESIGN: A systematic review and Bayesian network meta-analysis (NMA). METHODS: Randomized, controlled trials were identified through a comprehensive, systematic literature exploration, primarily utilizing the PubMed, EMBASE, Ovid, and Cochrane Library databases. The efficacy and safety outcomes consist of the proportion of patients reporting either 30% or 50% pain reduction and overall withdrawal or withdrawal due to adverse drug events, respectively. Effect estimates from Bayesian NMA were presented as odds ratio (OR) with 95% credible intervals (CrI). Heterogeneity and convergence were assessed by using I2 and deviation information criteria. The risk of bias was evaluated by using Pedro Scale. RESULTS: A total of 3,246 potentially relevant trials were identified and screened, finally 43 trials consisting of 7,877 randomized patients met the inclusion criteria. Statistically significant treatment difference for 50% pain reduction was reported for duloxetine vs. placebo (OR: 2.50; CrI: 1.62-3.91), mirogabalin vs. placebo (OR: 3.25; CrI: 1.16-9.35), pregabalin vs. placebo (OR: 2.33; CrI: 1.69-3.27), duloxetine vs. carbamazepine (OR: 3.37; CrI: 1.07-10.90), mirogabalin vs. carbamazepine (OR: 4.39; CrI: 1.01-19.63), mirogabalin vs. lamotrigine (OR: 4.05: CrI: 1.07-15.77), pregabalin vs. lamotrigine (OR: 2.90, CrI: 1.19-7.22) and pregabalin vs. nortriptyline (OR: 4.10, CrI: 1.13-5.28). Nortriptyline reported the highest possibility of achieving 30% and 50% pain reduction. Sodium valproate and benztropine reported the highest probability of total withdrawals and withdrawals due to adverse drug events, respectively. LIMITATION: The different follow-up time of the included studies can result in the variation of intended results. CONCLUSION: Nortriptyline reported the advantage relative to other drugs in achieving 30% and 50% pain reduction from the baseline. Gabapentin reported a significance of 50% pain reduction relative to placebo.

Vitamin B12 Supplementation in Diabetic Neuropathy: A 1-Year, Randomized, Double-Blind, Placebo-Controlled Trial.

AIM: To investigate the effect of normalizing vitamin B12 (B12) levels with oral B12 (methylcobalamin) 1000 µg/day for one year in patients with diabetic neuropathy (DN). PATIENTS AND METHODS: In this prospective, double-blind, placebo-controlled trial, 90 patients with type 2 diabetes on metformin for at least four years and both peripheral and autonomic DN were randomized to an active treatment group (n = 44) receiving B12 and a control group (n = 46) receiving a placebo. All patients had B12 levels less than 400 pmol/L. Subjects underwent measurements of sural nerve conduction velocity (SNCV), sural nerve action potential (amplitude) (SNAP), and vibration perception threshold (VPT), and they performed cardiovascular autonomic reflex tests (CARTs: mean circular resultant (MCR), Valsalva test, postural index, and orthostatic hypotension). Sudomotor function was assessed with the SUDOSCAN that measures electrochemical skin conductance in hands and feet (ESCH and ESCF, respectively). We also used the Michigan Neuropathy Screening Instrument Questionnaire and Examination (MNSIQ and MNSIE, respectively) and questionnaires to evaluate quality of life (QoL) and level of pain (pain score). RESULTS: B12 levels increased from 232.0 ± 71.8 at baseline to 776.7 ± 242.3 pmol/L at follow-up, p < 0.0001, in the active group but not in the control group. VPT, MNSIQ, QoL, pain score, SNCV, SNAP, and ESCF significantly improved in the active group (p < 0.001, p = 0.002, p < 0.0001, p < 0.000, p < 0.0001, p < 0.0001, and p = 0.014, respectively), whereas CARTS and MNSIE improved but not significantly. MCR, MNSIQ, SNCV, SNAP, and pain score significantly deteriorated in the control group (p = 0.025, p = 0.017, p = 0.045, p < 0.0001, and p < 0.0001, respectively). CONCLUSIONS: The treatment of patients with DN with 1 mg of oral methylcobalamin for twelve months increased plasma B12 levels and improved all neurophysiological parameters, sudomotor function, pain score, and QoL, but it did not improve CARTS and MNSIE.