Neuropathic Patients Research Articles

Role of Arthrodesis in Adult-acquired Flatfoot Deformity

ABSTRACT Adult-acquired flatfoot deformity (AAFD) is composed of multi-structure problems. Failure of tendons, capsular, and other ligamentous structures lead to significant deformity and disability. Several therapeutic approaches are used to treat this disease. Arthrodesis reconstruction type procedure was raised as a satisfactory operation with high patient satisfaction. Ability to reduce most severe and fix deformities made it a procedure of choice in dealing with advance stage AAFD. Malunion, nonunion, lateral wound breakdown, and adjacent joint osteoarthritis are leading problems associated with this operation. However, there are some situations that patient will be best undergone these operations. Realigned triple arthrodesis along with its modifications are currently wide-accepted treatment for rigid arthritic flatfoot. Severe flexible AAFD and failed flatfoot reconstruction while choosing patients properly are also possible indications to treat with the fusion techniques. Lastly, some specific patient factors (age, morbid obesity, preexisting degenerative joint disease, and neuropathic patients) could be important factors to influence type of operations. How to cite this article: Kirinpanu A. Role of Arthrodesis in Adult-acquired Flatfoot Deformity. J Foot Ankle Surg (Asia Pacific) 2021;8(2):60–65.

The Effect of Pregabalin on Chemokines in Patients with Neuropathic Pain

We attempt to discuss the effect of pregabalin on chemokines and clinical efficacy in neuropathic pain patients. We selected 40 patients with neuropathic pain from December 2018 to December 2020 as research objects and divided them into two groups, one is observation group (20 cases) and the other is control group (20 cases) randomly. Treated observation group with pregabalin and treated control group with gabapentin. Extracted cerebrospinal fluid from the patients and detected its concentration levels of C-X3-C motif chemokine ligand 1, C-X-C motif chemokine ligand 1, C-X-C motif chemokine ligand 8 and C-C motif chemokine ligand 2 of both groups, compared the concentration levels, the adverse drug reactions and clinical effects of both groups. After treatment, the concentration levels of cerebrospinal fluid chemokines C-X3-C motif chemokine ligand 1, C-X-C motif chemokine ligand 1, C-X-C motif chemokine ligand 8 and C-C motif chemokine ligand 2 decreased in both groups. Contrast control groups, observation group decreased more obvious (p<0.05) and observation group had higher clinical remission rate than the other (p<0.05), both of which had statistical significance. For patients with neuropathic pain, pregabalin treatment can reduce the chemokines in cerebrospinal fluid of patients and significantly relieve patient’s pain.

Enhancement of morphine-induced antinociception after electroconvulsive shock in mice.

Electroconvulsive therapy (ECT) has been applied for chronic pain for decades. The amounts of opioids to treat pain are sometimes reduced after a series of ECT. The effect of ECT on morphine-induced analgesia and its mechanism underlying the reduction of morphine requirement has yet to be clarified. Therefore, we administered electroconvulsive shocks (ECS) to mice and investigated the antinociceptive effect of morphine in a hot plate test. We examined the expression level of µ-opioid receptor in the thalami of mice 25 h after administration of ECS compared to the thalami of mice without ECS administration using western blotting. ECS disturbed the development of a decrease in the percentage of maximal possible effect (%MPE), which was observed 24 h after a morphine injection, when ECS was applied 25, 23, 21, and 12 h before the second administration of morphine. We also examined the effect of ECS on the dose-response curve of %MPE to morphine-antinociception. Twenty-five hours after ECS, the dose-response curve was shifted to the left, and the EC50 of morphine given to ECS-pretreated mice decreased by 30.1% compared to the mice that were not pretreated with ECS. We also found that the expression level of µ-opioid receptors was significantly increased after ECS administration. These results confirm previous clinical reports showing that ECT decreased the required dose of opioids in neuropathic pain patients and suggest the hypothesis that this effect of ECT works through the thalamus.

The serotonin receptor 2A (HTR2A) rs6313 variant is associated with higher ongoing pain and signs of central sensitization in neuropathic pain patients.

The serotonin receptor 2A (HTR2A) has been described as an important facilitation mediator of spinal nociceptive processing leading to central sensitization (CS) in animal models of chronic pain. However, whether HTR2A single nucleotide variants (SNVs) modulate neuropathic pain states in patients has not been investigated so far. The aim of this study was to elucidate the potential association of HTR2A variants with sensory abnormalities or ongoing pain in neuropathic pain patients. At total of 240 neuropathic pain patients and 253 healthy volunteers were included. Patients were phenotypically characterized using standardized quantitative sensory testing (QST). Patients and controls were genotyped for HTR2A g.-1438G>A (rs6311) and c.102C>T (rs6313). Genotype-related differences in QST parameters were assessed considering QST profile clusters, principal somatosensory components and sex. There was an equal distribution of rs6313 and linked rs6311 between patients and controls. However, the rs6313 variant was significantly associated with a principal component of pinprick hyperalgesia and dynamic mechanical allodynia, indicating enhanced CS in patients with sensory loss (-0.34±0.15 vs. +0.31±0.11 vs., p<.001). In this cluster, the variant allele was also associated with single QST parameters of pinprick hyperalgesia (MPT, +0.64±0.18 vs. -0.34±0.23 p=.002; MPS, +0.66±0.17 vs. -0.09±0.23, p=.009) and ongoing pain was increased by 30%. The specific association of the rs6313 variant with pinprick hyperalgesia and increased levels of ongoing pain suggests that the HTR2A receptor might be an important modulator in the development of CS in neuropathic pain. This article presents new insights into serotonin receptor 2A-mediating mechanisms of central sensitization in neuropathic pain patients. The rs6313 variant allele was associated with increased mechanical pinprick sensitivity and increased levels of ongoing pain supporting a contribution of central sensitization in the genesis of ongoing pain providing a possible route for mechanism-based therapies.

An Investigation into Proteomic Constituents of Cerebrospinal Fluid in Patients with Chronic Peripheral Neuropathic Pain Medicated with Opioids- a Pilot Study.

The pharmacodynamics of opioids for chronic peripheral neuropathic pain are complex and likely extend beyond classical opioid receptor theory. Preclinical evidence of opioid modulation of central immune signalling has not been identified in vivo in humans. Examining the cerebrospinal fluid (CSF) of patients medicated with opioids is required to identify potential pharmacodynamic mechanisms. We compared CSF samples of chronic peripheral neuropathic pain patients receiving opioids (n = 7) versus chronic peripheral neuropathic pain patients not taking opioids (control group, n = 13). Baseline pain scores with demographics were recorded. Proteome analysis was performed using mass spectrometry and secreted neuropeptides were measured by enzyme-linked immunosorbent assay. Based on Gene Ontology analysis, proteins involved in the positive regulation of nervous system development and myeloid leukocyte activation were increased in patients taking opioids versus the control group. The largest decrease in protein expression in patients taking opioids were related to neutrophil mediated immunity. In addition, notably higher expression levels of neural proteins (85%) and receptors (80%) were detected in the opioid group compared to the control group. This study suggests modulation of CNS homeostasis, possibly attributable to opioids, thus highlighting potential mechanisms for the pharmacodynamics of opioids. We also provide new insights into the immunomodulatory functions of opioids in vivo.

Videocapillaroscopy of the Oral Mucosa in Patients with Diabetic Foot: Possible Diagnostic Role of Microangiopathic Damage?

Introduction: Diabetic foot represents one of the most serious and expensive complications of diabetes and is subject to a high percentage of amputations that are almost always preceded by ulcers ascribable to neuropathy and/or vasculopathy. Videocapillaroscopy (VCS) can be a valuable aid in order to uncover morpho-structural anomalies in the vascular bed, both at the level of the oral mucosa and at the level of the terminal vessels of the lower limb. Materials and methods: Sixty subjects divided into 4 groups were enrolled: 15 healthy subjects; 15 patients with diabetes for more than 10 years without ulcerative foot lesions; 15 patients with neuropathic diabetic foot (clinical diagnosis, MDNS); 15 patients with ischemic diabetic foot (clinical diagnosis, ABI, lower limb doppler). A complete videocapillaroscopic mapping of the oral mucosa was carried out on each patient. The areas investigated were: labial mucosa, the retro-commissural region of the buccal mucosa, and the vestibular masticatory mucosa (II and V sextant). Results: The analysis of the morphological and densitometric characteristics of the capillaries revealed the following: a significant reduction in capillary density in neuropathic (mean ± SD 7.32 ± 2.1) and ischemic patients (mean ± SD 4.32 ± 3.2) compared to the control group of patients (both diabetic mean ± SD 12.98 ± 3.1 and healthy mean ± SD 19.04 ± 3.16) (ANOVA test and Bonferroni t test p < 0.05); a reduction in the average length of the capillaries and a significant increase in tortuosity (ANOVA test and Bonferroni t test p < 0.05). In the neuropathic patients, a recurrent capillaroscopic pattern that we defined as “sun” was found, with capillaries arranged radially around an avascular area. Conclusions: The data obtained from this preliminary study suggest a potential diagnostic role of oral capillaroscopy in the early and subclinical identification of microangiopathic damage in patients with diabetic foot.

Altered Interoceptive Perception and the Effects of Interoceptive Analgesia in Musculoskeletal, Primary, and Neuropathic Chronic Pain Conditions.

Chronic pain (CP) severely disrupts the daily life of millions. Interoception (i.e., sensing the physiological condition of the body) plays a pivotal role in the aetiology and maintenance of CP. As pain is inherently an interoceptive signal, interoceptive frameworks provide important, but underutilized, approaches to this condition. Here we first investigated three facets of interoceptive perception in CP, compared with pain-free controls. We then introduce a novel interoceptive treatment and demonstrate its capacity to reduce pain severity in CP, potentially providing complementary analgesic treatments. Study 1 measured interoceptive accuracy, confidence and sensibility in patients (N = 60) with primary, secondary musculoskeletal, and neuropathic CP. Compared with matched controls, CP participants exhibited significantly lower interoceptive accuracy and interoceptive confidence. Pain severity was predicted positively by interoceptive accuracy, anxiety and depression, and negatively by interoceptive confidence. Study 2 tested a promising new interoceptive treatment for CP, in a single-blind between-subjects design (N = 51) with primary, secondary musculoskeletal, and neuropathic CP patients. The treatment specifically activates the C-Tactile system, by means of controlled stimulation of interoceptive unmyelinated afferents, at 3 cm/s with a force of 2.5 mN. This treatment led to significant pain reduction (mean 23%) in the CP treatment group after only 11 min, while CP controls who received comparable but non-interoceptive stimulation reported no change in pain intensity. These studies highlight the importance of interoceptive approaches to CP and demonstrate the potential of this novel method of C-Tactile stimulation to provide complementary analgesic treatments.

Abnormal Intrinsic Brain Activity and Neuroimaging-Based fMRI Classification in Patients With Herpes Zoster and Postherpetic Neuralgia.

Objective: Neuroimaging studies on neuropathic pain have discovered abnormalities in brain structure and function. However, the brain pattern changes from herpes zoster (HZ) to postherpetic neuralgia (PHN) remain unclear. The present study aimed to compare the brain activity between HZ and PHN patients and explore the potential neural mechanisms underlying cognitive impairment in neuropathic pain patients.Methods: Resting-state functional magnetic resonance imaging (MRI) was carried out among 28 right-handed HZ patients, 24 right-handed PHN patients, and 20 healthy controls (HC), using a 3T MRI system. The amplitude of low-frequency fluctuation (ALFF) was analyzed to detect the brain activity of the patients. Correlations between ALFF and clinical pain scales were assessed in two groups of patients. Differences in brain activity between groups were examined and used in a support vector machine (SVM) algorithm for the subjects' classification.Results: Spontaneous brain activity was reduced in both patient groups. Compared with HC, patients from both groups had decreased ALFF in the precuneus, posterior cingulate cortex, and middle temporal gyrus. Meanwhile, the neural activities of angular gyrus and middle frontal gyrus were lowered in HZ and PHN patients, respectively. Reduced ALFF in these regions was associated with clinical pain scales in PHN patients only. Using SVM algorithm, the decreased brain activity in these regions allowed for the classification of neuropathic pain patients (HZ and PHN) and HC. Moreover, HZ and PHN patients are also roughly classified by the same model.Conclusion: Our study indicated that mean ALFF values in these pain-related regions can be used as a functional MRI-based biomarker for the classification of subjects with different pain conditions. Altered brain activity might contribute to PHN-induced pain.

A step closer in the management of uncontrolled neuropathic pain: gabapentin-nortriptyline combination

&lt;p class="abstract"&gt;Neuropathic pain is extremely distressing as it significantly hampers the performance of daily activities and impedes overall quality of life. A large number of illnesses are linked with neuropathic pain like radiculopathy, sciatica, diabetes, herpes infection, spinal injury, stroke, etc. Treating neuropathic pain is challenging as response to the treatment is at times uncertain and associated with undesirable side effects. Uncontrolled neuropathic pain is observed in large group of patients receiving current treatment regimen. Almost half of the neuropathic pain patients need more than two drugs for pain relief. Various clinical trials have demonstrated better efficacy of combination therapy in reducing pain than monotherapy. Utilizing drug combination with different mechanism of action or acting on two different sites has demonstrated superior analgesic effect in painful neuropathic condition. The first tier agents recommended by various guidelines are calcium channel alpha-2-delta ligands and tricyclic antidepressants that act on different pain pathways. A clinical trial has shown enhanced pain relief with no increase in side effects with the administration of gabapentin and nortriptyline combination in patients suffering from neuropathic pain. Moreover, symptoms associated with neuropathic pain like sleep disturbances, altered mood, decreased walking ability, depression and quality of life were also significantly improved. Hence, combination therapy of gabapentin and nortriptyline offers a pivotal modality in the management of uncontrolled neuropathic pain.&lt;/p&gt;

Quantitative sensory phenotyping in chronic neuropathic pain patients treated with unilateral L4-dorsal root ganglion stimulation

BackgroundIn a previous study, we reported that selective dorsal root ganglion stimulation (DRGSTIM) at DRG level L4 promoted a favorable outcome for complex regional pain syndrome (CRPS) patients along with DRGSTIM-related changes of inflammatory biomarkers in blood and saliva. The impact on somatosensation is largely unknown. Herein, we assessed the quantitative sensory profile to quantify L4-DRGSTIM effects in CRPS patients.MethodsTwelve refractory CRPS patients (4 female; 8 male; mean age 69 ± 9 years) received standardized quantitative sensory testing (QST) protocol at baseline and after 3 months of unilateral L4-DRGSTIM assessing nociceptive and non-nociceptive thermal and mechanical sensitivity of the knee affected by CRPS and the contralateral non-painful knee area.ResultsAt baseline, CRPS subjects showed significantly increased thresholds for warmth, tactile and vibration detection (WDT, MDT and VDT) and exaggerated pain summation (WUR). After 3 months of unilateral L4-DRGSTIM all pain parameters exhibited trends towards normalization of sensitivity accumulating to a significant overall normalization for pain sensitivity (effect size: 0.91, p < 0.01), while with the one exception of WDT all non-nociceptive QST parameters remained unchanged. Overall change of non-nociceptive detection was negligible (effect size: 0.25, p > 0.40). Notably, reduction of pain summation (WUR) correlated significantly with pain reduction after 3 months of L4-DRGSTIM.ConclusionsSelective L4-DRGSTIM lowered ongoing pain in CRPS patients and evoked significant normalization in the pain domain of the somatosensory profile. Thermoreception and mechanoreception remained unchanged. However, larger randomized, sham-controlled trials are highly warranted to shed more light on effects and mechanisms of dorsal root ganglion stimulation on quantitative sensory characteristics.The study protocol was registered at the 15.11.2016 on German Register for Clinical Trials (DRKS ID 00011267).https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00011267

Plantar Foot Ulcer Recurrence in Neuropathic Patients Undergoing Percutaneous Tendo-Achilles Lengthening

Equinus contracture carries 3- and 4-fold associations with diabetes and plantar foot ulceration, respectively. Percutaneous tendo-Achilles lengthening is a useful method to alleviate peak plantar pressure resulting from equinus. We aimed to evaluate the effectiveness of percutaneous tendo-Achilles lengthening and estimate the relative longevity of the approach in reducing ulcer recurrence. The medical records of patients with equinus contracture who underwent percutaneous tendo-Achilles lengthening from 2010 to 2017 were reviewed. Included patients presented with plantar ulcers and a gastroc-soleus equinus of any angle <10° of ankle dorsiflexion with the affected knee extended and flexed. Patients who received concomitant tendon lengthening procedures (including anterior tibial tendon or flexor digitorum longus) were excluded. Outcome measures included time to wound healing, time to ulcer recurrence, and development of transfer lesion. Ninety-one patients underwent percutaneous tendo-Achilles lengthening with subsequent pedal ulceration without concomitant procedures. A total of 69 (75.8%) patients had a plantar forefoot ulcer, 7 (7.7%) had midfoot ulcers, 5 (5.5%) had hindfoot ulcers, and 3 (3.3%) had ulcers in multiple locations. Seven patients received prophylactic tendo-Achilles lengthening. At a mean follow-up of 31.6 months (±26), 66 (78.6%) wounds healed at a median 12.9 weeks. A total of 29 patients (43.9%) experienced ulcer recurrence at a mean of 12 months. Twelve patients (13%) experienced a transfer lesion at a mean of 16.6 months. Tendo-Achilles lengthening can be an effective adjunctive approach to achieve wound healing and reduce long-term ulcer recurrence in patients with equinus contracture and neuropathic plantar foot ulcers. A relengthening procedure may be needed within approximately 12 months from index surgery.

Balneotherapy decreases mechanical hyperalgesia by reversing BDNF and NOS2 immunocontent in spinal cord of mice with neuropathic pain

In the last decades, balneotherapy or thermalism has been used for health promotion and in the treatment of inflammatory and chronic processes. We found that balneotherapy reduced mechanical hyperalgesia, as well the increase of BDNF and NOS2 levels in the spinal cord, while increased BDNF and NOS1 in the paw. The data presented herein demonstrated for the first time in a murine model of neuropathic pain, the analgesic effect of balneotherapy with the water from the natural springs of Santo Amaro da Imperatriz-Brazil. Nevertheless, future clinical trials should be conducted to test the effectiveness of balneotherapy in neuropathic pain patients.

Sciatic Nerve Ligation Downregulates Mitochondrial Clusterin in the Rat Prefrontal Cortex

The concentration of the multifunctional protein clusterin is reduced in the plasma of subjects with degenerative scoliosis (DS) and carpal tunnel syndrome (CTS) but elevated in the cerebrospinal fluid of neuropathic pain patients successfully treated with spinal cord stimulation. The present work tries to increase the knowledge of pain-associated changes of plasma and brain clusterin by using an animal model of neuropathy. We studied the effects of sciatic nerve ligation on mechanical allodynia (von Frey test), anxiety (elevated plus maze test), plasma clusterin (enzyme-linked immunosorbent assay) and clusterin expression in the nucleus accumbens (NAC) and prefrontal cortex (PFC) of adult male Wistar rats (western blot). The possible modulatory role of high fat (HF) dieting was also studied, bearing in mind that obesity has been also reported to influence nociception, clusterin levels and prefrontal cortex activation. Animals with nerve ligation showed mechanical allodynia, anxiety and a marked downregulation of clusterin in the mitochondrial fraction of the prefrontal cortex. Animals fed on HF also exhibited a slight increase of the sensitivity to mechanical stimuli and anxiety; however, the diet did not potentiate the effects of nerve ligation. The results did not confirm a parallelism between neuropathy, obesity and alterations of plasma levels of clusterin, but strongly suggest that the protein could be involved in the functional reorganization of the prefrontal cortex which has been recently reported in chronic pain conditions.

Factors associated with sclerostin levels – A calcification inhibitor – In individuals with type 2 diabetes mellitus; Is autonomic neuropathy the missing link?

BackgroundSclerostin inhibits bone formation and its expression is upregulated in the vasculature during the arterial calcification process as a counterregulatory mechanism preventing further calcification. Lower extremity arterial calcification (LEAC) is common in neuropathic patients with type 2 diabetes (T2DM). Herein, we investigated for associations between plasma sclerostin levels and diabetic neuropathy as well as LEAC in subjects with T2DM. MethodsA total of 74 individuals with and 76 without T2DMwere recruited. Plasma sclerostin levels were measured by ELISA. Diagnosis of cardiac autonomic neuropathy (CAN) was based on the battery of the four autonomic tests, while of somatosensory peripheral neuropathy (DPN) on neuropathy symptom score and neuropathy disability score. LEAC was assessed with conventional ankle and foot x-rays. ResultsPlasma sclerostin levels were higher in participants with LEAC vs. those without LEAC in both diabetes and non-diabetes cohorts (p = 0.035 and p = 0.003, respectively). In the diabetes cohort, patients with CAN, but not with DPN, had higher sclerostin levels when compared with those without CAN (p < 0.001). Multivariate analysis in the diabetes cohort demonstrated that sclerostin levels were associated positively with CAN and LEAC, while in the non-diabetes cohort there was a trend for a positive association with male gender and presence of LEAC. ConclusionPlasma sclerostin levels are increased in individuals with LEAC irrespectively of diabetes status. In addition, plasma sclerostin concentrations are associated independently with LEAC and CAN in people with T2DM.

Antiallodynic Effect of Piperine in Neuropathic Rats

Neuropathic pain is a disabling syndrome difficult to manage. Currently, pharmacological treatment of neuropathic patients provides an unsatisfactory relief of pain. Recent reports suggested that piperine has anti-inflammatory and antinociceptive effects. Therefore, the aim of this study was to investigate the antiallodynic effect of piperine, as well as the possible antinociceptive mechanism involved in its antiallodynic effect. Piper nigrum L., Piperaceae, was used to extract the piperine. Spinal nerve ligation L5/L6 model was used to induce allodynia in rats. Intraperitoneal administration of increasing doses of piperine (3.1–100 mg/kg) reduced allodynia in rats. The administration of capsazepine (selective TRPV1 antagonist, 5 and 30 μg/i.t.) and bicuculline (GABAA antagonist, 3 and 30 μg/i.t.), but not SKF-96365 (TRPC antagonist, 3 and 30 μg/i.t.), prevented the piperine-induced (56 mg/kg, i.p.) antiallodynic effect in a dose-dependent manner. HC-030031 (selective TRPA1 antagonist, 3 and 30 μg/i.t.) avoided only partially piperine-induced (56 mg/kg, i.p.) antiallodynic effect. Data suggest that piperine induces antiallodynic effect in neuropathic rats, and its antiallodynic effect involves the activation of TRPV1 and GABAA receptors. Piperine could be useful to treat neuropathic pain in human beings.

Benzodiazepine Use Is Associated With Poorer Spinal Cord Stimulation Outcome in 373 Neuropathic Pain Patients

The aim of the study is to investigate whether benzodiazepine use differs between patients with favorable and unfavorable spinal cord stimulation (SCS) treatment outcome. We hypothesize that the patients with unfavorable SCS outcome would exhibit a higher level of benzodiazepine use. Using a case-control study setting, we examined benzodiazepine use in SCS patients and in matched population controls as a potential risk factor poor SCS outcome. A total of 373 consecutive SCS patients treated in Kuopio University Hospital between 1997 and 2014 and their 1117 matched population controls were followed until patient death or the end of March 2016. Benzodiazepines were used during the 24-month period before or after SCS implantation by 42.3% of the SCS patients who had the device explanted, 39.5% who had an unsuccessful trial stimulation, 28.0% who still had the device at the end of the follow-up period, and 8.0% of the controls. Diazepam use before SCS increased the odds for explanting of SCS by 2.4-fold (95% Cl: 1.0-5.4). Starting clonazepam use after SCS was associated with a 5.2-fold (95% CI: 1.5-18.9) increase in the odds of unsuccessful trial stimulation. The benzodiazepine use in patients with poor SCS outcome illustrates the role of anxiety in SCS outcomes and the need for multidisciplinary treatment of pain.

Prevalence, Clinical Aspects and Outcomes in a Large Cohort of Persons with Diabetic Foot Disease: Comparison between Neuropathic and Ischemic Ulcers.

This study aims to evaluate clinical and ulcer characteristics as well the outcomes of patients with diabetic foot ulcers (DFUs). The study group was composed of DFUs patients managed by a limb salvage protocol according to guidance. Clinical and ulcers findings were described, and 1-year outcomes defined as limb salvage, healing, healing time, major amputation and death were compared between neuropathic and ischemic DFUs. One thousand, one hundred and ninety-eight subjects were included; 386 (32.2%) neuropathic and 812 (67.8%) ischemic DFUs. Neuropathic patients were younger (69.5 ± 11.5 vs. 74.5 ± 11.5, p < 0.0001) and reported less cases of nephropathy (22.8 vs. 39.6%, p < 0.0001), ischemic heart disease (22.8 vs. 36.9, p = 0.0004), cerebrovascular disease (8.3 vs. 17.2%, p = 0.002), heart failure (10.1 vs. 24.7%, p = 0.0002) and end-stage-renal-disease (ESRD) (5.4 vs. 27%, p = 0.0001) than ischemic patients; they also showed less cases of large (>5 cm2) (10.3 vs. 22.9%, p = 0.0007), infected (40.4 vs. 55.7%, p = 0.0005) and deep to the bone (22.3 vs. 39.2, p = 0.0002) ulcers, as well less multiple ulcerations (21.8 vs. 32.8%, p = 0.006) than patients with ischemic DFUs. The outcomes for neuropathic and ischemic DFUs were limb salvage (98.4 vs. 82.3%, p < 0.0001), healing (97.3 vs. 79.6%, p < 0.0001), healing time (34.9 vs. 35.6 weeks, p = 0.8), major amputation (0.5 vs. 6.6%, p = 0.0001), death (1.1 vs. 11%, p < 0.0001) respectively. Revascularization failure and ESRD were independent predictors of major amputation, while heart failure and number of co-morbidities (≥5) were independent predictors of death. Ischemic DFUs patients showed more severe clinical and ulcers features as well worse outcomes than neuropathic DFUs patients.

Electroencephalography During Nociceptive Stimulation in Chronic Pain Patients: A Systematic Review.

With its high temporal resolution, electroencephalography (EEG), a technique that records electrical activity of cortical neuronal cells, is a potentially suitable technique to investigate human somatosensory processing. By using EEG, the processing of (nociceptive) stimuli can be investigated, along with the functionality of the nociceptive pathway. Therefore, it can be applied in chronic pain patients to objectify whether changes have occurred in nociceptive processing. Typically, so-called event-related potential (ERP) recordings are used, where EEG signals are recorded in response to specific stimuli and characterized by latency and amplitude. To summarize whether differences in somatosensory processing occur between chronic pain patients and healthy controls, measured with ERPs, and determine whether this response is related to the subjective pain intensity. Systematic review. PubMed, Web of Science, and Embase were consulted, and 18 case-control studies were finally included. The chronic pain patients suffered from tension-type headache, back pain, migraine, fibromyalgia, carpal tunnel syndrome, prostatitis, or complex regional pain syndrome. Chronic neuropathic pain patients showed increased latencies of the N2 and P2 components, along with a decreased amplitude of the N2-P2 complex, which was also obtained in FM patients with small fiber dysfunction. The latter also showed a decreased amplitude of the N2-P3 and N1-P1 complex. For the other chronic pain patients, the latencies and the amplitudes of the ERP components did not seem to differ from healthy controls. One paper indicated that the N2-P3 peak-to-peak amplitude correlates with the subjective experience of the stimulus. Differences in ERPs with healthy controls can mostly be found in chronic pain populations that suffer from neuropathic pain or where fiber dysfunction is present. In chronic pain populations with other etiological mechanisms, limited differences were found or agreed upon across studies.

Optimizing footwear for the diabetic foot: Data-driven custom-made footwear concepts and their effect on pressure relief to prevent diabetic foot ulceration.

AimsTo assess the effect of data-driven custom-made footwear concepts on plantar pressure relief to prevent diabetic foot ulceration.MethodsTwenty-four neuropathic diabetic patients at high risk of foot ulceration were measured for in-shoe plantar pressures during walking in four data-driven custom-made footwear conditions, an athletic shoe and an off-the-shelf non-therapeutic shoe. Two evidence-based footwear conditions (Shoe-A; Insole-A) follow a scientific-based design protocol, are handmade, and use in-shoe plantar pressure guided optimization. One evidence-based insole condition (Insole-B) uses a barefoot plantar pressure and 3D foot shape-based computer-assisted design and manufacturing (CADCAM) routine. And one insole condition (Insole-C) uses a barefoot and in-shoe plantar pressure and 3D foot shape-based CADCAM design and optimization routine. Patient satisfaction was scored on walking comfort, shoe fit, weight and appearance.ResultsAll data-driven footwear conditions significantly reduced metatarsal head peak pressure compared with the non-therapeutic shoe (17–53% relief). Shoe-A and Insole-A showed the lowest metatarsal head peak pressures (mean 112–155 kPa, 90–98% of cases <200 kPa), significantly lower than for Insole-B and Insole-C (mean 119–199 kPa, 52–100% <200 kPa). Patient satisfaction was not significantly different between footwear concepts.ConclusionsThis study proves the offloading efficacy of a scientific-based, handmade, and in-shoe plantar pressure data-driven approach to custom-made footwear design, and advocates its implementation to optimize diabetic footwear for plantar foot ulcer prevention.

GABAergic modulation of secondary hyperalgesia: A randomized controlled 4-way crossover trial with the α2-subunit preferring GABA positive allosteric modulator, N-desmethyl-clobazam in healthy volunteers.

The antihyperalgesic and sedative effects of the α2-subunit preferring GABAA positive allosteric modulator (GAM), N-desmethyl-clobazam (NDMC), 20 and 60mg, were assessed in a randomized, placebo and active-controlled (clonazepam 1,5mg), 4-way crossover study, in healthy volunteers, using the ultraviolet B-induced experimental pain model. Single (20, 40, 60mg) and repeated doses (20mg over 15days) of NDMC pharmacokinetics were evaluated. Thirty-two subjects participated in the study. Primary outcome parameter was maximal change in the area of cutaneous UVB irradiation-induced secondary hyperalgesia (ASH). ASH decreased under all treatments. Mean (SD) relative change was 79 (22)%, 83 (24)%, 77 (30)% and 92 (16)% for placebo, NDMC20, NDMC60 and clonazepam, respectively. Neither absolute change nor relative change in ASH was significantly different between NDMC60 and placebo (mean difference=2.3cm2 [95% CI 4.0-8.5], p=.462 and 0.4% [-11.9 to 12.6], p=.952, respectively). An overall treatment effect was found on level of sedation. Compared to placebo, sedation was higher under clonazepam (mean difference=39mm [30-49] on a visual analogue scale, p<.001) while NDMC was free of sedative effect. NDMC pharmacokinetics after single doses showed poor absorption, but was linear. Steady-state plasma concentrations of NDMC20 were attained within 14days, with low between-subjects variability. Mean steady-state concentration (CS-S , SD) reached 209 (22) ng/ml. NDMC absence of sedative effect and its overall well-characterized safety coming from years of utilization as a metabolite from clobazam, raise the prospect of dose escalating trials in patients to quantify its clinical utility. SIGNIFICANCE: This article, presenting the Phase I data of the new antihyperalgesic compound, α2-subunit GABAA positive allosteric modulator, N-desmethyl-clobazam (NDMC) is exploring the modulation of a new target in the treatment of neuropathic pain. Based on these results and on its preclinical properties NDMC would qualify as a good tool compound to seek confirmation of the clinical utility of selective GABA allosteric modulators in neuropathic pain patients.