Chronic Neuropathic Pain Research Articles

Expert Perspectives on Prescription Practices and Management Strategies for Neuropathy and Vitamin B12 Deficiency in Indian Settings

Objective: To gather expert opinion regarding prescription practices and management strategies for neuropathy and vitamin B12 deficiency with a special focus on methylcobalamin among clinicians in Indian settings. Methodology: This cross-sectional study utilized a 24-item, multiple-response questionnaire to gather expert opinion from specialists in managing neuropathy and vitamin B12 deficiency. The survey encompassed questions about current prescription practices, clinical observations, preferences, and experiences related to managing neuropathy and vitamin B12 deficiency in patients in routine settings. Results: The survey included 81 experts, with more than half (62.96%) of clinicians identifying diabetes as a significant confounding factor for neuropathy in patients. As indicated by 46% and 44% of the clinicians, an appropriate diet for nutrition and maintaining glycemic levels helps to overcome the progression of neuropathy. A significant proportion of experts (60.49%) reported that 26% to 50% of patients with neuropathy have vitamin B12 deficiency. Additionally, 73% of clinicians noted that diabetes mellitus is a common co-morbid condition with vitamin B12 deficiency. In patients with neuropathy complications, 74% of clinicians preferred benfotiamine alongside vitamin B12. As stated by 44% of clinicians, besides those patients with neuropathy, elderly patients are also recommended with methylcobalamin 1500 mcg. About 43% of clinicians suggested a 12-week duration for prescribing a combination of benfotiamine and methylcobalamin for patients with neuropathy. Additionally, more than half (54.32%) of clinicians favored prescribing a combination of methylcobalamin 1500 mcg, pregabalin 75 mg, and nortriptyline 10 mg tablets to patients with chronic neuropathic pain. Conclusion: The survey highlights diabetes as a significant factor in neuropathy management, emphasizing the importance of nutrition and glycemic control. A high prevalence of vitamin B12 deficiency is noted among diabetic patients with neuropathy, leading to recommendations for benfotiamine and methylcobalamin supplementation. Additionally, the use of combination therapy for chronic neuropathic pain demonstrates a comprehensive approach to improving patient outcomes.

Examination of the antiallodynic effect of rosmarinic acid in neuropathic pain and possible mechanisms of action

This study aimed to explore the potential antiallodynic effects of rosmarinic acid, a natural antioxidant with a demonstrated safety profile across a broad dose range. Using a chronic constriction injury-induced neuropathic pain model, the impact of rosmarinic acid on allodynia was investigated. Furthermore, the involvement of adrenergic and opioidergic mechanisms in its activity was assessed. To evaluate rosmarinic acid’s efficacy, doses of 10, 20, and 40 mg/kg were administered and the electronic von Frey test was utilized along with an activity cage apparatus. % MPE values were calculated to gauge the extent of pain relief. Mechanistic insights were obtained by pretreating animals with the β-adrenergic receptor antagonist propranolol, the α1-adrenergic receptor antagonist prazosin, α2-adrenergic receptor antagonist yohimbine, and the opioid receptor antagonist naloxone. Rosmarinic acid demonstrated a statistically significant antiallodynic effect that was independent of locomotor activity. This effect was noteworthy as it resembled both the level and duration of relief provided by pregabalin. Additionally, the %MPE value of the group treated with 40 mg/kg rosmarinic acid showed a significant difference compared to the value of the pregabalin-treated group (P<0.001). Pre-administration of the antagonists revealed that the antiallodynic activity was shown to be mediated by the stimulation of opioid and adrenergic receptors, with a primary contribution from α2-adrenergic receptor stimulation. Our findings suggest that rosmarinic acid may hold promise as a potential therapeutic agent for neuropathic pain. By elucidating the involvement of adrenergic and opioidergic mechanisms, we have provided valuable preclinical data that could inform novel treatment approaches.

Determining the frequency of occurrence of the neuropathic component of chronic cancer pain

The original study was conducted to study the prevalence and incidence of the neuropathic component of chronic pain in patients with malignant neoplasms. The cohort study sample was formed in the Regional Oncology Dispensary of Karaganda. The study included 374 cancer patients. Neuropathic chronic pain of varying intensity and localization was diagnosed in 106 patients. The sample patients were divided into the main and control groups using the envelope method. Each group was analyzed in detail, the main clinical characteristics of each patient were described. Gender, age, localization and prevalence of the primary focus of malignant neoplasm, and the type of antitumor treatment were analyzed.The original study found that the neuropathic component of chronic pain is more common in women over 50 years of age. In the vast majority of cases, such patients are diagnosed with stage III breast cancer who have undergone complex or combined treatment. Given the identified cohort of patients who develop chronic neuropathic pain, it is possible to begin preventive measures earlier. These measures will reduce the burden of developing a difficult-to-treat type of chronic pain among cancer patients.

Upregulation of Phosphodiesterase 7A Contributes to Concurrent Pain and Depression via Inhibition of cAMP-PKA-CREB-BDNF Signaling and Neuroinflammation in the Hippocampus of Mice.

Phosphodiesterases (PDEs) are enzymes that catalyze the hydrolysis of cyclic adenosine monophosphate AMP (cAMP) and/or cyclic guanosine monophosphate (cGMP). PDE inhibitors can mitigate chronic pain and depression when these disorders occur individually; however, there is limited understanding of their role in concurrent chronic pain and depression. We aimed to evaluate the mechanisms of action of PDE using 2 mouse models of concurrent chronic pain and depression. C57BL/6J mice were subjected to partial sciatic nerve ligation (PSNL) to induce chronic neuropathic pain or injected with complete Freund's adjuvant (CFA) to induce inflammatory pain, and both animals showed depression-like behavior. First, we determined the change in PDE expression in both animal models. Next, we determined the effect of PDE7 inhibitor BRL50481 or hippocampal PDE7A knockdown on PSNL- or CFA-induced chronic pain and depression-like behavior. We also investigated the role of cAMP-protein kinase A (PKA)-cAMP response element binding protein (CREB)-brain-derived neurotrophic factor (BDNF) signaling and neuroinflammation in the effect of PDE7A inhibition on PSNL- or CFA-induced chronic pain and depression-like behavior. This induction of chronic pain and depression in the 2 animal models upregulated hippocampal PDE7A. Oral administration of PDE7 inhibitor, BRL50481, or hippocampal PDE7A knockdown significantly reduced mechanical hypersensitivity and depression-like behavior. Hippocampal PDE7 inhibition reversed PSNL- or CFA-induced downregulation of cAMP and BDNF and the phosphorylation of PKA, CREB, and p65. cAMP agonist forskolin reversed these changes and caused milder behavioral symptoms of pain and depression. BRL50481 reversed neuroinflammation in the hippocampus in PSNL mice. Hippocampal PDE7A mediated concurrent chronic pain and depression in both mouse models by inhibiting cAMP-PKA-CREB-BDNF signaling. Inhibiting PDE7A or activating cAMP-PKA-CREB-BDNF signaling are potential strategies to treat concurrent chronic pain and depression.

Classical, spaced, or accelerated transcranial magnetic stimulation of motor cortex for treating neuropathic pain: A 3-arm parallel non-inferiority study

BackgroundRepetitive transcranial magnetic stimulation (rTMS) of the primary motor cortex (M1) at high frequency (HF) is an effective treatment of neuropathic pain. The classical HF-rTMS protocol (CHF-rTMS) includes a daily session for one week as an induction phase of treatment followed by more spaced sessions. Another type of protocol without an induction phase and based solely on spaced sessions of HF-rTMS (SHF-rTMS) has also been shown to produce neuropathic pain relief. However, CHF-rTMS and SHF-rTMS of M1 have never been compared regarding their analgesic potential. Another type of rTMS paradigm, called accelerated intermittent theta burst stimulation (ACC-iTBS), has recently been proposed for the treatment of depression, the other clinical condition for which HF-rTMS is proposed as an effective therapeutic strategy. ACC-iTBS combines a high number of pulses delivered in short sessions grouped into a few days of stimulation. This type of protocol has never been applied to M1 for the treatment of pain. Methods/DesignThe objective of this single-centre randomized study is to compare the efficacy of three different rTMS protocols for the treatment of chronic neuropathic pain: CHF-rTMS, SHF-rTMS, and ACC-iTBS. The CHF-rTMS will consists of 10 stimulation sessions, including 5 daily sessions of 10Hz-rTMS (3,000 pulses per session) over one week, then one session per week for 5 weeks, for a total of 30,000 pulses delivered in 10 stimulation days. The SHF-rTMS protocol will only include 4 sessions of 20Hz-rTMS (1,600 pulses per session), one every 15 days, for a total of 6,400 pulses delivered in 4 stimulation days. The ACC-iTBS protocol will comprise 5 sessions of iTBS (600 pulses per session) completed in half a day for 2 consecutive days, repeated 5 weeks later, for a total of 30,000 pulses delivered in 4 stimulation days. Thus, CHF-rTMS and ACC-iTBS protocols will share a higher total number of TMS pulses (30,000 pulses) compared to SHF-rTMS protocol (6,400 pulses), while CHF-rTMS protocol will include a higher number of stimulation days (10 days) compared to ACC-iTBS and SHF-rTMS protocols (4 days). In all protocols, the M1 target will be defined in the same way and stimulated at the same intensity using a navigated rTMS (nTMS) procedure. The evaluation will be based on clinical outcomes with various scales and questionnaires assessed every week, from two weeks before the 7-week period of therapeutic stimulation until 4 weeks after. Additionally, three sets of neurophysiological outcomes (resting-state electroencephalography (EEG), nTMS-EEG recordings, and short intracortical inhibition measurement with threshold tracking method) will be assessed the week before and after the 7-week period of therapeutic stimulation. DiscussionThis study will make it possible to compare the analgesic efficacy of the CHF-rTMS and SHF-rTMS protocols and to appraise that of the ACC-iTBS protocol for the first time. This study will also make it possible to determine the respective influence of the total number of pulses and days of stimulation delivered to M1 on the extent of pain relief. Thus, if their analgesic efficacy is not inferior to that of CHF-rTMS, SHF-rTMS and especially the new ACC-iTBS protocol could be an optimal compromise of a more easy-to-perform rTMS protocol for the treatment of patients with chronic neuropathic pain.

A home-based self-directed EEG neurofeedback intervention for people with chronic neuropathic pain following spinal cord injury (the StoPain Trial): description of the intervention.

Randomised controlled trial. The objective is to describe an electroencephalography (EEG) neurofeedback intervention that will be provided in a randomised controlled trial for people with neuropathic pain following spinal cord injury (SCI): the StoPain Trial. In this trial, participants in the treatment group will implement an EEG neurofeedback system as an analgesic intervention at home, while participants in the control group will continue with the treatments available to them in the community. University-based study in Sydney, Australia. This manuscript describes the rationale and components of the EEG neurofeedback intervention designed for individuals with SCI neuropathic pain and intended for home-based implementation. Our report is based on the criteria of the Template for Intervention Description and Replication (TIDieR) checklist, and includes why the efficacy of EEG neurofeedback will be investigated, what will be provided, who will administer it, and how, where, when, and how much the EEG neurofeedback intervention will be administered. This manuscript provides a detailed description of a complex intervention used in a randomised controlled trial. This description will facilitate the subsequent interpretation of the trial results and allow for the replication of the intervention in clinical practice and future trials. Australian Government Medical Research Future Fund (2020 Rare Cancers Rare Diseases and Unmet Needs Scheme: 2006020).

EFFICACY OF KETAMINE THERAPY FOR NEUROPATHIC PAIN IN AN ELDERLY PATIENT: A CASE STUDY

Chronic neuropathic pain is pain that lasts over 3 months and is caused by a disease or a lesion of the central or pe­ripheral nervous system. It is estimated that about 6-8 % of the general population suffers from neuropathic pain, therefore proper pain management protocols are needed, as at least 50 % of patients do not experience pain relief with medication. We report a case of 75 years-old woman who was suffering from neuropathic pain. After numerous unsuccessful treatment options, three weekly 10 mg Ke­tamine infusions made a significant improvement in the patient’s pain score and overall quality of life. We also briefly review scientific literature and current guidelines regarding pain and underline the necessity of expanding the arsenal of medication for chronic pain treatment.

Reductions in Chronic Postsurgical Neuropathic Pain and Mechanical Allodynia in Breast Cancer Patients Treated With Laser Acupuncture: A Retrospective Observational Study

IntroductionChronic postsurgical neuropathic pain (CPSNP) and related static mechanical allodynia (SMA) is recognised as a significant long-term complication after breast cancer surgery (BCS). This study investigates the effectiveness of a novel laser acupuncture technique in treating CPSNP and SMA post-BCS whilst patients underwent standard cancer treatments. MethodsThirty patients with significant breast area CPSNP and SMA (DN4 ≥ 4) were treated with 60Milliwatt, 658nm laser acupuncture at Austin Hospital between January 2021 and 2024. Patient data was analysed retrospectively: 29 with CPSNP, 22 with SMA. The cohort had exposures to pain aggravating cancer therapies (e.g. chemotherapy, radiotherapy and antihormonal drugs). An online patient questionnaire assessed treatment outcomes qualitatively. ResultsPatients received an average of 6·4 treatments and their average CPSNP showed significant reduction from 6·86 to 1.29 (P < .001), with a mean 5.57 point decrease (95% CI, 4.90-6.24). Average SMA showed significant reduction from an average of 6.77-1.75 (P < .001), with a mean 5.02-point decrease (95% CI, 4.09-5.96). Pain reductions occurred despite NP aggravating treatment and ongoing usage by 40% of the cohort. 92% of patients reported acute reductions in SMA in the online questionnaire. ConclusionThe significant pain reductions observed may indicate effectiveness of laser acupuncture in reducing both CPSNP and SMA in breast cancer patients post-BCS.

Nerve injury augments Cacna2d1 transcription via CK2-mediated phosphorylation of the histone deacetylase HDAC2 in dorsal root ganglia

Development of chronic neuropathic pain involves complex synaptic and epigenetic mechanisms. Nerve injury causes sustained upregulation of α2δ-1 (encoded by the Cacna2d1 gene) in the dorsal root ganglion (DRG), contributing to pain hypersensitivity by directly interacting with and augmenting presynaptic NMDA receptor activity in the spinal dorsal horn. Under normal conditions, histone deacetylase 2 (HDAC2) is highly enriched at the Cacna2d1 gene promoter in the DRG, which constitutively suppresses Cacna2d1 transcription. However, nerve injury leads to HDAC2 dissociation from the Cacna2d1 promoter, promoting the enrichment of active histone marks and Cacna2d1 transcription in primary sensory neurons. In this study, we determined the mechanism by which nerve injury diminishes HDAC2 occupancy at the Cacna2d1 promoter in the DRG. Spinal nerve injury in rats increased serine-394 phosphorylation of HDAC2 in the DRG. Coimmunoprecipitation showed that nerve injury enhanced the physical interaction between HDAC2 and casein kinase II (CK2) in the DRG. Furthermore, repeated intrathecal treatment with CX-4945, a potent and specific CK2 inhibitor, markedly reversed nerve injury–induced pain hypersensitivity, HDAC2 phosphorylation, and α2δ-1 expression levels in the DRG. In addition, treatment with CX-4945 largely restored HDAC2 enrichment at the Cacna2d1 promoter and reduced the elevated levels of acetylated H3 and H4 histones, particularly H3K9ac and H4K5ac, at the Cacna2d1 promoter in the injured DRG. These findings suggest that nerve injury increases CK2 activity and CK2-HDAC2 interactions, which enhance HDAC2 phosphorylation in the DRG. This, in turn, diminishes HDAC2 enrichment at the Cacna2d1 promoter, thereby promoting Cacna2d1 transcription.

Design of a Multicenter, Randomized Controlled Trial for the Treatment of Peripheral Neuropathic Pain (COMFORT Study) with a Micro-Implantable Pulse Generator.

Peripheral Nerve Stimulation (PNS) is an established therapy for chronic neuropathic pain of peripheral origin, typically following nerve injury. However, there is a paucity of Randomized Controlled Trials (RCTs) demonstrating the therapeutic benefits of PNS. The goals of the current study (COMFORT Study) are to document the safety and efficacy of the Nalu Neurostimulation in a PNS RCT, compared to conventional medical management (CMM). This is a prospective, multicenter, RCT evaluating the treatment of neuropathic pain with PNS therapy. One of the following four regions will be targeted for treatment: low back, shoulder, knee or foot/ankle. Consented subjects will undergo a baseline evaluation, after which they are randomized 2:1 (PNS+CMM arm to CMM arm). Subjects randomized to PNS+CMM arm will undergo a trial implant period using best clinical practices. Subjects who pass the trial phase, by showing a ≥ 50% reduction in pain relative to baseline, will receive the permanent implant. All subjects receiving a permanent implant will be followed for a total of 36 months. At the 3-month primary end point, subjects in CMM arm will be given the option to crossover into PNS+CMM arm, beginning with a trial implant. The study duration is expected to be 5.5 years from first enrollment to last follow-up of last subject and subsequent study closure. Adverse events will be captured throughout the study. The COMFORT study, described here, has the potential to demonstrate the efficacy and safety of the Nalu Neurostimulation System in the treatment of peripheral neuropathy. Results of this study will be the first Level-I evidence, out to 36 months, validating the use of this PNS system in the treatment of chronic pain. This study is designed to enroll the largest cohort, to date, of subjects comparing PNS+CMM vs CMM alone.

Involvement of basolateral amygdala-rostral anterior cingulate cortex in mechanical allodynia and anxiety-like behaviors and potential mechanisms of electroacupuncture.

Chronic pain is highly associated with anxiety. Electroacupuncture (EA) is effective in relieving pain and anxiety. Currently, little is known about the neural mechanisms underlying the comorbidity of chronic pain and anxiety and the EA mechanism. This study investigated a potential neural circuit underlying the comorbid and EA mechanisms. Spared nerve injury (SNI) surgery established the chronic neuropathic pain mouse model. The neural circuit was activated or inhibited using the chemogenetic method to explore the relationship between the neural circuit and mechanical allodynia and anxiety-like behaviors. EA combined with the chemogenetic method was used to explore whether the effects of EA were related to this neural circuit. EA attenuated mechanical allodynia and anxiety-like behaviors in SNI mice, which may be associated with the activity of CaMKII neurons in the basolateral amygdala (BLA). Inhibition of BLACaMKII-rACC induced mechanical allodynia and anxiety-like behaviors in sham mice. Activation of the BLACaMKII-rACC alleviated neuropathic pain and anxiety-like behaviors in SNI mice. The analgesic and anxiolytic effects of 2 Hz EA were antagonized by the inhibition of the BLACaMKII-rACC. BLACaMKII-rACC mediates mechanical allodynia and anxiety-like behaviors. The analgesic and anxiolytic effects of 2 Hz EA may be associated with the BLACaMKII-rACC.

Relationship Between Patient-reported Outcome Measures and Accelerometer-measured Physical Activity and Sleep in Patients With Postherpetic Neuralgia.

Available treatment for chronic neuropathic pain is still limited, and the positive effects are modest. Thus, clinicians aim to improve activity and quality of life despite pain. The objective monitoring of activity is attracting attention in chronic pain assessments. Therefore, we objectively evaluated daytime activity and sleep in patients with postherpetic neuralgia (PHN), using actigraphy to determine risk factors for decreased activity. Participants with PHN wore an actigraph (a wristwatch-like accelerometer) on the nondominant hand. The actigraph measured day-time activity and sleep, which were compared with participant-reported subjective pain and sleep assessments. Fifty-four individuals with PHN who visited our outpatient clinic completed questionnaires and a week of actigraph monitoring. Subjective scores of pain intensity, neuropathic pain, disability in daily life, pain-catastrophizing thoughts, and insomnia were all well correlated. However, the actigraph-monitored activity levels, using 2 equations, and sleep quality were not associated with any pain or sleep-related subjective scores. The discrepancy between the subjective and objective scores in this study may be due to (1) features of PHN, an archetype of peripheral neuropathic pain affecting no motor nerves, (2) actigraph measurement limitations regarding the sedentary life of the elderly, or (3) activity misperception, a new proposition explaining the discrepancy between subjective and objective measures of activity, similar to the sleep state misperception. In patients with PHN, high pain intensity may be reported in those with highly maintained activity, in which treatment must be selected cautiously to prevent interruption of their physical abilities.

Resting-state frontal electroencephalography (EEG) biomarkers for detecting the severity of chronic neuropathic pain

Increasing evidence is present to enable pain measurement by using frontal channel EEG-based signals with spectral analysis and phase-amplitude coupling. To identify frontal channel EEG-based biomarkers for quantifying pain severity, we investigated band-power features to more complex features and employed various machine learning algorithms to assess the viability of these features. We utilized a public EEG dataset obtained from 36 patients with chronic pain during an eyes-open resting state and performed correlation analysis between clinically labelled pain scores and EEG features from Fp1 and Fp2 channels (EEG band-powers, phase-amplitude couplings (PAC), and its asymmetry features). We also conducted regression analysis with various machine learning models to predict patients’ pain intensity. All the possible feature sets combined with five machine learning models (Linear Regression, random forest and support vector regression with linear, non-linear and polynomial kernels) were intensively checked, and regression performances were measured by adjusted R-squared value. We found significant correlations between beta power asymmetry (r = −0.375), gamma power asymmetry (r = −0.433) and low beta to low gamma coupling (r = −0.397) with pain scores while band power features did not show meaningful results. In the regression analysis, Support Vector Regression with a polynomial kernel showed the best performance (R squared value = 0.655), enabling the regression of pain intensity within a clinically usable error range. We identified the four most selected features (gamma power asymmetry, PAC asymmetry of theta to low gamma, low beta to low/high gamma). This study addressed the importance of complex features such as asymmetry and phase-amplitude coupling in pain research and demonstrated the feasibility of objectively observing pain intensity using the frontal channel-based EEG, that are clinically crucial for early intervention.

Neuropathic component of chronic musculoskeletal pain in patients with post-COVID-19: A cross-sectional study

Objectives: This study aimed to evaluate the neuropathic component of chronic musculoskeletal pain in post-coronavirus disease 2019 (COVID-19) and examine the relationship between neuropathic pain and clinical and demographic characteristics. Patients and methods: This cross-sectional study included 163 adult patients (85 females, 78 males; mean age: 41.7±4.3 years; range, 22 to 50 years) with post-COVID-19 musculoskeletal pain between February 1, 2021, and April 30, 2021. Demographic and clinical characteristics, including age, sex, affected site, duration, and severity of post-COVID-19 musculoskeletal pain using the Visual Analog Scale (VAS), as well as a neuropathic component of pain using the Leeds assessment of neuropathic symptoms and signs (LANSS), were collected. The most common post-COVID-19 symptoms, presence of hospitalization, and length of hospital stay during active COVID-19 infection were recorded from the patient records. Results: The mean duration and severity of pain were 7.85±1.53 months and 5.09±1.95, respectively. Half of the patients were hospitalized, and the mean length of hospital stay was 12.15±18.06 days. The most common pain sites were upper and lower back pain, followed by leg and arm pain. A total of 92 (56.4%) patients had previously received pharmacological or nonpharmacological treatment for post-COVID-19 musculoskeletal pain. Based on the LANSS (scores &gt;12), 31 (19%) patients had neuropathic pain. There was a significant correlation between the presence of neuropathic pain and pulmonary involvement/symptoms. The presence and length of hospital stay were correlated with LANNS scores (p&lt;0.05). The frequency, LANSS scores, and VAS-pain scores of the patients with and without neuropathic pain were similar between male and female patients (p&gt;0.05). Conclusion: The neuropathic component of chronic musculoskeletal pain may be common, as one-fifth of our patients had neuropathic pain as assessed by the LANNS. Therefore, the awareness of post-COVID-19 chronic neuropathic musculoskeletal pain should be increased. We believe that focusing on the identification of pain phenotypes would provide adequate and tailored chronic neuropathic musculoskeletal pain management in the post-COVID-19 period.

Mechanism of gabapentinoid potentiation of opioid effects on cyclic AMP signaling in neuropathic pain

Over half of spinal cord injury (SCI) patients develop opioid-resistant chronic neuropathic pain. Safer alternatives to opioids for treatment of neuropathic pain are gabapentinoids (e.g., pregabalin and gabapentin). Clinically, gabapentinoids appear to amplify opioid effects, increasing analgesia and overdose-related adverse outcomes, but in vitro proof of this amplification and its mechanism are lacking. We previously showed that after SCI, sensitivity to opioids is reduced by fourfold to sixfold in rat sensory neurons. Here, we demonstrate that after injury, gabapentinoids restore normal sensitivity of opioid inhibition of cyclic AMP (cAMP) generation, while reducing nociceptor hyperexcitability by inhibiting voltage-gated calcium channels (VGCCs). Increasing intracellular Ca2+ or activation of L-type VGCCs (L-VGCCs) suffices to mimic SCI effects on opioid sensitivity, in a manner dependent on the activity of the Raf1 proto-oncogene, serine/threonine-protein kinase C-Raf, but independent of neuronal depolarization. Together, our results provide a mechanism for potentiation of opioid effects by gabapentinoids after injury, via reduction of calcium influx through L-VGCCs, and suggest that other inhibitors targeting these channels may similarly enhance opioid treatment of neuropathic pain.

Corticothalamic input derived from corticospinal neurons contributes to chronic neuropathic pain after spinal cord injury

Neuropathic pain is a significant and persistent issue for individuals with spinal cord injuries (SCI), severely impacting their quality of life. While changes at the peripheral and spinal levels are known to contribute to SCI-related pain, whether and how supraspinal centers contribute to post SCI chronic neuropathic pain is poorly understood. Here, we first validated delayed development of chronic neuropathic pain in mice with moderate contusion SCI. To identify supraspinal regions involved in the pathology of neuropathic pain after SCI, we next performed an activity dependent genetic screening and identified multiple cortical and subcortical regions that were activated by innocuous tactile stimuli at a late stage following contusion SCI. Notably, chemogenetic inactivation of pain trapped neurons in the lateral thalamus alleviated neuropathic pain and reduced tactile stimuli evoked cortical overactivation. Retrograde tracing showed that contusion SCI led to enhanced corticothalamic axonal sprouting and over-activation of corticospinal neurons. Mechanistically, ablation or silencing of corticospinal neurons prevented the establishment or maintenance of chronic neuropathic pain following contusion SCI. These results highlighted a corticospinal-lateral thalamic feed-forward loop whose activation is required for the development and maintenance of chronic neuropathic pain after SCI. Our data thus shed lights into the central mechanisms underlying chronic neuropathic pain associated with SCI and the development of novel therapeutic avenues to treat refractory pain caused by traumatic brain or spinal cord injuries.

Feasibility and Safety of a Home-based Electroencephalogram Neurofeedback Intervention to Reduce Chronic Neuropathic Pain: A Cohort Clinical Trial

ObjectiveTo evaluate the feasibility, safety, and potential health benefits of an 8-week home-based neurofeedback intervention. DesignSingle-group preliminary study. SettingCommunity-based. ParticipantsNine community dwelling adults with chronic neuropathic pain, 6 women and 3 men, with an average age of 51.9 years (range, 19-78 years) and with a 7-day average minimum pain score of 4 of 10 on the visual analog pain scale. InterventionsA minimum of 5 neurofeedback sessions per week (40min/session) for 8 consecutive weeks was undertaken with a 12-week follow-up baseline electroencephalography recording period. Main Outcome MeasuresPrimary feasibility outcomes: accessibility, tolerability, safety (adverse events and resolution), and human and information technology (IT) resources required. Secondary outcomes: pain, sensitization, catastrophization, anxiety, depression, sleep, health-related quality of life, electroencephalographic activity, and simple participant feedback. ResultsOf the 23 people screened, 11 were eligible for recruitment. One withdrew and another completed insufficient sessions for analysis, which resulted in 9 datasets analyzed. Three participants withdrew from the follow-up baselines, leaving 6 who completed the entire trial protocol. Thirteen adverse events were recorded and resolved: 1 was treatment-related, 4 were equipment-related, and 8 were administrative-related (eg, courier communication issues). The human and IT resources necessary for trial implementation were identified. There were also significant improvements in pain levels, depression, and anxiety. Six of 9 participants perceived minimal improvement or no change in symptoms after the trial, and 5 of 9 participants were satisfied with the treatment received. ConclusionsIt is feasible and safe to conduct a home-based trial of a neurofeedback intervention for people with chronic neuropathic pain, when the human and IT resources are provided and relevant governance processes are followed. Improvements in secondary outcomes merit investigation with a randomized controlled trial.

Neuropeptide Y Y2 Receptors in Sensory Neurons Tonically Suppress Nociception and Itch but Facilitate Postsurgical and Neuropathic Pain Hypersensitivity.

Neuropeptide Y (NPY) Y2 receptor (Y2) antagonist BIIE0246 can both inhibit and facilitate nociception. The authors hypothesized that Y2 function depends on inflammation or nerve injury status. The authors implemented a battery of behavioral tests in mice of both sexes that received (1) no injury; (2) an incision model of postoperative pain; (3) a spared nerve injury model of neuropathic pain; and (4) a latent sensitization model of chronic postsurgical pain. In addition to Y2 gene expression assays, spinal Y2 G-protein coupling was studied with guanosine-5'-O-(3-[35S]thio)triphosphate ([35S]GTPγS) binding assays. The authors report that intrathecal BIIE0246 increased mechanical and cold hypersensitivity, produced behavioral signs of spontaneous nociception and itch, and produced conditioned place aversion and preference in normal, uninjured mice. BIIE0246 did not change heat hypersensitivity or motor coordination. Conditional (sensory neuron-specific) Y2 deletion prevented BIIE0246-induced mechanical and cold hypersensitivity, nocifensive behaviors, and aversion. Both conditional deletion and pharmacologic blockade of Y2 reduced mechanical and thermal hypersensitivity after incision or nerve injury. SNI did not change the sensitivity of Y2 G-protein coupling with the Y2 agonist peptide YY (3-36) (PYY3-36), but increased the population of Y2 that effectively coupled G-proteins. Intrathecal PYY3-36 failed to reduce spared nerve injury- or incision-induced hypersensitivity in C57BL/6N mice. Incision did not change Npy2r gene expression in dorsal root ganglion. The authors conclude that Y2 at central terminals of primary afferent neurons provides tonic inhibition of mechanical and cold nociception and itch. This switches to the promotion of mechanical and thermal hyperalgesia in models of acute and chronic postsurgical and neuropathic pain, perhaps due to an increase in the population of Y2 that effectively couples to G-proteins. These results support the development of Y2 antagonists for the treatment of chronic postsurgical and neuropathic pain.

A Three-way Attack on the Gastrointestinal System- COVID-19, Ehler-Danlos Syndrome, and Anorexia Nervosa Leading to Severe Gastroparesis in a Young Female

A 28-year-old female with a past medical history of Major Depressive Disorder, Generalized Anxiety Disorder, Anorexia Nervosa, Chronic Pain Syndrome, and Gastro-esophageal Reflux presented to our clinic for establishing care in November 2022 with severe gastric dysmotility ever since contracting COVID-19 virus in December 2021. The patient’s symptoms were refractory to Erythromycin and metoclopramide therapy. A GI motility study in February 2022 showed delayed gastric emptying based on which the patient was diagnosed with Post COVID Gastroparesis. Based on an extensive clinical review of the patient’s past medical and surgical history, the patient was found to have cumulative symptoms of GERD, joint instability, abdominal hernia and chronic neuropathic pain, raising the suspicion of Ehler-Danlos syndrome- Hypermobility type. Given the failure of treatment with prokinetic agents and over 60 pounds of weight loss the patient underwent Percutaneous Endoscopic Gastrostomy-Jejunostomy in August 2022, the patient was started on Organic Tube Feeding Formula. To this date, the patient is using the PEG-J for feeding and remains nil per oral. Multiple trials of reintroducing oral feeding have been attempted but the patient still is unable to tolerate oral feeds completely and continues to complain of early satiety, nausea, and vomiting on reintroducing feeds.

Quantitative analysis of nortriptyline’s analgesic properties: a comparative systematic review and meta-analysis

ObjectivesThis study aims to quantitatively analyse nortriptyline’s analgesic potency, safety and tolerability.DesignSystematic review and meta-analysis.Data sourcesThe systematic search was conducted in Scopus, Web of Science and PubMed in February 2023.Eligibility...